Rare Diseases

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

While the typical dose of methotrexate (MTX) for inflammatory disease in pediatric patients varies in published studies, the maximum dose is considered to be 1 mg/kg and not to exceed 25 mg/week. In addition, test doses are not necessary for pediatric patients starting low dose (1 mg/kg or less) MTX for inflammatory skin disease, and the onset of efficacy with MTX may take 8-16 weeks.

Those are among 46 evidence- and consensus-based recommendations about the use of MTX for inflammatory skin disease in pediatric patients that were developed by a committee of 23 experts and published online in Pediatric Dermatology.

“Methotrexate is a cost-effective, readily accessible, well-tolerated, useful, and time-honored option for children with a spectrum of inflammatory skin diseases,” project cochair Elaine C. Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, told this news organization. “Although considered an ‘immune suppressant’ by some, it is more accurately classified as an immune modulator and has been widely used for more than 50 years, and remains the standard of care when administered at very high doses and intrathecally in children with acute lymphoblastic leukemia – a practice that supports safety. But many details that support optimized treatment are not widely appreciated.”

• MTX can be discontinued abruptly without adverse effects, other than the risk of disease worsening.
• Folic acid supplementation (starting at 1 mg/day, regardless of weight) is an effective approach to minimizing associated gastrointestinal adverse effects.
• Concomitant use of MTX and antibiotics (including trimethoprim-sulfamethoxazole) and NSAIDS are not contraindicated for most pediatric patients treated for inflammatory skin disease.
• Live virus vaccine boosters such as varicella-zoster virus (VZV) and measles, mumps, and rubella (MMR) are not contraindicated in patients taking MTX; there are insufficient data to make recommendations for or against primary immunization with MMR vaccine in patients taking MTX; inactivated vaccines should be given to patients taking MTX.
• Routine surveillance laboratory monitoring (i.e., CBC with differential, alanine transaminase, aspartate aminotransferase, creatinine) is recommended at baseline, after 1 month of treatment, and every 3-4 months thereafter.
• Transient transaminase elevation (≤ 3 upper limit normal for < 3 months) is not uncommon with low-dose MTX and does not usually require interruption of MTX. The most likely causes are concomitant viral infection, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (such as acetaminophen), and/or recent alcohol consumption.
• Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX.

According to Dr. Siegfried, consensus of the committee members was lowest on the need for a test dose of MTX.

Overall, she said in the interview, helping to craft the guidelines caused her to reflect on how her approach to using MTX has evolved over the past 35 years, after treating “many hundreds” of patients. “I was gratified to confirm similar practice patterns among my colleagues,” she added.

The project’s other cochair was Heather Brandling-Bennett, MD, a dermatologist at Seattle Children’s Hospital. This work was supported by a grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association and the National Psoriasis Foundation. Dr. Siegfried disclosed ties with AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica. She has participated in contracted research for AI Therapeutics, and has served as principal investigator for Janssen. Many of the guideline coauthors disclosed having received grant support and other funding from pharmaceutical companies.

The U.S. Food and Drug Administration has approved rozanolixizumab (Rystiggo) to treat adults with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) or anti–muscle-specific tyrosine kinase (MuSK) antibody, the drug’s manufacturer, UCB, has announced.

Olivier Le Moal/Getty Images

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved rozanolixizumab (Rystiggo) to treat adults with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) or anti–muscle-specific tyrosine kinase (MuSK) antibody, the drug’s manufacturer, UCB, has announced.

Olivier Le Moal/Getty Images

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved rozanolixizumab (Rystiggo) to treat adults with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) or anti–muscle-specific tyrosine kinase (MuSK) antibody, the drug’s manufacturer, UCB, has announced.

Olivier Le Moal/Getty Images

A version of this article first appeared on Medscape.com.

Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Since the early 2000s, new discoveries about GIST genomics have contributed to better, more targeted treatments. Some genomic mutations have been linked to specific gut regions,⁷ which may further help guide therapy as well.

GIST: What Is It, Who Gets It, and How Is It Diagnosed?

What, How Many, Where?

Even though GIST is considered rare—representing less than 1% of gastrointestinal tumors⁸—it is the most common sarcoma, which is a family of mesenchymal neoplasms. GISTs are thought to arise from the interstitial cells of Cajal, or the pacemaker cells of the gut that control peristalsis. In the United States, the incidence of GIST is roughly 4,000 to 6,000 new cases diagnosed per year, with most cases found in the stomach (60%) or small intestine (35%). Other gut regions in which GISTs may be identified include the rectum and esophagus.⁸

Although asymptomatic tumors are often discovered incidentally, GISTs that originate in the stomach—the most common primary tumor site—may present with nonspecific subjective symptoms such as pain, nausea, loss of appetite, early satiety, or bloating.⁹ Symptoms may vary according to tumor location (eg, stomach vs rectum vs esophagus), size, and pattern of growth. More objective signs could include anemia related to gastrointestinal bleeding, weight loss, or a palpable mass.⁹

Who?

Most cases of GIST occur in patients later in life, with a median age of 64 years at diagnosis. A slight predominance of men has been noted, along with African American and Asian individuals affected somewhat more frequently than White or Hispanic populations.¹⁰ GIST is rare in children and adolescents, and the symptoms and pathology differ from those in most adults.⁹ Previously age was considered a determining factor in the differences in GIST, with cases in children classified as “pediatric-type” GIST or “wild-type” GIST. These cases generally present in the stomach, are more likely to include lymph node involvement, and can also spread to the liver and abdominal lining. Importantly, they are usually not associated with the tyrosine-protein kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) gene mutations found in most adults.⁹ About 80% of these cases have hereditary mutations of the succinate dehydrogenase (SDH) enzyme complex. Because some adult cases of GIST share the distinct characteristics found in most pediatric cases, distinguishing them based on age, rather than on the specific genetic characteristics of the tumor, is unwarranted.⁹

How?

When GIST is suspected or when symptoms mandate further investigation, coordination among colleagues in imaging, gastroenterology, pathology, surgery, and oncology is critical for accurate diagnosis, staging, and treatment. Abdominal imaging may be ordered using modalities such as ultrasound, computed tomography, magnetic resonance imaging, and, occasionally, positron emission tomography.¹¹ Endoscopic ultrasound is useful to identify and biopsy lesions in the stomach or rectum, as these tumors arise below the lining of the stomach or rectum. GIST diagnosis can be confirmed by biopsy during endoscopic ultrasound, which is the preferred approach, or by percutaneous biopsy when endoscopic biopsy is not feasible or safe.¹¹

According to the European Society for Medical Oncology (ESMO) and European Reference Group for Rare Adult Solid Cancers (EURACAN) Clinical Practice Guidelines, the “standard approach to tumors ≥ 2 cm in size is excision, because they are associated with a higher risk of progression if confirmed as GIST. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic or laparotomic excision is the standard approach.”¹¹

Genetic Mutations

A diagnosis of GIST is made based on the combination of the clinical scenario, the tumor’s anatomic location, immunohistochemistry patterns, and molecular features.¹² Research has shown that genetic mutations in the KIT, PDGFRA, or SDH genes are present in most cases of GIST (70-80%,¹³ 10%,¹² and less than 10% of cases^12,14 respectively) and their presence can be used for diagnosis. A growing number of rarer mutations have also been discovered,¹³ meaning that gene-based diagnosis of GIST is becoming increasingly sensitive. In addition, antigens on the surface of cancer cells can help classify them as GIST. For example, researchers have discovered that most GIST cells have the marker CD117, the protein product of the KIT gene that is commonly mutated in GIST, on their surfaces. A different marker, DOG1 (ie, Discovered On GIST 1), is also present on the vast majority of GISTs, but not unanimously overlapping with CD117. A tumor that is positive for both CD117 and DOG1 has a high probability (> 97%) of being GIST.¹⁵

Next-generation sequencing (NGS) is considered the best tool for determining both germline and somatic mutations in patients with GIST, and NGS is recommended by both the NCCN⁶ and the ESMO¹¹ for individualizing systemic therapy. Despite these recommendations, most patients do not undergo genetic testing, both in the United States¹⁶ and internationally.¹⁷ Several barriers to genetic testing have been cited, predominately inadequate tissue and high cost. However, a study demonstrated that costs of up to $3,730 for genetic testing were ultimately cost-effective for tailoring therapy with first-line imatinib for patients with newly diagnosed metastatic GIST.¹⁸ Moreover, genetic testing also should be strongly considered for patients with nonmetastatic disease in whom systemic therapy is being considered.

Increasing evidence has emerged that gastric GIST mutations are related to tumor location within the gastrointestinal tract (Figure).⁷ The anatomic location of the GIST may provide clues for clinical decision-making and may guide selective confirmatory genomic testing when access to testing is limited.

Treatment of GIST

Surgery 

Surgery remains the main treatment for localized GIST, especially if the tumor is discovered at an early stage. Unfortunately, up to a quarter of patients present with metastatic disease at diagnosis. The goal of surgery is to resect the tumor with histologically negative margins. Every effort should be made to avoid rupturing the tumor capsule during resection. Studies have shown that laparoscopic resection is feasible and safe for gastric GISTs and is less invasive than traditional open surgery, with similar oncological outcomes.¹⁹

Debulking surgery is sometimes considered for patients with metastatic disease, especially for patients who demonstrate sensitivity to TKI and whose disease has not yet progressed.^20,21 Other interventions, such as microwave ablation or transhepatic arterial embolization, are sometimes used to control hepatic metastases.

Systemic Therapies

Whether systemic therapy is being considered in the neoadjuvant (preoperative), adjuvant (postoperative), or advanced disease setting, mutations in GIST determine the likelihood of treatment success. Both NCCN⁶ and ESMO¹¹ strongly encourage use of mutational analyses and genetic testing for patients with GIST before systemic therapy is initiated.

In some cases of locally advanced GIST, tumors may be situated in particularly challenging anatomic locations(eg, esophagus, duodenum, rectum) or may require a highly morbid, multivisceral resection. In such situations, neoadjuvant treatment with imatinib,^22,23 if deemed appropriate per mutational profiling, should be considered.

Patients who are determined to be at high risk for recurrence after surgery, based on tumor size, mitotic index determined by pathologist review of dividing cells, tumor location, and tumor rupture, may be eligible for adjuvant treatment with imatinib.²⁴ Although the ideal duration of adjuvant therapy is not yet known, the current standard is at least 3 years,²⁵ but many practitioners advocate for lifelong therapy.

Imatinib. Because chemotherapy was ineffective against GIST, prognosis was dismal for patients diagnosed with advanced disease before the approval of imatinib in the early 2000s.² A selective TKI, imatinib targets the KIT and PDGFRA receptor kinases, and most patients experience clinical benefit,²⁶ at least initially. Unfortunately, many tumors eventually develop resistance, and discontinuation of imatinib is associated with a risk for disease progression.²⁷

Sunitinib. The emergence of resistance to imatinib spurred the search for second-line agents that might be useful after disease progression. Another TKI, sunitinib, which has both antitumor and antiangiogenic activity, was approved in 2006 for management of advanced imatinib-resistant GIST.²⁸ Knowledge of a tumor’s driver mutation(s) can help optimize use of sunitinib.²⁹

Regorafenib. In 2013, the FDA approved regorafenib, another TKI, as a third-line agent for patients with advanced GIST that is refractory to imatinib and sunitinib.³⁰ Regorafenib exerts its activity against multiple targets, including VEGFR1-3, TIE2 (ie, antiangiogenic activity), PDGFR-β, FGFR (ie, stromal targets), and KIT, RET, and RAF (ie, oncogenic targets). As with other TKIs, common adverse effects associated with regorafenib treatment include hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue.

Larotrectinib/entrectinib. The FDA approved larotrectinib³¹ (2018) and entrectinib³² (2019) as the first tumor-agnostic agents, whose use is based on the presence of  specific genomic alteration, in this case NTRK. If a tumor, including a GIST, harbors a specific, albeit rare, gene fusion, it may be considered for treatment with one of these small-molecule TRK family inhibitors. Although these agents are not specifically indicated for GIST, some subjects enrolled in the trials had GIST harboring the target NTRK gene fusion and their tumors responded to treatment.

Ripretinib. FDA-approved in 2020,³³ ripretinib is a novel TKI indicated for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. A phase 3 trial demonstrated improved progression-free and overall survival when ripretinib was compared with placebo in patients who had disease progression after treatment with imatinib, sunitinib, or regorafenib.³⁴ Ripretinib is now being investigated in the second-line setting in selected patients with KIT mutations.

Avapritinib. Cases of GIST with PDGFRA D842V-mutant tumors often demonstrate primary resistance to imatinib and sunitinib. In 2020, avapritinib, a selective TKI that targets both KIT and PDGFRA, was approved³⁵ for treatment of patients with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including D842V mutations. However, it is noteworthy that many of the non-D842V mutations in PDGFRA respond to imatinib.

Dabrafenib/trametinib. In 2022, the FDA issued an approval for treatment based on a driver mutation rather than tumor type. Acknowledging that a BRAF mutation—specifically a V600E mutation—appears to be a critical target in several cancers, the FDA granted accelerated approval for the use of dabrafenib plus trametinib in adults and children 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.³⁶

Researchers have studied additional TKIs in the setting of unresectable, metastatic disease due to the varied genomic landscape of GIST. The NCCN Guidelines include evidence of some benefit for agents such as dasatinib, cabozantinib, everolimus (plus a TKI), nilotinib, pazopanib, and sorafenib “in certain circumstances.”⁶

The Future of GIST

The most critical step toward optimal treatment decision-making when a patient has been diagnosed with GIST is identification of physicians with expertise in the care of patients with GIST. With increasing knowledge of genomic variations in GIST, patient care has become less prescripted and much more personalized. To that end, determination of the tumor’s genetic mutational profile is critical to guiding treatment. Although factors such as cost, availability/accessibility, and insufficient tissue continue to represent substantial obstacles, pursing this information may be the most important way that clinicians can advocate for their patients. Moreover, now that the anatomic location of GIST has been linked to specific driver mutations, the ability to select and refine treatments may improve significantly.

Likewise, in view of the increasing complexity and multidisciplinary management of patients with GIST, efficient coordination is paramount among surgical and medical oncologists, as well as radiologists, gastroenterologists, and pathologists.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Adenosquamous carcinoma (ASC) of the lung is a rare, biphasic type of non-small cell lung cancer (NSCLC) that accounts for 2% to 4% of all lung cancers.¹ According to the World Health Organization (WHO) classification, the composition of ASC includes both adenocarcinoma (AC) and squamous cell carcinoma (SCC) histologies, with each subtype comprising at least 10% of the tumor.² As with other lung cancers, the average age at ASC diagnosis is about 70 years of age, it affects more men than women, and most patients are current or former smokers.^3,4 Despite these similarities, mounting evidence suggests that the molecular and genomic features of ASC are unique and they remain poorly understood.^5-8

Perhaps owing to the distinct genomics of these tumors, ASC of the lung is reported to be relatively aggressive compared to typical AC and SCC tumors. Studies indicate that ASCs at diagnosis have higher rates of lymph node invasion, metastasize rapidly, and carry a generally poor prognosis. Accordingly, the overall survival (OS) of patients with these tumors is relatively short compared to other NSCLC subtypes.^2,3,8-10 In a 2022 population-based study of the SEER database, 5-year postsurgical survival rates for early-stage cancers were reportedly 65% for ASC vs 69% for SCC P=0.003 and 77% for AC P<0.001.³ While it is clear that underlying biology driving ASC differs from more typical NSCLC subtypes, there is a lack of effective treatment options specific to ASC and a paucity of clinical research available to support therapeutic decisions for patients with ASC histology. Current management of NSCLC is based primarily on the stage of the tumor, and clinical features of the patient. In a more personalized era of targeted treatments, tumor histology is used only to predict the presence of actionable mutations in adenocarcinomas.^7,8 However, optimal treatment strategies for ASC remain a significant unmet need in lung cancer.

Diagnosis: Complex but Critically Important

Given the mixed histologies that characterize ASC of the lung, intratumoral heterogeneity often hinders and may delay diagnosis. Studies suggest that ASC is misdiagnosed as AC or SCC in at least half of biopsies prior to surgical pathology confirming an ASC diagnosis.¹¹ In one retrospective study, nearly all ASC cases (98%) were either misdiagnosed or undiagnosed preoperatively.¹² What’s more is that different types of biopsy samples may yield different results. One case report of a patient eventually diagnosed with ASC described 3 different results on workup: SCC on bronchial lavage and bronchial biopsy, AC on immunohistochemistry, and NSCLC undifferentiated on pleural effusion cytology.¹³ While a diagnosis can be made using biopsy and cytology samples, a definitive diagnosis may require larger samples (ie, several core biopsies or complete surgical resections) to fully evaluate all components of the tumor lesion.

Comprehensively evaluating entire tumor specimens can aid in further characterization ASC of the lung. ASCs may be sub-classified according to the proportions of AC and SCC histology components present. Tumors with either AC or SCC components comprising at least 60% of the tumor are referred to as AC- or SCC-predominant ASC, respectively. Those with a more even split of AC and SCC histologies (40% to 60% of each) are referred to as structure-balanced ASC and have been reported to have a better prognosis than either of the more imbalanced subtypes.^9,14

Adding to the complexity of diagnosing ASC of the lung is its unclear histologic origin and the transitional nature of these tumors over time. Some studies have pointed to possible precursor lesions, including AC with squamous metaplasia, collision tumor, and high-grade mucoepidermoid tumors.¹⁵ Reports have also shown that the molecular and histological features of the primary tumor can differ from that of metastases/recurrences.^16,17 In one case report, a patient with a resected ASC harboring an epidermal growth factor receptor (EGFR)-sensitizing mutation recurred several months later as SCC in the brain with the same EGFR mutation. A later recurrence in the lung was diagnosed as an AC and had the same EGFR mutation.¹⁶ In this example, if only the SCC component had been diagnosed, molecular testing would likely have never been ordered and the potentially actionable EGFR mutation would have been left undetected. Therefore, careful and accurate diagnosis of ASC is critically important in guiding testing for driver mutations, as well as in informing treatment choices in ASC.

Genomics

Studies indicate that ASC of the lung exhibits genomic features of both AC and SCC, with standard immunohistochemical profiles represented in each component. As expected, TTF1 positivity is common in the AC component while p63 and CK5/6 are expressed in the SCC component.¹⁸ However, evidence also indicates that ASC of the lung is a distinct entity rather than being a simple hybrid of AC and SCC histologies. That is, despite the seemingly dichotomous nature of ASC, this type of tumor is thought to have unique molecular and genomic features that have not yet been fully identified.^5-8

While the genomics of AC and SCC of the lung have been well studied, the inherent intratumoral heterogeneity that defines ASC, together with its relative rarity, complicates its analysis. There is a paucity of data available, but several groups have conducted molecular testing to better understand the genotype of ASC and potentially discover predictors about prognosis and treatment. To date, most studies on ASC lung samples have been small, and while some groups have reported overlapping results, other findings contrast with one another. In one of the most recent and comprehensive studies published on the topic, Wang et al. used next-generation sequencing (NGS) to identify a wide range of somatic mutations in 124 Chinese patients with ASC of the lung, including TP53 (66.9%), CDKN2A (21%), TERT (21%), and LRP1B (18.5%).⁶ Importantly, they found high rates of EGFR mutations (54.8%), of which 45.6% were EGFR 19del, 38.2% were EGFR L858R and 29.4% were EGFR amplifications.

Notably, not all studies have found such a strikingly increased rate of EGFR mutations in ASC versus AC of the lung.¹⁹ Other actionable mutations were found in the analysis by Wang and colleagues, including ALK and ROS1 fusions. Regarding known predictors of immunogenicity in these tumors, a subset of patients were associated with high tumor mutational burden (TMB), which was correlated with mutations in ARID2, BRCA1, and KEAP1. Immunohistochemical analyses demonstrated half of patients were positive for PD-L1 (≥ 1% tumor proportion score [TPS]).⁶ Interestingly, another study showed that PD-L1 expression in ASC differed between SCC (30% to 40%) and AC (11% to 15%) components.²⁰

Actionable mutation rates (ie, EGFR, ALK) in AC are known to vary between Asian and White patients, a finding that seems to be similar in ASC of the lung as well, although it is less clear given the limited sample size of ASC studies. Vassella et al. performed NGS and fluorescence in situ hybridization (FISH) on ASC samples from 16 White patients and found that 30% had EGFR mutations, while Tochigi et al reported an EGFR mutation rate of 13% in a study of 23 Western patients.5,12,21 In their analysis, Vassella and colleagues also found a high rate of mutations in the PI3K pathway (25%), but no KRAS mutations, which are the most common molecular driver in typical AC (30%), and thus supporting the notion that ASC has its own molecular genomic profile, distinct from AC or SCC.^5,21 Also of interest in this study was the finding that classifier miR-205 expression was intermediate between that of classical AC and SCC, suggesting that ASC of the lung may alternatively represent a transitional stage between these tumor types rather than an unrelated entity.⁵ These findings, along with others that have been reported on the genomic landscape of ASC, have advanced our understanding of the underlying biology of this malignancy, but also highlight the unmet need for more research to improve our ability to personalize treatment for ASCs.

Treatment

Owing to the heterogeneity of ASC of the lung, as well as its complex and incompletely characterized genomic landscape, treating patients with these tumors is challenging. In general, stage-based treatment approaches are used to manage ASC. The current treatment paradigm of all NSCLC has dramatically changed in recent years, with increasing incorporation of targeted treatments and immunotherapies across all stages and histologic types. Considering ASCs are composed of glandular cell components, they can contain substantial levels of relevant actionable driver mutations as described above. Therefore, if ASC is diagnosed or if a SCC has a glandular component,molecular testing is recommended and supported by guidelines, even on surgical specimens where EGFR may be targeted as adjuvant treatment.²³ However, while targeting actionable mutations and the PD1/PDL1 axis has been studied extensively in AC and SCC in all stages, the impact of these markers in ASC is unknown because patients with this histologic subtype are frequently excluded from clinical trials.

For patients with ASC and actionable mutations, EGFR inhibitors have been perhaps the best-studied targeted therapies. EGFR inhibitors have yielded responses in ASC, but the benefit has been highly variable in small case series and generally inferior to outcomes in patients with AC alone.¹⁹ Ongoing clinical trials are aiming to better understand the effects of EGFR inhibitors in ASC. As one example, first-line almonertinib is being compared to paclitaxel/carboplatin in the phase 2 ARISE clinical trial, which is specifically enrolling patients with EGFR mutation-positive locally advanced or metastatic pulmonary ASC (Clinicaltrials.gov NCT04354961). Most other reported studies are case studies or retrospective in nature.

Given that outcomes are usually reported from single patients or a group of only a few patients, contradictory findings are not uncommon. For example, crizotinib, a multi-kinase inhibitor approved for the treatment of advanced or metastatic ALK-positive and ROS1-positive NSCLC, was reported to have a clinical response in an ASC in a patient with recurrent ALK-positive disease which lasted for just over one year.²⁴ However, the response to second-line crizotinib in a case report of female non-smoking patient with ROS1-positive ASC was only 4 months.²⁵ Newer, more specific kinase inhibitors are currently in clinical practice and trials of ALK and ROS1 NSCLCs; however, their efficacy is ASC remains unclear.

In the absence of driver mutations, the optimal choice of chemotherapy (often given with immunotherapy) for neo-/adjuvant therapy or for metastatic disease has not yet been identified. While the AC component might typically be treated with pemetrexed plus a platinum agent, the SCC component may be better treated with taxane plus a platinum agent.²³ Especially in cases where neither histologic subtype is predominant, it can be difficult to decide which combination may be suitable for an individual patient. Whether the relative proportion of AC and SCC components affect treatment outcomes is not yet known. Outcomes of pemetrexed-based chemotherapy have been reported in a case study of 2 patients with relapsed disease harboring ALK and ROS1 mutations, pemetrexed alone or as part of a combination regimen (with pembrolizumab and carboplatin) was able to maintain stable disease for at least a year.²⁶

While immune checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, are currently recommended for patients with NSCLC²³, few studies have reported outcomes of patients with ASC specifically. One recent real-world analysis by Li et al. evaluated the effect of immunotherapy in 46 patients with ASC, of which 18 (39%) did not contain actionable driver mutations and 18 (39%) had unknown mutational status.²⁷ In this study, 28% of the overall cohort responded to checkpoint inhibitors, the median progression-free survival was 6 months, and the median OS was 24.7 months. Notably, similar efficacy was observed in the 20 patients receiving immunotherapy monotherapy vs 26 patients who received combination immunotherapy plus chemotherapy.²⁷ Among 4 patients with EGFR mutations, 2 received immunotherapy monotherapy and progressed immediately compared to the other 2 receiving combination immunotherapy with chemotherapy achieving disease control and improved OS (18 months).

As exemplified by the select few cases summarized above, conventional treatments used in NSCLC have achieved only modest responses in ASC, most with a shorter response duration. The lack of specific treatment strategies for ASC, based on our understanding of underlying tumor biology, limits optimal treatment outcomes for this increasingly common diagnosis. Novel therapies are sorely needed. A consensus should be developed to either study novel treatments specifically in this subtype or allow for the incorporation of ASCs into future NSCLC clinical trials.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence and Mortality

By 2040, the number of women diagnosed with ovarian cancer annually worldwide is expected to increase by 100% in low Human Development Index (HDI) countries, and by 19-28% in high HDI countries.² The causes of this increasing incidence are likely to be multifactorial, including both hereditary and modifiable risk factors.³ In addition to increasing population size, the growing prevalence of obesity, estrogen exposures, and nulliparity are particularly pertinent as potential causes of the rising incidence of ovarian cancer in younger women. The number of ovarian cancer-related deaths is also projected to rise from about 200,000 to nearly 314,000 annually, an increase of over 50% from 2020.^2,4 Although outcomes in developed regions and nations continue to improve somewhat, 5-year survival rates range from 36% to 46%.⁵ These outcomes are nevertheless dismal when compared with 5-year survival rates from other cancer types, such as breast cancer, which are approaching 90%.⁶

Principal Histotypes

The principal histotypes in ovarian cancer are epithelial in origin and include high-grade serous carcinoma, clear-cell carcinoma, endometrioid carcinoma, low-grade serous carcinoma, and mucinous carcinoma. Other rarer types are nonepithelial, ie, arising from stromal or germ cell lines.⁷ Incidence rates appear to be affected over time by trends such as birth rates, use of combination oral contraceptives, and menopausal hormone therapy.⁸ Figure 1 shows that most ovarian cancers—approximately 70%—are high-grade serous carcinoma, although in Asian countries clear cell and endometrioid carcinomas comprise a higher proportion.⁹

Into the Fallopian Tube

One of the most salient and dramatic discoveries of the last 2 decades has been the finding that high-grade, clear-cell, and endometrioid tumors appear to arise from tissues not normally present in the ovary.¹ As a result of risk-reducing efforts to prevent serous cancers in women with genetic predisposition to develop ovarian cancer (ie, those with BRCA1 or BRCA2 mutations), it became increasingly clear that many early cancers arose in the fallopian tube,^10-12 with the distal portion—the fimbria—as the most common site of origin.^13-16

Figure 2 depicts the female reproductive tract, including the location of the fimbria compared with the ovaries. Moreover, lesions observed in the fallopian tube fimbria—serous tubal intraepithelial carcinomas (STICs)—were identified as precursors of ovarian cancer, with a window of 7 years between development of STIC and the beginning of an ovarian cancer.^14,16

Early Detection

Early, localized ovarian cancer is asymptomatic; by the time a patient presents with symptoms, even with nonspecific abdominal complaints, the disease is almost invariably advanced. The concept of early detection has improved both the rate of cancer diagnoses and outcomes for some malignancies, such as cervical, colorectal, breast, and lung cancers,¹⁷ but this strategy is yet to be effectively applied in ovarian cancer. A large, population-based study, for instance, yielded negative results when multimodal screening (using both measurement of CA125 blood levels and transvaginal ultrasound imaging) failed to improve survival, even though such screening was able to detect lower stage disease.¹⁸ Emerging technologies, such as liquid biopsies and uterine lavage, which seek to detect potential biomarkers (new types of blood tests) of ovarian cancer at an early stage and closer to the site of tumor origin, are being investigated and refined but are not yet ready for clinical use, particularly at the population level for screening.¹⁹

Risk-Reducing Interventions

Use of oral contraceptives has been associated with a significant reduction in risk for ovarian cancer, but the potential risks (eg, increased risk for breast cancer, increased risk for venous thromboembolism) preclude its universal recommendation.^20-22 Simple removal of the fallopian tube, salpingectomy, was proposed as a potential intervention to “intercept” the progression of a STIC to cancer. Researchers recently compared simple salpingectomy with salpingo-oophorectomy as a risk-reduction procedure in carriers of BRCA 1/2 pathogenic variants after they had completed childbearing.²³

These investigators proposed that later removal of the ovaries would delay menopause and would contribute to fewer/less severe symptoms, such as hot flashes, disturbed sleep, and sexual issues, as well as maintain or improve overall quality of life. The hypothesis was supported by results, which showed that patients had better menopause-related quality of life after salpingectomy than after salpingo-oophorectomy, regardless of the use of hormone replacement therapy.²³ The oncologic safety of this approach was subsequently demonstrated by other studies that showed a significantly lower incidence of ovarian cancers in women who had undergone opportunistic salpingectomy.^22,24,25

An international prospective trial, TUBA-WISPII, is now underway to test the hypothesis that postponement of oophorectomy after salpingectomy is non-inferior to standard salpingo-oophorectomy in terms of ovarian cancer risk for patients at high risk.²⁶

Treatment

First-Line Therapy
Currently, there are no durable curative therapies for ovarian cancer once advanced disease has been diagnosed.

Surgery plus platinum-based chemotherapy. Most patients, even those diagnosed with advanced disease, are treated initially with debulking surgery, ideally by a gynecologic oncologist, and adjuvant chemotherapy. Most ovarian carcinomas are initially platinum-sensitive, but resistance and disease recurrence are almost inevitable. According to the National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer,²⁷ preferred chemotherapy regimens include paclitaxel and carboplatin with or without bevacizumab, docetaxel and carboplatin, or carboplatin and liposomal doxorubicin. Numerous other regimens, combinations, and agents are included in the guidelines to help providers customize treatment plans.

Neoadjuvant vs adjuvant regimens. Neoadjuvant chemotherapy has been used for other malignancies to gauge sensitivity to systemic treatments and to improve surgical margins.²⁸ Thus far, though, outcomes in ovarian cancer have been similar whether patients were given neoadjuvant or adjuvant treatment in the perioperative period. Individualizing these decisions based on ability to surgically resect, patient age, tumor histology, disease stage, and performance status is recommended.²⁹

Intraperitoneal chemotherapy. Other approaches have been explored to reduce risk for micrometastases after surgery. Hyperthermic intraperitoneal chemotherapy,³² for instance, administered immediately after cytoreductive surgery was studied as a technique that might prevent some of the risks and adverse effects associated with intraperitoneal chemotherapy.³¹ Results showed some improvement in progression-free survival and overall survival in a subgroup of patients who underwent interval cytoreductive surgery after neoadjuvant therapy, but no differences were observed for the larger population with advanced epithelial ovarian cancer. Adverse reactions to intraperitoneal chemotherapy were also observed.

Angiogenesis inhibition. Tumors need energy and oxygen to grow. Angiogenesis is the process of new blood vessel formation that provides the tumor with nutrients. Blocking angiogenesis can thwart tumor growth and improve patient outcomes. Bevacizumab is an antiangiogenic agent that has been extensively studied for 2 decades for many cancers including ovarian carcinoma. The NCCN guidelines note that bevacizumab may be considered as part of a first-line regimen with platinum agents, as maintenance in patients with wild-type or unknown BRCA mutation status and a good response to first-line therapy, or in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor in eligible patients.²⁷

PARP inhibitors. Approximately half of all high-grade serous ovarian carcinomas exhibit some defect in the ability to repair DNA damage using the homologous recombination (HR) pathway. These tumors include those with mutations in the BRCA1, BRCA2, and other HR genes. Defects in HR make tumors more dependent on back-up DNA repair systems, including the activity of PARP. PARP inhibitors were developed to specifically target HR-deficient tumors. To date, 3 PARP inhibitors have been approved for use in ovarian cancer—olaparib, rucaparib, and niraparib. Their use has expanded from later-line use in patients with BRCA1/2-mutated tumors to include frontline maintenance regimens for women with high-grade serous and high-grade endometrioid carcinomas, as well as women with recurrent disease.³² Numerous clinical trials are ongoing to develop next-generation PARP inhibitors and to explore their efficacy in combination with chemotherapy and other targeted agents.

Resistance and Disease Progression: Second-Line and Subsequent Treatment

A number of second-line and subsequent systemic treatment regimens may be considered when primary platinum-based chemotherapy and/or maintenance are no longer effective.^33,34 As emphasized by the NCCN, a clinical trial is always an appropriate option, depending on eligibility, and sometimes a second cytoreductive surgery^35,36 may be considered for patients who experience radiographic and/or clinical relapse after a long disease-free interval (6+ months). Each line of treatment is associated with progressively lower response rates and shorter durations of response. According to the NCCN guidelines, as patient performance status decreases and the toxicities of each line of therapy accumulate, assessment for palliative care should be considered and discussed.²⁷

Investigational Approaches

With the high mortality rate associated with ovarian cancer, the challenges of detecting the disease at its early stages, and the lack of therapies that can significantly extend progression-free and overall survival in patients with advanced disease, many investigators are focused on novel treatment approaches. Preclinical observations, for instance, showing synergy between ataxia telangiectasia and RAD3-related (ATR) kinase inhibitors and PARP inhibitors led researchers to initiate a phase 2 study of olaparib plus ceralasertib (an ATR inhibitor) in patients with recurrent, platinum-resistant epithelial ovarian cancer.³⁷ No objective responses were noted, but some signals of activity were seen among patients with BRCA1 mutations.

Due to success in other malignancies, immunotherapy is also being explored. Although some promising signals were reported at 6 months when nivolumab, a PD-1 (programmed cell death protein 1) inhibitor, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 antibody, were combined to treat patients with platinum-resistant epithelial ovarian cancer; final results are not yet available.³⁸

Ovarian cancer is sometimes characterized as immunologically “cold.” This description means that immune cells, especially T cells, are not able to enter the tumor and destroy the cancer cells. It also means that these tumors are not as responsive to immune-based treatments. Therefore, some researchers are examining novel alternative immunotherapy strategies, such as chimeric antigen receptor T-cell (CAR-T) therapy.³⁹ When a CAR T-cell encounters a tumor antigen, the CAR T-cell becomes activated. Activated CAR T-cells multiply, signal to other immune cells, and ultimately kill the tumor cells. Although CAR T-cell therapy has been tremendously successful in hematologic malignancies, to date, the benefits in solid tumors have been modest.³⁹ However, there is significant enthusiasm for novel tumor antigens that can be targeted by CAR-T therapy, including mesothelin, folate receptor, Claudin-6, B7-H3, B7-H4, HER2, CD47, and L1-CAM, among others.⁴⁰

Other investigational strategies include a p53 vaccine that would enhance the patient’s immunologic response to abnormal proteins produced by a mutated p53 gene, which is the most common finding in ovarian tumors.

Although researchers are investigating many approaches to treating advanced ovarian cancer, one strategy that has been pursued in other cancer settings—development of antibody-drug conjugates (ADCs)⁴¹—has seen promising results. In the late fall of 2022, the US Food and Drug Administration granted accelerated approval for mirvetuximab soravtansine-gynx for use in patients with a specific type of type of tumor (folate receptor alpha [FRα]-positive) when platinum resistance emerges.⁴² A companion diagnostic assay was also approved for selecting patients with FRα-positive disease. Several other clinical trials are investigating the efficacy of targeting other ovarian tumor antigens using the ADC approach. These targets include NaPi2b, mesothelin, B7-H4, Claudin-6, and Trop-2.^43,44

Progress to Come 

Progress in ovarian cancer will be made through a multipronged approach that includes interventions that may proactively “intercept” the development of cancer (eg, salpingectomy for women planning to have other simple gynecologic procedures after childbearing is complete). Although prophylactic surgeries are often undertaken by individuals at high risk for ovarian cancer because of genetic findings, such as BRCA1/2 abnormalities, even women with normal risk may consider when planning tubal ligation, removing their tubes, and other routine procedures. A substantial number of malignant tumors, and associated morbidity and mortality, may be thwarted as a result. The question of whether to treat when a STIC is detected remains to be answered.

The search for better methods of early detection continues, as local therapies for early-stage disease are invariably more effective than treatments in the advanced and/or metastatic setting.

Finally, as with certain other malignancies, even in the advanced setting, effective, often targeted, treatments can significantly prolong both progression-free and overall survival, transforming an often-lethal disease into a chronic one that allows patients to enjoy a better life expectancy with good quality of life.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

A 65-year-old African American man presented to an Otolaryngology Head and Neck Surgery clinic at a tertiary Veterans Health Administration (VHA) facility for evaluation. The patient recalled a past diagnosis of oropharyngeal cancer (OPC), possibly associated with the human papillomavirus (HPV). After receiving the diagnosis at another VHA facility, the patient opted to seek care at a local, non-VHA facility and received approximately 7 weeks of daily radiation and weekly infusions of chemotherapy.

Six years after his initial diagnosis and treatment, the patient said he had a persistent cough with any meaningful attempts to eat or drink. He also noted he lost at least 10 lbs in the last 3 months and had been hospitalized twice during the past winter. During his second hospitalization he spent 4 days on a ventilator in the intensive care unit.

On examination, the patient appeared frail and cachectic, with significant fibrosis of the neck skin and moderate trismus. His dentition was in poor health, and an in-clinic flexible endoscopy demonstrated clear silent aspiration of oral secretions. Given his failure to thrive, the patient was urgently admitted to the hospital. A modified barium swallow study performed by the head and neck Speech Pathology team demonstrated gross aspiration with all consistencies. After extensive counseling, the patient agreed to the placement of a gastrostomy tube. He was discharged in stable condition with adequate supplies and self-care training. He was advised to continue follow-up in the Head and Neck Cancer Survivorship clinic.

Two years later, in the early phase of the COVID-19 pandemic, the patient was admitted to the hospital with COVID pneumonia. Given the damage to his lungs over the previous decade from recurrent episodes of aspiration pneumonia, the patient succumbed.

An Unexpected, Unrelenting Epidemic

Shifting population dynamics and behaviors have led to an explosion in the incidence of cancers associated with infection by oncogenic subtypes of HPV, among which cancer of the oropharynx represents the most common malignancy.^1,2 OPC now afflicts more than 30,000 new patients in the United States each year.³ Given current vaccination rates against oncogenic HPV, the overall trend of increasing incidence is not expected to stabilize until the 2040s.³ Traditional cancers of the head and neck region were previously fatal after 5 years in more than 60% of cases; however, today patients with HPV-associated OPC can expect a more than 80% chance of being alive 5 years after treatment.^4-7 Combining the increasing incidence of OPC with a high chance of oncologic cure has led to an ever-expanding cohort of OPC survivors.

Enthusiasm about a high rate of survival after an HPV-associated OPC diagnosis is now partially dampened by an increasing realization that neither oncologists nor healthcare systems are remotely prepared for this rapidly expanding cohort of OPC survivors. Their unique needs and problems have yet to be objectively defined and quantified.

Relationship Between Survival and Long-Term Toxicity in HPV-Associated OPC

Survivorship care after OPC treatment is a growing challenge in terms of the number of patients affected, the negative impact on quality of life (QOL), and the potential burden on the healthcare system. The rapidly growing number of OPC survivors who are living long enough to develop delayed adverse effects related to their past OPC treatment^1,2,8 includes many patients in whom toxicities can be truly debilitating,^9,10 generating significant unmet needs.

Tumor and Treatment Toxicity

Although HPV-associated OPC demonstrates an excellent response to conventional chemoradiotherapy (CRT), this finding cannot be interpreted to mean that reducing treatment intensity is safe for patients with this disease. Prospective trials have now demonstrated that neither replacing or eliminating conventional chemotherapy, nor significantly reducing radiation doses, can be considered safe at this time.^11-15 As a result, a patient with newly diagnosed HPV-associated OPC in 2025, and potentially even 2030, is likely to receive the same treatment as patients who were treated in the late 2010s.¹⁴

Three decades ago, the chronic effects of tumor and treatment were largely limited to a small cohort of survivors; however, today they affect more patients.^1,2,7 Chronic xerostomia, dysphagia, trismus, radiation fibrosis, and osteoradionecrosis (ORN) now confront tens of thousands of OPC survivors; over the coming decades, these treatment effects have the potential to affect millions of patients.^16-22

While most acute toxicities resolve within several months of completing CRT, late CRT sequelae tend to be dynamic and can progress silently over many years.^16,23 Adverse effects vary widely, with many toxicities (eg, dysphagia, ORN) being particularly debilitating. Many of these effects occur in a radiation dose–dependent fashion, but radiation dose does not fully predict late toxicities, pointing to a role for other, yet unidentified contributing factors.^24,25

Dysphagia in Survivors of OPC

About two-thirds of survivors of head and neck cancer (HNC) who seek follow-up care 5 years after treatment report dysphagia and at least partial dependence on a feeding tube.²⁶ The incidence of dysphagia increases proportionately with higher radiation doses delivered to the pharyngeal constrictors and supraglottic larynx.¹⁸ Dysphagia can severely reduce QOL years after treatment, necessitating substantial changes in diet and social behavior among OPC survivors. Often, patients are forced to choose between chronic malnutrition or starvation and feeding tube dependence.²⁷ Loss of a normal oral diet is frequently one of the most affected QOL measures for OPC survivors.²⁸

In addition to effects on QOL, dysphagia can have life-threatening consequences. In a recent systematic review and meta-analysis, life-threatening aspiration occurred after > 24 months at a reported incidence ranging from 3% to nearly 35%. Although a reduction in radiation dose to the pharyngeal constrictors can reduce chronic dysphagia,²⁷ whether this can be done safely in most OPC patients, particularly those with bulky primary tumors, remains unclear.

Osteoradionecrosis (ORN) in Survivors of OPC

ORN is one of the most potentially serious complications of CRT and may not manifest for years after treatment. Its median time of onset after radiotherapy is 8 years in patients with OPC.²⁴ Bone injury and impaired healing of the alveolar mucosa are signs of ORN, which occurs in ~7% of patients receiving intensity-modulated radiation therapy for OPC.¹⁷ ORN is accompanied by pain, difficulties with chewing, exacerbation of concomitant dysphagia and, in the advanced stage—gross cosmetic deformity secondary to mandibular or maxillary fracture and/or decay.²⁹ Despite the severity of this complication, we are just beginning to understand why ORN develops in a subset of patients. Although ORN is generally more common in patients with advanced-stage OPC who receive higher doses of radiation to a larger overall bone volume,^17,19,24,30 comprehensive translational research efforts focused on ORN (as well as other late toxicities of OPC treatment) are still in their infancy.

Unmet Needs in Predicting and Evaluating Late Toxicities

Predicting which patients will experience long-term treatment toxicities or which types of late toxicities they may develop is not yet possible. Whereas increased data collection and prognostic models can help inform healthcare systems as to the expected frequencies of toxicity, they are unlikely to be prognostic at the individual patient level. As such, there is a critical need for individualized biomarker strategies that can predict one’s risk of toxicity and identify normal tissue shifts in biology and function early in the process to initiate interventions before significant deterioration. Adding to the complexity of predicting late toxicities is the lack of standardization in instruments used to categorize them. Examples of tools that may be used to categorize dysphagia include the Common Terminology Criteria for Adverse Events v4.0 grading scale, the Radiation Therapy Oncology Group grading system, and the European Organization for Research and Treatment of Cancer Performance Status Scale for Head and Neck Cancer.²⁰ The MD Anderson Symptom Inventory for head and neck cancer may also be used to catalog dysphagia and other common symptoms of HNC, as well as treatment-related concerns.³¹ Magnetic resonance imaging-based techniques coupled with machine learning approaches represent emerging tools that may have a role in identifying early radiation-induced bone changes that can facilitate early detection of ORN.^32,33 Although conventional and newer tools can be used to generate objective metrics of treatment-related toxicity, consistent and appropriate deployment across the entire cohort of OPC survivors in the United States remains a distant goal.

Calibrating Treatment Intensity to Disease Intensity 

Given the risk of severe and potentially life-threatening consequences of radiation-based treatment, there is a large unmet need to better calibrate treatment intensity to the intensity of HPV-associated OPC.^14,34 In light of the good prognosis of the disease in most patients, recent efforts have focused on identifying ways to de-escalate treatment intensity while preserving the good outcomes known to be possible for patients with HPV-associated OPC. Improving tolerability and limiting the risk of late effects of radiation-based treatment is especially important with the aging population of HPV-associated OPC survivors, who would also be expected to have unrelated comorbidities.¹

Various modes of de-escalation have been studied, including adding surgery to CRT, reducing radiation dose, and modifying systemic therapy regimens. Most of these efforts have largely failed to identify a safe regimen for treatment de-escalation that applies to a majority or even a significant plurality of patients with OPC.^14,35,36 Although CheckMate 141 and KEYNOTE-048 garnered excitement when immune checkpoint inhibitors (ICIs) significantly prolonged overall survival and had a more favorable safety profile than standard systemic therapy in recurrent and metastatic OPC,^11,37,38 adding definitive frontline avelumab to CRT failed to prolong progression-free survival versus CRT alone in the phase 3 JAVELIN Head and Neck 100 trial.¹³ Combined with additional recent trial data, these findings make it unlikely that an ICI-based regimen will provide previously unavailable de-escalation options for patients with OPC in the near future.

Considering continued de-escalation efforts, it is important to remember that survival is not uniform among all patients with HPV-associated OPC. For example, patients with HPV-associated OPC and a history of current or prior heavy tobacco use have not experienced the same dramatic prolongation in overall survival as their nonsmoking counterparts.³⁶ Patients with recurrent disease also face a dismal prognosis, with failure rates of about 70% with salvage treatment with surgery, re-irradiation, or systemic therapy.^38-41 Therefore, de-escalation may not be appropriate in all patients, but identifying which patients are at risk of overtreatment is not straightforward. Better risk stratification of patients may provide part of the solution but will require rigorous testing and long-term follow-up to establish.

Discussion

There is an urgent need to carefully consider how to manage long-term survivors of HPV-associated OPC. With ever-increasing numbers of patients who are living years beyond their OPC treatment, continual reevaluation of treatment strategies in certain subsets of patients and making concerted efforts to identify and manage late toxicities early is paramount. Yet there remains a critical gap in knowledge due to insufficient metrics for both toxicity intensity and the frequency of debilitating, life-threatening toxicity. Unfortunately, the lack of tools available combined with the mismatch in disease intensity with treatment intensity likely results in excessive treatment-induced toxicity for many patients.

In the absence of clear evidence about which treatment strategy to use for individual patients, clinicians are tasked with making therapeutic choices without being fully able to predict outcomes. Patient preference is important to consider, but these conversations can be complicated. How does one talk to a patient about their willingness to risk a cancer recurrence and potentially risk late toxicities when the clinician does not know whether that individual patient will develop late toxicities, or know how severe they will be? It is a tradeoff between QOL (ie, possible feeding tube dependence) and survival—yet the magnitude of the effect on QOL remains impossible to predict at present for the individual patient.

Moreover, the needs of individual OPC survivors vary. A cross-sectional study performed at Princess Margaret Cancer Centre found that 61% of the 158 participants had unmet needs related to their cancer survivorship.⁴² Meeting the needs of survivors may require the development of better screening instruments that can manage various complications early and effectively. Continuing to follow OPC survivors with a multidisciplinary team would most certainly be beneficial and has been reported to improve QOL.⁴³ Continual Speech Pathology management and therapy from the time of diagnosis into the survivorship phase of care has been suggested as one way to improve functional outcomes.⁴⁴ Given that coordinating long-term care teams is logistically challenging, well-planned research is warranted to equip these teams to provide OPC survivors with the care they need. These efforts will be particularly important considering the large number of survivors who will need this type of care in the coming decades. The time to start is now well past.

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

While people living with rare cancers continue to face daunting obstacles, progress is being made, and there are reasons to hope for a better future. Advances in genomic testing and precision medicine provide increasing evidence that rare cancers can be more efficiently and effectively diagnosed and treated. Genomic tests examine tumor DNA to identify mutations that are unique to an individual’s cancer. This genetic information enables a more precise diagnosis and targeted treatment approach. Jim Palma, Co-Lead of the NORD Rare Cancer Coalition, said “There is promise for rare cancer patients due to increased legislative efforts to cover the costs of genomic testing coupled by an increase in FDA approvals for targeted and tissue agnostic therapies.”

In 2019, the National Cancer Institute established MyPART, a vast pediatric and adult rare tumor network that aims to bolster patient involvement in research and develop effective therapies through tumor sample collection, shared data, shared samples, new methods to test treatments, and new trial designs. In 2022, MyPART welcomed NORD’s Rare Cancer Coalition as an advocacy partner.

Meanwhile, advocacy organizations are giving rare cancer a rising voice. NORD’s Rare Cancer Coalition unites rare cancer patient advocacy organizations and helps them drive progress together. The coalition promotes research and awareness through its annual Rare Cancer Day (September 30) campaign. Additionally, NORD has produced over 22 continuing medical education modules on rare cancers in collaboration with PlatformQ Health, providing updates on new therapies and treatment approaches. NORD also offers rare disease reports and educational videos on rare cancers, sessions inclusive of rare cancer topics at the annual NORD Summit, and a quarterly e-newsletter, “Caring for Rare” for healthcare professionals. Please visit us at rarediseases.org to access these resources.

Much work on rare cancers remains to be done, but the progress over recent years points to better outcomes moving forward. We are grateful for the work you do and your dedication to your patients, including those with rare cancers and other rare conditions. We hope you will find the information in this special issue useful for your clinical practice.

– Katie Kowalski, MPH
Associate Director of Education
National Organization for Rare Disorders

Click to read more from 2023 Rare Diseases Report: Cancers

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

This edition of Rare Diseases Report: Cancers highlights the latest breakthroughs and remaining unmet needs in the management of rare cancers. In addition to celebrating the great progress that has been made in recent years, we also discuss new challenges, such as how the healthcare system can prepare to manage the growing number of rare cancer survivors who are living longer due to improvements in disease management. 

INTRODUCTION

NORD: Making Progress Through Collaboration
By Katie Kowalski, MPH

IN THIS ISSUE

The Complex Challenge of Survival After HPV-Associated Oropharyngeal Cancer
By Vlad C. Sandulache, MD, PhD

Progress in Ovarian Cancer: Discovery of Fallopian Tube Involvement
By Ronny Drapkin, MD, PhD

An Evolving Understanding of Adenosquamous Carcinoma of the Lung
By Rajwanth Veluswamy, MD, MSCR

Gastrointestinal Stromal Tumor: Reflecting on 2 Decades of Clinical Advancements
By Jason K. Sicklick, MD, FACS

Progress in Treating Testicular Cancer
By Liang Cheng, MD

Strategies to Improve Long-Term Outcomes in Younger Patients with Hodgkin Lymphoma
By Ann LaCasce, MD, MMSc

Targeted Therapies in Younger and Older Patients with Mantle Cell Lymphoma
By Reem Karmali, MD, MS

Advances in Management of Relapsed/Refractory Hairy Cell Leukemia
By Robert J. Kreitman, MD

Treatment Needs of Older Adults With Newly Diagnosed Acute Myeloid Leukemia
By Harry Erba, MD, PhD

Progress in Management of Advanced Acute Lymphocytic Leukemia in Children
By Susan Colace, MD, MSCI

The Food and Drug Administration approved ritlecitinib on June 23 for the treatment of severe alopecia areata in people ages 12 and older, the manufacturer announced.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3 (JAK3). The recommended dose of ritlecitinib, which will be marketed as Litfulo, is 50 mg once a day, according to the statement announcing the approval from Pfizer.

Olivier Le Moal/Getty Images

It is the second JAK inhibitor approved for treating alopecia areata, following approval of baricitinib (Olumiant) in June 2022 for AA in adults. Ritlecitinib is the first JAK inhibitor approved for children ages 12 and older with AA.  

The European Medicines Agency has also accepted the Marketing Authorization Application for ritlecitinib in the same population and a decision is expected in the fourth quarter of this year.
 

Approval based on ALLEGRO trials

Approval was based on  previously announced results from trials, including the phase 2b/3 ALLEGRO study of ritlecitinib in 718 patients aged 12 years and older with alopecia areata, with 50% of more scalp hair loss, as measured by the Severity of Alopecia Tool (SALT), including patients with alopecia totalis (complete scalp hair loss) and alopecia universalis (complete scalp, face, and body hair loss).

Patients in the trial were experiencing a current episode of alopecia areata that had lasted between 6 months and 10 years. They were randomized to receive once-daily ritlecitinib at doses of 30 mg or 50 mg (with or without 1 month of initial treatment with once-daily ritlecitinib 200 mg), ritlecitinib 10 mg, or placebo.

Statistically significantly higher proportions of patients treated with ritlecitinib 30 mg and 50 mg (with or without the loading dose) had 80% or more scalp hair coverage, as measured by a SALT score of 20 or less after 6 months of treatment versus placebo. After 6 months of treatment, among those on the 50-mg dose, 23% had achieved a SALT score of 20 or less, compared with 2% of those on placebo. The results were published in The Lancet.

According to the company release, efficacy and safety of ritlecitinib was consistent between those ages 12-17 and adults, and the most common adverse events reported in the study, in at least 4% of patients treated with ritlecitinib, were headache (10.8%), diarrhea (10%), acne (6.2%), rash (5.4%), and urticaria (4.6%). 

Ritlecitinib labeling includes the boxed warning about the risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, which is included in the labels for other JAK inhibitors.
 

Ritlecitinib evaluated for other diseases

In addition to alopecia areata, ritlecitinib has shown efficacy and acceptable safety in treating ulcerative colitis and is being evaluated for treating vitiligo, Crohn’s disease, and rheumatoid arthritis.

In the statement, the company says that ritlecitinib will be available “in the coming weeks.” The manufacturer says it also has completed regulatory submissions for ritlecitinib in the United Kingdom, China, and Japan, and expects decisions this year.

Alopecia areata affects about 6.8 million people in the United States and 147 million globally.

In a statement, Nicole Friedland, president and CEO of the National Alopecia Areata Foundation, said that NAAF “is thrilled to have a second FDA-approved treatment for alopecia areata, which is the first approved for adolescents.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration approved ritlecitinib on June 23 for the treatment of severe alopecia areata in people ages 12 and older, the manufacturer announced.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3 (JAK3). The recommended dose of ritlecitinib, which will be marketed as Litfulo, is 50 mg once a day, according to the statement announcing the approval from Pfizer.

Olivier Le Moal/Getty Images

It is the second JAK inhibitor approved for treating alopecia areata, following approval of baricitinib (Olumiant) in June 2022 for AA in adults. Ritlecitinib is the first JAK inhibitor approved for children ages 12 and older with AA.  

The European Medicines Agency has also accepted the Marketing Authorization Application for ritlecitinib in the same population and a decision is expected in the fourth quarter of this year.
 

Approval based on ALLEGRO trials

Approval was based on  previously announced results from trials, including the phase 2b/3 ALLEGRO study of ritlecitinib in 718 patients aged 12 years and older with alopecia areata, with 50% of more scalp hair loss, as measured by the Severity of Alopecia Tool (SALT), including patients with alopecia totalis (complete scalp hair loss) and alopecia universalis (complete scalp, face, and body hair loss).

Patients in the trial were experiencing a current episode of alopecia areata that had lasted between 6 months and 10 years. They were randomized to receive once-daily ritlecitinib at doses of 30 mg or 50 mg (with or without 1 month of initial treatment with once-daily ritlecitinib 200 mg), ritlecitinib 10 mg, or placebo.

Statistically significantly higher proportions of patients treated with ritlecitinib 30 mg and 50 mg (with or without the loading dose) had 80% or more scalp hair coverage, as measured by a SALT score of 20 or less after 6 months of treatment versus placebo. After 6 months of treatment, among those on the 50-mg dose, 23% had achieved a SALT score of 20 or less, compared with 2% of those on placebo. The results were published in The Lancet.

According to the company release, efficacy and safety of ritlecitinib was consistent between those ages 12-17 and adults, and the most common adverse events reported in the study, in at least 4% of patients treated with ritlecitinib, were headache (10.8%), diarrhea (10%), acne (6.2%), rash (5.4%), and urticaria (4.6%). 

Ritlecitinib labeling includes the boxed warning about the risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, which is included in the labels for other JAK inhibitors.
 

Ritlecitinib evaluated for other diseases

In addition to alopecia areata, ritlecitinib has shown efficacy and acceptable safety in treating ulcerative colitis and is being evaluated for treating vitiligo, Crohn’s disease, and rheumatoid arthritis.

In the statement, the company says that ritlecitinib will be available “in the coming weeks.” The manufacturer says it also has completed regulatory submissions for ritlecitinib in the United Kingdom, China, and Japan, and expects decisions this year.

Alopecia areata affects about 6.8 million people in the United States and 147 million globally.

In a statement, Nicole Friedland, president and CEO of the National Alopecia Areata Foundation, said that NAAF “is thrilled to have a second FDA-approved treatment for alopecia areata, which is the first approved for adolescents.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration approved ritlecitinib on June 23 for the treatment of severe alopecia areata in people ages 12 and older, the manufacturer announced.

Taken as a once-daily pill, ritlecitinib is a dual inhibitor of the TEC family of tyrosine kinases and of Janus kinase 3 (JAK3). The recommended dose of ritlecitinib, which will be marketed as Litfulo, is 50 mg once a day, according to the statement announcing the approval from Pfizer.

Olivier Le Moal/Getty Images

It is the second JAK inhibitor approved for treating alopecia areata, following approval of baricitinib (Olumiant) in June 2022 for AA in adults. Ritlecitinib is the first JAK inhibitor approved for children ages 12 and older with AA.  

The European Medicines Agency has also accepted the Marketing Authorization Application for ritlecitinib in the same population and a decision is expected in the fourth quarter of this year.
 

Approval based on ALLEGRO trials

Approval was based on  previously announced results from trials, including the phase 2b/3 ALLEGRO study of ritlecitinib in 718 patients aged 12 years and older with alopecia areata, with 50% of more scalp hair loss, as measured by the Severity of Alopecia Tool (SALT), including patients with alopecia totalis (complete scalp hair loss) and alopecia universalis (complete scalp, face, and body hair loss).

Patients in the trial were experiencing a current episode of alopecia areata that had lasted between 6 months and 10 years. They were randomized to receive once-daily ritlecitinib at doses of 30 mg or 50 mg (with or without 1 month of initial treatment with once-daily ritlecitinib 200 mg), ritlecitinib 10 mg, or placebo.

Statistically significantly higher proportions of patients treated with ritlecitinib 30 mg and 50 mg (with or without the loading dose) had 80% or more scalp hair coverage, as measured by a SALT score of 20 or less after 6 months of treatment versus placebo. After 6 months of treatment, among those on the 50-mg dose, 23% had achieved a SALT score of 20 or less, compared with 2% of those on placebo. The results were published in The Lancet.

According to the company release, efficacy and safety of ritlecitinib was consistent between those ages 12-17 and adults, and the most common adverse events reported in the study, in at least 4% of patients treated with ritlecitinib, were headache (10.8%), diarrhea (10%), acne (6.2%), rash (5.4%), and urticaria (4.6%). 

Ritlecitinib labeling includes the boxed warning about the risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis, which is included in the labels for other JAK inhibitors.
 

Ritlecitinib evaluated for other diseases

In addition to alopecia areata, ritlecitinib has shown efficacy and acceptable safety in treating ulcerative colitis and is being evaluated for treating vitiligo, Crohn’s disease, and rheumatoid arthritis.

In the statement, the company says that ritlecitinib will be available “in the coming weeks.” The manufacturer says it also has completed regulatory submissions for ritlecitinib in the United Kingdom, China, and Japan, and expects decisions this year.

Alopecia areata affects about 6.8 million people in the United States and 147 million globally.

In a statement, Nicole Friedland, president and CEO of the National Alopecia Areata Foundation, said that NAAF “is thrilled to have a second FDA-approved treatment for alopecia areata, which is the first approved for adolescents.”

A version of this article first appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

A version of this article first appeared on Medscape.com.