Liam Davenport

PHOENIX – A liquid biopsy test may accurately predict recurrence of human papillomavirus (HPV)–driven oropharyngeal squamous cell carcinoma (OPSCC) earlier than standard clinical and imaging assessments, a new analysis indicates.

Of 80 patients who tested positive for circulating tumor tissue–modified viral (TTMV)-HPV DNA during surveillance, 74% (n = 59) had no other evidence of disease or had indeterminate disease status.

And of those patients, 93% (n = 55) “later had proven recurrent, metastatic disease on imaging and/or biopsy,” according to Glenn Hanna, MD, from the Dana-Farber Cancer Institute, Boston, who presented the results Feb. 24 at the 2022 Multidisciplinary Head and Neck Cancers Symposium.

“This is the first study to demonstrate broad clinical utility and validity of the biomarker in HPV-driven oropharyngeal cancer,” Dr. Hanna said in a press release.

Although patients with HPV-driven OPSCC generally have favorable outcomes, up to 25% will experience recurrence after treatment.

Post-treatment surveillance currently relies on physical examinations and imaging, but Dr. Hanna and colleagues wanted to determine whether a routine circulating cell-free TTMV-HPV DNA test could detect occult recurrence sooner.

Dr. Hanna and colleagues analyzed the records of 1,076 patients with HPV-driven OPSCC at 118 sites in the U.S. who had completed therapy more than 3 months previously and undergone an TTMV-HPV DNA test (NavDx, Naveris) between June 2020 and November 2021.

The results of the test, which used ultrasensitive digital droplet PCR to identify HPV subtypes 16, 18, 31, 33, and 35, were compared with subsequent clinical evidence of OPSCC via nasopharyngolaryngoscopy, radiologic evaluations, or tissue biopsy.

Approximately 7% of the patients tested positive (n = 80) for circulating TTMV-HPV DNA. Of those, 26.2% (n = 21) had known clinical recurrence, while 73.8% (n = 59) had no other evidence of disease or an intermediate disease status.

Among those with no clinical evidence of recurrence, 93.2% (n = 55) had their recurrence subsequently confirmed using imaging or biopsy. Of the 4 remaining patients, 2 had clinically suspicious lesions, and 2 had no other evidence of disease.

Overall, the data indicate that the biomarker test demonstrated a 95% positive predictive value (76 of 80 patients) for recurrence or persistence of HPV-driven OPSCC.

According to Dr. Hanna, a positive TTMV-HPV DNA test was the first indicator of recurrence for 72% of patients, and almost half of recurrences were detected more than 12 months after completing therapy.

“Incorporating a test for TTMV-HPV DNA into routine post-treatment follow-up can enable physicians to detect recurrent cancers earlier and allow us to start recommended interventions more quickly to improve outcomes,” Dr. Hanna said in the release.

The study was supported by Naveris, which developed the TTMV-HPV DNA test studied. Dr. Hanna declares relationships with Actuate Therapeutics, Altor BioScience, Bicara, BMS, GSK, Merck, Regeneron, Sanofi/Genzyme, and others.

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

PHOENIX – A liquid biopsy test may accurately predict recurrence of human papillomavirus (HPV)–driven oropharyngeal squamous cell carcinoma (OPSCC) earlier than standard clinical and imaging assessments, a new analysis indicates.

Of 80 patients who tested positive for circulating tumor tissue–modified viral (TTMV)-HPV DNA during surveillance, 74% (n = 59) had no other evidence of disease or had indeterminate disease status.

And of those patients, 93% (n = 55) “later had proven recurrent, metastatic disease on imaging and/or biopsy,” according to Glenn Hanna, MD, from the Dana-Farber Cancer Institute, Boston, who presented the results Feb. 24 at the 2022 Multidisciplinary Head and Neck Cancers Symposium.

“This is the first study to demonstrate broad clinical utility and validity of the biomarker in HPV-driven oropharyngeal cancer,” Dr. Hanna said in a press release.

Although patients with HPV-driven OPSCC generally have favorable outcomes, up to 25% will experience recurrence after treatment.

Post-treatment surveillance currently relies on physical examinations and imaging, but Dr. Hanna and colleagues wanted to determine whether a routine circulating cell-free TTMV-HPV DNA test could detect occult recurrence sooner.

Dr. Hanna and colleagues analyzed the records of 1,076 patients with HPV-driven OPSCC at 118 sites in the U.S. who had completed therapy more than 3 months previously and undergone an TTMV-HPV DNA test (NavDx, Naveris) between June 2020 and November 2021.

The results of the test, which used ultrasensitive digital droplet PCR to identify HPV subtypes 16, 18, 31, 33, and 35, were compared with subsequent clinical evidence of OPSCC via nasopharyngolaryngoscopy, radiologic evaluations, or tissue biopsy.

Approximately 7% of the patients tested positive (n = 80) for circulating TTMV-HPV DNA. Of those, 26.2% (n = 21) had known clinical recurrence, while 73.8% (n = 59) had no other evidence of disease or an intermediate disease status.

Among those with no clinical evidence of recurrence, 93.2% (n = 55) had their recurrence subsequently confirmed using imaging or biopsy. Of the 4 remaining patients, 2 had clinically suspicious lesions, and 2 had no other evidence of disease.

Overall, the data indicate that the biomarker test demonstrated a 95% positive predictive value (76 of 80 patients) for recurrence or persistence of HPV-driven OPSCC.

According to Dr. Hanna, a positive TTMV-HPV DNA test was the first indicator of recurrence for 72% of patients, and almost half of recurrences were detected more than 12 months after completing therapy.

“Incorporating a test for TTMV-HPV DNA into routine post-treatment follow-up can enable physicians to detect recurrent cancers earlier and allow us to start recommended interventions more quickly to improve outcomes,” Dr. Hanna said in the release.

The study was supported by Naveris, which developed the TTMV-HPV DNA test studied. Dr. Hanna declares relationships with Actuate Therapeutics, Altor BioScience, Bicara, BMS, GSK, Merck, Regeneron, Sanofi/Genzyme, and others.

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

PHOENIX – A liquid biopsy test may accurately predict recurrence of human papillomavirus (HPV)–driven oropharyngeal squamous cell carcinoma (OPSCC) earlier than standard clinical and imaging assessments, a new analysis indicates.

Of 80 patients who tested positive for circulating tumor tissue–modified viral (TTMV)-HPV DNA during surveillance, 74% (n = 59) had no other evidence of disease or had indeterminate disease status.

And of those patients, 93% (n = 55) “later had proven recurrent, metastatic disease on imaging and/or biopsy,” according to Glenn Hanna, MD, from the Dana-Farber Cancer Institute, Boston, who presented the results Feb. 24 at the 2022 Multidisciplinary Head and Neck Cancers Symposium.

“This is the first study to demonstrate broad clinical utility and validity of the biomarker in HPV-driven oropharyngeal cancer,” Dr. Hanna said in a press release.

Although patients with HPV-driven OPSCC generally have favorable outcomes, up to 25% will experience recurrence after treatment.

Post-treatment surveillance currently relies on physical examinations and imaging, but Dr. Hanna and colleagues wanted to determine whether a routine circulating cell-free TTMV-HPV DNA test could detect occult recurrence sooner.

Dr. Hanna and colleagues analyzed the records of 1,076 patients with HPV-driven OPSCC at 118 sites in the U.S. who had completed therapy more than 3 months previously and undergone an TTMV-HPV DNA test (NavDx, Naveris) between June 2020 and November 2021.

The results of the test, which used ultrasensitive digital droplet PCR to identify HPV subtypes 16, 18, 31, 33, and 35, were compared with subsequent clinical evidence of OPSCC via nasopharyngolaryngoscopy, radiologic evaluations, or tissue biopsy.

Approximately 7% of the patients tested positive (n = 80) for circulating TTMV-HPV DNA. Of those, 26.2% (n = 21) had known clinical recurrence, while 73.8% (n = 59) had no other evidence of disease or an intermediate disease status.

Among those with no clinical evidence of recurrence, 93.2% (n = 55) had their recurrence subsequently confirmed using imaging or biopsy. Of the 4 remaining patients, 2 had clinically suspicious lesions, and 2 had no other evidence of disease.

Overall, the data indicate that the biomarker test demonstrated a 95% positive predictive value (76 of 80 patients) for recurrence or persistence of HPV-driven OPSCC.

According to Dr. Hanna, a positive TTMV-HPV DNA test was the first indicator of recurrence for 72% of patients, and almost half of recurrences were detected more than 12 months after completing therapy.

“Incorporating a test for TTMV-HPV DNA into routine post-treatment follow-up can enable physicians to detect recurrent cancers earlier and allow us to start recommended interventions more quickly to improve outcomes,” Dr. Hanna said in the release.

The study was supported by Naveris, which developed the TTMV-HPV DNA test studied. Dr. Hanna declares relationships with Actuate Therapeutics, Altor BioScience, Bicara, BMS, GSK, Merck, Regeneron, Sanofi/Genzyme, and others.

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

Although the risk of developing lymphoma in association with a breast implant is “considered to be low,” the disease is “serious and can lead to death,” according to the U.S. Food and Drug Administration.

The immediate treatment is surgical removal of the implant, which is sometimes followed with chemotherapy.

New data show that women who develop breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) who require chemotherapy can achieve excellent results with a combination of chemotherapy (cyclophosphamide, doxorubicin, and prednisone) and the antibody–drug conjugate brentuximab vedotin.

The findings were published in Blood.

The authors, led by Fabien Le Bras, MD, from the Henri Mondor Hospital, Créteil, France, note that despite BIA-ALCL being recently recognized as a provisional entity by the World Health Organization, its pathogenesis has yet to be fully elucidated, and a standard of care has not been established.

Results from the ECHELON 2 trial established brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV-CHP) as a new standard of care in CD30-positive peripheral T-cell lymphoma.

That trial included 316 patients with ACLC, although none of these cases were associated with breast implants.

The principal investigator on that trial, Steven Horwitz, MD, from Memorial Sloan Kettering Center, New York, told this news organization that although BIA-ALCL is “incredibly rare,” it causes “distress” to patients, as “many of them made a choice for reconstruction ... that they thought was safe.”

He said that the latest data from France is “interesting” and that the application of the ECHELON-2 findings to BIA-ALCL is “very logical.”

“For the people who need systemic therapy,” it appears from the current results that BV-CHP “is a very good option,” he said.

The “difficulty” in interpreting the data, however, is that “perhaps 80% of people with BIA-ALCL don’t need any systemic therapy” and are “cured with surgery alone.”

Dr. Horwitz said that while patients with infiltrative disease have a “higher risk of recurrence ... many of those are still cured with surgery alone.”

The main outstanding question he has is how many of the patients who received BV-CHP “might have been okay with observation.”
 

Details of the new data from France

For their study, Dr. Le Bras and colleagues analyzed data from the Lymphoma Study Association registry between 2009 and 2021 and identified 85 patients with BIA-ALCL, including 73 in France and 12 in Belgium.

Most of these patients (whose median age was 57 years) had unilateral lymphoma (94.1%), and only a few patients (5.9%) had bilateral disease.

The team notes that 41.2% of these women had received breast implants once, 41.2% received implants twice, and 17.6% received them three times or more.

In 45.9% of cases, the first implant followed mastectomy for breast cancer.

All patients had at least one textured implant. These have been associated with more cases of BIA-ALCL than smooth implants, and in 2019, Allergan recalled all BioCell textured breast implant products from the United States and around the world, due to the risk for BIA-ALCL, as reported, at the time, by this news organization.

For the women in this registry, the median time from the last implant to BIA-ALCL diagnosis was 7 years.

The most common presentation was seroma, which occurred in 75.3% of patients, while 21.2% of had a breast tumor mass with or without seroma.

Stage I-II disease was identified in 76.5% of patients, and 21.2% of cases were stage IV. Infiltrative disease was present in 24.7%.

Implant removal with total capsulectomy was performed in 77.6%; 29.4% of women also received chemotherapy, with 11.8% receiving BV-CHP.

A complete response was achieved in 84% of patients who received chemotherapy, while 8% failed to respond. Among the patients who received BV-CHP, 80% achieved a complete response.

After a median follow-up of 28.6 months, 91.8% patients were alive and progression free. All patients treated with BV-CHP were alive and progression free after a median follow-up of 1 year.

Patients with infiltrative disease had a significantly worse 2-year progression-free survival than those with in situ/mixed disease, at 73.8% versus 96.7%, or a hazard ratio for progression of 5.3 (P = .0039).

They also had worse 2-year overall survival, at 78.7% versus 100%, or a hazard ratio for death of 8.5 (P = .0022).

The authors note that these patients with infiltrative disease had significantly worse survival outcomes and may benefit most from BV-CHP.

No funding for the study was declared. Dr. Le Bras reports relationships with Novartis, Celgene, BMS, Takeda, Kite, and Gilead. Other authors declare numerous relevant financial relationships.

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

Although the risk of developing lymphoma in association with a breast implant is “considered to be low,” the disease is “serious and can lead to death,” according to the U.S. Food and Drug Administration.

The immediate treatment is surgical removal of the implant, which is sometimes followed with chemotherapy.

New data show that women who develop breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) who require chemotherapy can achieve excellent results with a combination of chemotherapy (cyclophosphamide, doxorubicin, and prednisone) and the antibody–drug conjugate brentuximab vedotin.

The findings were published in Blood.

The authors, led by Fabien Le Bras, MD, from the Henri Mondor Hospital, Créteil, France, note that despite BIA-ALCL being recently recognized as a provisional entity by the World Health Organization, its pathogenesis has yet to be fully elucidated, and a standard of care has not been established.

Results from the ECHELON 2 trial established brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV-CHP) as a new standard of care in CD30-positive peripheral T-cell lymphoma.

That trial included 316 patients with ACLC, although none of these cases were associated with breast implants.

The principal investigator on that trial, Steven Horwitz, MD, from Memorial Sloan Kettering Center, New York, told this news organization that although BIA-ALCL is “incredibly rare,” it causes “distress” to patients, as “many of them made a choice for reconstruction ... that they thought was safe.”

He said that the latest data from France is “interesting” and that the application of the ECHELON-2 findings to BIA-ALCL is “very logical.”

“For the people who need systemic therapy,” it appears from the current results that BV-CHP “is a very good option,” he said.

The “difficulty” in interpreting the data, however, is that “perhaps 80% of people with BIA-ALCL don’t need any systemic therapy” and are “cured with surgery alone.”

Dr. Horwitz said that while patients with infiltrative disease have a “higher risk of recurrence ... many of those are still cured with surgery alone.”

The main outstanding question he has is how many of the patients who received BV-CHP “might have been okay with observation.”
 

Details of the new data from France

For their study, Dr. Le Bras and colleagues analyzed data from the Lymphoma Study Association registry between 2009 and 2021 and identified 85 patients with BIA-ALCL, including 73 in France and 12 in Belgium.

Most of these patients (whose median age was 57 years) had unilateral lymphoma (94.1%), and only a few patients (5.9%) had bilateral disease.

The team notes that 41.2% of these women had received breast implants once, 41.2% received implants twice, and 17.6% received them three times or more.

In 45.9% of cases, the first implant followed mastectomy for breast cancer.

All patients had at least one textured implant. These have been associated with more cases of BIA-ALCL than smooth implants, and in 2019, Allergan recalled all BioCell textured breast implant products from the United States and around the world, due to the risk for BIA-ALCL, as reported, at the time, by this news organization.

For the women in this registry, the median time from the last implant to BIA-ALCL diagnosis was 7 years.

The most common presentation was seroma, which occurred in 75.3% of patients, while 21.2% of had a breast tumor mass with or without seroma.

Stage I-II disease was identified in 76.5% of patients, and 21.2% of cases were stage IV. Infiltrative disease was present in 24.7%.

Implant removal with total capsulectomy was performed in 77.6%; 29.4% of women also received chemotherapy, with 11.8% receiving BV-CHP.

A complete response was achieved in 84% of patients who received chemotherapy, while 8% failed to respond. Among the patients who received BV-CHP, 80% achieved a complete response.

After a median follow-up of 28.6 months, 91.8% patients were alive and progression free. All patients treated with BV-CHP were alive and progression free after a median follow-up of 1 year.

Patients with infiltrative disease had a significantly worse 2-year progression-free survival than those with in situ/mixed disease, at 73.8% versus 96.7%, or a hazard ratio for progression of 5.3 (P = .0039).

They also had worse 2-year overall survival, at 78.7% versus 100%, or a hazard ratio for death of 8.5 (P = .0022).

The authors note that these patients with infiltrative disease had significantly worse survival outcomes and may benefit most from BV-CHP.

No funding for the study was declared. Dr. Le Bras reports relationships with Novartis, Celgene, BMS, Takeda, Kite, and Gilead. Other authors declare numerous relevant financial relationships.

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

Although the risk of developing lymphoma in association with a breast implant is “considered to be low,” the disease is “serious and can lead to death,” according to the U.S. Food and Drug Administration.

The immediate treatment is surgical removal of the implant, which is sometimes followed with chemotherapy.

New data show that women who develop breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) who require chemotherapy can achieve excellent results with a combination of chemotherapy (cyclophosphamide, doxorubicin, and prednisone) and the antibody–drug conjugate brentuximab vedotin.

The findings were published in Blood.

The authors, led by Fabien Le Bras, MD, from the Henri Mondor Hospital, Créteil, France, note that despite BIA-ALCL being recently recognized as a provisional entity by the World Health Organization, its pathogenesis has yet to be fully elucidated, and a standard of care has not been established.

Results from the ECHELON 2 trial established brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (BV-CHP) as a new standard of care in CD30-positive peripheral T-cell lymphoma.

That trial included 316 patients with ACLC, although none of these cases were associated with breast implants.

The principal investigator on that trial, Steven Horwitz, MD, from Memorial Sloan Kettering Center, New York, told this news organization that although BIA-ALCL is “incredibly rare,” it causes “distress” to patients, as “many of them made a choice for reconstruction ... that they thought was safe.”

He said that the latest data from France is “interesting” and that the application of the ECHELON-2 findings to BIA-ALCL is “very logical.”

“For the people who need systemic therapy,” it appears from the current results that BV-CHP “is a very good option,” he said.

The “difficulty” in interpreting the data, however, is that “perhaps 80% of people with BIA-ALCL don’t need any systemic therapy” and are “cured with surgery alone.”

Dr. Horwitz said that while patients with infiltrative disease have a “higher risk of recurrence ... many of those are still cured with surgery alone.”

The main outstanding question he has is how many of the patients who received BV-CHP “might have been okay with observation.”
 

Details of the new data from France

For their study, Dr. Le Bras and colleagues analyzed data from the Lymphoma Study Association registry between 2009 and 2021 and identified 85 patients with BIA-ALCL, including 73 in France and 12 in Belgium.

Most of these patients (whose median age was 57 years) had unilateral lymphoma (94.1%), and only a few patients (5.9%) had bilateral disease.

The team notes that 41.2% of these women had received breast implants once, 41.2% received implants twice, and 17.6% received them three times or more.

In 45.9% of cases, the first implant followed mastectomy for breast cancer.

All patients had at least one textured implant. These have been associated with more cases of BIA-ALCL than smooth implants, and in 2019, Allergan recalled all BioCell textured breast implant products from the United States and around the world, due to the risk for BIA-ALCL, as reported, at the time, by this news organization.

For the women in this registry, the median time from the last implant to BIA-ALCL diagnosis was 7 years.

The most common presentation was seroma, which occurred in 75.3% of patients, while 21.2% of had a breast tumor mass with or without seroma.

Stage I-II disease was identified in 76.5% of patients, and 21.2% of cases were stage IV. Infiltrative disease was present in 24.7%.

Implant removal with total capsulectomy was performed in 77.6%; 29.4% of women also received chemotherapy, with 11.8% receiving BV-CHP.

A complete response was achieved in 84% of patients who received chemotherapy, while 8% failed to respond. Among the patients who received BV-CHP, 80% achieved a complete response.

After a median follow-up of 28.6 months, 91.8% patients were alive and progression free. All patients treated with BV-CHP were alive and progression free after a median follow-up of 1 year.

Patients with infiltrative disease had a significantly worse 2-year progression-free survival than those with in situ/mixed disease, at 73.8% versus 96.7%, or a hazard ratio for progression of 5.3 (P = .0039).

They also had worse 2-year overall survival, at 78.7% versus 100%, or a hazard ratio for death of 8.5 (P = .0022).

The authors note that these patients with infiltrative disease had significantly worse survival outcomes and may benefit most from BV-CHP.

No funding for the study was declared. Dr. Le Bras reports relationships with Novartis, Celgene, BMS, Takeda, Kite, and Gilead. Other authors declare numerous relevant financial relationships.

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

Patients diagnosed with breast cancer during incarceration are unlikely to receive neoadjuvant therapy and have an increase time to surgery if they have the procedure upfront compared to other patients, suggests a new study.

The study was presented at the 2021 San Antonio Breast Cancer Symposium on Dec. 10 (Abstract P5-14-10).

Examining the records of more than 4,300 patients with breast cancer who were treated between 2014 and 2020 in North Carolina, researchers identified 34 who were either incarcerated at the time of diagnosis or who were diagnosed before they were imprisoned.

They found that neoadjuvant therapy was not given to incarcerated breast cancer patients as compared to 8% of women who were never incarcerated and 20% of women incarcerated later. Incarcerated patients treated with surgery upfront had to wait on average more than 3 weeks longer than other patients for their procedure. Their findings were followed by a recently published study in JAMA Network Open indicating that young people with a history of incarceration were significantly more likely to experience early mortality and that mortality was higher among Black prisoners.

“These findings are concerning for missed treatment opportunities within the carceral system,” wrote researchers who were led by Oluwadamilola “Lola” Fayanju, MD, MPHS, FACS, chief of breast surgery for the University of Pennsylvania Health System, Philadelphia.

Dr. Fayanju told this news organization that she was “not surprised by the finding that there was no neoadjuvant chemotherapy given to patients at all. Even in the practice of care outside of the carceral system it is striking how much variation there is in regards to treatment sequence if it is not approached in an evidence-based way. Many of the social ills that contribute to incarceration also contribute to this variation in care, and it’s not surprising that in women who are experiencing incarceration, there is geometric escalation of disparities with regards to their opportunities for treatment.”

Erica L. Mayer, MD, MPH, a medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Faber Cancer Institute, Boston, said “this is really interesting and important work showing some worrisome trends. On the one hand, this is a very small experience and such a small sample size is always vulnerable to bias or skew from factors that become more important. However, this is not the first observation that there are disparities of care in incarcerated populations,”said Dr. Mayer, who was not involved in the study. “This is a topic that has been studied in diseases outside of oncology, such as heart disease and diabetes. There is a theme that patients who are incarcerated have a disparity and inequity of care compared to those who are not.”

The current findings “fit in with general themes,” she said. As rates of cancer are expected to grow in the coming years, “understanding how to provide the best possible care in those settings is very important. This is early data but it’s an important signal and is suggesting to us that a greater understanding of health care access for incarcerated individuals is a very important area of study, and hopefully an area for which one could provide interventions that might help to reduce these disparities.”

Dr. Fayanju and associates. set out to determine the disease and treatment characteristics of individuals with breast cancer and a history of incarceration. They focused on women who had a breast cancer diagnosis at the University of North Carolina Hospitals between April 2014 and December 2020. They gathered data on patient demographics, incarceration status, disease characteristics, treatment types, and dates of receipt of treatment, but there were few data available. “It is really striking how little data there is available. This is a very small study and is the best we could glean from a large state-wide dataset,” she said.

Of 4,332 breast cancer cases, 34 (0.8%) were diagnosed while incarcerated (70.6%) or before incarceration (29.4%). Those who were diagnosed during incarceration were significantly more likely to be single (P < .001), use illicit drugs at the time of diagnosis (P = .01), and have a family history of breast cancer (P = .03) as compared with patients who were never incarcerated and those who were diagnosed before incarceration.

The results also showed that patients diagnosed with breast cancer during incarceration were significantly less likely to receive neoadjuvant therapy at 0% versus 8.2% for those who were never incarcerated, and 20% for those who were diagnosed before incarceration (P = .01 for trend).

“Further research is needed to understand the full scope of cancer inequities and identify factors that contribute to them among patients who experience incarceration,” Dr. Fayanju said.

No funding or relevant financial relationships were declared for this featured study.

Patients diagnosed with breast cancer during incarceration are unlikely to receive neoadjuvant therapy and have an increase time to surgery if they have the procedure upfront compared to other patients, suggests a new study.

The study was presented at the 2021 San Antonio Breast Cancer Symposium on Dec. 10 (Abstract P5-14-10).

Examining the records of more than 4,300 patients with breast cancer who were treated between 2014 and 2020 in North Carolina, researchers identified 34 who were either incarcerated at the time of diagnosis or who were diagnosed before they were imprisoned.

They found that neoadjuvant therapy was not given to incarcerated breast cancer patients as compared to 8% of women who were never incarcerated and 20% of women incarcerated later. Incarcerated patients treated with surgery upfront had to wait on average more than 3 weeks longer than other patients for their procedure. Their findings were followed by a recently published study in JAMA Network Open indicating that young people with a history of incarceration were significantly more likely to experience early mortality and that mortality was higher among Black prisoners.

“These findings are concerning for missed treatment opportunities within the carceral system,” wrote researchers who were led by Oluwadamilola “Lola” Fayanju, MD, MPHS, FACS, chief of breast surgery for the University of Pennsylvania Health System, Philadelphia.

Dr. Fayanju told this news organization that she was “not surprised by the finding that there was no neoadjuvant chemotherapy given to patients at all. Even in the practice of care outside of the carceral system it is striking how much variation there is in regards to treatment sequence if it is not approached in an evidence-based way. Many of the social ills that contribute to incarceration also contribute to this variation in care, and it’s not surprising that in women who are experiencing incarceration, there is geometric escalation of disparities with regards to their opportunities for treatment.”

Erica L. Mayer, MD, MPH, a medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Faber Cancer Institute, Boston, said “this is really interesting and important work showing some worrisome trends. On the one hand, this is a very small experience and such a small sample size is always vulnerable to bias or skew from factors that become more important. However, this is not the first observation that there are disparities of care in incarcerated populations,”said Dr. Mayer, who was not involved in the study. “This is a topic that has been studied in diseases outside of oncology, such as heart disease and diabetes. There is a theme that patients who are incarcerated have a disparity and inequity of care compared to those who are not.”

The current findings “fit in with general themes,” she said. As rates of cancer are expected to grow in the coming years, “understanding how to provide the best possible care in those settings is very important. This is early data but it’s an important signal and is suggesting to us that a greater understanding of health care access for incarcerated individuals is a very important area of study, and hopefully an area for which one could provide interventions that might help to reduce these disparities.”

Dr. Fayanju and associates. set out to determine the disease and treatment characteristics of individuals with breast cancer and a history of incarceration. They focused on women who had a breast cancer diagnosis at the University of North Carolina Hospitals between April 2014 and December 2020. They gathered data on patient demographics, incarceration status, disease characteristics, treatment types, and dates of receipt of treatment, but there were few data available. “It is really striking how little data there is available. This is a very small study and is the best we could glean from a large state-wide dataset,” she said.

Of 4,332 breast cancer cases, 34 (0.8%) were diagnosed while incarcerated (70.6%) or before incarceration (29.4%). Those who were diagnosed during incarceration were significantly more likely to be single (P < .001), use illicit drugs at the time of diagnosis (P = .01), and have a family history of breast cancer (P = .03) as compared with patients who were never incarcerated and those who were diagnosed before incarceration.

The results also showed that patients diagnosed with breast cancer during incarceration were significantly less likely to receive neoadjuvant therapy at 0% versus 8.2% for those who were never incarcerated, and 20% for those who were diagnosed before incarceration (P = .01 for trend).

“Further research is needed to understand the full scope of cancer inequities and identify factors that contribute to them among patients who experience incarceration,” Dr. Fayanju said.

No funding or relevant financial relationships were declared for this featured study.

Patients diagnosed with breast cancer during incarceration are unlikely to receive neoadjuvant therapy and have an increase time to surgery if they have the procedure upfront compared to other patients, suggests a new study.

The study was presented at the 2021 San Antonio Breast Cancer Symposium on Dec. 10 (Abstract P5-14-10).

Examining the records of more than 4,300 patients with breast cancer who were treated between 2014 and 2020 in North Carolina, researchers identified 34 who were either incarcerated at the time of diagnosis or who were diagnosed before they were imprisoned.

They found that neoadjuvant therapy was not given to incarcerated breast cancer patients as compared to 8% of women who were never incarcerated and 20% of women incarcerated later. Incarcerated patients treated with surgery upfront had to wait on average more than 3 weeks longer than other patients for their procedure. Their findings were followed by a recently published study in JAMA Network Open indicating that young people with a history of incarceration were significantly more likely to experience early mortality and that mortality was higher among Black prisoners.

“These findings are concerning for missed treatment opportunities within the carceral system,” wrote researchers who were led by Oluwadamilola “Lola” Fayanju, MD, MPHS, FACS, chief of breast surgery for the University of Pennsylvania Health System, Philadelphia.

Dr. Fayanju told this news organization that she was “not surprised by the finding that there was no neoadjuvant chemotherapy given to patients at all. Even in the practice of care outside of the carceral system it is striking how much variation there is in regards to treatment sequence if it is not approached in an evidence-based way. Many of the social ills that contribute to incarceration also contribute to this variation in care, and it’s not surprising that in women who are experiencing incarceration, there is geometric escalation of disparities with regards to their opportunities for treatment.”

Erica L. Mayer, MD, MPH, a medical oncologist and clinical investigator in the Breast Oncology Center at the Dana-Faber Cancer Institute, Boston, said “this is really interesting and important work showing some worrisome trends. On the one hand, this is a very small experience and such a small sample size is always vulnerable to bias or skew from factors that become more important. However, this is not the first observation that there are disparities of care in incarcerated populations,”said Dr. Mayer, who was not involved in the study. “This is a topic that has been studied in diseases outside of oncology, such as heart disease and diabetes. There is a theme that patients who are incarcerated have a disparity and inequity of care compared to those who are not.”

The current findings “fit in with general themes,” she said. As rates of cancer are expected to grow in the coming years, “understanding how to provide the best possible care in those settings is very important. This is early data but it’s an important signal and is suggesting to us that a greater understanding of health care access for incarcerated individuals is a very important area of study, and hopefully an area for which one could provide interventions that might help to reduce these disparities.”

Dr. Fayanju and associates. set out to determine the disease and treatment characteristics of individuals with breast cancer and a history of incarceration. They focused on women who had a breast cancer diagnosis at the University of North Carolina Hospitals between April 2014 and December 2020. They gathered data on patient demographics, incarceration status, disease characteristics, treatment types, and dates of receipt of treatment, but there were few data available. “It is really striking how little data there is available. This is a very small study and is the best we could glean from a large state-wide dataset,” she said.

Of 4,332 breast cancer cases, 34 (0.8%) were diagnosed while incarcerated (70.6%) or before incarceration (29.4%). Those who were diagnosed during incarceration were significantly more likely to be single (P < .001), use illicit drugs at the time of diagnosis (P = .01), and have a family history of breast cancer (P = .03) as compared with patients who were never incarcerated and those who were diagnosed before incarceration.

The results also showed that patients diagnosed with breast cancer during incarceration were significantly less likely to receive neoadjuvant therapy at 0% versus 8.2% for those who were never incarcerated, and 20% for those who were diagnosed before incarceration (P = .01 for trend).

“Further research is needed to understand the full scope of cancer inequities and identify factors that contribute to them among patients who experience incarceration,” Dr. Fayanju said.

No funding or relevant financial relationships were declared for this featured study.

Combining a polygenic risk score (PRS) that takes into account genetically determined ancestral risk differences with clinical factors markedly improves breast cancer risk stratification over a standard risk model, potentially enhancing risk reduction and preventive strategies, suggests a data analysis.

Elisha Hughes, PhD, director of research biostatistics at Myriad Genetics (which funded the study), and colleagues combined a risk model containing 149 single-nucleotide polymorphisms (SNPs), of which just over one-third were related to genetic ancestry, with the Tyrer-Cuzick (TC) breast cancer risk model.

The resulting combined risk score, which was developed in a cohort of over 145,000 women and validated in another group of almost 69,000 women, was not only well calibrated, but also able to reclassify just over 17% of women into a different risk group versus the clinical model.

The research (abstract P2-11-21) was presented at the San Antonio Breast Cancer Symposium on Dec. 8.

“This is the first breast cancer risk model based on a polygenic score, the 149-SNP PRS, that incorporates genetically determined ancestral composition and is validated for diverse ancestries,” the team reported.

The combined model substantially improved risk stratification over TC alone and may “lead to enhanced breast cancer risk reduction strategies, such as increased surveillance and use of preventive medications,” the researchers reported.

Breast cancer has a substantial genetic component that can “inform risk prediction and personalized preventive measures.” However, polygenic risk scores are largely derived from studies of women of European descent and tend to have poor performance in non-European ancestries.
 

Combined score substantially improved risk stratification over TC alone

The research team developed a polygenic risk score based on 149 SNPs for women of diverse backgrounds who did not have pathologic variants in breast cancer susceptibility genes, and included 56 ancestry-informative variants with 93 BC-associated variants. They combined the 149-SNP polygenic risk score with the TC risk model to create a combined risk score that was developed in a cohort of 145,786 women who were unaffected by breast cancer, following a fixed-stratified model to avoid double counting between confounded factors.

Of the women included in the cohort, 69.1% were of European descent, while 10.2% were Hispanic, 10.0% Black/African, 1.9% Asian, and 8.8% all other groups.

An independent cohort of 68,803 women of a similar ethnic distribution was then used to evaluate the calibration of the combined risk score against the TC risk model alone, and to examine the relative contributions of the 149-SNP PRS, family history, and other clinical factors.

The results showed that, overall, the combined risk score was well calibrated across ancestries and percentiles of risks, and the absolute lifetime risks were similar to those derived from the TC risk model alone. The only exception was Hispanic carriers of a protective Amerindian SNP who had a lower score on the combined risk score than the TC model.

Using an ANOVA model, the team found that family history contributed 48% to the lifetime risk of breast cancer, while the 149-SNP PRS contributed 35% and other factors 17%. Family history was weakly, but significantly correlated with the 149-SNP PRS.

Determining the impact of adding the 149-SNP PRS to the TC risk model on risk classification, the team showed that across all ancestries, 17.3% of women were reclassified by the combined risk score versus the TC model alone, with 10.8% having their lifetime risk increased to high risk and 29.1% having their risk decreased by the combined model to low risk.

The largest reclassifications were seen for women of European descent, while the smallest were for Black/African women.
 

Study may have ‘cracked the code’

“What’s exciting is that I think we kind-of ‘cracked the code’ to some extent of how to do this across diseases for all ancestries,” Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview. “The adaptation for breast cancer risk stratification and the new panel [is] for breast cancer across all ancestries, but what we developed is something that could be used across diabetes, or colon cancer, or anything.”

He explained that they realized that “for each one of these little hot spots” in the SNPs, “that make one person different from another, you really need to find out where in the world that originated from. So, if you have genetic ancestry on an individual, you can say this spot in the genome has more of an African ancestry to it, or a European ancestry, and then you can weight it appropriately by the population.”

Dr. Slavin said that standard PRSs that simply add up SNPs are “pretty good” and “add a lot” to risk stratification, “but to fine-tune it a little bit and make the best risk model, you really do need to bring in clinical and family history factors.”

Montserrat García-Closas, MD, DrPH, deputy director of the cancer epidemiology and genetics for the National Cancer Institute, said the study is of interest, but “does not give information on how ancestry was considered in the models used to derive the scores.” She also cautioned that the method used in the study to calibrate the model seems “to mean a comparison of scores, rather than comparing the observed and expected risk in prospective cohorts by ancestry groups. This would be a way to estimate bias in risk prediction by ancestry.”

Nevertheless, Dr. García-Closas said the degree of risk reclassification seen with the combined risk score is as expected and pointed to recent work by her and her colleagues in which they tested an integrated model incorporating classical risk factors and a 313-variant PRS to predict breast-cancer risk and achieved similar results.

Several study authors disclosed ties with Myriad Genetics, as well as AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Helix BioPharma, Konica Minolta, Ambry Genetics, Invitae, Stryker, GAIL, Phenogen Sciences, Novartis, Pfizer, CancerIQ, Tempus, 54gene, Color Genetics, Roche/Genentech, ImpediMed, Prelude Therapeutics, BD, Agendia, Targeted Medical Education, Cerebrotech Medical Systems, Integra LifeSciences, Puma Biotechnology, GeneDX/BioReference, Change Health Care, Research to Practice, Clinical Care Options, Physician Education Resource, and Daiichi Sankyo.

The headline for this article was updated on 1/6/22.

Combining a polygenic risk score (PRS) that takes into account genetically determined ancestral risk differences with clinical factors markedly improves breast cancer risk stratification over a standard risk model, potentially enhancing risk reduction and preventive strategies, suggests a data analysis.

Elisha Hughes, PhD, director of research biostatistics at Myriad Genetics (which funded the study), and colleagues combined a risk model containing 149 single-nucleotide polymorphisms (SNPs), of which just over one-third were related to genetic ancestry, with the Tyrer-Cuzick (TC) breast cancer risk model.

The resulting combined risk score, which was developed in a cohort of over 145,000 women and validated in another group of almost 69,000 women, was not only well calibrated, but also able to reclassify just over 17% of women into a different risk group versus the clinical model.

The research (abstract P2-11-21) was presented at the San Antonio Breast Cancer Symposium on Dec. 8.

“This is the first breast cancer risk model based on a polygenic score, the 149-SNP PRS, that incorporates genetically determined ancestral composition and is validated for diverse ancestries,” the team reported.

The combined model substantially improved risk stratification over TC alone and may “lead to enhanced breast cancer risk reduction strategies, such as increased surveillance and use of preventive medications,” the researchers reported.

Breast cancer has a substantial genetic component that can “inform risk prediction and personalized preventive measures.” However, polygenic risk scores are largely derived from studies of women of European descent and tend to have poor performance in non-European ancestries.
 

Combined score substantially improved risk stratification over TC alone

The research team developed a polygenic risk score based on 149 SNPs for women of diverse backgrounds who did not have pathologic variants in breast cancer susceptibility genes, and included 56 ancestry-informative variants with 93 BC-associated variants. They combined the 149-SNP polygenic risk score with the TC risk model to create a combined risk score that was developed in a cohort of 145,786 women who were unaffected by breast cancer, following a fixed-stratified model to avoid double counting between confounded factors.

Of the women included in the cohort, 69.1% were of European descent, while 10.2% were Hispanic, 10.0% Black/African, 1.9% Asian, and 8.8% all other groups.

An independent cohort of 68,803 women of a similar ethnic distribution was then used to evaluate the calibration of the combined risk score against the TC risk model alone, and to examine the relative contributions of the 149-SNP PRS, family history, and other clinical factors.

The results showed that, overall, the combined risk score was well calibrated across ancestries and percentiles of risks, and the absolute lifetime risks were similar to those derived from the TC risk model alone. The only exception was Hispanic carriers of a protective Amerindian SNP who had a lower score on the combined risk score than the TC model.

Using an ANOVA model, the team found that family history contributed 48% to the lifetime risk of breast cancer, while the 149-SNP PRS contributed 35% and other factors 17%. Family history was weakly, but significantly correlated with the 149-SNP PRS.

Determining the impact of adding the 149-SNP PRS to the TC risk model on risk classification, the team showed that across all ancestries, 17.3% of women were reclassified by the combined risk score versus the TC model alone, with 10.8% having their lifetime risk increased to high risk and 29.1% having their risk decreased by the combined model to low risk.

The largest reclassifications were seen for women of European descent, while the smallest were for Black/African women.
 

Study may have ‘cracked the code’

“What’s exciting is that I think we kind-of ‘cracked the code’ to some extent of how to do this across diseases for all ancestries,” Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview. “The adaptation for breast cancer risk stratification and the new panel [is] for breast cancer across all ancestries, but what we developed is something that could be used across diabetes, or colon cancer, or anything.”

He explained that they realized that “for each one of these little hot spots” in the SNPs, “that make one person different from another, you really need to find out where in the world that originated from. So, if you have genetic ancestry on an individual, you can say this spot in the genome has more of an African ancestry to it, or a European ancestry, and then you can weight it appropriately by the population.”

Dr. Slavin said that standard PRSs that simply add up SNPs are “pretty good” and “add a lot” to risk stratification, “but to fine-tune it a little bit and make the best risk model, you really do need to bring in clinical and family history factors.”

Montserrat García-Closas, MD, DrPH, deputy director of the cancer epidemiology and genetics for the National Cancer Institute, said the study is of interest, but “does not give information on how ancestry was considered in the models used to derive the scores.” She also cautioned that the method used in the study to calibrate the model seems “to mean a comparison of scores, rather than comparing the observed and expected risk in prospective cohorts by ancestry groups. This would be a way to estimate bias in risk prediction by ancestry.”

Nevertheless, Dr. García-Closas said the degree of risk reclassification seen with the combined risk score is as expected and pointed to recent work by her and her colleagues in which they tested an integrated model incorporating classical risk factors and a 313-variant PRS to predict breast-cancer risk and achieved similar results.

Several study authors disclosed ties with Myriad Genetics, as well as AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Helix BioPharma, Konica Minolta, Ambry Genetics, Invitae, Stryker, GAIL, Phenogen Sciences, Novartis, Pfizer, CancerIQ, Tempus, 54gene, Color Genetics, Roche/Genentech, ImpediMed, Prelude Therapeutics, BD, Agendia, Targeted Medical Education, Cerebrotech Medical Systems, Integra LifeSciences, Puma Biotechnology, GeneDX/BioReference, Change Health Care, Research to Practice, Clinical Care Options, Physician Education Resource, and Daiichi Sankyo.

The headline for this article was updated on 1/6/22.

Combining a polygenic risk score (PRS) that takes into account genetically determined ancestral risk differences with clinical factors markedly improves breast cancer risk stratification over a standard risk model, potentially enhancing risk reduction and preventive strategies, suggests a data analysis.

Elisha Hughes, PhD, director of research biostatistics at Myriad Genetics (which funded the study), and colleagues combined a risk model containing 149 single-nucleotide polymorphisms (SNPs), of which just over one-third were related to genetic ancestry, with the Tyrer-Cuzick (TC) breast cancer risk model.

The resulting combined risk score, which was developed in a cohort of over 145,000 women and validated in another group of almost 69,000 women, was not only well calibrated, but also able to reclassify just over 17% of women into a different risk group versus the clinical model.

The research (abstract P2-11-21) was presented at the San Antonio Breast Cancer Symposium on Dec. 8.

“This is the first breast cancer risk model based on a polygenic score, the 149-SNP PRS, that incorporates genetically determined ancestral composition and is validated for diverse ancestries,” the team reported.

The combined model substantially improved risk stratification over TC alone and may “lead to enhanced breast cancer risk reduction strategies, such as increased surveillance and use of preventive medications,” the researchers reported.

Breast cancer has a substantial genetic component that can “inform risk prediction and personalized preventive measures.” However, polygenic risk scores are largely derived from studies of women of European descent and tend to have poor performance in non-European ancestries.
 

Combined score substantially improved risk stratification over TC alone

The research team developed a polygenic risk score based on 149 SNPs for women of diverse backgrounds who did not have pathologic variants in breast cancer susceptibility genes, and included 56 ancestry-informative variants with 93 BC-associated variants. They combined the 149-SNP polygenic risk score with the TC risk model to create a combined risk score that was developed in a cohort of 145,786 women who were unaffected by breast cancer, following a fixed-stratified model to avoid double counting between confounded factors.

Of the women included in the cohort, 69.1% were of European descent, while 10.2% were Hispanic, 10.0% Black/African, 1.9% Asian, and 8.8% all other groups.

An independent cohort of 68,803 women of a similar ethnic distribution was then used to evaluate the calibration of the combined risk score against the TC risk model alone, and to examine the relative contributions of the 149-SNP PRS, family history, and other clinical factors.

The results showed that, overall, the combined risk score was well calibrated across ancestries and percentiles of risks, and the absolute lifetime risks were similar to those derived from the TC risk model alone. The only exception was Hispanic carriers of a protective Amerindian SNP who had a lower score on the combined risk score than the TC model.

Using an ANOVA model, the team found that family history contributed 48% to the lifetime risk of breast cancer, while the 149-SNP PRS contributed 35% and other factors 17%. Family history was weakly, but significantly correlated with the 149-SNP PRS.

Determining the impact of adding the 149-SNP PRS to the TC risk model on risk classification, the team showed that across all ancestries, 17.3% of women were reclassified by the combined risk score versus the TC model alone, with 10.8% having their lifetime risk increased to high risk and 29.1% having their risk decreased by the combined model to low risk.

The largest reclassifications were seen for women of European descent, while the smallest were for Black/African women.
 

Study may have ‘cracked the code’

“What’s exciting is that I think we kind-of ‘cracked the code’ to some extent of how to do this across diseases for all ancestries,” Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview. “The adaptation for breast cancer risk stratification and the new panel [is] for breast cancer across all ancestries, but what we developed is something that could be used across diabetes, or colon cancer, or anything.”

He explained that they realized that “for each one of these little hot spots” in the SNPs, “that make one person different from another, you really need to find out where in the world that originated from. So, if you have genetic ancestry on an individual, you can say this spot in the genome has more of an African ancestry to it, or a European ancestry, and then you can weight it appropriately by the population.”

Dr. Slavin said that standard PRSs that simply add up SNPs are “pretty good” and “add a lot” to risk stratification, “but to fine-tune it a little bit and make the best risk model, you really do need to bring in clinical and family history factors.”

Montserrat García-Closas, MD, DrPH, deputy director of the cancer epidemiology and genetics for the National Cancer Institute, said the study is of interest, but “does not give information on how ancestry was considered in the models used to derive the scores.” She also cautioned that the method used in the study to calibrate the model seems “to mean a comparison of scores, rather than comparing the observed and expected risk in prospective cohorts by ancestry groups. This would be a way to estimate bias in risk prediction by ancestry.”

Nevertheless, Dr. García-Closas said the degree of risk reclassification seen with the combined risk score is as expected and pointed to recent work by her and her colleagues in which they tested an integrated model incorporating classical risk factors and a 313-variant PRS to predict breast-cancer risk and achieved similar results.

Several study authors disclosed ties with Myriad Genetics, as well as AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Helix BioPharma, Konica Minolta, Ambry Genetics, Invitae, Stryker, GAIL, Phenogen Sciences, Novartis, Pfizer, CancerIQ, Tempus, 54gene, Color Genetics, Roche/Genentech, ImpediMed, Prelude Therapeutics, BD, Agendia, Targeted Medical Education, Cerebrotech Medical Systems, Integra LifeSciences, Puma Biotechnology, GeneDX/BioReference, Change Health Care, Research to Practice, Clinical Care Options, Physician Education Resource, and Daiichi Sankyo.

The headline for this article was updated on 1/6/22.

A hitherto unknown hormonal complex that regulates extracellular energy production in pancreatic islet (beta) cells could be a novel target to not only treat both type 1 and type 2 diabetes but also potentially to prevent their development in the first place, suggests basic science research led by U.S. investigators.

Fatty acid–binding protein 4 (FABP4), a recently identified hormone, was known to be elevated in type 2 diabetes, but the researchers now show that it is not only increased in type 1 diabetes but also that those increases predate its development.

They also show that antibodies against the hormone in mice models prevent type 1 diabetes and improve glycemic control in type 2 disease.

Moreover, it forms a complex with two other proteins that the researchers termed “Fabkin.”

The research, published in Nature, indicates that increased levels of the complex blunts beta cell function, while antibody treatment improves beta cell function.

“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes (fat cells) to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, MD, PhD, in a press release. “We now have identified Fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
 

Still a long way to go

Dr. Hotamisligil, who is director of the Sabri Ülker Center for Metabolic Research at the Harvard School of Public Health, Boston, explained in an interview that taking the findings to the clinic entails answering a number of questions.

“That will keep us busy for a long time, and there are also translational questions, which are extremely exciting,” but the team is very “optimistic” that the findings will transfer well into humans, he said.

One reason is that, in mice and humans with type 1 and type 2 diabetes, “we see exactly the same pattern of regulation” of Fabkin levels and that, “equally importantly,” sustained high levels of the hormone “correlate with poor diabetes control” in type 1 diabetes and disease severity in type 2 disease.

“This is the first strong indication that it will translate well, and the second is that, if we take human islets ... and then apply this hormone into those islets, we see the same suppression of insulin secretion and viability that we see in mice islets,” Dr. Hotamisligil said.

Moreover, blocking the hormone prevents the “negative effects” that we see on the islets, which is a “really critical” factor in suggesting that Fabkin could be a viable treatment target in humans, Dr. Hotamisligil explained.

He continued that, encouragingly, “nature has done some experiments in humans” with Fabkin, showing that “you can have a safe and healthy life with a mutation in the components of this complex ... that reduces levels of the hormone.

“These individuals have a greatly reduced risk for both diabetes and cardiovascular disease,” he said, “so this tells us that, if we can establish a safe agent that can be used in humans, this will be well tolerated for life, and it will have beneficial effects.”

Lastly, Dr. Hotamisligil said that such an agent already exists, “so it’s really just a matter of making it suitable for human use and taking it through the testing procedures.”

He cautioned, however, that “these are important pillars” for translational research “that we rarely, if ever, find in many of our projects,” and there is still a long way to go.
 

Study details: FABP4 levels associated with glycemic control

The team said the research was “inspired” by previous studies showing that FABP4 knockout mice had higher beta-cell mass in the pancreas and significantly increased glucose-stimulated insulin secretion.

While it is “well established” that FABP4 is increased in type 2 diabetes, they initially examined whether levels are also regulated in type 1 diabetes, independently of adiposity and insulin resistance.

Looking at serum samples from normoglycemic individuals and those with new-onset type 1 diabetes in the BABYDIAB and DiMELLI cohorts, they found that FABP4 was increased approximately 1.6-fold in the latter.

In another cohort of older patients with type 1 diabetes of variation durations, serum FABP4 levels were correlated with hemoglobin A1c levels (P = .005), “which suggests that FABP4 is associated with glycemic control.”

Mouse studies indicate that FABP4 levels are increased both shortly before and during new-onset type 1 diabetes, implying that the hormone “may have a role in beta-cell failure and pathogenesis” in both type 1 and type 2 diabetes.

Antibody targeting of FABP4 levels in mice also revealed that treatment from 10 weeks of age protected against the development of type 1 diabetes, while antibody-treated mice with diabetes had significantly reduced blood glucose and increased plasma insulin levels versus mice given control antibodies.

This, the team said, “suggests that these mice had a less severe diabetes phenotype” with the protection against type 1 diabetes similar to that seen in FABP4 knockout mice.

Mice with diet-induced obesity and nonobese mice with diabetes treated with anti-FABP4 antibodies had improved glucose tolerance tests and a significant increase in islet number and beta-cell mass versus controls.

Further work enabled the team to identify a complex formed by circulating FABP4, adenosine kinase, and nucleoside diphosphate kinase, which could be targeted by anti-FABP4 antibodies via both FABP4 and NPDK.

“We propose the name Fabkin for this new hormone complex formed by NDPK to indicate its unique constitution of a fatty acid–binding protein and kinases,” the researchers wrote.

The team then found that the Fabkin complex alters calcium homeostasis in the endoplasmic reticulum.

This, “results in [endoplasmic reticulum] dysfunction, increased sensitivity to environmental stress and potentiation of beta-cell death in vitro,” which are mechanisms “critical” to the pathogenesis of both type 1 and 2 diabetes.

Finally, they showed that targeting Fabkin with anti-FABP4 antibodies “preserves beta-cell mass and enhances beta-cell function to protect against diabetes in multiple models.”

Funding for this study came from National Institutes of Health and Juvenile Diabetes Research Foundation grants. The Hotamisligil Lab at the Sabri Ülker Center has generated intellectual property (assigned to Harvard University) related to hormonal FABP4 and its therapeutic targeting and receives funding for this project from Lab1636, an affiliate of Deerfield Management. Dr. Hotamisligil is on the scientific advisory board of Crescenta Pharmaceuticals and holds equity. The other authors have no conflicts of interest to declare.

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

A hitherto unknown hormonal complex that regulates extracellular energy production in pancreatic islet (beta) cells could be a novel target to not only treat both type 1 and type 2 diabetes but also potentially to prevent their development in the first place, suggests basic science research led by U.S. investigators.

Fatty acid–binding protein 4 (FABP4), a recently identified hormone, was known to be elevated in type 2 diabetes, but the researchers now show that it is not only increased in type 1 diabetes but also that those increases predate its development.

They also show that antibodies against the hormone in mice models prevent type 1 diabetes and improve glycemic control in type 2 disease.

Moreover, it forms a complex with two other proteins that the researchers termed “Fabkin.”

The research, published in Nature, indicates that increased levels of the complex blunts beta cell function, while antibody treatment improves beta cell function.

“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes (fat cells) to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, MD, PhD, in a press release. “We now have identified Fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
 

Still a long way to go

Dr. Hotamisligil, who is director of the Sabri Ülker Center for Metabolic Research at the Harvard School of Public Health, Boston, explained in an interview that taking the findings to the clinic entails answering a number of questions.

“That will keep us busy for a long time, and there are also translational questions, which are extremely exciting,” but the team is very “optimistic” that the findings will transfer well into humans, he said.

One reason is that, in mice and humans with type 1 and type 2 diabetes, “we see exactly the same pattern of regulation” of Fabkin levels and that, “equally importantly,” sustained high levels of the hormone “correlate with poor diabetes control” in type 1 diabetes and disease severity in type 2 disease.

“This is the first strong indication that it will translate well, and the second is that, if we take human islets ... and then apply this hormone into those islets, we see the same suppression of insulin secretion and viability that we see in mice islets,” Dr. Hotamisligil said.

Moreover, blocking the hormone prevents the “negative effects” that we see on the islets, which is a “really critical” factor in suggesting that Fabkin could be a viable treatment target in humans, Dr. Hotamisligil explained.

He continued that, encouragingly, “nature has done some experiments in humans” with Fabkin, showing that “you can have a safe and healthy life with a mutation in the components of this complex ... that reduces levels of the hormone.

“These individuals have a greatly reduced risk for both diabetes and cardiovascular disease,” he said, “so this tells us that, if we can establish a safe agent that can be used in humans, this will be well tolerated for life, and it will have beneficial effects.”

Lastly, Dr. Hotamisligil said that such an agent already exists, “so it’s really just a matter of making it suitable for human use and taking it through the testing procedures.”

He cautioned, however, that “these are important pillars” for translational research “that we rarely, if ever, find in many of our projects,” and there is still a long way to go.
 

Study details: FABP4 levels associated with glycemic control

The team said the research was “inspired” by previous studies showing that FABP4 knockout mice had higher beta-cell mass in the pancreas and significantly increased glucose-stimulated insulin secretion.

While it is “well established” that FABP4 is increased in type 2 diabetes, they initially examined whether levels are also regulated in type 1 diabetes, independently of adiposity and insulin resistance.

Looking at serum samples from normoglycemic individuals and those with new-onset type 1 diabetes in the BABYDIAB and DiMELLI cohorts, they found that FABP4 was increased approximately 1.6-fold in the latter.

In another cohort of older patients with type 1 diabetes of variation durations, serum FABP4 levels were correlated with hemoglobin A1c levels (P = .005), “which suggests that FABP4 is associated with glycemic control.”

Mouse studies indicate that FABP4 levels are increased both shortly before and during new-onset type 1 diabetes, implying that the hormone “may have a role in beta-cell failure and pathogenesis” in both type 1 and type 2 diabetes.

Antibody targeting of FABP4 levels in mice also revealed that treatment from 10 weeks of age protected against the development of type 1 diabetes, while antibody-treated mice with diabetes had significantly reduced blood glucose and increased plasma insulin levels versus mice given control antibodies.

This, the team said, “suggests that these mice had a less severe diabetes phenotype” with the protection against type 1 diabetes similar to that seen in FABP4 knockout mice.

Mice with diet-induced obesity and nonobese mice with diabetes treated with anti-FABP4 antibodies had improved glucose tolerance tests and a significant increase in islet number and beta-cell mass versus controls.

Further work enabled the team to identify a complex formed by circulating FABP4, adenosine kinase, and nucleoside diphosphate kinase, which could be targeted by anti-FABP4 antibodies via both FABP4 and NPDK.

“We propose the name Fabkin for this new hormone complex formed by NDPK to indicate its unique constitution of a fatty acid–binding protein and kinases,” the researchers wrote.

The team then found that the Fabkin complex alters calcium homeostasis in the endoplasmic reticulum.

This, “results in [endoplasmic reticulum] dysfunction, increased sensitivity to environmental stress and potentiation of beta-cell death in vitro,” which are mechanisms “critical” to the pathogenesis of both type 1 and 2 diabetes.

Finally, they showed that targeting Fabkin with anti-FABP4 antibodies “preserves beta-cell mass and enhances beta-cell function to protect against diabetes in multiple models.”

Funding for this study came from National Institutes of Health and Juvenile Diabetes Research Foundation grants. The Hotamisligil Lab at the Sabri Ülker Center has generated intellectual property (assigned to Harvard University) related to hormonal FABP4 and its therapeutic targeting and receives funding for this project from Lab1636, an affiliate of Deerfield Management. Dr. Hotamisligil is on the scientific advisory board of Crescenta Pharmaceuticals and holds equity. The other authors have no conflicts of interest to declare.

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

A hitherto unknown hormonal complex that regulates extracellular energy production in pancreatic islet (beta) cells could be a novel target to not only treat both type 1 and type 2 diabetes but also potentially to prevent their development in the first place, suggests basic science research led by U.S. investigators.

Fatty acid–binding protein 4 (FABP4), a recently identified hormone, was known to be elevated in type 2 diabetes, but the researchers now show that it is not only increased in type 1 diabetes but also that those increases predate its development.

They also show that antibodies against the hormone in mice models prevent type 1 diabetes and improve glycemic control in type 2 disease.

Moreover, it forms a complex with two other proteins that the researchers termed “Fabkin.”

The research, published in Nature, indicates that increased levels of the complex blunts beta cell function, while antibody treatment improves beta cell function.

“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes (fat cells) to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, MD, PhD, in a press release. “We now have identified Fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
 

Still a long way to go

Dr. Hotamisligil, who is director of the Sabri Ülker Center for Metabolic Research at the Harvard School of Public Health, Boston, explained in an interview that taking the findings to the clinic entails answering a number of questions.

“That will keep us busy for a long time, and there are also translational questions, which are extremely exciting,” but the team is very “optimistic” that the findings will transfer well into humans, he said.

One reason is that, in mice and humans with type 1 and type 2 diabetes, “we see exactly the same pattern of regulation” of Fabkin levels and that, “equally importantly,” sustained high levels of the hormone “correlate with poor diabetes control” in type 1 diabetes and disease severity in type 2 disease.

“This is the first strong indication that it will translate well, and the second is that, if we take human islets ... and then apply this hormone into those islets, we see the same suppression of insulin secretion and viability that we see in mice islets,” Dr. Hotamisligil said.

Moreover, blocking the hormone prevents the “negative effects” that we see on the islets, which is a “really critical” factor in suggesting that Fabkin could be a viable treatment target in humans, Dr. Hotamisligil explained.

He continued that, encouragingly, “nature has done some experiments in humans” with Fabkin, showing that “you can have a safe and healthy life with a mutation in the components of this complex ... that reduces levels of the hormone.

“These individuals have a greatly reduced risk for both diabetes and cardiovascular disease,” he said, “so this tells us that, if we can establish a safe agent that can be used in humans, this will be well tolerated for life, and it will have beneficial effects.”

Lastly, Dr. Hotamisligil said that such an agent already exists, “so it’s really just a matter of making it suitable for human use and taking it through the testing procedures.”

He cautioned, however, that “these are important pillars” for translational research “that we rarely, if ever, find in many of our projects,” and there is still a long way to go.
 

Study details: FABP4 levels associated with glycemic control

The team said the research was “inspired” by previous studies showing that FABP4 knockout mice had higher beta-cell mass in the pancreas and significantly increased glucose-stimulated insulin secretion.

While it is “well established” that FABP4 is increased in type 2 diabetes, they initially examined whether levels are also regulated in type 1 diabetes, independently of adiposity and insulin resistance.

Looking at serum samples from normoglycemic individuals and those with new-onset type 1 diabetes in the BABYDIAB and DiMELLI cohorts, they found that FABP4 was increased approximately 1.6-fold in the latter.

In another cohort of older patients with type 1 diabetes of variation durations, serum FABP4 levels were correlated with hemoglobin A1c levels (P = .005), “which suggests that FABP4 is associated with glycemic control.”

Mouse studies indicate that FABP4 levels are increased both shortly before and during new-onset type 1 diabetes, implying that the hormone “may have a role in beta-cell failure and pathogenesis” in both type 1 and type 2 diabetes.

Antibody targeting of FABP4 levels in mice also revealed that treatment from 10 weeks of age protected against the development of type 1 diabetes, while antibody-treated mice with diabetes had significantly reduced blood glucose and increased plasma insulin levels versus mice given control antibodies.

This, the team said, “suggests that these mice had a less severe diabetes phenotype” with the protection against type 1 diabetes similar to that seen in FABP4 knockout mice.

Mice with diet-induced obesity and nonobese mice with diabetes treated with anti-FABP4 antibodies had improved glucose tolerance tests and a significant increase in islet number and beta-cell mass versus controls.

Further work enabled the team to identify a complex formed by circulating FABP4, adenosine kinase, and nucleoside diphosphate kinase, which could be targeted by anti-FABP4 antibodies via both FABP4 and NPDK.

“We propose the name Fabkin for this new hormone complex formed by NDPK to indicate its unique constitution of a fatty acid–binding protein and kinases,” the researchers wrote.

The team then found that the Fabkin complex alters calcium homeostasis in the endoplasmic reticulum.

This, “results in [endoplasmic reticulum] dysfunction, increased sensitivity to environmental stress and potentiation of beta-cell death in vitro,” which are mechanisms “critical” to the pathogenesis of both type 1 and 2 diabetes.

Finally, they showed that targeting Fabkin with anti-FABP4 antibodies “preserves beta-cell mass and enhances beta-cell function to protect against diabetes in multiple models.”

Funding for this study came from National Institutes of Health and Juvenile Diabetes Research Foundation grants. The Hotamisligil Lab at the Sabri Ülker Center has generated intellectual property (assigned to Harvard University) related to hormonal FABP4 and its therapeutic targeting and receives funding for this project from Lab1636, an affiliate of Deerfield Management. Dr. Hotamisligil is on the scientific advisory board of Crescenta Pharmaceuticals and holds equity. The other authors have no conflicts of interest to declare.

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

In a shocking, yet low-key, announcement, the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (Forxiga, AstraZeneca) has been withdrawn from the market in all EU countries for the indication of type 1 diabetes.

Courtesy AstraZeneca

This includes withdrawal in the U.K., which was part of the EU when dapagliflozin was approved for type 1 diabetes in 2019, but following Brexit, is no longer.

AstraZeneca said the decision is not motivated by safety concerns but points nevertheless to an increased risk of diabetic ketoacidosis (DKA) associated with SGLT2 inhibitors in those with type 1 diabetes, which it said might cause “confusion” among physicians using the drug to treat numerous other indications for which this agent is now approved.

DKA is a potentially dangerous side effect resulting from acid build-up in the blood and is normally accompanied by very high glucose levels. DKA is flagged as a potential side effect in type 2 diabetes but is more common in those with type 1 diabetes. It can also occur as “euglycemic” DKA, which is ketosis but with relatively normal glucose levels (and therefore harder for patients to detect). Euglycemic DKA is thought to be more of a risk in those with type 1 diabetes than in those with type 2 diabetes.

One charity believes concerns around safety are the underlying factor for the withdrawal of dapagliflozin for type 1 diabetes in Europe, suggesting that AstraZeneca might not want to risk income from more lucrative indications – such as type 2 diabetes with much larger patient populations – because of potential concerns from doctors, who may be deterred from prescribing the drug due to concerns about DKA.

JDRF International, a leading global type 1 diabetes charity, called on AstraZeneca in a statement “to explain to people affected by type 1 diabetes why the drug has been withdrawn.”

It added that dapagliflozin is the “only other drug besides insulin” to be licensed in Europe for the treatment of type 1 diabetes and represents a “major advancement since the discovery of insulin 100 years ago.”

Karen Addington, U.K. Chief Executive of JDRF, said it is “appalling” that the drug has been withdrawn, as “many people with type 1 are finding it an effective and useful tool to help manage their glucose levels.”
 

SGLT2 inhibitors never approved for type 1 diabetes in U.S.

Dapagliflozin and other drugs from the SGLT2 inhibitor class had already been approved for the treatment of type 2 diabetes for a number of years when dapagliflozin was approved in early 2019 for the treatment of adults with type 1 diabetes meeting certain criteria by the European Medicines Agency (EMA), which at that time included the U.K. in its remit, based on data from the DEPICT series of phase 3 trials.

SGLT2 inhibitors have also recently shown benefit in other indications, such as heart failure and chronic kidney disease – even in the absence of diabetes – leaving some to label them a new class of wonder drugs.

Following the 2019 EU approval for type 1 diabetes, dapagliflozin was subsequently recommended for this use on the National Health Service (NHS) in England and Wales and was accompanied by guidance from the National Institute for Health and Care Excellence (NICE), which has now had to be withdrawn.

Of note, dapagliflozin was never approved for use in type 1 diabetes in the United States (where it is known as Farxiga), with the U.S. Food and Drug Administration turning it down in July 2019.

An advisory panel for the FDA also later turned down another SGLT2 inhibitor for type 1 diabetes, empagliflozin (Jardiance, Boehringer Ingelheim) in Nov. 2019, as reported by this news organization.
 

Discontinuation ‘not due to safety concerns,’ says AZ

The announcement to discontinue dapagliflozin for the indication of type 1 diabetes in certain adults just two and a half years after its approval in the EU comes as a big surprise, especially as it was made with little fanfare just last month.

In the U.K., AstraZeneca sent a letter to health care professionals on Nov. 2 stating that, from Oct. 25, dapagliflozin 5 mg was “no longer authorized” for the treatment of type 1 diabetes and “should no longer be used” in this patient population.

However, it underlined that other indications for dapagliflozin 5 mg and 10 mg were “not affected by this licensing change,” and it remains available for adults with type 2 diabetes, as well as for the management of symptomatic chronic heart feature with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD).

In the letter, sent by Tom Keith-Roach, country president of AstraZeneca UK, the company asserts that the removal of the type 1 diabetes indication from dapagliflozin is “not due to any safety concern” with the drug “in any indication, including type 1 diabetes.”

It nevertheless goes on to highlight that DKA is a known common side effect of dapagliflozin in type 1 diabetes and, following the announcement, “additional risk minimization measures ... will no longer be available.”

In a separate statement, AstraZeneca said that the decision to remove the indication was made “voluntarily” and had been “agreed” with the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain and the equivalent body in Northern Ireland.

“It follows discussions regarding product information changes needed post-approval for dapagliflozin 5 mg specific to type 1 diabetes,” the company said, “which might cause confusion” among physicians treating patients with type 2 diabetes, chronic heart feature with reduced ejection fraction, or CKD.

AstraZeneca told this news organization that similar communications about the withdrawal were issued to health care agencies and health care professionals in all countries of the EU.
 

‘Appalling, devastating, disappointing’ for patients

The announcement has been met with disappointment in some quarters and outrage in others, and questions have been raised as to the explanation given by AstraZeneca for the drug’s withdrawal.

“Although only a small number of people with type 1 diabetes have been using dapagliflozin, we know that those who have been using it will have been benefitting from tighter control of their condition,” Simon O’Neill, director of health intelligence and professional liaison at Diabetes UK, told this news organization.

“It’s disappointing that these people will now need to go back to the drawing board and will have to work with their clinical team to find other ways of better managing their condition.”

Mr. O’Neill said it was “disappointing that AstraZeneca and the MHRA were unable to find a workable solution to allow people living with type 1 diabetes to continue using the drug safely without leading to confusion for clinicians or people living with type 2 diabetes, who also use it.”

Sanjoy Dutta, JDRF International vice president of research, added that the news is “devastating.”

“The impending negative impact of removing a drug like dapagliflozin from any market can be detrimental in the potential for other national medical ruling boards to have confidence in approving it for their citizens,” he added.

“We stand with our type 1 diabetes communities across the globe in demanding an explanation to clarify this removal.”
 

Why not an educational campaign about DKA risk?

In an interview, Hilary Nathan, policy & communications director at JDRF International, explained that the charity has its theories as to why dapagliflozin has been withdrawn for type 1 diabetes.

What AstraZeneca is saying, “and what we don’t agree with them on,” is that the “black triangle” warning that has to be put onto the drug due to the increased risk of DKA in type 1 diabetes is “misunderstood by health care practitioners” outside of that specialty and that “by having that black triangle, it will inhibit take-up in those other markets.”

In other words, “there will be less desire to prescribe it,” ventured Ms. Nathan.

She continued: “For us, we feel that if a medicine is deemed safe and efficacious, it should not be withdrawn because of other patient constituencies.”

“We asked: ‘Why can’t you do an educational awareness campaign about the black triangle?’ And the might of AstraZeneca said it would be too big a task.”

Ms. Nathan was also surprised at how the drug could be withdrawn without any warning or real explanation.

“How is it possible that, when a drug is approved there are multiple stakeholders that are involved in putting forward views and experiences – both from the clinical and patient advocacy communities, as well as obviously the pharmaceutical community – yet [a drug] can be withdrawn by a ... company that may well have conflicts of interest around commercial take-up.”

She added: “I feel that there are potentially motives around the withdrawal that AstraZeneca are still not being clear about.”

Perhaps a further clue as to the real motives behind the withdrawal can be found in an announcement, just last week, by the British MHRA.

“The decision by the marketing authorization holder to voluntarily withdraw the indication in type 1 diabetes followed commercial considerations due to a specific European-wide regulatory requirement for this authorization,” it said.

“The decision was not driven by any new safety concerns, such as the already known increased risk of DKA in type 1 diabetes compared with type 2 diabetes.”

Separately, a new in-depth investigation into when Johnson & Johnson, which markets another SGLT2 inhibitor, canagliflozin (Invokana), first knew that its agent was associated with DKA has revealed multiple discrepancies in staff accounts. Some claim the company knew as early as 2010 that canagliflozin – first approved for type 2 diabetes in the United States in 2013 – could increase the risk of DKA. It was not until May 2015 that the FDA first issued a warning about the potential risk of DKA associated with use of SGLT2 inhibitors, with the EMA following suit a month later. In Dec. 2015, the FDA updated the labels for all SGLT2 inhibitors approved in the United States at that time – canagliflozin, empagliflozin, and dapagliflozin – to include the risks for ketoacidosis (and urinary tract infections).

Forxiga (dapagliflozin) is manufactured by AstraZeneca. No relevant financial relationships declared.

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

In a shocking, yet low-key, announcement, the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (Forxiga, AstraZeneca) has been withdrawn from the market in all EU countries for the indication of type 1 diabetes.

Courtesy AstraZeneca

This includes withdrawal in the U.K., which was part of the EU when dapagliflozin was approved for type 1 diabetes in 2019, but following Brexit, is no longer.

AstraZeneca said the decision is not motivated by safety concerns but points nevertheless to an increased risk of diabetic ketoacidosis (DKA) associated with SGLT2 inhibitors in those with type 1 diabetes, which it said might cause “confusion” among physicians using the drug to treat numerous other indications for which this agent is now approved.

DKA is a potentially dangerous side effect resulting from acid build-up in the blood and is normally accompanied by very high glucose levels. DKA is flagged as a potential side effect in type 2 diabetes but is more common in those with type 1 diabetes. It can also occur as “euglycemic” DKA, which is ketosis but with relatively normal glucose levels (and therefore harder for patients to detect). Euglycemic DKA is thought to be more of a risk in those with type 1 diabetes than in those with type 2 diabetes.

One charity believes concerns around safety are the underlying factor for the withdrawal of dapagliflozin for type 1 diabetes in Europe, suggesting that AstraZeneca might not want to risk income from more lucrative indications – such as type 2 diabetes with much larger patient populations – because of potential concerns from doctors, who may be deterred from prescribing the drug due to concerns about DKA.

JDRF International, a leading global type 1 diabetes charity, called on AstraZeneca in a statement “to explain to people affected by type 1 diabetes why the drug has been withdrawn.”

It added that dapagliflozin is the “only other drug besides insulin” to be licensed in Europe for the treatment of type 1 diabetes and represents a “major advancement since the discovery of insulin 100 years ago.”

Karen Addington, U.K. Chief Executive of JDRF, said it is “appalling” that the drug has been withdrawn, as “many people with type 1 are finding it an effective and useful tool to help manage their glucose levels.”
 

SGLT2 inhibitors never approved for type 1 diabetes in U.S.

Dapagliflozin and other drugs from the SGLT2 inhibitor class had already been approved for the treatment of type 2 diabetes for a number of years when dapagliflozin was approved in early 2019 for the treatment of adults with type 1 diabetes meeting certain criteria by the European Medicines Agency (EMA), which at that time included the U.K. in its remit, based on data from the DEPICT series of phase 3 trials.

SGLT2 inhibitors have also recently shown benefit in other indications, such as heart failure and chronic kidney disease – even in the absence of diabetes – leaving some to label them a new class of wonder drugs.

Following the 2019 EU approval for type 1 diabetes, dapagliflozin was subsequently recommended for this use on the National Health Service (NHS) in England and Wales and was accompanied by guidance from the National Institute for Health and Care Excellence (NICE), which has now had to be withdrawn.

Of note, dapagliflozin was never approved for use in type 1 diabetes in the United States (where it is known as Farxiga), with the U.S. Food and Drug Administration turning it down in July 2019.

An advisory panel for the FDA also later turned down another SGLT2 inhibitor for type 1 diabetes, empagliflozin (Jardiance, Boehringer Ingelheim) in Nov. 2019, as reported by this news organization.
 

Discontinuation ‘not due to safety concerns,’ says AZ

The announcement to discontinue dapagliflozin for the indication of type 1 diabetes in certain adults just two and a half years after its approval in the EU comes as a big surprise, especially as it was made with little fanfare just last month.

In the U.K., AstraZeneca sent a letter to health care professionals on Nov. 2 stating that, from Oct. 25, dapagliflozin 5 mg was “no longer authorized” for the treatment of type 1 diabetes and “should no longer be used” in this patient population.

However, it underlined that other indications for dapagliflozin 5 mg and 10 mg were “not affected by this licensing change,” and it remains available for adults with type 2 diabetes, as well as for the management of symptomatic chronic heart feature with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD).

In the letter, sent by Tom Keith-Roach, country president of AstraZeneca UK, the company asserts that the removal of the type 1 diabetes indication from dapagliflozin is “not due to any safety concern” with the drug “in any indication, including type 1 diabetes.”

It nevertheless goes on to highlight that DKA is a known common side effect of dapagliflozin in type 1 diabetes and, following the announcement, “additional risk minimization measures ... will no longer be available.”

In a separate statement, AstraZeneca said that the decision to remove the indication was made “voluntarily” and had been “agreed” with the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain and the equivalent body in Northern Ireland.

“It follows discussions regarding product information changes needed post-approval for dapagliflozin 5 mg specific to type 1 diabetes,” the company said, “which might cause confusion” among physicians treating patients with type 2 diabetes, chronic heart feature with reduced ejection fraction, or CKD.

AstraZeneca told this news organization that similar communications about the withdrawal were issued to health care agencies and health care professionals in all countries of the EU.
 

‘Appalling, devastating, disappointing’ for patients

The announcement has been met with disappointment in some quarters and outrage in others, and questions have been raised as to the explanation given by AstraZeneca for the drug’s withdrawal.

“Although only a small number of people with type 1 diabetes have been using dapagliflozin, we know that those who have been using it will have been benefitting from tighter control of their condition,” Simon O’Neill, director of health intelligence and professional liaison at Diabetes UK, told this news organization.

“It’s disappointing that these people will now need to go back to the drawing board and will have to work with their clinical team to find other ways of better managing their condition.”

Mr. O’Neill said it was “disappointing that AstraZeneca and the MHRA were unable to find a workable solution to allow people living with type 1 diabetes to continue using the drug safely without leading to confusion for clinicians or people living with type 2 diabetes, who also use it.”

Sanjoy Dutta, JDRF International vice president of research, added that the news is “devastating.”

“The impending negative impact of removing a drug like dapagliflozin from any market can be detrimental in the potential for other national medical ruling boards to have confidence in approving it for their citizens,” he added.

“We stand with our type 1 diabetes communities across the globe in demanding an explanation to clarify this removal.”
 

Why not an educational campaign about DKA risk?

In an interview, Hilary Nathan, policy & communications director at JDRF International, explained that the charity has its theories as to why dapagliflozin has been withdrawn for type 1 diabetes.

What AstraZeneca is saying, “and what we don’t agree with them on,” is that the “black triangle” warning that has to be put onto the drug due to the increased risk of DKA in type 1 diabetes is “misunderstood by health care practitioners” outside of that specialty and that “by having that black triangle, it will inhibit take-up in those other markets.”

In other words, “there will be less desire to prescribe it,” ventured Ms. Nathan.

She continued: “For us, we feel that if a medicine is deemed safe and efficacious, it should not be withdrawn because of other patient constituencies.”

“We asked: ‘Why can’t you do an educational awareness campaign about the black triangle?’ And the might of AstraZeneca said it would be too big a task.”

Ms. Nathan was also surprised at how the drug could be withdrawn without any warning or real explanation.

“How is it possible that, when a drug is approved there are multiple stakeholders that are involved in putting forward views and experiences – both from the clinical and patient advocacy communities, as well as obviously the pharmaceutical community – yet [a drug] can be withdrawn by a ... company that may well have conflicts of interest around commercial take-up.”

She added: “I feel that there are potentially motives around the withdrawal that AstraZeneca are still not being clear about.”

Perhaps a further clue as to the real motives behind the withdrawal can be found in an announcement, just last week, by the British MHRA.

“The decision by the marketing authorization holder to voluntarily withdraw the indication in type 1 diabetes followed commercial considerations due to a specific European-wide regulatory requirement for this authorization,” it said.

“The decision was not driven by any new safety concerns, such as the already known increased risk of DKA in type 1 diabetes compared with type 2 diabetes.”

Separately, a new in-depth investigation into when Johnson & Johnson, which markets another SGLT2 inhibitor, canagliflozin (Invokana), first knew that its agent was associated with DKA has revealed multiple discrepancies in staff accounts. Some claim the company knew as early as 2010 that canagliflozin – first approved for type 2 diabetes in the United States in 2013 – could increase the risk of DKA. It was not until May 2015 that the FDA first issued a warning about the potential risk of DKA associated with use of SGLT2 inhibitors, with the EMA following suit a month later. In Dec. 2015, the FDA updated the labels for all SGLT2 inhibitors approved in the United States at that time – canagliflozin, empagliflozin, and dapagliflozin – to include the risks for ketoacidosis (and urinary tract infections).

Forxiga (dapagliflozin) is manufactured by AstraZeneca. No relevant financial relationships declared.

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

In a shocking, yet low-key, announcement, the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (Forxiga, AstraZeneca) has been withdrawn from the market in all EU countries for the indication of type 1 diabetes.

Courtesy AstraZeneca

This includes withdrawal in the U.K., which was part of the EU when dapagliflozin was approved for type 1 diabetes in 2019, but following Brexit, is no longer.

AstraZeneca said the decision is not motivated by safety concerns but points nevertheless to an increased risk of diabetic ketoacidosis (DKA) associated with SGLT2 inhibitors in those with type 1 diabetes, which it said might cause “confusion” among physicians using the drug to treat numerous other indications for which this agent is now approved.

DKA is a potentially dangerous side effect resulting from acid build-up in the blood and is normally accompanied by very high glucose levels. DKA is flagged as a potential side effect in type 2 diabetes but is more common in those with type 1 diabetes. It can also occur as “euglycemic” DKA, which is ketosis but with relatively normal glucose levels (and therefore harder for patients to detect). Euglycemic DKA is thought to be more of a risk in those with type 1 diabetes than in those with type 2 diabetes.

One charity believes concerns around safety are the underlying factor for the withdrawal of dapagliflozin for type 1 diabetes in Europe, suggesting that AstraZeneca might not want to risk income from more lucrative indications – such as type 2 diabetes with much larger patient populations – because of potential concerns from doctors, who may be deterred from prescribing the drug due to concerns about DKA.

JDRF International, a leading global type 1 diabetes charity, called on AstraZeneca in a statement “to explain to people affected by type 1 diabetes why the drug has been withdrawn.”

It added that dapagliflozin is the “only other drug besides insulin” to be licensed in Europe for the treatment of type 1 diabetes and represents a “major advancement since the discovery of insulin 100 years ago.”

Karen Addington, U.K. Chief Executive of JDRF, said it is “appalling” that the drug has been withdrawn, as “many people with type 1 are finding it an effective and useful tool to help manage their glucose levels.”
 

SGLT2 inhibitors never approved for type 1 diabetes in U.S.

Dapagliflozin and other drugs from the SGLT2 inhibitor class had already been approved for the treatment of type 2 diabetes for a number of years when dapagliflozin was approved in early 2019 for the treatment of adults with type 1 diabetes meeting certain criteria by the European Medicines Agency (EMA), which at that time included the U.K. in its remit, based on data from the DEPICT series of phase 3 trials.

SGLT2 inhibitors have also recently shown benefit in other indications, such as heart failure and chronic kidney disease – even in the absence of diabetes – leaving some to label them a new class of wonder drugs.

Following the 2019 EU approval for type 1 diabetes, dapagliflozin was subsequently recommended for this use on the National Health Service (NHS) in England and Wales and was accompanied by guidance from the National Institute for Health and Care Excellence (NICE), which has now had to be withdrawn.

Of note, dapagliflozin was never approved for use in type 1 diabetes in the United States (where it is known as Farxiga), with the U.S. Food and Drug Administration turning it down in July 2019.

An advisory panel for the FDA also later turned down another SGLT2 inhibitor for type 1 diabetes, empagliflozin (Jardiance, Boehringer Ingelheim) in Nov. 2019, as reported by this news organization.
 

Discontinuation ‘not due to safety concerns,’ says AZ

The announcement to discontinue dapagliflozin for the indication of type 1 diabetes in certain adults just two and a half years after its approval in the EU comes as a big surprise, especially as it was made with little fanfare just last month.

In the U.K., AstraZeneca sent a letter to health care professionals on Nov. 2 stating that, from Oct. 25, dapagliflozin 5 mg was “no longer authorized” for the treatment of type 1 diabetes and “should no longer be used” in this patient population.

However, it underlined that other indications for dapagliflozin 5 mg and 10 mg were “not affected by this licensing change,” and it remains available for adults with type 2 diabetes, as well as for the management of symptomatic chronic heart feature with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD).

In the letter, sent by Tom Keith-Roach, country president of AstraZeneca UK, the company asserts that the removal of the type 1 diabetes indication from dapagliflozin is “not due to any safety concern” with the drug “in any indication, including type 1 diabetes.”

It nevertheless goes on to highlight that DKA is a known common side effect of dapagliflozin in type 1 diabetes and, following the announcement, “additional risk minimization measures ... will no longer be available.”

In a separate statement, AstraZeneca said that the decision to remove the indication was made “voluntarily” and had been “agreed” with the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain and the equivalent body in Northern Ireland.

“It follows discussions regarding product information changes needed post-approval for dapagliflozin 5 mg specific to type 1 diabetes,” the company said, “which might cause confusion” among physicians treating patients with type 2 diabetes, chronic heart feature with reduced ejection fraction, or CKD.

AstraZeneca told this news organization that similar communications about the withdrawal were issued to health care agencies and health care professionals in all countries of the EU.
 

‘Appalling, devastating, disappointing’ for patients

The announcement has been met with disappointment in some quarters and outrage in others, and questions have been raised as to the explanation given by AstraZeneca for the drug’s withdrawal.

“Although only a small number of people with type 1 diabetes have been using dapagliflozin, we know that those who have been using it will have been benefitting from tighter control of their condition,” Simon O’Neill, director of health intelligence and professional liaison at Diabetes UK, told this news organization.

“It’s disappointing that these people will now need to go back to the drawing board and will have to work with their clinical team to find other ways of better managing their condition.”

Mr. O’Neill said it was “disappointing that AstraZeneca and the MHRA were unable to find a workable solution to allow people living with type 1 diabetes to continue using the drug safely without leading to confusion for clinicians or people living with type 2 diabetes, who also use it.”

Sanjoy Dutta, JDRF International vice president of research, added that the news is “devastating.”

“The impending negative impact of removing a drug like dapagliflozin from any market can be detrimental in the potential for other national medical ruling boards to have confidence in approving it for their citizens,” he added.

“We stand with our type 1 diabetes communities across the globe in demanding an explanation to clarify this removal.”
 

Why not an educational campaign about DKA risk?

In an interview, Hilary Nathan, policy & communications director at JDRF International, explained that the charity has its theories as to why dapagliflozin has been withdrawn for type 1 diabetes.

What AstraZeneca is saying, “and what we don’t agree with them on,” is that the “black triangle” warning that has to be put onto the drug due to the increased risk of DKA in type 1 diabetes is “misunderstood by health care practitioners” outside of that specialty and that “by having that black triangle, it will inhibit take-up in those other markets.”

In other words, “there will be less desire to prescribe it,” ventured Ms. Nathan.

She continued: “For us, we feel that if a medicine is deemed safe and efficacious, it should not be withdrawn because of other patient constituencies.”

“We asked: ‘Why can’t you do an educational awareness campaign about the black triangle?’ And the might of AstraZeneca said it would be too big a task.”

Ms. Nathan was also surprised at how the drug could be withdrawn without any warning or real explanation.

“How is it possible that, when a drug is approved there are multiple stakeholders that are involved in putting forward views and experiences – both from the clinical and patient advocacy communities, as well as obviously the pharmaceutical community – yet [a drug] can be withdrawn by a ... company that may well have conflicts of interest around commercial take-up.”

She added: “I feel that there are potentially motives around the withdrawal that AstraZeneca are still not being clear about.”

Perhaps a further clue as to the real motives behind the withdrawal can be found in an announcement, just last week, by the British MHRA.

“The decision by the marketing authorization holder to voluntarily withdraw the indication in type 1 diabetes followed commercial considerations due to a specific European-wide regulatory requirement for this authorization,” it said.

“The decision was not driven by any new safety concerns, such as the already known increased risk of DKA in type 1 diabetes compared with type 2 diabetes.”

Separately, a new in-depth investigation into when Johnson & Johnson, which markets another SGLT2 inhibitor, canagliflozin (Invokana), first knew that its agent was associated with DKA has revealed multiple discrepancies in staff accounts. Some claim the company knew as early as 2010 that canagliflozin – first approved for type 2 diabetes in the United States in 2013 – could increase the risk of DKA. It was not until May 2015 that the FDA first issued a warning about the potential risk of DKA associated with use of SGLT2 inhibitors, with the EMA following suit a month later. In Dec. 2015, the FDA updated the labels for all SGLT2 inhibitors approved in the United States at that time – canagliflozin, empagliflozin, and dapagliflozin – to include the risks for ketoacidosis (and urinary tract infections).

Forxiga (dapagliflozin) is manufactured by AstraZeneca. No relevant financial relationships declared.

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

Black women with metastatic triple-negative breast cancer (mTNBC) have outcomes in response to the antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy, Gilead) comparable to those of the overall patient population, with the drug showing similar efficacy and safety, shows a prespecified analysis of ASCENT.

A heterogenous disease with few treatment options and poor outcomes, mTNBC has an incidence rate twice as high in Black as in White women.

Black women with mTNBC may also experience worse outcomes than other groups, with a greater risk of mortality related to disparities in access to health care and in income, delays in treatment, a higher prevalence of comorbidities, and differences in tumor biology.

Previously presented data from the phase 3 ASCENT trial showed that SG nearly doubled overall survival versus single-agent chemotherapy in pretreated women with mTNBC, with the benefit observed across patient subgroups.

Based on these findings, the Food and Drug Administration approved SG for patients with mTNBC who have received at least two prior chemotherapies, at least one of which is to have been given in the metastatic setting.

Now, an analysis of the ASCENT data in just over 60 Black women with mTNBC showed that they can expect to see their progression-free survival (PFS) improve by 56% and their overall survival increase by a nonsignificant 36% when given SG as opposed to single-agent chemotherapy.

The research (abstract P5-16-07) was presented at the San Antonio Breast Cancer Symposium on Dec. 10.

The team says that Black women with mTNBC “derived a similar clinical benefit” from SG versus chemotherapy to other women in the study, and had a “manageable” safety profile, which was “consistent with the full trial population.”

Consequently, SG “should be considered a treatment option for Black patients with mTNBC who have received ≥ 2 prior chemotherapies,” at least one of which having been given in the metastatic setting.

Lead researcher Lisa A. Carey, MD, told this news organiztion that it is “very important” to show that the drug works in Black patients, adding: “We know that certain drugs don’t perform so well and it’s also true that people of color are particularly affected by TNBC.”

She said there were “only 62” Black patients in ASCENT, “so if you look at the entire trial and make assumptions that the drug performs the same in all the subsets, then sometimes you’re wrong.”

Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., said there is “emerging interest” in racial disparities in cancer outcomes.

“Black patients have more trouble with access to care,” she said, noting that “in trial populations, [the outcomes] generally seem similar because the patients who go onto the trials tend to be those that can participate, but you never know until you look.”

Overall, Dr. Carey said the current results suggest that, “at least from the standpoint of the therapeutic implications of this drug – which is really a pretty remarkable drug in the overall study – it behaves very similarly in this group.”

Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said: “We have known that minority patients, especially Black patients, have a higher rate of triple negative breast cancer and aggressive biologies, and have had worse breast cancer outcomes in many published series.”

She told this news organization that, “additionally, they are often underrepresented in breast cancer clinical trials.”

Dr. Litton said “the very favorable outcomes” reported in “this important subset of patients who participated in the ASCENT trial” confirm the use of SG in patients with mTNBC.

To examine the clinical outcomes of Black patients in the ASCENT study, the team conduced a prespecified analysis of participants self-reporting Black race who had been randomized to SG or single-agent chemotherapy of physician’s choice, including those with and without brain metastases.

Of the 529 patients enrolled to ASCENT, 62 (12%) were Black, of whom 28 were assigned to SG and 34 to single agent chemotherapy. The two groups were generally well balanced, although six patients in the chemotherapy arm had known brain metastases at baseline versus none of those given SG.

After a median treatment duration of 5.3 months with SG and 1.6 months for single-agent chemotherapy, there was a significant improvement in PFS with SG, at 5.4 months versus 2.2 months for chemotherapy, and a hazard ratio of 0.44 (P = .008).

There was also a nonsignificant improvement in overall survival with SG at 13.8 months versus 8.5 months for chemotherapy, and a hazard ratio of 0.64 (P = .159).

The objective response rate was 32% with SG versus 6% in patients given chemotherapy, while the median duration of response was 9.2 months in the SG arm and not evaluable for chemotherapy.

The researchers note that these efficacy findings were “consistent” with those seen in the full ASCENT study population.

In terms of safety, the most common treatment-related adverse events were neutropenia, seen in 64% of SG and 61% of chemotherapy patients, diarrhea in 64% and 13%, respectively, and fatigue, in 52% and 39%, respectively.

The most common grade ≥3 events were neutropenia, in 48% and 42% of SG and chemotherapy patients, respectively, followed by anemia, in 12% and 6%, respectively, leukopenia in 8% and 16%, respectively, and febrile neutropenia in 8% and 3%, respectively.

No treatment-related deaths occurred in either treatment arm.

Dose reduction due to treatment-emergent adverse events was recorded in 28% of patients receiving SG and 35% of those assigned to single-agent chemotherapy, and discontinuations occurred in 0% and 3%, respectively.

The study was sponsored by Gilead Sciences. Dr. Carey reports research funding from Sanofi, Novartis, Genentech/Roche, and GSK; spouse serves on the board of Falcon Therapeutics.

Black women with metastatic triple-negative breast cancer (mTNBC) have outcomes in response to the antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy, Gilead) comparable to those of the overall patient population, with the drug showing similar efficacy and safety, shows a prespecified analysis of ASCENT.

A heterogenous disease with few treatment options and poor outcomes, mTNBC has an incidence rate twice as high in Black as in White women.

Black women with mTNBC may also experience worse outcomes than other groups, with a greater risk of mortality related to disparities in access to health care and in income, delays in treatment, a higher prevalence of comorbidities, and differences in tumor biology.

Previously presented data from the phase 3 ASCENT trial showed that SG nearly doubled overall survival versus single-agent chemotherapy in pretreated women with mTNBC, with the benefit observed across patient subgroups.

Based on these findings, the Food and Drug Administration approved SG for patients with mTNBC who have received at least two prior chemotherapies, at least one of which is to have been given in the metastatic setting.

Now, an analysis of the ASCENT data in just over 60 Black women with mTNBC showed that they can expect to see their progression-free survival (PFS) improve by 56% and their overall survival increase by a nonsignificant 36% when given SG as opposed to single-agent chemotherapy.

The research (abstract P5-16-07) was presented at the San Antonio Breast Cancer Symposium on Dec. 10.

The team says that Black women with mTNBC “derived a similar clinical benefit” from SG versus chemotherapy to other women in the study, and had a “manageable” safety profile, which was “consistent with the full trial population.”

Consequently, SG “should be considered a treatment option for Black patients with mTNBC who have received ≥ 2 prior chemotherapies,” at least one of which having been given in the metastatic setting.

Lead researcher Lisa A. Carey, MD, told this news organiztion that it is “very important” to show that the drug works in Black patients, adding: “We know that certain drugs don’t perform so well and it’s also true that people of color are particularly affected by TNBC.”

She said there were “only 62” Black patients in ASCENT, “so if you look at the entire trial and make assumptions that the drug performs the same in all the subsets, then sometimes you’re wrong.”

Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., said there is “emerging interest” in racial disparities in cancer outcomes.

“Black patients have more trouble with access to care,” she said, noting that “in trial populations, [the outcomes] generally seem similar because the patients who go onto the trials tend to be those that can participate, but you never know until you look.”

Overall, Dr. Carey said the current results suggest that, “at least from the standpoint of the therapeutic implications of this drug – which is really a pretty remarkable drug in the overall study – it behaves very similarly in this group.”

Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said: “We have known that minority patients, especially Black patients, have a higher rate of triple negative breast cancer and aggressive biologies, and have had worse breast cancer outcomes in many published series.”

She told this news organization that, “additionally, they are often underrepresented in breast cancer clinical trials.”

Dr. Litton said “the very favorable outcomes” reported in “this important subset of patients who participated in the ASCENT trial” confirm the use of SG in patients with mTNBC.

To examine the clinical outcomes of Black patients in the ASCENT study, the team conduced a prespecified analysis of participants self-reporting Black race who had been randomized to SG or single-agent chemotherapy of physician’s choice, including those with and without brain metastases.

Of the 529 patients enrolled to ASCENT, 62 (12%) were Black, of whom 28 were assigned to SG and 34 to single agent chemotherapy. The two groups were generally well balanced, although six patients in the chemotherapy arm had known brain metastases at baseline versus none of those given SG.

After a median treatment duration of 5.3 months with SG and 1.6 months for single-agent chemotherapy, there was a significant improvement in PFS with SG, at 5.4 months versus 2.2 months for chemotherapy, and a hazard ratio of 0.44 (P = .008).

There was also a nonsignificant improvement in overall survival with SG at 13.8 months versus 8.5 months for chemotherapy, and a hazard ratio of 0.64 (P = .159).

The objective response rate was 32% with SG versus 6% in patients given chemotherapy, while the median duration of response was 9.2 months in the SG arm and not evaluable for chemotherapy.

The researchers note that these efficacy findings were “consistent” with those seen in the full ASCENT study population.

In terms of safety, the most common treatment-related adverse events were neutropenia, seen in 64% of SG and 61% of chemotherapy patients, diarrhea in 64% and 13%, respectively, and fatigue, in 52% and 39%, respectively.

The most common grade ≥3 events were neutropenia, in 48% and 42% of SG and chemotherapy patients, respectively, followed by anemia, in 12% and 6%, respectively, leukopenia in 8% and 16%, respectively, and febrile neutropenia in 8% and 3%, respectively.

No treatment-related deaths occurred in either treatment arm.

Dose reduction due to treatment-emergent adverse events was recorded in 28% of patients receiving SG and 35% of those assigned to single-agent chemotherapy, and discontinuations occurred in 0% and 3%, respectively.

The study was sponsored by Gilead Sciences. Dr. Carey reports research funding from Sanofi, Novartis, Genentech/Roche, and GSK; spouse serves on the board of Falcon Therapeutics.

Black women with metastatic triple-negative breast cancer (mTNBC) have outcomes in response to the antibody–drug conjugate sacituzumab govitecan (SG) (Trodelvy, Gilead) comparable to those of the overall patient population, with the drug showing similar efficacy and safety, shows a prespecified analysis of ASCENT.

A heterogenous disease with few treatment options and poor outcomes, mTNBC has an incidence rate twice as high in Black as in White women.

Black women with mTNBC may also experience worse outcomes than other groups, with a greater risk of mortality related to disparities in access to health care and in income, delays in treatment, a higher prevalence of comorbidities, and differences in tumor biology.

Previously presented data from the phase 3 ASCENT trial showed that SG nearly doubled overall survival versus single-agent chemotherapy in pretreated women with mTNBC, with the benefit observed across patient subgroups.

Based on these findings, the Food and Drug Administration approved SG for patients with mTNBC who have received at least two prior chemotherapies, at least one of which is to have been given in the metastatic setting.

Now, an analysis of the ASCENT data in just over 60 Black women with mTNBC showed that they can expect to see their progression-free survival (PFS) improve by 56% and their overall survival increase by a nonsignificant 36% when given SG as opposed to single-agent chemotherapy.

The research (abstract P5-16-07) was presented at the San Antonio Breast Cancer Symposium on Dec. 10.

The team says that Black women with mTNBC “derived a similar clinical benefit” from SG versus chemotherapy to other women in the study, and had a “manageable” safety profile, which was “consistent with the full trial population.”

Consequently, SG “should be considered a treatment option for Black patients with mTNBC who have received ≥ 2 prior chemotherapies,” at least one of which having been given in the metastatic setting.

Lead researcher Lisa A. Carey, MD, told this news organiztion that it is “very important” to show that the drug works in Black patients, adding: “We know that certain drugs don’t perform so well and it’s also true that people of color are particularly affected by TNBC.”

She said there were “only 62” Black patients in ASCENT, “so if you look at the entire trial and make assumptions that the drug performs the same in all the subsets, then sometimes you’re wrong.”

Dr. Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, N.C., said there is “emerging interest” in racial disparities in cancer outcomes.

“Black patients have more trouble with access to care,” she said, noting that “in trial populations, [the outcomes] generally seem similar because the patients who go onto the trials tend to be those that can participate, but you never know until you look.”

Overall, Dr. Carey said the current results suggest that, “at least from the standpoint of the therapeutic implications of this drug – which is really a pretty remarkable drug in the overall study – it behaves very similarly in this group.”

Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said: “We have known that minority patients, especially Black patients, have a higher rate of triple negative breast cancer and aggressive biologies, and have had worse breast cancer outcomes in many published series.”

She told this news organization that, “additionally, they are often underrepresented in breast cancer clinical trials.”

Dr. Litton said “the very favorable outcomes” reported in “this important subset of patients who participated in the ASCENT trial” confirm the use of SG in patients with mTNBC.

To examine the clinical outcomes of Black patients in the ASCENT study, the team conduced a prespecified analysis of participants self-reporting Black race who had been randomized to SG or single-agent chemotherapy of physician’s choice, including those with and without brain metastases.

Of the 529 patients enrolled to ASCENT, 62 (12%) were Black, of whom 28 were assigned to SG and 34 to single agent chemotherapy. The two groups were generally well balanced, although six patients in the chemotherapy arm had known brain metastases at baseline versus none of those given SG.

After a median treatment duration of 5.3 months with SG and 1.6 months for single-agent chemotherapy, there was a significant improvement in PFS with SG, at 5.4 months versus 2.2 months for chemotherapy, and a hazard ratio of 0.44 (P = .008).

There was also a nonsignificant improvement in overall survival with SG at 13.8 months versus 8.5 months for chemotherapy, and a hazard ratio of 0.64 (P = .159).

The objective response rate was 32% with SG versus 6% in patients given chemotherapy, while the median duration of response was 9.2 months in the SG arm and not evaluable for chemotherapy.

The researchers note that these efficacy findings were “consistent” with those seen in the full ASCENT study population.

In terms of safety, the most common treatment-related adverse events were neutropenia, seen in 64% of SG and 61% of chemotherapy patients, diarrhea in 64% and 13%, respectively, and fatigue, in 52% and 39%, respectively.

The most common grade ≥3 events were neutropenia, in 48% and 42% of SG and chemotherapy patients, respectively, followed by anemia, in 12% and 6%, respectively, leukopenia in 8% and 16%, respectively, and febrile neutropenia in 8% and 3%, respectively.

No treatment-related deaths occurred in either treatment arm.

Dose reduction due to treatment-emergent adverse events was recorded in 28% of patients receiving SG and 35% of those assigned to single-agent chemotherapy, and discontinuations occurred in 0% and 3%, respectively.

The study was sponsored by Gilead Sciences. Dr. Carey reports research funding from Sanofi, Novartis, Genentech/Roche, and GSK; spouse serves on the board of Falcon Therapeutics.

The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

The cutoff for programmed death–ligand 1 (PD-L1) combined positive score (CPS) of at least 10 for using pembrolizumab (Keytruda) to treat metastatic triple-negative breast cancer (mTNBC) is able to identify patients who are expected to derive most benefit, shows an analysis of KEYNOTE-355 recently presented at the San Antonio Breast Cancer Symposium.

Patients enrolled in KEYNOTE-355 – which is a phase 3, placebo-controlled trial of 847 patients – were stratified by CPS scores of at least 1 and at least 10, with the latter group in which adding pembrolizumab to chemotherapy was shown to significantly improve both overall survival and progression-free survival.

As it was unclear whether taking a more fine-grained approach would reveal specific CPS scores at which pembrolizumab would be beneficial, Javier Cortes, MD, PhD, International Breast Cancer Center, Barcelona, and colleagues divided the patients into four CPS levels: less than 1, 1-9, 10-19, and at least 20.

Patients with a CPS 10-19 and at least 20 given pembrolizumab alongside chemotherapy had an overall survival benefit of 29% and 28%, respectively, while the PFS improvement was 30% and 38%. In the CPS of less than 1 and 1-9 groups, there were no discernible benefits from adding the checkpoint inhibitor.

“Given the similar outcomes in the CPS 10-19 and the CPS ≥20 subgroups, a CPS of 10 or more is a reasonable cutoff to define the population of patients with metastatic TNBC that might have benefit from the addition of pembrolizumab to chemotherapy,” Dr. Cortes said. “In my opinion, these results provide further support for pembrolizumab in combination with chemotherapy as a good option, maybe a standard of care for some patients ... with local recurrent unresectable or metastatic TNBC whose tumors express PD-1 CPS ≥10.”

Invited discussant Hope S. Rugo, MD, said the study demonstrates that PD-L1 CPS of at least 10 is “clearly the optimal cutoff for differentiating benefit from pembrolizumab” and confirms the combination with chemotherapy as a “standard of care in this population”.

However, there are a number of outstanding questions in the metastatic setting, she said, including the test used to determine PD-L1 expression.

“Clearly the test that you order should be matched to the planned checkpoint inhibitor, and we look forward to additional data” on the relative overlap of the assays used in both the current study and in KEYNOTE-522.

However, IMpassion130 showed there is “incomplete overlap in terms of the two antibodies and tests that have been used to define PD-L1 positivity in breast cancer,” said Dr. Rugo, professor of medicine in hematology and oncology at the University of California, San Francisco.

“For excellent responders, can chemotherapy and eventually immunotherapy be discontinued, and when is it optimal? How long should we be continuing the combination and how long should we continue the checkpoint inhibitor alone?” she asked.

“Certainly in my own clinical practice,” Dr. Rugo explained, “in those excellent responders, it’s difficult to know when to stop the checkpoint inhibitor, but sometimes toxicity tells us the answer to that question. At some point, we need to stop therapy and understand what happens to those patients.”

She said that only 38% of patients in the current study benefited from pembrolizumab. “How can we amplify the immune response in those patients who do not have PD-L1–positive disease to further extend this benefit, and can we extend the efficacy to other subtypes? There are ongoing studies evaluating this question,” Dr. Rugo said.

Dr. Cortes said that KEYNOTE-355 showed the addition of pembrolizumab to chemotherapy led to clinically meaningful improvements in both PFS and overall survival versus chemotherapy alone in the first-line treatment of mTNBC.

However, that benefit was seen only in patients with a PD-L1 CPS of at least 10, while there was no statistically significant improvement in either PFS or overall survival in those with a CPS of at least 1.

He explained that 847 patients with previously untreated locally recurrent or metastatic TNBC, or those who had been treated at least 6 months prior to disease recurrence, were randomized 2:1 to pembrolizumab or placebo plus chemotherapy.

For the current analysis, they substratified patients by PD-L1 CPS into less than 1, which accounted for 24.9% of patients; 1-9, seen in 36.2%-38.4%; 10-19, accounting for 13.9%-14.1%; and at least 20, seen in 22.8%-24.7% of patients.

Dr. Cortes said the overall survival rate among patients with CPS of at least 10 was 70.5% for patients treated with pembrolizumab plus chemotherapy versus 81.6% for those assigned to placebo, at a significant hazard ratio of 0.73 (P = .0093).

Among patients with CPS of at least 1, the overall survival rate was 79.1% with pembrolizumab plus chemotherapy and 83.9% in those given placebo, at a nonsignificant hazard ratio of 0.86. This translated into an HR of 0.89 in the intention-to-treat analysis.

Turning to the novel subgroups, Dr. Cortes showed that the HR for overall survival for pembrolizumab versus placebo was nonsignificant in patients with CPS of at least 1, at 0.97, and in those with CPS 1-9, at 1.09.

However, the HRs were markedly improved in patients with CPD 10-19, at 0.71, and in those with CPS of at least 20, at 0.72, showing that the “relative benefit of adding pembrolizumab to chemotherapy was pretty much the same ... suggesting that CPS ≥10 could be a reasonable cutoff.”

In both of these groups, there was a sustained separation in the overall survival curves starting at around 10 months.

Turning to the PFS results, Dr Cortes said the event-free rate was 65.5% with the addition of pembrolizumab to chemotherapy in patients with PD-L1 CPS of at least 10, while those given placebo had a rate of 78.6%, at an HR of 0.66.

In patients with PD-L1 CPS of at least 1, the HR was 0.75, or 0.82 in the intention-to-treat analysis.

“As with overall survival,” he said, there was a “trend toward improved efficacy with PD-L1 enrichment with the addition of pembrolizumab to chemotherapy, although the PFS benefit in the pembro arm was slightly greater in the CPS ≥20 subgroup, compared to the CPS 10-19 subgroup.”

However, they highlighted that the difference was “small and the confidence intervals clearly overlapped.”

Why does PD-L1 expression play a role in response to pembrolizumab in mTNBC, but not in the early disease setting as seen in KEYNOTE-522?

“This is a question we have raised many, many times and have had many debates on,” Dr. Cortes said. “They are two completely different populations with the early breast cancer setting completely different to that in metastatic disease. Maybe the microenvironment plays a different role there, maybe we have to explore more in detail other biomarkers. I also think that different drugs were used in the neoadjuvant setting. We still have many unanswered questions.”

Dr. Rugo suggested that previous studies have given some clues to these questions with reductions in PD-L1 expression and tumor-infiltrating leukocytes observed between primary and metastatic disease.

The immune differences between primary and metastatic disease lead to immune escape, she said, adding: “This is clearly complicated by mutational complexity under the pressure of treatment.”

The study was funded by Merck Sharp and Dohme. Dr. Cortes and Dr. Rugo reported relationships with numerous pharmaceutical companies.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The benefit of giving pembolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant setting to patients with early triple-negative breast cancer (TNBC) extends across subgroups and clinical situations, suggests the latest analysis from KEYNOTE-522.

The original trial data in more than 1,100 patients with early-stage TNBC indicated that adding pembrolizumab to chemotherapy prior to surgery and giving the drug for a year afterward improves event-free survival (EFS) over placebo by 37%.

Now, the researchers conducted a series of prespecified sensitivity and subgroup analyses, finding remarkably consistent EFS outcomes whether considering the addition of adjuvant chemotherapy, positive surgical margins, or disease characteristics such as nodal status and disease stage.

The analyses showed that the benefit with pembrolizumab over placebo was “robust,” said study presenter Peter Schmid, MD, PhD, Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London.

“These results further support pembrolizumab plus platinum-containing neoadjuvant chemotherapy followed by adjuvant pembrolizumab after surgery as a new standard of care treatment regimen for patients with high-risk, early-stage TNBC,” he said.

The research was presented at the San Antonio Breast Cancer Symposium on Dec. 7.

Hope S. Rugo, MD, who was invited to comment on the findings, noted that, while the sensitivity analyses showed the benefit with pembrolizumab was seen across the board, the numbers in each group of interest were “very small, making any impact unlikely.”

She continued that there also remain a number of unanswered questions, chief among them being: “Does everybody need a checkpoint inhibitor? Perhaps studies ... could help us understand which patients might do well with chemotherapy alone.”

Dr. Rugo, who is professor of medicine in the division of hematology and oncology at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, , added that “we need to understand the balance of risk and toxicity” asking whether there are patients whose risk of an immunotoxicity is “so high that we should not give them a checkpoint inhibitor.”

It is not clear what constitutes the optimal chemotherapy backbone. “Does everybody need carboplatin? Does everyone need a year of pembrolizumab, even with a pathologic complete response given the intriguing data from GeparNUEVO and previously the I-SPY trial?” she asked.

“Of course, we don’t know the answers to those questions,” she said, but it is nevertheless possible to draw a roadmap for the treatment of early TNBC, although the choice of adjuvant therapy following surgery is less clear.

Dr. Rugo conducted a Twitter poll to canvas opinion on what to give to patients following surgery, depending on whether or not they have a pathological complete response.

At 73%, most of almost 200 respondents said patients with a pathological complete response should continue pembrolizumab for 1 year, while 72% said that patients without a pathological complete response should receive combination therapy of pembrolizumab and either capecitabine or olaparib, depending on mutational status.

Dr. Schmid began his presentation by noting that KEYNOTE-522 was the first prospective, randomized, phase 3 trial of pembrolizumab in early TNBC in the neoadjuvant and adjuvant setting.

Previously presented results showed that adding neoadjuvant pembrolizumab to chemotherapy was associated with a clinically meaningful increase in pathological complete response, while continuing with adjuvant chemotherapy after surgery led to a clinically meaningful improvement in EFS.

Consequently, the Food and Drug Administration approved pembrolizumab in this setting for patients with high-risk early-stage TNBC.

He reminded the audience that the trial included 1,174 patients randomized 2:1 to pembrolizumab or placebo every 3 weeks alongside eight cycles of chemotherapy, followed by pembrolizumab over placebo alone for up to nine cycles after undergoing definitive surgery.

After a median follow-up of 39.1 months, 15.7% of patients treated with pembrolizumab experienced an event versus 23.9% of those in the placebo group, at a hazard ratio of 0.63 (P = .00031). At 36 months, the EFS rate was 84.5% with pembrolizumab and 76.8% in patients treated with placebo.

Dr. Schmid said that they then performed five prespecified sensitivity analyses, which revealed that the results were “consistent with the primary EFS in all five sensitivity analyses, showing the robustnesses of the event-free survival benefit in the pembrolizumab arm.”

The first analysis, he continued, is of “particular interest as it considered the impact of postsurgery new anticancer therapy. For example, the use of adjuvant capecitabine.”

Censoring 31 patients from the pembrolizumab arm who received the drug and 13 of those given placebo, the team found that the hazard ratio for EFS for pembrolizumab versus placebo was 0.64.

Removing “positive margin at last surgery” as part of the definition of EFS also did not change the results substantially, with the HR for EFS for pembrolizumab versus placebo at 0.65.

Subgroup analysis revealed “consistent EFS results,” Dr. Schmid said, irrespective of whether stratifying the patients by nodal status, overall disease stage, menopausal status, HER2 status, or lactate dehydrogenase levels.

While patients in both treatment arms who had nodal involvement had worse outcomes than those without, those in the pembrolizumab arm “still had improved outcomes, compared with placebo, suggesting that it provides benefit regardless of nodal status.”

“Similarly, the EFS benefit with pembrolizumab was irrespective of disease stage,” Dr. Schmid said. Although the EFS improvement was greater in patients with stage II rather than III disease, at a HR of 0.60 versus 0.68, it highlights “the importance of early intervention.”

He said that the “rate of adverse events with pembrolizumab was low, especially in the adjuvant setting.”

Following his presentation, Dr. Schmid was asked whether he would consider retrying immunotherapy in patients after progression on pembrolizumab.

He replied that this is currently a “data-free zone.”

However, he said: “If a patient responded immunotherapy initially, had a disease-free interval and then has recurrence, then I would consider, if the patient is PD-L1 [programmed death–ligand 1] positive, at that time to add immunotherapy. We can’t say whether those patients will derive the same benefit” as that seen in randomized controlled trials in later stage TNBC, he added, “but there is, in my opinion, little to lose, especially if we have already established the patient tolerates immunotherapy well in that setting.”

Dr. Schmid continued that he “personally found it reassuring” that, in the current study, even patients without a complete pathological response “still showed a substantially better event-free survival compared to patients without immunotherapy, so I personally would consider immunotherapy for those patients when they relapse but we can discuss what the optimal disease-free interval is.”

The study was funded by Merck Sharp and Dohme. Both Dr. Rugo and Dr. Schmid reported relationships numerous pharmaceutical companies.

.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.