BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

BY ALICIA AULT

The Centers for Disease Control and Prevention is alerting clinicians to be on the lookout for a severe antifungal-resistant form of tinea, as it was recently detected in two patients in New York.

Tinea, or ringworm, one of the most common fungal infections, is responsible for almost 5 million outpatient visits and 690 hospitalizations annually, according to the CDC.

Over the past 10 years, severe, antifungal-resistant tinea has spread in South Asia, in part because of the rise of a new dermatophyte species known as Trichophyton indotineae, wrote the authors of a report on the two patients with the drug-resistant strain. This epidemic “has likely been driven by misuse and overuse of topical antifungals and corticosteroids,” added the authors, in Morbidity and Mortality Weekly Report.

The cases were detected by a New York City dermatologist. In the first case, a 28-year-old woman developed a widespread pruritic eruption in the summer of 2021. She did not consult a dermatologist until December, when she was in the third trimester of pregnancy. She had large, annular, scaly, pruritic plaques on her neck, abdomen, pubic region, and buttocks, but had no underlying medical conditions, no known exposures to someone with a similar rash, and no recent international travel history.

After she gave birth in January, she started oral terbinafine therapy but had no improvement after 2 weeks. Clinicians administered a 4-week course of itraconazole, which resolved the infection.

The second patient, a 47-year-old woman with no medical conditions, developed a rash while in Bangladesh in the summer of 2022. Other family members had a similar rash. She was treated with topical antifungal and steroid combination creams but had no resolution. Back in the United States, she was prescribed hydrocortisone 2.5% ointment and diphenhydramine, clotrimazole cream, and terbinafine cream in three successive emergency department visits. In December 2022, dermatologists, observing widespread, discrete, scaly, annular, pruritic plaques on the thighs and buttocks, prescribed a 4-week course of oral terbinafine. When the rash did not resolve, she was given 4 weeks of griseofulvin. The rash persisted, although there was 80% improvement. Clinicians are now considering itraconazole. The woman’s son and husband are also being evaluated, as they have similar rashes.

In both cases, skin culture isolates were initially identified as Trichophyton mentagrophytes. Further analysis at the New York State Department of Health’s lab, using Sanger sequencing of the internal transcribed spacer region of the ribosomal gene, followed by phylogenetic analysis, identified the isolates as T. indotineae.

The authors note that culture-based techniques used by most clinical laboratories typically misidentify T. indotineae as T. mentagrophytes or T. interdigitale. Genomic sequencing must be used to properly identify T. indotineae, they wrote.

Clinicians should consider T. indotineae in patients with widespread ringworm, especially if they do not improve with topical antifungals or oral terbinafine, said the authors. If T. indotineae is suspected, state or local public health departments can direct clinicians to testing.

The authors report no relevant financial relationships.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

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

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

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

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

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

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (FIGURE 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (FIGURES 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (FIGURE 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (FIGURE 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas are benign tumors of the sweat glands that are fairly common and appear to have a predilection for women. Although most of the literature classifies them as eccrine neoplasms, the term syringoma can be used to describe neoplasms of either apocrine or eccrine lineage.¹ To rule out an apocrine lineage of the tumor in our patient, we performed immunohistochemistry for gross cystic disease fluid protein, a marker of apocrine differentiation. This stain highlighted normal apocrine glands that were not involved in the tumor proliferation.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulvar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (FIGURES 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (FIGURE 3).Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems. ●

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

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

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

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

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

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

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Photo: antoniodiaz/Shutterstock

Mendoza M, Bonacina E, Garcia-Manau P, et al. Aspirin discontinuation at 24 to 28 weeks’ gestation in pregnancies at high risk of preterm preeclampsia: a randomized clinical trial. JAMA. 2023;329:542-550. doi:10.1001/jama.2023.0691.

EXPERT COMMENTARY

Aspirin is, to date, the only proven preventative treatment to reduce the risk of preeclampsia in pregnancy. While aspirin initiation, optimally prior to 16 weeks, generally is accepted, the best timing for discontinuation remains uncertain due to conflicting data on risk of bleeding and different doses used. The American College of Obstetricians and Gynecologists recommends a broad range of patients eligible for low-dose aspirin with continuation through delivery, citing data that support no increase in either maternal or fetal/neonatal complications, including bleeding complications.¹ Other guidelines recommend reduction in pregnancy exposure to aspirin with strict guidelines for which patients are considered “high risk” as well as discontinuation at 36 weeks prior to labor onset to reduce the risk of potential bleeding complications.

Recently, Mendoza and colleagues tested the hypothesis that, in patients at high risk for preterm preeclampsia (based on high-risk first-trimester screening followed by a low risk of preeclampsia at 24 to 28 weeks based on a normal sFlt-1:PlGF [soluble fms-like tyrosine kinase-1 to placental growth factor] ratio), discontinuing aspirin is noninferior in preventing preterm preeclampsia compared with continuing aspirin until 36 weeks.²

Details of the study

Mendoza and colleagues conducted a multicenter, open label, randomized, phase 3, noninferiority trial that randomly assigned 968 participants prior to stopping recruitment based on the findings from a planned interim analysis.²

The patient population included women with singleton pregnancies between 24 and 28 weeks who had initiated aspirin 150 mg daily by 16 6/7 weeks due to high-risk first- trimester screening for preterm preeclampsia. Additionally, these patients also had an sFlt-1:PlGR ratio of 38 or less between 24 and 28 weeks’ gestation, which prior studies have demonstrated to exclude the diagnosis of preeclampsia.

Patients were randomly assigned to either discontinue aspirin at 24 to 28 weeks’ gestation (intervention group) or continue aspirin until 36 weeks’ gestation (control group). The primary outcome was delivery due to preeclampsia at less than 37 weeks, with secondary outcomes of preeclampsia at less than 34 weeks, preeclampsia at 37 or more weeks, or other adverse pregnancy outcomes.

Results. For the primary outcome (936 participants’ data analyzed), the incidence of preeclampsia at less than 37 weeks was 1.48% in the intervention group and 1.73% in the control group (absolute difference, -0.25%, which meets study criteria for noninferiority).

No difference occurred in the secondary outcomes of adverse outcomes at less than 34 weeks or at less than 37 weeks. While there was no difference in the incidence of the individual adverse outcomes at 37 or more weeks, the intervention group had a decrease in the incidence of having “any” adverse outcome (-5.04%) as well as a decrease in minor antepartum hemorrhage (nose and/or gum bleeding) (-4.7%).

The authors therefore concluded that aspirin discontinuation at 24 to 28 weeks’ gestation in pregnant patients at high risk for preterm preeclampsia and a normal sFlt-1:PlGF ratio is noninferior to aspirin continuation for prevention of preterm preeclampsia. They also suggested that this discontinuation may reduce the risk of adverse pregnancy outcomes at 37 or more weeks as well as minor bleeding complications.

Study strengths and limitations

The authors cited the novelty of this study at considering using aspirin for the prevention of preterm preeclampsia in a specific patient group for the shortest amount of time needed to achieve this goal. Potential benefits could be decreased bleeding complications, cost, anxiety, and visits.

They also noted the following study limitations: open-label design, a predominantly White patient population, early termination due to the interim analysis, inadequate power for more rare complications, and a query as to the appropriate choice for the threshold for noninferiority. Noninferiority trials have inherent weaknesses as a group that should be considered before major practice changes occur as a result of their findings.

Several other factors in the study limit the generalizability of the authors’ recommendations, especially to patient populations in the United States. For example, the study used an aspirin dose of 150 mg daily, which is almost double the dose recommended in the United States (81 mg). The reasoning for this was that doses higher than 100 mg have been shown to be the most effective for preeclampsia prevention but also may have higher rates of bleeding complications, including placental abruption. The demonstrated increase in complications may not hold at a lower dose.

Additionally, patients in this study were selected for aspirin by a first-trimester algorithm that may not be in general use everywhere (and differs from the US Preventive Services Task Force recommendations for low-dose aspirin use in pregnancy). Finally, although extremely interesting, the use of the sFlt-1:PlFG ratio at 24 to 28 weeks is not in widespread use in the United States and may incur an additional cost not equivalent to the low cost of a daily aspirin.

Essentially, this is an extremely limited study for a very specific population. Before globally discontinuing low-dose aspirin in high-risk patients, the different doses and eligibility criteria should be studied for effect of early discontinuation. ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure,but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; [email protected]

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure,but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; [email protected]

THE CASE

A 23-year-old woman sought care from her primary care physician (PCP) after being sick for 7 days. The illness started with a headache and fatigue, and by Day 6, she also had fever, chills, sore throat, nausea, a poor appetite, and intractable vomiting. The patient had no significant medical history and was socially isolating due to the COVID-19 pandemic. She had no known sick contacts or recent sexual activity and did not use any illicit drugs.

On examination, her vital signs were normal although she appeared ill and diaphoretic. A shallow tonsil ulcer and tonsillar adenopathy were present. Laboratory tests included a complete blood count (CBC), comprehensive metabolic panel, Monospot test, and Epstein-Barr virus (EBV) antibody test. Results were notable for leukocytosis with atypical lymphocytes on her CBC. Her Monospot test and EBV immunoglobulin (Ig) M antibody were positive, and her EBV IgG antibody was negative. She was given a diagnosis of infectious mononucleosis (IM) and told to get adequate rest, drink a lot of fluids, and take ibuprofen or acetaminophen for pain control.

Two days later, she returned to her PCP with scleral icterus (FIGURE 1A), increasingly tender cervical lymphadenopathy, and left-side abdominal pain. Her liver function tests (LFTs) had worsened (TABLE). An abdominal ultrasound revealed mild diffuse decreased hepatic echogenicity and prominent periportal echogenicity, likely related to diffuse hepatic parenchymal disease, as well as splenomegaly and a mildly thickened gallbladder with no gallstones. She also had severe throat discomfort, with bilateral tonsillar exudates and pharyngeal erythema (FIGURE 1B).

THE DIAGNOSIS

Based on her symptoms and the results of her physical examination, LFTs, EBV serologic assays, and abdominal ultrasound, this patient was given a diagnosis of acute EBV hepatitis.

DISCUSSION

EBV infection, which is the most common cause of IM, causes asymptomatic liver enzyme abnormalities in 80% to 90% of patients.^1-3 Although not common, patients can develop acute EBV hepatitis and require hospitalization.⁴

Be aware of potential complications. Prompt assessment of elevated liver enzymes and accurate diagnosis are key.⁵ Although acute EBV hepatitis is usually self-limiting, there can be serious gastrointestinal complications such as splenic rupture, liver failure due to acute and/or chronic EBV infection, autoimmune hepatitis, and hepatocellular carcinoma.² It’s rare for EBV hepatitis to lead to acute liver failure,but when that occurs, it can be fatal.^6-9 One case series revealed that while primary EBV infection accounts for less than 1% of adult acute liver failure cases, it has a high case fatality rate of 50%.⁹

Treatment for patients with EBV hepatitis is usually supportive and includes rest, analgesia, and avoidance of vigorous activity for 1 month to reduce the risk for splenic rupture.¹ In patients with nausea and vomiting, intravenous fluids may be necessary and can be administered at an outpatient infusion center. For individuals with severe tonsillar hypertrophy, prednisone (40-60 mg/d for 2-3 days, with subsequent tapering over 1-2 weeks) is indicated to prevent airway obstruction.¹ Acyclovir may be used to reduce EBV viral shedding; however, it has no significant clinical impact.¹

Continue to: Patients who are hemodynamially stable...

Patients who are hemodynamically stable and have appropriate access to follow-up care can be managed at home.² If follow-up cannot occur remotely within 1 week or the patient’s clinical status begins to worsen (ie, the patient’s liver enzymes or bilirubin levels dramatically increase), hospitalization is necessary.¹⁰

Through shared decision-making, our patient was treated as an outpatient based on her hemodynamic stability and her ability to closely follow up in the clinic and by phone and to access an outpatient infusion center. She was reexamined within 2 days and given ondansetron 8 mg IV with 2 L of normal saline at our outpatient infusion center. We also prescribed ibuprofen (400 mg every 6 hours as needed) for analgesia and issued the standard recommendations that she avoid contact sports (for at least 6 weeks) and excessive alcohol consumption.

On Day 11, the patient followed up with her PCP by telephone. The patient was started on oral prednisone (40 mg/d for 3 days with taper over the next week as symptoms improved) for her severe throat discomfort, exudates, difficulty swallowing, and muffled voice. By Day 14, her aminotransferase levels began to decrease (TABLE), and her symptoms steadily improved thereafter.

THE TAKEAWAY

When a patient presents with unexplained elevated liver enzymes or cholestasis, it is important to assess for signs and symptoms of EBV hepatitis. Although EBV hepatitis is typically self-limiting, it can have serious complications or be fatal. Prompt initiation of outpatient management may avoid these complications and hospitalization.

CORRESPONDENCE
Lydia J. Schneider, MD, 225 East Chicago Avenue, Chicago, IL 60611; [email protected]

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.