MDedge ObGyn

SAN FRANCISCO — Women who used marijuana during pregnancy were significantly less likely to view it as risky even in a state where it was not legalized, according to prospectively collected data presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. But most of those women had not received any counseling about stopping its use, and more than half wanted more information about its effects on pregnancy complications.

“The biggest thing we recognized was that our counseling in prenatal visits was lower than what it really should have been,” Abigail M. Ramseyer, DO, of University of Michigan Health– Sparrow in Lansing, said in an interview. She said doctors really need to be asking their patients about marijuana use and having a conversation about the risks of its use during pregnancy.

An estimated 3%-30% of pregnant women use marijuana, depending on the population, but prevalence has been rising as more states legalize its use. Yet research has shown an association between marijuana use during pregnancy and multiple neonatal complications, including fetal growth restriction and low birth weight.

Pregnant women at a single center in Arkansas were invited during their prenatal visits to complete a 35-question, anonymous survey electronically or on paper. Of the 460 approached, 88.7% completed the survey and 11.8% of those women reported use of marijuana during pregnancy. Among those who used it while pregnant, 50% reported using it 2-3 times a week, 27% reported using it once weekly, and 18.8% reported using it daily.

The women who used it while pregnant were less likely to have a college degree and half (50%) were aged 18-24, with use declining with increasing age. A third of those who use it were White (33.3%), 52.1% were Black, and 6.3% were Hispanic.

More than half of the women (52.7%) who used marijuana during pregnancy reported that there had not been any discussion about substance use during pregnancy at the prenatal visit, and 82.4% said they had not received any counseling about stopping its use during pregnancy. Yet 54% of them wanted more information about pregnancy complications linked to cannabis use.

The other questions asked respondents on a 5-point Likert scale how much they agreed or disagreed with various statements related to perceptions of marijuana, its use during pregnancy, and its risks.

Most respondents strongly agreed that “marijuana isn’t as bad as other drugs like heroin, cocaine or meth,” but average agreement was higher among those who used marijuana (4.88) than who didn’t (4.02, P < .001).

Respondents largely neither agreed nor disagreed with its being okay to use marijuana during pregnancy with a prescription, but agreement was still higher among those who used it (3.68) than didn’t use it (2.82, P < .001). Those who used marijuana were more likely to agree that it’s “a natural substance and not a drug” (4.67 vs. 3.38, P < .001); to believe “marijuana has minimal health risks during and outside of pregnancy” (4.15 vs. 2.96, P < .001); and to believe “marijuana has less risk for treating symptoms in pregnancy than prescription medication from my provider” (4.19 vs. 3.01, P < .001).

It was not surprising that patients using marijuana would have more favorable opinions toward legalizing it, Dr. Ramseyer said, but it was interesting that the respondents’ attitude overall, regardless of use, was positive in a fairly conservative state where it was still illegal. She said her research group has data they are starting to analyze about the perceptions of patients’ partners and family members regarding marijuana use during pregnancy.

Animesh Upadhyay, MD, a resident at Yale–New Haven Medical Center in Connecticut, was also surprised by how positive the attitudes toward marijuana use and legalization were in a state where it’s illegal.

“The thing that disturbs me is that nobody has spoken about the risks of marijuana in pregnancy” to many of the respondents, said Dr. Upadhyay, who was not involved in the study. Based on the findings, Dr. Upadhyay said he would definitely begin asking patients more about their use of marijuana and their beliefs about it.

In a separate poster, Sarah Dzubay, BS, of Oregon Health & Science University, Portland, presented data examining potential associations between cannabis use and fertility. Previous research has suggested an association, but the cross-sectional analysis by Ms. Dzubay identified only a nonsignificant trend toward an association.

The researchers analyzed data from the 2013-2018 National Health and Nutrition Examination Study (NHANES) for woman aged 20-49 based on self-reported use of cannabis. Among 3166 women, 51% reported never using cannabis, 29% reported irregular use, and 20% reported regular use at least monthly.

“Women reporting regular use were younger, of lower income and educational attainment, and more likely to be single,” Ms. Dzubay reported. Those reporting irregular use, meanwhile, were more likely to be college graduates.

More of the women who used cannabis regularly (15.4%) reported an inability to conceive within one year than women who used cannabis irregularly (10.8%) or never (12.6%). The higher odds ratio of infertility among those using cannabis regularly (OR 1.47) compared to never using it was not statistically significant, however, nor was the reduced odds ratio among those using it irregularly (OR 0.83).

Because the results were not significant, the possibility of a link to infertility is “something to keep in mind,” Ms. Dzubay said, but “a lot more data has to be collected about this question before we can definitively say there’s a risk.”

The authors and Dr. Upadhyay had no disclosures. Neither study noted any external funding.

SAN FRANCISCO — Women who used marijuana during pregnancy were significantly less likely to view it as risky even in a state where it was not legalized, according to prospectively collected data presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. But most of those women had not received any counseling about stopping its use, and more than half wanted more information about its effects on pregnancy complications.

“The biggest thing we recognized was that our counseling in prenatal visits was lower than what it really should have been,” Abigail M. Ramseyer, DO, of University of Michigan Health– Sparrow in Lansing, said in an interview. She said doctors really need to be asking their patients about marijuana use and having a conversation about the risks of its use during pregnancy.

An estimated 3%-30% of pregnant women use marijuana, depending on the population, but prevalence has been rising as more states legalize its use. Yet research has shown an association between marijuana use during pregnancy and multiple neonatal complications, including fetal growth restriction and low birth weight.

Pregnant women at a single center in Arkansas were invited during their prenatal visits to complete a 35-question, anonymous survey electronically or on paper. Of the 460 approached, 88.7% completed the survey and 11.8% of those women reported use of marijuana during pregnancy. Among those who used it while pregnant, 50% reported using it 2-3 times a week, 27% reported using it once weekly, and 18.8% reported using it daily.

The women who used it while pregnant were less likely to have a college degree and half (50%) were aged 18-24, with use declining with increasing age. A third of those who use it were White (33.3%), 52.1% were Black, and 6.3% were Hispanic.

More than half of the women (52.7%) who used marijuana during pregnancy reported that there had not been any discussion about substance use during pregnancy at the prenatal visit, and 82.4% said they had not received any counseling about stopping its use during pregnancy. Yet 54% of them wanted more information about pregnancy complications linked to cannabis use.

The other questions asked respondents on a 5-point Likert scale how much they agreed or disagreed with various statements related to perceptions of marijuana, its use during pregnancy, and its risks.

Most respondents strongly agreed that “marijuana isn’t as bad as other drugs like heroin, cocaine or meth,” but average agreement was higher among those who used marijuana (4.88) than who didn’t (4.02, P < .001).

Respondents largely neither agreed nor disagreed with its being okay to use marijuana during pregnancy with a prescription, but agreement was still higher among those who used it (3.68) than didn’t use it (2.82, P < .001). Those who used marijuana were more likely to agree that it’s “a natural substance and not a drug” (4.67 vs. 3.38, P < .001); to believe “marijuana has minimal health risks during and outside of pregnancy” (4.15 vs. 2.96, P < .001); and to believe “marijuana has less risk for treating symptoms in pregnancy than prescription medication from my provider” (4.19 vs. 3.01, P < .001).

It was not surprising that patients using marijuana would have more favorable opinions toward legalizing it, Dr. Ramseyer said, but it was interesting that the respondents’ attitude overall, regardless of use, was positive in a fairly conservative state where it was still illegal. She said her research group has data they are starting to analyze about the perceptions of patients’ partners and family members regarding marijuana use during pregnancy.

Animesh Upadhyay, MD, a resident at Yale–New Haven Medical Center in Connecticut, was also surprised by how positive the attitudes toward marijuana use and legalization were in a state where it’s illegal.

“The thing that disturbs me is that nobody has spoken about the risks of marijuana in pregnancy” to many of the respondents, said Dr. Upadhyay, who was not involved in the study. Based on the findings, Dr. Upadhyay said he would definitely begin asking patients more about their use of marijuana and their beliefs about it.

In a separate poster, Sarah Dzubay, BS, of Oregon Health & Science University, Portland, presented data examining potential associations between cannabis use and fertility. Previous research has suggested an association, but the cross-sectional analysis by Ms. Dzubay identified only a nonsignificant trend toward an association.

The researchers analyzed data from the 2013-2018 National Health and Nutrition Examination Study (NHANES) for woman aged 20-49 based on self-reported use of cannabis. Among 3166 women, 51% reported never using cannabis, 29% reported irregular use, and 20% reported regular use at least monthly.

“Women reporting regular use were younger, of lower income and educational attainment, and more likely to be single,” Ms. Dzubay reported. Those reporting irregular use, meanwhile, were more likely to be college graduates.

More of the women who used cannabis regularly (15.4%) reported an inability to conceive within one year than women who used cannabis irregularly (10.8%) or never (12.6%). The higher odds ratio of infertility among those using cannabis regularly (OR 1.47) compared to never using it was not statistically significant, however, nor was the reduced odds ratio among those using it irregularly (OR 0.83).

Because the results were not significant, the possibility of a link to infertility is “something to keep in mind,” Ms. Dzubay said, but “a lot more data has to be collected about this question before we can definitively say there’s a risk.”

The authors and Dr. Upadhyay had no disclosures. Neither study noted any external funding.

SAN FRANCISCO — Women who used marijuana during pregnancy were significantly less likely to view it as risky even in a state where it was not legalized, according to prospectively collected data presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. But most of those women had not received any counseling about stopping its use, and more than half wanted more information about its effects on pregnancy complications.

“The biggest thing we recognized was that our counseling in prenatal visits was lower than what it really should have been,” Abigail M. Ramseyer, DO, of University of Michigan Health– Sparrow in Lansing, said in an interview. She said doctors really need to be asking their patients about marijuana use and having a conversation about the risks of its use during pregnancy.

An estimated 3%-30% of pregnant women use marijuana, depending on the population, but prevalence has been rising as more states legalize its use. Yet research has shown an association between marijuana use during pregnancy and multiple neonatal complications, including fetal growth restriction and low birth weight.

Pregnant women at a single center in Arkansas were invited during their prenatal visits to complete a 35-question, anonymous survey electronically or on paper. Of the 460 approached, 88.7% completed the survey and 11.8% of those women reported use of marijuana during pregnancy. Among those who used it while pregnant, 50% reported using it 2-3 times a week, 27% reported using it once weekly, and 18.8% reported using it daily.

The women who used it while pregnant were less likely to have a college degree and half (50%) were aged 18-24, with use declining with increasing age. A third of those who use it were White (33.3%), 52.1% were Black, and 6.3% were Hispanic.

More than half of the women (52.7%) who used marijuana during pregnancy reported that there had not been any discussion about substance use during pregnancy at the prenatal visit, and 82.4% said they had not received any counseling about stopping its use during pregnancy. Yet 54% of them wanted more information about pregnancy complications linked to cannabis use.

The other questions asked respondents on a 5-point Likert scale how much they agreed or disagreed with various statements related to perceptions of marijuana, its use during pregnancy, and its risks.

Most respondents strongly agreed that “marijuana isn’t as bad as other drugs like heroin, cocaine or meth,” but average agreement was higher among those who used marijuana (4.88) than who didn’t (4.02, P < .001).

Respondents largely neither agreed nor disagreed with its being okay to use marijuana during pregnancy with a prescription, but agreement was still higher among those who used it (3.68) than didn’t use it (2.82, P < .001). Those who used marijuana were more likely to agree that it’s “a natural substance and not a drug” (4.67 vs. 3.38, P < .001); to believe “marijuana has minimal health risks during and outside of pregnancy” (4.15 vs. 2.96, P < .001); and to believe “marijuana has less risk for treating symptoms in pregnancy than prescription medication from my provider” (4.19 vs. 3.01, P < .001).

It was not surprising that patients using marijuana would have more favorable opinions toward legalizing it, Dr. Ramseyer said, but it was interesting that the respondents’ attitude overall, regardless of use, was positive in a fairly conservative state where it was still illegal. She said her research group has data they are starting to analyze about the perceptions of patients’ partners and family members regarding marijuana use during pregnancy.

Animesh Upadhyay, MD, a resident at Yale–New Haven Medical Center in Connecticut, was also surprised by how positive the attitudes toward marijuana use and legalization were in a state where it’s illegal.

“The thing that disturbs me is that nobody has spoken about the risks of marijuana in pregnancy” to many of the respondents, said Dr. Upadhyay, who was not involved in the study. Based on the findings, Dr. Upadhyay said he would definitely begin asking patients more about their use of marijuana and their beliefs about it.

In a separate poster, Sarah Dzubay, BS, of Oregon Health & Science University, Portland, presented data examining potential associations between cannabis use and fertility. Previous research has suggested an association, but the cross-sectional analysis by Ms. Dzubay identified only a nonsignificant trend toward an association.

The researchers analyzed data from the 2013-2018 National Health and Nutrition Examination Study (NHANES) for woman aged 20-49 based on self-reported use of cannabis. Among 3166 women, 51% reported never using cannabis, 29% reported irregular use, and 20% reported regular use at least monthly.

“Women reporting regular use were younger, of lower income and educational attainment, and more likely to be single,” Ms. Dzubay reported. Those reporting irregular use, meanwhile, were more likely to be college graduates.

More of the women who used cannabis regularly (15.4%) reported an inability to conceive within one year than women who used cannabis irregularly (10.8%) or never (12.6%). The higher odds ratio of infertility among those using cannabis regularly (OR 1.47) compared to never using it was not statistically significant, however, nor was the reduced odds ratio among those using it irregularly (OR 0.83).

Because the results were not significant, the possibility of a link to infertility is “something to keep in mind,” Ms. Dzubay said, but “a lot more data has to be collected about this question before we can definitively say there’s a risk.”

The authors and Dr. Upadhyay had no disclosures. Neither study noted any external funding.

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

Adding atezolizumab to chemotherapy in patients with anti–programmed death ligand 1 (PD-L1)–positive triple-negative breast cancer (TNBC) who have relapsed within 12 months of their last curative treatment does not improve their survival, results of the IMpassion132 trial show.

Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

“These patients have a dismal prognosis and represent a high unmet need,” she added. 

The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.

Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.

“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”

IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.

Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.

Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.

Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.

The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.

The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.

After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).

A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.

Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”

The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.

There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.

“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”

The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.

Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse. 

This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.” 

The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.

IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.

“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”

The study was sponsored by Hoffmann-La Roche.

Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.

A version of this article appeared on Medscape.com .

Adding atezolizumab to chemotherapy in patients with anti–programmed death ligand 1 (PD-L1)–positive triple-negative breast cancer (TNBC) who have relapsed within 12 months of their last curative treatment does not improve their survival, results of the IMpassion132 trial show.

Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

“These patients have a dismal prognosis and represent a high unmet need,” she added. 

The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.

Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.

“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”

IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.

Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.

Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.

Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.

The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.

The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.

After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).

A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.

Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”

The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.

There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.

“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”

The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.

Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse. 

This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.” 

The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.

IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.

“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”

The study was sponsored by Hoffmann-La Roche.

Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.

A version of this article appeared on Medscape.com .

Adding atezolizumab to chemotherapy in patients with anti–programmed death ligand 1 (PD-L1)–positive triple-negative breast cancer (TNBC) who have relapsed within 12 months of their last curative treatment does not improve their survival, results of the IMpassion132 trial show.

Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

“These patients have a dismal prognosis and represent a high unmet need,” she added. 

The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.

Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.

“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”

IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.

Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.

Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.

Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.

The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.

The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.

After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).

A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.

Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”

The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.

There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.

“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”

The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.

Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse. 

This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.” 

The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.

IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.

“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”

The study was sponsored by Hoffmann-La Roche.

Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.

A version of this article appeared on Medscape.com .

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.

At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue. 

About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.

She had three pressing questions for me:

Q: How had this happened while she had taken the birth control pills faithfully?

A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold: 

• Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
• The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
• Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.

Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?

A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.

Q: What would happen to her weight loss efforts?

A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy. 

After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful. 

*Patient’s name changed. 

A version of this article appeared on Medscape.com.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

Only about 3% to 5% of patients with metastatic colorectal cancer have tumors that are positive for human epidermal growth factor receptor 2 (HER2), and until recently there was no treatment approved by the US Food and Drug Administration (FDA) for this subset of patients.

That all changed, in January of 2023. At that time, the FDA granted accelerated approval to tucatinib (Tukysa) in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

The combination was the first FDA-approved treatment for this patient population.

The only other FDA-approved therapy for metastatic HER2-positive CRC is the antibody-drug conjugate trastuzumab deruxtecan (Enhertu). That drug received accelerated approval from the FDA for metastatic HER2-positive CRC for which no other suitable therapeutic option exists, on April 5, 2024. This FDA action represented an expansion of the drug’s earlier approvals for treating several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer and adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.

More than a year after tucatinib-trastuzumab’s approval, the dual HER2 blockade is bringing substantial clinical benefits to a population with few therapeutic options.
 

Drug Combo’s Use With Capecitabine in Breast Cancer

Tucatinib is a potent oral tyrosine kinase inhibitor (TKI) that has been shown to be highly selective for HER2. Prior to approval of the colorectal cancer indication, tucatinib had received FDA approval (in April 2020) in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who had received one or more prior anti-HER2-based regimens in the metastatic setting.

In these patients the combination was associated with significant improvements in both progression-free survival (PFS) and overall survival compared with trastuzumab and capecitabine.

Approval for the colorectal cancer indication was based on results of the phase 2 MOUNTAINEER trial, which were published in The Lancet Oncology.
 

Real-World Setting

Clinical experience with the combination in a real-world setting is still limited due to the relatively uncommon RAS wild-type HER2-positive CRC subtype, so most of what’s known about the efficacy and safety of tucatinib plus trastuzumab comes from clinical trials. But oncologists interviewed for this article emphasized that the tucatinib-trastuzumab combination nonetheless represents a major breakthrough.

“The population of RAS wild-type HER2-positive is small in colorectal cancer, but the benefit of this treatment is really remarkable. With this combination therapy there was a 38% response rate, and there was a very respectable duration of response. So the population is small, but the benefit of the treatment is by no means small,” said Afsaneh Barzi, MD, PhD, a medical oncologist specializing in gastrointestinal cancers at City of Hope in Duarte, California.

Another medical oncologist interviewed for this piece, who treats patients with HER2-positive metastatic CRC, said that the performance of tucatinib in the real-world setting is in keeping with the efficacy seen in clinical trials.

“There is a group of patients who have a very good response to HER2 [targeted] therapy. Often these are patients who have higher degrees of HER2 amplification, and they do not have concomitant other mutations that activate the pathway, such as RAS mutations,” said Kanwal PS Raghav, MD, MBBS, from the University of Texas MD Anderson Cancer Center in Houston.
 

Why It Works

In an interview, MOUNTAINEER coinvestigator Tanios S. Bekaii-Saab, MD, from the Mayo Clinic Comprehensive Cancer Center in Phoenix, Arizona, explained why dual HER2 blockade with tucatinib and trastuzumab is an important breakthrough for this population.

“HER2 as a target was already well established in breast cancer and in gastric cancer. In colon cancer we had signals [of anti-HER2 efficacy] but these signals were primarily with dual targeted therapy,” he said.

“What’s unique about tucatinib versus neratinib [Nerlynx], lapatinib [Tykerb] and some of the others is that this is a highly selective tyrosine kinase inhibitor, meaning it is potent just against HER2 and has limited activity against other receptors, classically EGFR, which also goes by the name of HER1,” said MOUNTAINEER trial chair John H. Strickler, MD, of Duke Cancer Center in Durham, North Carolina.

“The reason why that’s valuable is that when you inhibit other receptors like HER1 or EGFR, you can cause significant skin rash and other symptoms that can limit tolerability, which limits your ability to give the full dose. With tucatinib you can more completely inhibit HER2 with fewer side effects,” Dr. Strickler said in an interview.

Dr. Raghav noted that the primary adverse events of therapy with tucatinib have been diarrhea and fatigue, and other common side effects include abdominal pain, fever, nausea, rash, and infusion reactions.
 

Barriers to Treatment

Dr. Barzi pointed out that in the day-to-day practice setting there are two potential barriers to treatment with tucatinib and trastuzumab for patients with HER2-positive colorectal cancer, hurdles that they would not encounter if they were enrolled in clinical trials.

The first barrier is the requirement for HER2 testing, either through immunohistochemistry or fluorescence in situ hybridization.

“The adoption of HER2 testing in colorectal cancer lags behind other molecular testing, such as testing for KRAS or BRAF, so the provider needs to be aware that HER2 positivity is a possibility,” she said.

The second and more difficult-to-surmount barrier is imposed by the healthcare system. Although the combination is included in National Comprehensive Cancer Network guidelines and, therefore, should not be subject to restrictions or denials by insurers, “the challenge is that this is an oral and IV drug combination,” Dr. Barzi said.

While patients in real-world settings receive intravenous drugs such as trastuzumab in treatment centers, the oral drug component, tucatinib, is dispensed by pharmacies, and patients are often required to shell out high copays for such agents.

Dr. Barzi cited as an example the case of one of her patients who was receiving an oral agent — not tucatinib — for treatment of a different type of colorectal cancer.

“He has very good insurance, and after insurance his out-of-pocket cost on a monthly basis to obtain the drug is $275,” she said.
 

What’s Next

In colorectal cancer the combination of tucatinib and trastuzumab is approved only in the metastatic setting, but it is also being explored as a first-line therapy in combination with the mFOLFOX6 regimen (5-Fluorouracil, leucovorin, and oxaliplatin) in the MOUNTAINEER-03 trial, which is currently recruiting.

MOUNTAINEER was sponsored by Seagen and Merck. Dr. Strickler reported support from Seagen for the Lancet Oncology manuscript; institutional grants, consulting fees, and travel support from Seagen, and similar relationships with other companies. Dr. Bekaii-Saab reported institutional research and consulting fees from various companies, including Merck, personal consulting fees from various companies, and independent monitoring board/scientific advisory board activities. Dr. Raghav disclosed honoraria and an advisory/consulting role for Seagen and others. Dr. Barzi reported no relevant conflicts of interest.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

NEW YORK — Systemic autoimmune disease is well-recognized as a major risk factor for cardiovascular disease (CVD), but less recognized as a cardiovascular risk factor is a history of pregnancy complications, including preeclampsia, and cardiologists and rheumatologists need to include an obstetric history when managing patients with autoimmune diseases, a specialist in reproductive health in rheumatology told attendees at the 4th Annual Cardiometabolic Risk in Inflammatory Conditions conference.

“Autoimmune diseases, lupus in particular, increase the risk for both cardiovascular disease and maternal placental syndromes,” Lisa R. Sammaritano, MD, a professor at Hospital for Special Surgery in New York City and a specialist in reproductive health issues in rheumatology patients, told attendees. “For those patients who have complications during pregnancy, it further increases their already increased risk for later cardiovascular disease.”
 

CVD Risk Double Whammy

A history of systemic lupus erythematosus (SLE) and problematic pregnancy can be a double whammy for CVD risk. Dr. Sammaritano cited a 2022 meta-analysis that showed patients with SLE had a 2.5 times greater risk for stroke and almost three times greater risk for myocardial infarction than people without SLE.

Maternal placental syndromes include pregnancy loss, restricted fetal growth, preeclampsia, premature membrane rupture, placental abruption, and intrauterine fetal demise, Dr. Sammaritano said. Hypertensive disorders of pregnancy, formerly called adverse pregnancy outcomes, she noted, include gestational hypertension, preeclampsia, and eclampsia.

Pregnancy complications can have an adverse effect on the mother’s postpartum cardiovascular health, Dr. Sammaritano noted, a fact borne out by the cardiovascular health after maternal placental syndromes population-based retrospective cohort study and a 2007 meta-analysis that found a history of preeclampsia doubles the risk for venous thromboembolism, stroke, and ischemic heart disease up to 15 years after pregnancy.

“It is always important to obtain a reproductive health history from patients with autoimmune diseases,” Dr. Sammaritano told this news organization in an interview. “This is an integral part of any medical history. In the usual setting, this includes not only pregnancy history but also use of contraception in reproductive-aged women. Unplanned pregnancy can lead to adverse outcomes in the setting of active or severe autoimmune disease or when teratogenic medications are used.”

Pregnancy history can be a factor in a woman’s cardiovascular health more than 15 years postpartum, even if a woman is no longer planning a pregnancy or is menopausal. “As such, this history is important in assessing every woman’s risk profile for CVD in addition to usual traditional risk factors,” Dr. Sammaritano said.

“It is even more important for women with autoimmune disorders, who have been shown to have an already increased risk for CVD independent of their pregnancy history, likely related to a chronic inflammatory state and other autoimmune-related factors such as presence of antiphospholipid antibodies [aPL] or use of corticosteroids.”

Timing of disease onset is also an issue, she said. “In patients with SLE, for example, onset of CVD is much earlier than in the general population,” Dr. Sammaritano said. “As a result, these patients should likely be assessed for risk — both traditional and other risk factors — earlier than the general population, especially if an adverse obstetric history is present.”

At the younger end of the age continuum, women with autoimmune disease, including SLE and antiphospholipid syndrome, who are pregnant should be put on guideline-directed low-dose aspirin preeclampsia prophylaxis, Dr. Sammaritano said. “Whether every patient with SLE needs this is still uncertain, but certainly, those with a history of renal disease, hypertension, or aPL antibody clearly do,” she added.

The evidence supporting hydroxychloroquine (HCQ) in these patients is controversial, but Dr. Sammaritano noted two meta-analyses, one in 2022 and the other in 2023, that showed that HCQ lowered the risk for preeclampsia in women.

“The clear benefit of HCQ in preventing maternal disease complications, including flare, means we recommend it regardless for all patients with SLE at baseline and during pregnancy [if tolerated],” Dr. Sammaritano said. “The benefit or optimal use of these medications in other autoimmune diseases is less studied and less certain.”

Dr. Sammaritano added in her presentation, “We really need better therapies and, hopefully, those will be on the way, but I think the takeaway message, particularly for practicing rheumatologists and cardiologists, is to ask the question about obstetric history. Many of us don’t. It doesn’t seem relevant in the moment, but it really is in terms of the patient’s long-term risk for cardiovascular disease.”
 

The Case for Treatment During Pregnancy

Prophylaxis against pregnancy complications in patients with autoimmune disease may be achievable, Taryn Youngstein, MBBS, consultant rheumatologist and codirector of the Centre of Excellence in Vasculitis Research, Imperial College London, London, England, told this news organization after Dr. Sammaritano’s presentation. At the 2023 American College of Rheumatology Annual Meeting, her group reported the safety and effectiveness of continuing tocilizumab in pregnant women with Takayasu arteritis, a large-vessel vasculitis predominantly affecting women of reproductive age.

“What traditionally happens is you would stop the biologic particularly before the third trimester because of safety and concerns that the monoclonal antibody is actively transported across the placenta, which means the baby gets much more concentration of the drug than the mum,” Dr. Youngstein said.

It’s a situation physicians must monitor closely, she said. “The mum is donating their immune system to the baby, but they’re also donating drug.”

“In high-risk patients, we would share decision-making with the patient,” Dr. Youngstein continued. “We have decided it’s too high of a risk for us to stop the drug, so we have been continuing the interleukin-6 [IL-6] inhibitor throughout the entire pregnancy.”

The data from Dr. Youngstein’s group showed that pregnant women with Takayasu arteritis who continued IL-6 inhibition therapy all carried to term with healthy births.

“We’ve shown that it’s relatively safe to do that, but you have to be very careful in monitoring the baby,” she said. This includes not giving the infant any live vaccines at birth because it will have the high levels of IL-6 inhibition, she said.

Dr. Sammaritano and Dr. Youngstein had no relevant financial relationships to disclose.

A version of this article appeared on Medscape.com.

Hysteroscopy is a crucial examination for the diagnosis of endometrial cancer. In Brazil, women with postmenopausal bleeding who need to undergo this procedure in the public health system wait in line alongside patients with less severe complaints. Until now, there has been no system to prioritize patients at high risk for cancer. But this situation may change, thanks to a Brazilian study published in February in the Journal of Clinical Medicine. 

Researchers from the Municipal Hospital of Vila Santa Catarina in São Paulo, a public unit managed by Hospital Israelita Albert Einstein, have developed the Endometrial Malignancy Prediction System (EMPS), a nomogram to identify patients at high risk for endometrial cancer and prioritize them in the hysteroscopy waiting list.

Bruna Bottura, MD, a gynecologist and obstetrician at Hospital Israelita Albert Einstein and the study’s lead author, told this news organization that the idea to create the nomogram arose during the COVID-19 pandemic. “We noticed that ... when outpatient clinics resumed, we were seeing many patients for intrauterine device (IUD) removal. We thought it was unfair for a patient with postmenopausal bleeding, who has a chance of having cancer, to have to wait in the same line as a patient needing IUD removal,” she said. This realization motivated the development of the tool, which was overseen by Renato Moretti-Marques, MD, PhD.
 

The EMPS Score

The team conducted a retrospective case-control study involving 1945 patients with suspected endometrial cancer who had undergone diagnostic hysteroscopy at Hospital Israelita Albert Einstein between March 2019 and March 2022. Among these patients, 107 were diagnosed with precursor lesions or endometrial cancer on the basis of biopsy. The other 1838 participants, who had had cancer ruled out by biopsy, formed the control group.

Through bivariate and multivariate linear regression analysis, the authors determined that the presence or absence of hypertension, diabetes, postmenopausal bleeding, endometrial polyps, uterine volume, number of pregnancies, body mass index, age, and endometrial thickness were the main risk factors for endometrial cancer diagnosis.

On the basis of these data, the group developed the EMPS nomogram. Physicians can use it to classify the patient’s risk according to the sum of the scores assigned to each of these factors.

The Table shows the classification system. The scoring tables available in the supplemental materials of the article can be accessed here.

Medscape Medical News

Focus on Primary Care

The goal is not to remove patients classified as low risk from the hysteroscopy waiting list, but rather to prioritize those classified as high risk to get the examination, according to Dr. Bottura.

At the Municipal Hospital of Vila Santa Catarina, the average wait time for hysteroscopy was 120 days. But because the unit is focused on oncologic patients and has a high level of organization, this time is much shorter than observed in other parts of Brazil’s National Health Service, said Dr. Bottura. “Many patients are on the hysteroscopy waiting list for 2 years. Considering patients in more advanced stages [of endometrial cancer], it makes a difference,” she said.

Although the nomogram was developed in tertiary care, it is aimed at professionals working in primary care. The reason is that physicians from primary care health units refer women with clinical indications for hysteroscopy to specialized national health services, such as the Municipal Hospital of Vila Santa Catarina. “Our goal is the primary sector, to enable the clinic to refer this high-risk patient sooner. By the time you reach the tertiary sector, where hysteroscopies are performed, all patients will undergo the procedure. Usually, it is not the hospitals that predetermine the line, but rather the health clinics,” she explained.

The researchers hope to continue the research, starting with a prospective study. “We intend to apply and evaluate the tool within our own service to observe whether any patient with a high [EMPS] score patient ended up waiting too long to be referred. In fact, this will be a system validation step,” said Dr. Bottura.

In parallel, the team has a proposal to take the tool to health clinics in the same region as the study hospital. “We know this involves changing the protocol at a national level, so it’s more challenging,” said Dr. Bottura. She added that the final goal is to create a calculator, possibly an app, that allows primary care doctors to calculate the risk score in the office. This calculator could enable risk classification to be linked to patient referrals.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Hysteroscopy is a crucial examination for the diagnosis of endometrial cancer. In Brazil, women with postmenopausal bleeding who need to undergo this procedure in the public health system wait in line alongside patients with less severe complaints. Until now, there has been no system to prioritize patients at high risk for cancer. But this situation may change, thanks to a Brazilian study published in February in the Journal of Clinical Medicine. 

Researchers from the Municipal Hospital of Vila Santa Catarina in São Paulo, a public unit managed by Hospital Israelita Albert Einstein, have developed the Endometrial Malignancy Prediction System (EMPS), a nomogram to identify patients at high risk for endometrial cancer and prioritize them in the hysteroscopy waiting list.

Bruna Bottura, MD, a gynecologist and obstetrician at Hospital Israelita Albert Einstein and the study’s lead author, told this news organization that the idea to create the nomogram arose during the COVID-19 pandemic. “We noticed that ... when outpatient clinics resumed, we were seeing many patients for intrauterine device (IUD) removal. We thought it was unfair for a patient with postmenopausal bleeding, who has a chance of having cancer, to have to wait in the same line as a patient needing IUD removal,” she said. This realization motivated the development of the tool, which was overseen by Renato Moretti-Marques, MD, PhD.
 

The EMPS Score

The team conducted a retrospective case-control study involving 1945 patients with suspected endometrial cancer who had undergone diagnostic hysteroscopy at Hospital Israelita Albert Einstein between March 2019 and March 2022. Among these patients, 107 were diagnosed with precursor lesions or endometrial cancer on the basis of biopsy. The other 1838 participants, who had had cancer ruled out by biopsy, formed the control group.

Through bivariate and multivariate linear regression analysis, the authors determined that the presence or absence of hypertension, diabetes, postmenopausal bleeding, endometrial polyps, uterine volume, number of pregnancies, body mass index, age, and endometrial thickness were the main risk factors for endometrial cancer diagnosis.

On the basis of these data, the group developed the EMPS nomogram. Physicians can use it to classify the patient’s risk according to the sum of the scores assigned to each of these factors.

The Table shows the classification system. The scoring tables available in the supplemental materials of the article can be accessed here.

Medscape Medical News

Focus on Primary Care

The goal is not to remove patients classified as low risk from the hysteroscopy waiting list, but rather to prioritize those classified as high risk to get the examination, according to Dr. Bottura.

At the Municipal Hospital of Vila Santa Catarina, the average wait time for hysteroscopy was 120 days. But because the unit is focused on oncologic patients and has a high level of organization, this time is much shorter than observed in other parts of Brazil’s National Health Service, said Dr. Bottura. “Many patients are on the hysteroscopy waiting list for 2 years. Considering patients in more advanced stages [of endometrial cancer], it makes a difference,” she said.

Although the nomogram was developed in tertiary care, it is aimed at professionals working in primary care. The reason is that physicians from primary care health units refer women with clinical indications for hysteroscopy to specialized national health services, such as the Municipal Hospital of Vila Santa Catarina. “Our goal is the primary sector, to enable the clinic to refer this high-risk patient sooner. By the time you reach the tertiary sector, where hysteroscopies are performed, all patients will undergo the procedure. Usually, it is not the hospitals that predetermine the line, but rather the health clinics,” she explained.

The researchers hope to continue the research, starting with a prospective study. “We intend to apply and evaluate the tool within our own service to observe whether any patient with a high [EMPS] score patient ended up waiting too long to be referred. In fact, this will be a system validation step,” said Dr. Bottura.

In parallel, the team has a proposal to take the tool to health clinics in the same region as the study hospital. “We know this involves changing the protocol at a national level, so it’s more challenging,” said Dr. Bottura. She added that the final goal is to create a calculator, possibly an app, that allows primary care doctors to calculate the risk score in the office. This calculator could enable risk classification to be linked to patient referrals.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Hysteroscopy is a crucial examination for the diagnosis of endometrial cancer. In Brazil, women with postmenopausal bleeding who need to undergo this procedure in the public health system wait in line alongside patients with less severe complaints. Until now, there has been no system to prioritize patients at high risk for cancer. But this situation may change, thanks to a Brazilian study published in February in the Journal of Clinical Medicine. 

Researchers from the Municipal Hospital of Vila Santa Catarina in São Paulo, a public unit managed by Hospital Israelita Albert Einstein, have developed the Endometrial Malignancy Prediction System (EMPS), a nomogram to identify patients at high risk for endometrial cancer and prioritize them in the hysteroscopy waiting list.

Bruna Bottura, MD, a gynecologist and obstetrician at Hospital Israelita Albert Einstein and the study’s lead author, told this news organization that the idea to create the nomogram arose during the COVID-19 pandemic. “We noticed that ... when outpatient clinics resumed, we were seeing many patients for intrauterine device (IUD) removal. We thought it was unfair for a patient with postmenopausal bleeding, who has a chance of having cancer, to have to wait in the same line as a patient needing IUD removal,” she said. This realization motivated the development of the tool, which was overseen by Renato Moretti-Marques, MD, PhD.
 

The EMPS Score

The team conducted a retrospective case-control study involving 1945 patients with suspected endometrial cancer who had undergone diagnostic hysteroscopy at Hospital Israelita Albert Einstein between March 2019 and March 2022. Among these patients, 107 were diagnosed with precursor lesions or endometrial cancer on the basis of biopsy. The other 1838 participants, who had had cancer ruled out by biopsy, formed the control group.

Through bivariate and multivariate linear regression analysis, the authors determined that the presence or absence of hypertension, diabetes, postmenopausal bleeding, endometrial polyps, uterine volume, number of pregnancies, body mass index, age, and endometrial thickness were the main risk factors for endometrial cancer diagnosis.

On the basis of these data, the group developed the EMPS nomogram. Physicians can use it to classify the patient’s risk according to the sum of the scores assigned to each of these factors.

The Table shows the classification system. The scoring tables available in the supplemental materials of the article can be accessed here.

Medscape Medical News

Focus on Primary Care

The goal is not to remove patients classified as low risk from the hysteroscopy waiting list, but rather to prioritize those classified as high risk to get the examination, according to Dr. Bottura.

At the Municipal Hospital of Vila Santa Catarina, the average wait time for hysteroscopy was 120 days. But because the unit is focused on oncologic patients and has a high level of organization, this time is much shorter than observed in other parts of Brazil’s National Health Service, said Dr. Bottura. “Many patients are on the hysteroscopy waiting list for 2 years. Considering patients in more advanced stages [of endometrial cancer], it makes a difference,” she said.

Although the nomogram was developed in tertiary care, it is aimed at professionals working in primary care. The reason is that physicians from primary care health units refer women with clinical indications for hysteroscopy to specialized national health services, such as the Municipal Hospital of Vila Santa Catarina. “Our goal is the primary sector, to enable the clinic to refer this high-risk patient sooner. By the time you reach the tertiary sector, where hysteroscopies are performed, all patients will undergo the procedure. Usually, it is not the hospitals that predetermine the line, but rather the health clinics,” she explained.

The researchers hope to continue the research, starting with a prospective study. “We intend to apply and evaluate the tool within our own service to observe whether any patient with a high [EMPS] score patient ended up waiting too long to be referred. In fact, this will be a system validation step,” said Dr. Bottura.

In parallel, the team has a proposal to take the tool to health clinics in the same region as the study hospital. “We know this involves changing the protocol at a national level, so it’s more challenging,” said Dr. Bottura. She added that the final goal is to create a calculator, possibly an app, that allows primary care doctors to calculate the risk score in the office. This calculator could enable risk classification to be linked to patient referrals.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.