Women's Health

Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.

For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”

Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.

“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.

One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.

Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.

There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.

“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.

Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.

Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.

“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.

Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.

Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.

“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.

“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.

They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”

Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.

“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.

James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.

“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.

However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.

“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”

Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.

Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.

For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”

Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.

“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.

One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.

Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.

There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.

“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.

Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.

Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.

“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.

Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.

Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.

“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.

“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.

They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”

Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.

“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.

James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.

“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.

However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.

“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”

Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.

Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.

For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”

Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.

“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.

One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.

Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.

There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.

“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.

Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.

Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.

“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.

Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.

Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.

“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.

“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.

They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”

Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.

“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.

James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.

“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.

However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.

“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”

Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

A federal judge has paused the recent Texas abortion law that bans nearly all abortions in the state.

Robert Pitman, a federal district court judge in Austin, sided with the Biden administration and granted the Justice Department’s request to halt enforcement of the new law. The Biden administration sued to stop the law, and Mr. Pitman’s decision pauses the law while it moves through federal courts, The New York Times reported.

In a 113-page ruling, Mr. Pitman criticized the law, also known as Senate Bill 8, for delegating enforcement to private individuals, who can sue anyone who performs abortions or “aids and abets” them. Plaintiffs are encouraged to file lawsuits because they recover legal fees and $10,000 if they win.

“From the moment S.B. 8 went into effect, women have been unlawfully prevented from exercising control over their own lives in ways that are protected by the Constitution,” Mr. Pitman wrote in the ruling.

“This court will not sanction one more day of this offensive deprivation of such an important right,” he said.

The Texas law bans abortions once fetal cardiac activity can be detected, which is usually around 6 weeks of pregnancy. Women may not know they’re pregnant yet during that time frame.

It’s not yet clear what effect Mr. Pitman’s ruling will have on women in Texas, the Times reported. Since the law went into effect about a month ago, women have sought abortion providers in other states. Mr. Pitman’s ruling pauses the enforcement of the law, but clinics may still face retroactive lawsuits for abortions provided while the law was temporarily suspended.

Whole Woman’s Health, which operates four clinics in Texas, said Wednesday that it was “making plans to resume abortion care up to 18 weeks as soon as possible,” the newspaper reported. The Center for Reproductive Rights also said that clinics “hope to resume full abortion services as soon as they are able.”

Late Oct. 6, Texas said it would appeal the ruling. The U.S. Court of Appeals for the Fifth Circuit is one of the most conservative in the country, according to the Times, and another decision could come soon.

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

Dr. Paula Braveman, director of the Center on Social Disparities in Health at the University of California, San Francisco, says her latest research revealed an “astounding” level of evidence that racism is a decisive “upstream” cause of higher rates of preterm birth among Black women.

The tipping point for Dr. Paula Braveman came when a longtime patient of hers at a community clinic in San Francisco’s Mission District slipped past the front desk and knocked on her office door to say goodbye. He wouldn’t be coming to the clinic anymore, he told her, because he could no longer afford it.

It was a decisive moment for Dr. Braveman, who decided she wanted not only to heal ailing patients but also to advocate for policies that would help them be healthier when they arrived at her clinic. In the nearly four decades since, Dr. Braveman has dedicated herself to studying the “social determinants of health” – how the spaces where we live, work, play and learn, and the relationships we have in those places influence how healthy we are.

As director of the Center on Social Disparities in Health at the University of California, San Francisco, Dr. Braveman has studied the link between neighborhood wealth and children’s health, and how access to insurance influences prenatal care. A longtime advocate of translating research into policy, she has collaborated on major health initiatives with the health department in San Francisco, the federal Centers for Disease Control and Prevention, and the World Health Organization.

Dr. Braveman has a particular interest in maternal and infant health. Her latest research reviews what’s known about the persistent gap in preterm birth rates between Black and White women in the United States. Black women are about 1.6 times as likely as White women to give birth more than three weeks before the due date. That statistic bears alarming and costly health consequences, as infants born prematurely are at higher risk for breathing, heart, and brain abnormalities, among other complications.

Dr. Braveman coauthored the review with a group of experts convened by the March of Dimes that included geneticists, clinicians, epidemiologists, biomedical experts, and neurologists. They examined more than two dozen suspected causes of preterm births – including quality of prenatal care, environmental toxics, chronic stress, poverty and obesity – and determined that racism, directly or indirectly, best explained the racial disparities in preterm birth rates.

(Note: In the review, the authors make extensive use of the terms “upstream” and “downstream” to describe what determines people’s health. A downstream risk is the condition or factor most directly responsible for a health outcome, while an upstream factor is what causes or fuels the downstream risk – and often what needs to change to prevent someone from becoming sick. For example, a person living near drinking water polluted with toxic chemicals might get sick from drinking the water. The downstream fix would be telling individuals to use filters. The upstream solution would be to stop the dumping of toxic chemicals.)

KHN spoke with Dr. Braveman about the study and its findings. The excerpts have been edited for length and style.
 

Q: You have been studying the issue of preterm birth and racial disparities for so long. Were there any findings from this review that surprised you?

The process of systematically going through all of the risk factors that are written about in the literature and then seeing how the story of racism was an upstream determinant for virtually all of them. That was kind of astounding.

The other thing that was very impressive: When we looked at the idea that genetic factors could be the cause of the Black-White disparity in preterm birth. The genetics experts in the group, and there were three or four of them, concluded from the evidence that genetic factors might influence the disparity in preterm birth, but at most the effect would be very small, very small indeed. This could not account for the greater rate of preterm birth among Black women compared to White women.
 

Q: You were looking to identify not just what causes preterm birth but also to explain racial differences in rates of preterm birth. Are there examples of factors that can influence preterm birth that don’t explain racial disparities?

It does look like there are genetic components to preterm birth, but they don’t explain the Black-White disparity in preterm birth. Another example is having an early elective C-section. That’s one of the problems contributing to avoidable preterm birth, but it doesn’t look like that’s really contributing to the Black-White disparity in preterm birth.
 

Q: You and your colleagues listed exactly one upstream cause of preterm birth: racism. How would you characterize the certainty that racism is a decisive upstream cause of higher rates of preterm birth among Black women?

It makes me think of this saying: A randomized clinical trial wouldn’t be necessary to give certainty about the importance of having a parachute on if you jump from a plane. To me, at this point, it is close to that.

Going through that paper – and we worked on that paper over a three- or four-year period, so there was a lot of time to think about it – I don’t see how the evidence that we have could be explained otherwise.
 

Q: What did you learn about how a mother’s broader lifetime experience of racism might affect birth outcomes versus what she experienced within the medical establishment during pregnancy?

There were many ways that experiencing racial discrimination would affect a woman’s pregnancy, but one major way would be through pathways and biological mechanisms involved in stress and stress physiology. In neuroscience, what’s been clear is that a chronic stressor seems to be more damaging to health than an acute stressor.

So it doesn’t make much sense to be looking only during pregnancy. But that’s where most of that research has been done: stress during pregnancy and racial discrimination, and its role in birth outcomes. Very few studies have looked at experiences of racial discrimination across the life course.

My colleagues and I have published a paper where we asked African American women about their experiences of racism, and we didn’t even define what we meant. Women did not talk a lot about the experiences of racism during pregnancy from their medical providers; they talked about the lifetime experience and particularly experiences going back to childhood. And they talked about having to worry, and constant vigilance, so that even if they’re not experiencing an incident, their antennae have to be out to be prepared in case an incident does occur.

Putting all of it together with what we know about stress physiology, I would put my money on the lifetime experiences being so much more important than experiences during pregnancy. There isn’t enough known about preterm birth, but from what is known, inflammation is involved, immune dysfunction, and that’s what stress leads to. The neuroscientists have shown us that chronic stress produces inflammation and immune system dysfunction.

Q: What policies do you think are most important at this stage for reducing preterm birth for Black women?

I wish I could just say one policy or two policies, but I think it does get back to the need to dismantle racism in our society. In all of its manifestations. That’s unfortunate, not to be able to say, “Oh, here, I have this magic bullet, and if you just go with that, that will solve the problem.”

If you take the conclusions of this study seriously, you say, well, policies to just go after these downstream factors are not going to work. It’s up to the upstream investment in trying to achieve a more equitable and less racist society. Ultimately, I think that’s the take-home, and it’s a tall, tall order.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Dr. Paula Braveman, director of the Center on Social Disparities in Health at the University of California, San Francisco, says her latest research revealed an “astounding” level of evidence that racism is a decisive “upstream” cause of higher rates of preterm birth among Black women.

The tipping point for Dr. Paula Braveman came when a longtime patient of hers at a community clinic in San Francisco’s Mission District slipped past the front desk and knocked on her office door to say goodbye. He wouldn’t be coming to the clinic anymore, he told her, because he could no longer afford it.

It was a decisive moment for Dr. Braveman, who decided she wanted not only to heal ailing patients but also to advocate for policies that would help them be healthier when they arrived at her clinic. In the nearly four decades since, Dr. Braveman has dedicated herself to studying the “social determinants of health” – how the spaces where we live, work, play and learn, and the relationships we have in those places influence how healthy we are.

As director of the Center on Social Disparities in Health at the University of California, San Francisco, Dr. Braveman has studied the link between neighborhood wealth and children’s health, and how access to insurance influences prenatal care. A longtime advocate of translating research into policy, she has collaborated on major health initiatives with the health department in San Francisco, the federal Centers for Disease Control and Prevention, and the World Health Organization.

Dr. Braveman has a particular interest in maternal and infant health. Her latest research reviews what’s known about the persistent gap in preterm birth rates between Black and White women in the United States. Black women are about 1.6 times as likely as White women to give birth more than three weeks before the due date. That statistic bears alarming and costly health consequences, as infants born prematurely are at higher risk for breathing, heart, and brain abnormalities, among other complications.

Dr. Braveman coauthored the review with a group of experts convened by the March of Dimes that included geneticists, clinicians, epidemiologists, biomedical experts, and neurologists. They examined more than two dozen suspected causes of preterm births – including quality of prenatal care, environmental toxics, chronic stress, poverty and obesity – and determined that racism, directly or indirectly, best explained the racial disparities in preterm birth rates.

(Note: In the review, the authors make extensive use of the terms “upstream” and “downstream” to describe what determines people’s health. A downstream risk is the condition or factor most directly responsible for a health outcome, while an upstream factor is what causes or fuels the downstream risk – and often what needs to change to prevent someone from becoming sick. For example, a person living near drinking water polluted with toxic chemicals might get sick from drinking the water. The downstream fix would be telling individuals to use filters. The upstream solution would be to stop the dumping of toxic chemicals.)

KHN spoke with Dr. Braveman about the study and its findings. The excerpts have been edited for length and style.
 

Q: You have been studying the issue of preterm birth and racial disparities for so long. Were there any findings from this review that surprised you?

The process of systematically going through all of the risk factors that are written about in the literature and then seeing how the story of racism was an upstream determinant for virtually all of them. That was kind of astounding.

The other thing that was very impressive: When we looked at the idea that genetic factors could be the cause of the Black-White disparity in preterm birth. The genetics experts in the group, and there were three or four of them, concluded from the evidence that genetic factors might influence the disparity in preterm birth, but at most the effect would be very small, very small indeed. This could not account for the greater rate of preterm birth among Black women compared to White women.
 

Q: You were looking to identify not just what causes preterm birth but also to explain racial differences in rates of preterm birth. Are there examples of factors that can influence preterm birth that don’t explain racial disparities?

It does look like there are genetic components to preterm birth, but they don’t explain the Black-White disparity in preterm birth. Another example is having an early elective C-section. That’s one of the problems contributing to avoidable preterm birth, but it doesn’t look like that’s really contributing to the Black-White disparity in preterm birth.
 

Q: You and your colleagues listed exactly one upstream cause of preterm birth: racism. How would you characterize the certainty that racism is a decisive upstream cause of higher rates of preterm birth among Black women?

It makes me think of this saying: A randomized clinical trial wouldn’t be necessary to give certainty about the importance of having a parachute on if you jump from a plane. To me, at this point, it is close to that.

Going through that paper – and we worked on that paper over a three- or four-year period, so there was a lot of time to think about it – I don’t see how the evidence that we have could be explained otherwise.
 

Q: What did you learn about how a mother’s broader lifetime experience of racism might affect birth outcomes versus what she experienced within the medical establishment during pregnancy?

There were many ways that experiencing racial discrimination would affect a woman’s pregnancy, but one major way would be through pathways and biological mechanisms involved in stress and stress physiology. In neuroscience, what’s been clear is that a chronic stressor seems to be more damaging to health than an acute stressor.

So it doesn’t make much sense to be looking only during pregnancy. But that’s where most of that research has been done: stress during pregnancy and racial discrimination, and its role in birth outcomes. Very few studies have looked at experiences of racial discrimination across the life course.

My colleagues and I have published a paper where we asked African American women about their experiences of racism, and we didn’t even define what we meant. Women did not talk a lot about the experiences of racism during pregnancy from their medical providers; they talked about the lifetime experience and particularly experiences going back to childhood. And they talked about having to worry, and constant vigilance, so that even if they’re not experiencing an incident, their antennae have to be out to be prepared in case an incident does occur.

Putting all of it together with what we know about stress physiology, I would put my money on the lifetime experiences being so much more important than experiences during pregnancy. There isn’t enough known about preterm birth, but from what is known, inflammation is involved, immune dysfunction, and that’s what stress leads to. The neuroscientists have shown us that chronic stress produces inflammation and immune system dysfunction.

Q: What policies do you think are most important at this stage for reducing preterm birth for Black women?

I wish I could just say one policy or two policies, but I think it does get back to the need to dismantle racism in our society. In all of its manifestations. That’s unfortunate, not to be able to say, “Oh, here, I have this magic bullet, and if you just go with that, that will solve the problem.”

If you take the conclusions of this study seriously, you say, well, policies to just go after these downstream factors are not going to work. It’s up to the upstream investment in trying to achieve a more equitable and less racist society. Ultimately, I think that’s the take-home, and it’s a tall, tall order.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Dr. Paula Braveman, director of the Center on Social Disparities in Health at the University of California, San Francisco, says her latest research revealed an “astounding” level of evidence that racism is a decisive “upstream” cause of higher rates of preterm birth among Black women.

The tipping point for Dr. Paula Braveman came when a longtime patient of hers at a community clinic in San Francisco’s Mission District slipped past the front desk and knocked on her office door to say goodbye. He wouldn’t be coming to the clinic anymore, he told her, because he could no longer afford it.

It was a decisive moment for Dr. Braveman, who decided she wanted not only to heal ailing patients but also to advocate for policies that would help them be healthier when they arrived at her clinic. In the nearly four decades since, Dr. Braveman has dedicated herself to studying the “social determinants of health” – how the spaces where we live, work, play and learn, and the relationships we have in those places influence how healthy we are.

As director of the Center on Social Disparities in Health at the University of California, San Francisco, Dr. Braveman has studied the link between neighborhood wealth and children’s health, and how access to insurance influences prenatal care. A longtime advocate of translating research into policy, she has collaborated on major health initiatives with the health department in San Francisco, the federal Centers for Disease Control and Prevention, and the World Health Organization.

Dr. Braveman has a particular interest in maternal and infant health. Her latest research reviews what’s known about the persistent gap in preterm birth rates between Black and White women in the United States. Black women are about 1.6 times as likely as White women to give birth more than three weeks before the due date. That statistic bears alarming and costly health consequences, as infants born prematurely are at higher risk for breathing, heart, and brain abnormalities, among other complications.

Dr. Braveman coauthored the review with a group of experts convened by the March of Dimes that included geneticists, clinicians, epidemiologists, biomedical experts, and neurologists. They examined more than two dozen suspected causes of preterm births – including quality of prenatal care, environmental toxics, chronic stress, poverty and obesity – and determined that racism, directly or indirectly, best explained the racial disparities in preterm birth rates.

(Note: In the review, the authors make extensive use of the terms “upstream” and “downstream” to describe what determines people’s health. A downstream risk is the condition or factor most directly responsible for a health outcome, while an upstream factor is what causes or fuels the downstream risk – and often what needs to change to prevent someone from becoming sick. For example, a person living near drinking water polluted with toxic chemicals might get sick from drinking the water. The downstream fix would be telling individuals to use filters. The upstream solution would be to stop the dumping of toxic chemicals.)

KHN spoke with Dr. Braveman about the study and its findings. The excerpts have been edited for length and style.
 

Q: You have been studying the issue of preterm birth and racial disparities for so long. Were there any findings from this review that surprised you?

The process of systematically going through all of the risk factors that are written about in the literature and then seeing how the story of racism was an upstream determinant for virtually all of them. That was kind of astounding.

The other thing that was very impressive: When we looked at the idea that genetic factors could be the cause of the Black-White disparity in preterm birth. The genetics experts in the group, and there were three or four of them, concluded from the evidence that genetic factors might influence the disparity in preterm birth, but at most the effect would be very small, very small indeed. This could not account for the greater rate of preterm birth among Black women compared to White women.
 

Q: You were looking to identify not just what causes preterm birth but also to explain racial differences in rates of preterm birth. Are there examples of factors that can influence preterm birth that don’t explain racial disparities?

It does look like there are genetic components to preterm birth, but they don’t explain the Black-White disparity in preterm birth. Another example is having an early elective C-section. That’s one of the problems contributing to avoidable preterm birth, but it doesn’t look like that’s really contributing to the Black-White disparity in preterm birth.
 

Q: You and your colleagues listed exactly one upstream cause of preterm birth: racism. How would you characterize the certainty that racism is a decisive upstream cause of higher rates of preterm birth among Black women?

It makes me think of this saying: A randomized clinical trial wouldn’t be necessary to give certainty about the importance of having a parachute on if you jump from a plane. To me, at this point, it is close to that.

Going through that paper – and we worked on that paper over a three- or four-year period, so there was a lot of time to think about it – I don’t see how the evidence that we have could be explained otherwise.
 

Q: What did you learn about how a mother’s broader lifetime experience of racism might affect birth outcomes versus what she experienced within the medical establishment during pregnancy?

There were many ways that experiencing racial discrimination would affect a woman’s pregnancy, but one major way would be through pathways and biological mechanisms involved in stress and stress physiology. In neuroscience, what’s been clear is that a chronic stressor seems to be more damaging to health than an acute stressor.

So it doesn’t make much sense to be looking only during pregnancy. But that’s where most of that research has been done: stress during pregnancy and racial discrimination, and its role in birth outcomes. Very few studies have looked at experiences of racial discrimination across the life course.

My colleagues and I have published a paper where we asked African American women about their experiences of racism, and we didn’t even define what we meant. Women did not talk a lot about the experiences of racism during pregnancy from their medical providers; they talked about the lifetime experience and particularly experiences going back to childhood. And they talked about having to worry, and constant vigilance, so that even if they’re not experiencing an incident, their antennae have to be out to be prepared in case an incident does occur.

Putting all of it together with what we know about stress physiology, I would put my money on the lifetime experiences being so much more important than experiences during pregnancy. There isn’t enough known about preterm birth, but from what is known, inflammation is involved, immune dysfunction, and that’s what stress leads to. The neuroscientists have shown us that chronic stress produces inflammation and immune system dysfunction.

Q: What policies do you think are most important at this stage for reducing preterm birth for Black women?

I wish I could just say one policy or two policies, but I think it does get back to the need to dismantle racism in our society. In all of its manifestations. That’s unfortunate, not to be able to say, “Oh, here, I have this magic bullet, and if you just go with that, that will solve the problem.”

If you take the conclusions of this study seriously, you say, well, policies to just go after these downstream factors are not going to work. It’s up to the upstream investment in trying to achieve a more equitable and less racist society. Ultimately, I think that’s the take-home, and it’s a tall, tall order.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

For women with extremely dense breasts, screening with MRI alone every 4 years is cost effective and delivers the greatest benefit, the first study of its kind indicates.

Alternatively, if a woman worries that the 4-year screening interval is too long, screening mammography may be offered every 2 years, with MRI screening offered for the second 2-year interval, according to the findings. This strategy would still require the patient to undergo MRI breast cancer screening every 4 years.

“MRI is more effective not only for selected patients. It is actually more effective than mammography for all women,” editorialist Christiane Kuhl, MD, PhD, University of Aachen (Germany), said in an interview.

“But the superior diagnostic accuracy of MRI is more often needed for women who are at higher risk for breast cancer, and therefore the cost-effectiveness is easier to achieve in women who are at higher risk,” she added.

The study was published online Sept. 29 in the Journal of the National Cancer Institute.
 

DENSE trial

The simulation model used for the study was based on results from the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, which showed that additional MRI screening for women with extremely dense breast tissue led to significantly fewer interval cancers in comparison with mammography alone (P < .001). In the DENSE trial, MRI participants underwent mammography plus MRI at 2-year intervals; the control group underwent mammography alone at 2-year intervals.

In the current study, “screening strategies varied in the number of MRIs and mammograms offered to women aged 50-75 years,” explains Amarens Geuzinge, MSc, University Medical Center, Rotterdam, the Netherlands, and colleagues, “and incremental cost-effectiveness ratios (ICERs) were calculated ... with a willingness-to-pay threshold of 22,000 euros (>$25,000 U.S.),” the investigators add.

Analyses indicated that screening every 2 years with mammography alone cost the least of all strategies that were evaluated, but it also resulted in the lowest number of quality-adjusted life years (QALYs) – in other words, it delivered the least amount of benefit for patients, coauthor Eveline Heijnsdijk, PhD, University Medical Center, Rotterdam, the Netherlands, explained to this news organization.

Offering an additional MRI every 2 years resulted in the highest costs but not the highest number of QALYs and was inferior to the other screening strategies analyzed, she added. Alternating mammography with MRI breast cancer screening, each conducted every 2 years, came close to providing the same benefits to patients as the every-4-year MRI screening strategy, Dr. Heijnsdijk noted.

However, when the authors applied the National Institute for Health and Care Excellence (NICE) threshold, MRI screening every 4 years yielded the highest acceptable incremental cost-effectiveness ratio (ICER), at 15,620 euros per QALYs, whereas screening every 3 years with MRI alone yielded an ICER of 37,181 euros per QALY.

If decision-makers are willing to pay more than 22,000 euros per QALY gained, “MRI every 2 or 3 years can also become cost effective,” the authors add.

Asked how acceptable MRI screening might be if performed only once every 4 years, Dr. Heijnsdijk noted that, in another of their studies, most of the women who had undergone MRI screening for breast cancer said that they would do so again. “MRI is not a pleasant test, but mammography is also not a pleasant test,” she said.

“So many women prefer MRI above mammography, especially because the detection rate with MRI is better than mammography,” she noted. Dr. Heijnsdijk also said that the percentage of women with extremely dense breasts who would be candidates for MRI screening is small – no more than 10% of women.

At a unit cost of slightly under 300 euros for MRI screening – compared with about 100 euros for screening mammography in the Netherlands – the cost of offering 10% of women MRI instead of mammography might increase, but any additional screening costs could be offset by reductions in the need to treat late-stage breast cancer more aggressively.
 

‘Interval’ cancers

Commenting further on the study, Dr. Kuhl pointed out that from 25% to 45% of cancers that occur in women who have undergone screening mammography are diagnosed as “interval” cancers, even among women who participate in the best mammography programs. “For a long time, people argued that these interval cancers developed only after the last respective mammogram, but that’s not true at all, because we know that with MRI screening, we can reduce the interval cancer rate down to zero,” Dr. Kuhl emphasized.

This is partially explained by the fact that mammography is “particularly blind” when it comes to detecting rapidly growing tumors. “The fact is that mammography has a modality-inherent tendency to preferentially detect slow-growing cancers, whereas rapidly growing tumors are indistinguishable from ubiquitous benign changes like cysts. [This] is why women who undergo screening mammography are frequently not diagnosed with the cancers that we really need to find,” she said.

Although there is ample talk about overdiagnosis when it comes to screening mammography, the overwhelmingly important problem is underdiagnosis. Even in exemplary mammography screening programs, at least 20% of tumors that are diagnosed on mammography have already advanced to a stage that is too late, Dr. Kuhl noted.

This means that at least half of women do not benefit from screening mammography nearly to the extent that they – and their health care practitioners – believe they should, she added. Dr. Kuhl underscored that this does not mean that clinicians should abandon screening mammography.

What it does mean is that physicians need to abandon the one-size-fits-all approach to screening mammography and start stratifying women on the basis of their individual risk of developing breast cancer by taking a family or personal history. Most women do undergo screening mammography at least once, Dr. Kuhl pointed out. From that mammogram, physicians can use information on breast density and breast architecture to better determine individual risk.

“We have good ideas about how to achieve risk stratification, but we’re not using them, because as long as mammography is the answer for everybody, there isn’t much motivation to dig deeper into the issue of how to determine risk,” Dr. Kuhl said.

“But we have to ensure the early diagnosis of aggressive cancers, and it’s exactly MRI that can do this, and we should start with women with very dense breasts because they are doubly underserved by mammography,” she said.

The study was supported by the University Medical Center Utrecht, Bayer HealthCare Medical Care, Matakina, and others. Ms. Geuzinge, Dr. Heijnsdijk, and Dr. Kuhl have disclosed no relevant financial relationships.

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

For women with extremely dense breasts, screening with MRI alone every 4 years is cost effective and delivers the greatest benefit, the first study of its kind indicates.

Alternatively, if a woman worries that the 4-year screening interval is too long, screening mammography may be offered every 2 years, with MRI screening offered for the second 2-year interval, according to the findings. This strategy would still require the patient to undergo MRI breast cancer screening every 4 years.

“MRI is more effective not only for selected patients. It is actually more effective than mammography for all women,” editorialist Christiane Kuhl, MD, PhD, University of Aachen (Germany), said in an interview.

“But the superior diagnostic accuracy of MRI is more often needed for women who are at higher risk for breast cancer, and therefore the cost-effectiveness is easier to achieve in women who are at higher risk,” she added.

The study was published online Sept. 29 in the Journal of the National Cancer Institute.
 

DENSE trial

The simulation model used for the study was based on results from the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, which showed that additional MRI screening for women with extremely dense breast tissue led to significantly fewer interval cancers in comparison with mammography alone (P < .001). In the DENSE trial, MRI participants underwent mammography plus MRI at 2-year intervals; the control group underwent mammography alone at 2-year intervals.

In the current study, “screening strategies varied in the number of MRIs and mammograms offered to women aged 50-75 years,” explains Amarens Geuzinge, MSc, University Medical Center, Rotterdam, the Netherlands, and colleagues, “and incremental cost-effectiveness ratios (ICERs) were calculated ... with a willingness-to-pay threshold of 22,000 euros (>$25,000 U.S.),” the investigators add.

Analyses indicated that screening every 2 years with mammography alone cost the least of all strategies that were evaluated, but it also resulted in the lowest number of quality-adjusted life years (QALYs) – in other words, it delivered the least amount of benefit for patients, coauthor Eveline Heijnsdijk, PhD, University Medical Center, Rotterdam, the Netherlands, explained to this news organization.

Offering an additional MRI every 2 years resulted in the highest costs but not the highest number of QALYs and was inferior to the other screening strategies analyzed, she added. Alternating mammography with MRI breast cancer screening, each conducted every 2 years, came close to providing the same benefits to patients as the every-4-year MRI screening strategy, Dr. Heijnsdijk noted.

However, when the authors applied the National Institute for Health and Care Excellence (NICE) threshold, MRI screening every 4 years yielded the highest acceptable incremental cost-effectiveness ratio (ICER), at 15,620 euros per QALYs, whereas screening every 3 years with MRI alone yielded an ICER of 37,181 euros per QALY.

If decision-makers are willing to pay more than 22,000 euros per QALY gained, “MRI every 2 or 3 years can also become cost effective,” the authors add.

Asked how acceptable MRI screening might be if performed only once every 4 years, Dr. Heijnsdijk noted that, in another of their studies, most of the women who had undergone MRI screening for breast cancer said that they would do so again. “MRI is not a pleasant test, but mammography is also not a pleasant test,” she said.

“So many women prefer MRI above mammography, especially because the detection rate with MRI is better than mammography,” she noted. Dr. Heijnsdijk also said that the percentage of women with extremely dense breasts who would be candidates for MRI screening is small – no more than 10% of women.

At a unit cost of slightly under 300 euros for MRI screening – compared with about 100 euros for screening mammography in the Netherlands – the cost of offering 10% of women MRI instead of mammography might increase, but any additional screening costs could be offset by reductions in the need to treat late-stage breast cancer more aggressively.
 

‘Interval’ cancers

Commenting further on the study, Dr. Kuhl pointed out that from 25% to 45% of cancers that occur in women who have undergone screening mammography are diagnosed as “interval” cancers, even among women who participate in the best mammography programs. “For a long time, people argued that these interval cancers developed only after the last respective mammogram, but that’s not true at all, because we know that with MRI screening, we can reduce the interval cancer rate down to zero,” Dr. Kuhl emphasized.

This is partially explained by the fact that mammography is “particularly blind” when it comes to detecting rapidly growing tumors. “The fact is that mammography has a modality-inherent tendency to preferentially detect slow-growing cancers, whereas rapidly growing tumors are indistinguishable from ubiquitous benign changes like cysts. [This] is why women who undergo screening mammography are frequently not diagnosed with the cancers that we really need to find,” she said.

Although there is ample talk about overdiagnosis when it comes to screening mammography, the overwhelmingly important problem is underdiagnosis. Even in exemplary mammography screening programs, at least 20% of tumors that are diagnosed on mammography have already advanced to a stage that is too late, Dr. Kuhl noted.

This means that at least half of women do not benefit from screening mammography nearly to the extent that they – and their health care practitioners – believe they should, she added. Dr. Kuhl underscored that this does not mean that clinicians should abandon screening mammography.

What it does mean is that physicians need to abandon the one-size-fits-all approach to screening mammography and start stratifying women on the basis of their individual risk of developing breast cancer by taking a family or personal history. Most women do undergo screening mammography at least once, Dr. Kuhl pointed out. From that mammogram, physicians can use information on breast density and breast architecture to better determine individual risk.

“We have good ideas about how to achieve risk stratification, but we’re not using them, because as long as mammography is the answer for everybody, there isn’t much motivation to dig deeper into the issue of how to determine risk,” Dr. Kuhl said.

“But we have to ensure the early diagnosis of aggressive cancers, and it’s exactly MRI that can do this, and we should start with women with very dense breasts because they are doubly underserved by mammography,” she said.

The study was supported by the University Medical Center Utrecht, Bayer HealthCare Medical Care, Matakina, and others. Ms. Geuzinge, Dr. Heijnsdijk, and Dr. Kuhl have disclosed no relevant financial relationships.

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

For women with extremely dense breasts, screening with MRI alone every 4 years is cost effective and delivers the greatest benefit, the first study of its kind indicates.

Alternatively, if a woman worries that the 4-year screening interval is too long, screening mammography may be offered every 2 years, with MRI screening offered for the second 2-year interval, according to the findings. This strategy would still require the patient to undergo MRI breast cancer screening every 4 years.

“MRI is more effective not only for selected patients. It is actually more effective than mammography for all women,” editorialist Christiane Kuhl, MD, PhD, University of Aachen (Germany), said in an interview.

“But the superior diagnostic accuracy of MRI is more often needed for women who are at higher risk for breast cancer, and therefore the cost-effectiveness is easier to achieve in women who are at higher risk,” she added.

The study was published online Sept. 29 in the Journal of the National Cancer Institute.
 

DENSE trial

The simulation model used for the study was based on results from the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, which showed that additional MRI screening for women with extremely dense breast tissue led to significantly fewer interval cancers in comparison with mammography alone (P < .001). In the DENSE trial, MRI participants underwent mammography plus MRI at 2-year intervals; the control group underwent mammography alone at 2-year intervals.

In the current study, “screening strategies varied in the number of MRIs and mammograms offered to women aged 50-75 years,” explains Amarens Geuzinge, MSc, University Medical Center, Rotterdam, the Netherlands, and colleagues, “and incremental cost-effectiveness ratios (ICERs) were calculated ... with a willingness-to-pay threshold of 22,000 euros (>$25,000 U.S.),” the investigators add.

Analyses indicated that screening every 2 years with mammography alone cost the least of all strategies that were evaluated, but it also resulted in the lowest number of quality-adjusted life years (QALYs) – in other words, it delivered the least amount of benefit for patients, coauthor Eveline Heijnsdijk, PhD, University Medical Center, Rotterdam, the Netherlands, explained to this news organization.

Offering an additional MRI every 2 years resulted in the highest costs but not the highest number of QALYs and was inferior to the other screening strategies analyzed, she added. Alternating mammography with MRI breast cancer screening, each conducted every 2 years, came close to providing the same benefits to patients as the every-4-year MRI screening strategy, Dr. Heijnsdijk noted.

However, when the authors applied the National Institute for Health and Care Excellence (NICE) threshold, MRI screening every 4 years yielded the highest acceptable incremental cost-effectiveness ratio (ICER), at 15,620 euros per QALYs, whereas screening every 3 years with MRI alone yielded an ICER of 37,181 euros per QALY.

If decision-makers are willing to pay more than 22,000 euros per QALY gained, “MRI every 2 or 3 years can also become cost effective,” the authors add.

Asked how acceptable MRI screening might be if performed only once every 4 years, Dr. Heijnsdijk noted that, in another of their studies, most of the women who had undergone MRI screening for breast cancer said that they would do so again. “MRI is not a pleasant test, but mammography is also not a pleasant test,” she said.

“So many women prefer MRI above mammography, especially because the detection rate with MRI is better than mammography,” she noted. Dr. Heijnsdijk also said that the percentage of women with extremely dense breasts who would be candidates for MRI screening is small – no more than 10% of women.

At a unit cost of slightly under 300 euros for MRI screening – compared with about 100 euros for screening mammography in the Netherlands – the cost of offering 10% of women MRI instead of mammography might increase, but any additional screening costs could be offset by reductions in the need to treat late-stage breast cancer more aggressively.
 

‘Interval’ cancers

Commenting further on the study, Dr. Kuhl pointed out that from 25% to 45% of cancers that occur in women who have undergone screening mammography are diagnosed as “interval” cancers, even among women who participate in the best mammography programs. “For a long time, people argued that these interval cancers developed only after the last respective mammogram, but that’s not true at all, because we know that with MRI screening, we can reduce the interval cancer rate down to zero,” Dr. Kuhl emphasized.

This is partially explained by the fact that mammography is “particularly blind” when it comes to detecting rapidly growing tumors. “The fact is that mammography has a modality-inherent tendency to preferentially detect slow-growing cancers, whereas rapidly growing tumors are indistinguishable from ubiquitous benign changes like cysts. [This] is why women who undergo screening mammography are frequently not diagnosed with the cancers that we really need to find,” she said.

Although there is ample talk about overdiagnosis when it comes to screening mammography, the overwhelmingly important problem is underdiagnosis. Even in exemplary mammography screening programs, at least 20% of tumors that are diagnosed on mammography have already advanced to a stage that is too late, Dr. Kuhl noted.

This means that at least half of women do not benefit from screening mammography nearly to the extent that they – and their health care practitioners – believe they should, she added. Dr. Kuhl underscored that this does not mean that clinicians should abandon screening mammography.

What it does mean is that physicians need to abandon the one-size-fits-all approach to screening mammography and start stratifying women on the basis of their individual risk of developing breast cancer by taking a family or personal history. Most women do undergo screening mammography at least once, Dr. Kuhl pointed out. From that mammogram, physicians can use information on breast density and breast architecture to better determine individual risk.

“We have good ideas about how to achieve risk stratification, but we’re not using them, because as long as mammography is the answer for everybody, there isn’t much motivation to dig deeper into the issue of how to determine risk,” Dr. Kuhl said.

“But we have to ensure the early diagnosis of aggressive cancers, and it’s exactly MRI that can do this, and we should start with women with very dense breasts because they are doubly underserved by mammography,” she said.

The study was supported by the University Medical Center Utrecht, Bayer HealthCare Medical Care, Matakina, and others. Ms. Geuzinge, Dr. Heijnsdijk, and Dr. Kuhl have disclosed no relevant financial relationships.

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

A phase 3, randomized, double-blind, controlled trial has shown that oteseconazole (Mycovia Pharmaceuticals), an oral antifungal agent, is safe and effective in treating acute and recurrent yeast infections (vulvovaginal candidiasis [VVC]) and in preventing  recurrence of acute VVC episodes.

Findings of the ultraVIOLET trial, which compared oteseconazole with the standard fluconazole, were presented at IDWeek 2021, an annual scientific meeting on infectious diseases, by lead author Mark G. Martens, MD, a professor in the department of obstetrics and gynecology at Drexel University College of Medicine in Philadelphia.

About 75% of all women will have a yeast infection in their lifetime, Dr. Martens noted. About 138 million women worldwide have recurring episodes (at least three acute episodes in the last year) of the debilitating condition.

“Recurrent vulvovaginal candidiasis typically requires treatment of the acute episode followed by long-term suppressive therapy with either weekly or biweekly fluconazole,” Dr. Martens said. However, when therapy stops, more than 50% of patients with recurrent VVC experience an infection within the next 6 months, which takes a significant toll on daily life.

Additionally, fluconazole has been linked with safety issues concerning chronic dosing, he said, citing liver toxicity, drug-drug interactions and “increased risk of miscarriage and birth defects when used during pregnancy.”

Topical treatments have been associated with messy application and burning, he noted.

For this study, researchers enrolled 219 women with a history of recurrent VVC at 51 U.S. sites. Participants were randomized either to 600 mg oteseconazole on day 1, 450 mg oteseconazole on day 2 or placebo capsules; or three sequential 150 mg doses (every 72 hours) of fluconazole together with matching placebo capsules.

In the maintenance phase, 185 women with resolved acute VVC (clinical signs and symptoms were scored below 3) on day 14 received 150 mg oteseconazole or placebo weekly for 11 weeks.

Oteseconazole was superior to fluconazole/placebo in the proportion of subjects with at least one culture-verified acute VVC episode through week 50 in the intent-to-treat population (P < .001) which included subjects who failed to clear their infection in the induction phase.

The average percentage of participants with at least one culture-verified acute VVC episode through week 50 was lower in the oteseconazole group (5.1%), compared with the fluconazole/placebo group (42.2%).

Oteseconazole was noninferior to fluconazole in the proportion of subjects with resolved acute VVC infections at day 14 – 93.2% for the oteseconazole group vs. 95.8% for the fluconazole/placebo group.

The percentages of women who had at least one treatment-emergent adverse event (TEAE) were similar – 54% in the oteseconazole group and 64% in the fluconazole/placebo group.  Most TEAEs were mild or moderate and there were no drug-related SAEs or adverse effects on liver function.

“There was no difference in the two groups in he baseline characteristics of age, race, and history of diabetes,” he said.

Oluwatosin Goje, MD, an ob.gyn. with the Cleveland Clinic told this news organization that the drug may offer another option for women who don’t respond to azoles.

“The CDC guidelines say, and I agree, that most episodes of recurrent VVC that are caused by Candida albicans will respond to topical azoles, to oral azoles, to the known drugs that are available. You just may have to use them for a prolonged period of time,” Dr. Goje said. But some patients won’t respond to azoles, the currently available drugs, and topical treatments – so new options are welcome for them, she noted.

She pointed out that the U.S. Food and Drug Administration in June approved ibrexafungerp (Brexafemme), the first oral nonazole treatment for vaginal yeast infections. It was the first approved medicine in a novel antifungal class in more than 2 decades.

Dr. Goje, who runs a large clinic with substantial numbers of women with recurrent yeast infections, said the psychosocial problems women with recurrent yeast infections face – and the time off work and money spent trying to get temporary relief from over-the-counter medications – is underestimated.

“Women have long suffered vaginitis. It can be a lot of social and economic burden. So anything in the toolbox to help women is welcome,” Dr. Goje said.

The study was sponsored by Mycovia Pharmaceuticals. Dr. Martens reports no relevant financial relationships. Several coauthors are either employees of Mycovia or receive support from the company. Dr. Goje has disclosed no relevant financial relationships.

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

A phase 3, randomized, double-blind, controlled trial has shown that oteseconazole (Mycovia Pharmaceuticals), an oral antifungal agent, is safe and effective in treating acute and recurrent yeast infections (vulvovaginal candidiasis [VVC]) and in preventing  recurrence of acute VVC episodes.

Findings of the ultraVIOLET trial, which compared oteseconazole with the standard fluconazole, were presented at IDWeek 2021, an annual scientific meeting on infectious diseases, by lead author Mark G. Martens, MD, a professor in the department of obstetrics and gynecology at Drexel University College of Medicine in Philadelphia.

About 75% of all women will have a yeast infection in their lifetime, Dr. Martens noted. About 138 million women worldwide have recurring episodes (at least three acute episodes in the last year) of the debilitating condition.

“Recurrent vulvovaginal candidiasis typically requires treatment of the acute episode followed by long-term suppressive therapy with either weekly or biweekly fluconazole,” Dr. Martens said. However, when therapy stops, more than 50% of patients with recurrent VVC experience an infection within the next 6 months, which takes a significant toll on daily life.

Additionally, fluconazole has been linked with safety issues concerning chronic dosing, he said, citing liver toxicity, drug-drug interactions and “increased risk of miscarriage and birth defects when used during pregnancy.”

Topical treatments have been associated with messy application and burning, he noted.

For this study, researchers enrolled 219 women with a history of recurrent VVC at 51 U.S. sites. Participants were randomized either to 600 mg oteseconazole on day 1, 450 mg oteseconazole on day 2 or placebo capsules; or three sequential 150 mg doses (every 72 hours) of fluconazole together with matching placebo capsules.

In the maintenance phase, 185 women with resolved acute VVC (clinical signs and symptoms were scored below 3) on day 14 received 150 mg oteseconazole or placebo weekly for 11 weeks.

Oteseconazole was superior to fluconazole/placebo in the proportion of subjects with at least one culture-verified acute VVC episode through week 50 in the intent-to-treat population (P < .001) which included subjects who failed to clear their infection in the induction phase.

The average percentage of participants with at least one culture-verified acute VVC episode through week 50 was lower in the oteseconazole group (5.1%), compared with the fluconazole/placebo group (42.2%).

Oteseconazole was noninferior to fluconazole in the proportion of subjects with resolved acute VVC infections at day 14 – 93.2% for the oteseconazole group vs. 95.8% for the fluconazole/placebo group.

The percentages of women who had at least one treatment-emergent adverse event (TEAE) were similar – 54% in the oteseconazole group and 64% in the fluconazole/placebo group.  Most TEAEs were mild or moderate and there were no drug-related SAEs or adverse effects on liver function.

“There was no difference in the two groups in he baseline characteristics of age, race, and history of diabetes,” he said.

Oluwatosin Goje, MD, an ob.gyn. with the Cleveland Clinic told this news organization that the drug may offer another option for women who don’t respond to azoles.

“The CDC guidelines say, and I agree, that most episodes of recurrent VVC that are caused by Candida albicans will respond to topical azoles, to oral azoles, to the known drugs that are available. You just may have to use them for a prolonged period of time,” Dr. Goje said. But some patients won’t respond to azoles, the currently available drugs, and topical treatments – so new options are welcome for them, she noted.

She pointed out that the U.S. Food and Drug Administration in June approved ibrexafungerp (Brexafemme), the first oral nonazole treatment for vaginal yeast infections. It was the first approved medicine in a novel antifungal class in more than 2 decades.

Dr. Goje, who runs a large clinic with substantial numbers of women with recurrent yeast infections, said the psychosocial problems women with recurrent yeast infections face – and the time off work and money spent trying to get temporary relief from over-the-counter medications – is underestimated.

“Women have long suffered vaginitis. It can be a lot of social and economic burden. So anything in the toolbox to help women is welcome,” Dr. Goje said.

The study was sponsored by Mycovia Pharmaceuticals. Dr. Martens reports no relevant financial relationships. Several coauthors are either employees of Mycovia or receive support from the company. Dr. Goje has disclosed no relevant financial relationships.

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

A phase 3, randomized, double-blind, controlled trial has shown that oteseconazole (Mycovia Pharmaceuticals), an oral antifungal agent, is safe and effective in treating acute and recurrent yeast infections (vulvovaginal candidiasis [VVC]) and in preventing  recurrence of acute VVC episodes.

Findings of the ultraVIOLET trial, which compared oteseconazole with the standard fluconazole, were presented at IDWeek 2021, an annual scientific meeting on infectious diseases, by lead author Mark G. Martens, MD, a professor in the department of obstetrics and gynecology at Drexel University College of Medicine in Philadelphia.

About 75% of all women will have a yeast infection in their lifetime, Dr. Martens noted. About 138 million women worldwide have recurring episodes (at least three acute episodes in the last year) of the debilitating condition.

“Recurrent vulvovaginal candidiasis typically requires treatment of the acute episode followed by long-term suppressive therapy with either weekly or biweekly fluconazole,” Dr. Martens said. However, when therapy stops, more than 50% of patients with recurrent VVC experience an infection within the next 6 months, which takes a significant toll on daily life.

Additionally, fluconazole has been linked with safety issues concerning chronic dosing, he said, citing liver toxicity, drug-drug interactions and “increased risk of miscarriage and birth defects when used during pregnancy.”

Topical treatments have been associated with messy application and burning, he noted.

For this study, researchers enrolled 219 women with a history of recurrent VVC at 51 U.S. sites. Participants were randomized either to 600 mg oteseconazole on day 1, 450 mg oteseconazole on day 2 or placebo capsules; or three sequential 150 mg doses (every 72 hours) of fluconazole together with matching placebo capsules.

In the maintenance phase, 185 women with resolved acute VVC (clinical signs and symptoms were scored below 3) on day 14 received 150 mg oteseconazole or placebo weekly for 11 weeks.

Oteseconazole was superior to fluconazole/placebo in the proportion of subjects with at least one culture-verified acute VVC episode through week 50 in the intent-to-treat population (P < .001) which included subjects who failed to clear their infection in the induction phase.

The average percentage of participants with at least one culture-verified acute VVC episode through week 50 was lower in the oteseconazole group (5.1%), compared with the fluconazole/placebo group (42.2%).

Oteseconazole was noninferior to fluconazole in the proportion of subjects with resolved acute VVC infections at day 14 – 93.2% for the oteseconazole group vs. 95.8% for the fluconazole/placebo group.

The percentages of women who had at least one treatment-emergent adverse event (TEAE) were similar – 54% in the oteseconazole group and 64% in the fluconazole/placebo group.  Most TEAEs were mild or moderate and there were no drug-related SAEs or adverse effects on liver function.

“There was no difference in the two groups in he baseline characteristics of age, race, and history of diabetes,” he said.

Oluwatosin Goje, MD, an ob.gyn. with the Cleveland Clinic told this news organization that the drug may offer another option for women who don’t respond to azoles.

“The CDC guidelines say, and I agree, that most episodes of recurrent VVC that are caused by Candida albicans will respond to topical azoles, to oral azoles, to the known drugs that are available. You just may have to use them for a prolonged period of time,” Dr. Goje said. But some patients won’t respond to azoles, the currently available drugs, and topical treatments – so new options are welcome for them, she noted.

She pointed out that the U.S. Food and Drug Administration in June approved ibrexafungerp (Brexafemme), the first oral nonazole treatment for vaginal yeast infections. It was the first approved medicine in a novel antifungal class in more than 2 decades.

Dr. Goje, who runs a large clinic with substantial numbers of women with recurrent yeast infections, said the psychosocial problems women with recurrent yeast infections face – and the time off work and money spent trying to get temporary relief from over-the-counter medications – is underestimated.

“Women have long suffered vaginitis. It can be a lot of social and economic burden. So anything in the toolbox to help women is welcome,” Dr. Goje said.

The study was sponsored by Mycovia Pharmaceuticals. Dr. Martens reports no relevant financial relationships. Several coauthors are either employees of Mycovia or receive support from the company. Dr. Goje has disclosed no relevant financial relationships.

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

Judy C. Washington, MD, a mentor of many young academic family physicians, particularly underrepresented-in-medicine (URM) physicians, advises her mentees on how to see ahead and plot paths to leadership.

Courtesy Dr. Judy C. Washington

For URM physicians, she also imparts a shared experience of being a minority in the field and helps prepare them for the challenges of facing racism or feeling marginalized or not equitably supported in academic life – and for making change.

While family medicine’s demographics have become more diverse over time, and more so than other specialties, they are not yet representative of the U.S. population. Within academia, male physicians who are Black or African American, or Hispanic or Latino, comprised about 4% and 5% of family medicine faculty, respectively, at the end of 2019, according to data from the Association of American Medical Colleges. For women, these numbers were about 9% and 4%, respectively. (Only those with an MD degree exclusively were included in the report.)

“When you have the privilege to serve in leadership, you have the responsibility to reach back and identify and help others who would not otherwise have the opportunity to be recognized,” Dr. Washington said.

Her mentorship work stems in large part from her long-time involvement and leadership roles in the Society of Teachers of Family Medicine (STFM) – roles she considers a pillar of her professional life. She currently serves as president of the STFM Foundation and is associate chief medical officer of the Atlantic Medical Group, a large multisite physician-led organization. She is also coordinator of women’s health for the Overlook Family Medicine Residency Program, which is affiliated with Atlantic Medical Group.

In Dr. Washington’s role as associate chief medical officer of Atlantic Medical Group in Summit, N.J., she focuses on physician engagement, satisfaction, and diversity. She also assists in areas such as population health. For the Overlook Family Medicine Residency Program also in Summit, she precepts residents in the obstetrics clinic and in the family medicine outpatient clinic.

Diana N. Carvajal, MD, MPH, one of Dr. Washington’s mentees, called her an “inspirational leader” for young academic faculty and said she is a familiar speaker at STFM meetings on topics of workforce diversity, equity, and leadership. She is “passionate” about mentorship, Dr. Carvajal said, and has understood “that URMs and women of color were not always getting [the mentorship they need to be successful].”
 

Guiding future leaders

Ivonne McLean, MD, assistant professor of family and community medicine at Icahn School of Medicine at Mount Sinai, New York, and an attending at a community health center in the Bronx, called Dr. Washington for advice a couple of years ago when she was considering her next career move.

Courtesy Society of Teachers of Family Medicine Foundation

“She took a genuine interest in me. She never said, this is what you should do. But the questions she asked and the examples she gave from her own life were incredibly helpful to me [in deciding to pursue a research fellowship] ... it was a pivotal conversation,” said Dr. McLean, associate director of a reproductive health fellowship and a research fellow in a New York State–funded program.

“From a lived experience angle, she also told me, here are some of the challenges you’ll have as a woman of color, and here are some of the ways you can approach that,” she said.

Dr. Carvajal, also a URM family physician, credits Dr. Washington’s mentorship with the development of a day-long workshop – held before the annual Society of Teachers of Family Medicine (STFM) meeting – on the low and declining rates of Black males in medicine. “We’d planned it as a presentation, and [she heard of it and] helped us expand it,” she said, calling Dr. Washington “warm, welcoming, and encouraging.

“That work and collaboration with her and the others she brought [into the process] have resulted in publications and more presentations and strategy building for diversifying the workforce,” said Dr. Carvajal, assistant professor, director of reproductive health education in family medicine, and codirector of the research section, all in the department of family and community medicine at the University of Maryland, Baltimore.

STFM involvement

Dr. Washington, who says that all or almost all of her mentees are now leaders in their academic institutions and communities, has been instrumental in developing STFM’s mentoring programming and in facilitating the organization’s multifaceted URM Initiative.

She has been active in STFM since the start of her academic career, and in 2009, while serving as assistant program director for the residency program in which she’d trained, she joined two other African American women, Monique Y. Davis-Smith, MD, and Joedrecka Brown-Speights, MD, in cochairing the society’s Group on Minority and Multicultural Health.

It was in this space, that Dr. Washington said she “heard people’s stories of being in major academic institutions and not feeling supported, not being given roadmaps to success, not getting assistance with publishing, or just kind of feeling like an outsider ... of not being pulled in.” Hispanic and African American females, in particular, “were feeling marginalized,” she said.

In 2018, having co-led development of the STFM Quality Mentoring Program for URM faculty, Dr. Washington was asked to join the STFM Foundation and subsequently led the STFM Foundation’s fundraising campaign for a new URM Initiative. She exceeded her goal, increasing support for URM participation in meetings and activities, and then participated in an STFM steering committee to create broader and longer-lasting support for URM faculty, community teachers, and medical students and residents going into academic family medicine.

Increasing the percentage of URM family medicine faculty in leadership positions – and raising awareness of structural barriers to achievement – is one of the current pillars of the URM Initiative.
 

Navigating the ‘minority tax’

As part of her mentoring, Dr. Washington helps URM physicians navigate the minority tax – a term referring to the uncompensated citizenship tasks that are more often assigned to Black and other URM physicians than to White physicians, and that take time away from scholarship, further perpetuating inequities.

Courtesy Society of Teahcers of Family Medicine Foundation

“Some of our young faculty members find themselves thrust into being the diversity and inclusion leaders in their institutions at a level at which they feel little power and little buy-in from [leadership],” she noted.

A commentary written by Dr. Washington and several colleagues on the minority tax as it impacts women – and the need to build a “tax shelter” to make academic medicine a more just environment for URM women – was published earlier this year in the Journal of Women’s Health.

She also answers e-mails and fields phone calls from young URM faculty who are mulling career moves and facing other familiar challenges.

Physicians who are URM, and African American physicians in particular, tend to “get pulled into the [often underserved] communities, into the patient care and community service areas,” Dr. Washington explained. “But unless you convert these projects into scholarship and publications, and unless you serve on a national committee outside of your institution, you’re not going to be promoted.”

Dr. Washington helps junior faculty envision themselves 5-plus years down the road, find what she calls scholarly “passion projects,” and prepare themselves for their next steps.

She helps her mentees navigate other parts of the continuum of unconscious bias and racism as well, from microaggressions from colleagues to overt discrimination from patients.

“I spend countless minutes fielding texts and phone calls from those who need support,” she wrote in a blog post. “They are a constant reminder that I must continue to speak up when I get the opportunity to do so.”
 

A journey through family medicine, and through bias and racism

Dr. Washington’s early days in medicine included graduating from Meharry Medical College in 1983 and the Mountainside Family Practice Residency Program in 1990. Following 6 years of working in a private practice in rural Maryland, she moved to academia, spending 6 years at East Tennessee State University and 4 years at the UMDNJ–New Jersey Medical School in Newark as an assistant professor of family medicine.

As had happened in rural Maryland, bias and racism have too often lurked during her career as a physician.

“I grew up in Alabama so I was pretty much ready to deal with racism in the South,” Dr. Washington said. “What I was not ready for was coming to the Northeast and seeing that you’re marginalized because you’re not invited into the room. Or if you do go into spaces when you’re the only one, you often don’t feel as welcomed as you thought you might be.”

Her ideas and contributions were too often dismissed, she wrote in a 2020 blog entry posted on her LinkedIn page. And during contract negotiations, “I was not aware of all the information that my White colleagues had. They had the advantage of inside information.”

Dr. Washington says that “it took a village” to make her who she is today: teachers in her segregated schools in Alabama, one of her college professors, her best friend in medical school – and STFM, “where the list [of her own mentors] is long.”

Judy C. Washington, MD, a mentor of many young academic family physicians, particularly underrepresented-in-medicine (URM) physicians, advises her mentees on how to see ahead and plot paths to leadership.

Courtesy Dr. Judy C. Washington

For URM physicians, she also imparts a shared experience of being a minority in the field and helps prepare them for the challenges of facing racism or feeling marginalized or not equitably supported in academic life – and for making change.

While family medicine’s demographics have become more diverse over time, and more so than other specialties, they are not yet representative of the U.S. population. Within academia, male physicians who are Black or African American, or Hispanic or Latino, comprised about 4% and 5% of family medicine faculty, respectively, at the end of 2019, according to data from the Association of American Medical Colleges. For women, these numbers were about 9% and 4%, respectively. (Only those with an MD degree exclusively were included in the report.)

“When you have the privilege to serve in leadership, you have the responsibility to reach back and identify and help others who would not otherwise have the opportunity to be recognized,” Dr. Washington said.

Her mentorship work stems in large part from her long-time involvement and leadership roles in the Society of Teachers of Family Medicine (STFM) – roles she considers a pillar of her professional life. She currently serves as president of the STFM Foundation and is associate chief medical officer of the Atlantic Medical Group, a large multisite physician-led organization. She is also coordinator of women’s health for the Overlook Family Medicine Residency Program, which is affiliated with Atlantic Medical Group.

In Dr. Washington’s role as associate chief medical officer of Atlantic Medical Group in Summit, N.J., she focuses on physician engagement, satisfaction, and diversity. She also assists in areas such as population health. For the Overlook Family Medicine Residency Program also in Summit, she precepts residents in the obstetrics clinic and in the family medicine outpatient clinic.

Diana N. Carvajal, MD, MPH, one of Dr. Washington’s mentees, called her an “inspirational leader” for young academic faculty and said she is a familiar speaker at STFM meetings on topics of workforce diversity, equity, and leadership. She is “passionate” about mentorship, Dr. Carvajal said, and has understood “that URMs and women of color were not always getting [the mentorship they need to be successful].”
 

Guiding future leaders

Ivonne McLean, MD, assistant professor of family and community medicine at Icahn School of Medicine at Mount Sinai, New York, and an attending at a community health center in the Bronx, called Dr. Washington for advice a couple of years ago when she was considering her next career move.

Courtesy Society of Teachers of Family Medicine Foundation

“She took a genuine interest in me. She never said, this is what you should do. But the questions she asked and the examples she gave from her own life were incredibly helpful to me [in deciding to pursue a research fellowship] ... it was a pivotal conversation,” said Dr. McLean, associate director of a reproductive health fellowship and a research fellow in a New York State–funded program.

“From a lived experience angle, she also told me, here are some of the challenges you’ll have as a woman of color, and here are some of the ways you can approach that,” she said.

Dr. Carvajal, also a URM family physician, credits Dr. Washington’s mentorship with the development of a day-long workshop – held before the annual Society of Teachers of Family Medicine (STFM) meeting – on the low and declining rates of Black males in medicine. “We’d planned it as a presentation, and [she heard of it and] helped us expand it,” she said, calling Dr. Washington “warm, welcoming, and encouraging.

“That work and collaboration with her and the others she brought [into the process] have resulted in publications and more presentations and strategy building for diversifying the workforce,” said Dr. Carvajal, assistant professor, director of reproductive health education in family medicine, and codirector of the research section, all in the department of family and community medicine at the University of Maryland, Baltimore.

STFM involvement

Dr. Washington, who says that all or almost all of her mentees are now leaders in their academic institutions and communities, has been instrumental in developing STFM’s mentoring programming and in facilitating the organization’s multifaceted URM Initiative.

She has been active in STFM since the start of her academic career, and in 2009, while serving as assistant program director for the residency program in which she’d trained, she joined two other African American women, Monique Y. Davis-Smith, MD, and Joedrecka Brown-Speights, MD, in cochairing the society’s Group on Minority and Multicultural Health.

It was in this space, that Dr. Washington said she “heard people’s stories of being in major academic institutions and not feeling supported, not being given roadmaps to success, not getting assistance with publishing, or just kind of feeling like an outsider ... of not being pulled in.” Hispanic and African American females, in particular, “were feeling marginalized,” she said.

In 2018, having co-led development of the STFM Quality Mentoring Program for URM faculty, Dr. Washington was asked to join the STFM Foundation and subsequently led the STFM Foundation’s fundraising campaign for a new URM Initiative. She exceeded her goal, increasing support for URM participation in meetings and activities, and then participated in an STFM steering committee to create broader and longer-lasting support for URM faculty, community teachers, and medical students and residents going into academic family medicine.

Increasing the percentage of URM family medicine faculty in leadership positions – and raising awareness of structural barriers to achievement – is one of the current pillars of the URM Initiative.
 

Navigating the ‘minority tax’

As part of her mentoring, Dr. Washington helps URM physicians navigate the minority tax – a term referring to the uncompensated citizenship tasks that are more often assigned to Black and other URM physicians than to White physicians, and that take time away from scholarship, further perpetuating inequities.

Courtesy Society of Teahcers of Family Medicine Foundation

“Some of our young faculty members find themselves thrust into being the diversity and inclusion leaders in their institutions at a level at which they feel little power and little buy-in from [leadership],” she noted.

A commentary written by Dr. Washington and several colleagues on the minority tax as it impacts women – and the need to build a “tax shelter” to make academic medicine a more just environment for URM women – was published earlier this year in the Journal of Women’s Health.

She also answers e-mails and fields phone calls from young URM faculty who are mulling career moves and facing other familiar challenges.

Physicians who are URM, and African American physicians in particular, tend to “get pulled into the [often underserved] communities, into the patient care and community service areas,” Dr. Washington explained. “But unless you convert these projects into scholarship and publications, and unless you serve on a national committee outside of your institution, you’re not going to be promoted.”

Dr. Washington helps junior faculty envision themselves 5-plus years down the road, find what she calls scholarly “passion projects,” and prepare themselves for their next steps.

She helps her mentees navigate other parts of the continuum of unconscious bias and racism as well, from microaggressions from colleagues to overt discrimination from patients.

“I spend countless minutes fielding texts and phone calls from those who need support,” she wrote in a blog post. “They are a constant reminder that I must continue to speak up when I get the opportunity to do so.”
 

A journey through family medicine, and through bias and racism

Dr. Washington’s early days in medicine included graduating from Meharry Medical College in 1983 and the Mountainside Family Practice Residency Program in 1990. Following 6 years of working in a private practice in rural Maryland, she moved to academia, spending 6 years at East Tennessee State University and 4 years at the UMDNJ–New Jersey Medical School in Newark as an assistant professor of family medicine.

As had happened in rural Maryland, bias and racism have too often lurked during her career as a physician.

“I grew up in Alabama so I was pretty much ready to deal with racism in the South,” Dr. Washington said. “What I was not ready for was coming to the Northeast and seeing that you’re marginalized because you’re not invited into the room. Or if you do go into spaces when you’re the only one, you often don’t feel as welcomed as you thought you might be.”

Her ideas and contributions were too often dismissed, she wrote in a 2020 blog entry posted on her LinkedIn page. And during contract negotiations, “I was not aware of all the information that my White colleagues had. They had the advantage of inside information.”

Dr. Washington says that “it took a village” to make her who she is today: teachers in her segregated schools in Alabama, one of her college professors, her best friend in medical school – and STFM, “where the list [of her own mentors] is long.”

Judy C. Washington, MD, a mentor of many young academic family physicians, particularly underrepresented-in-medicine (URM) physicians, advises her mentees on how to see ahead and plot paths to leadership.

Courtesy Dr. Judy C. Washington

For URM physicians, she also imparts a shared experience of being a minority in the field and helps prepare them for the challenges of facing racism or feeling marginalized or not equitably supported in academic life – and for making change.

While family medicine’s demographics have become more diverse over time, and more so than other specialties, they are not yet representative of the U.S. population. Within academia, male physicians who are Black or African American, or Hispanic or Latino, comprised about 4% and 5% of family medicine faculty, respectively, at the end of 2019, according to data from the Association of American Medical Colleges. For women, these numbers were about 9% and 4%, respectively. (Only those with an MD degree exclusively were included in the report.)

“When you have the privilege to serve in leadership, you have the responsibility to reach back and identify and help others who would not otherwise have the opportunity to be recognized,” Dr. Washington said.

Her mentorship work stems in large part from her long-time involvement and leadership roles in the Society of Teachers of Family Medicine (STFM) – roles she considers a pillar of her professional life. She currently serves as president of the STFM Foundation and is associate chief medical officer of the Atlantic Medical Group, a large multisite physician-led organization. She is also coordinator of women’s health for the Overlook Family Medicine Residency Program, which is affiliated with Atlantic Medical Group.

In Dr. Washington’s role as associate chief medical officer of Atlantic Medical Group in Summit, N.J., she focuses on physician engagement, satisfaction, and diversity. She also assists in areas such as population health. For the Overlook Family Medicine Residency Program also in Summit, she precepts residents in the obstetrics clinic and in the family medicine outpatient clinic.

Diana N. Carvajal, MD, MPH, one of Dr. Washington’s mentees, called her an “inspirational leader” for young academic faculty and said she is a familiar speaker at STFM meetings on topics of workforce diversity, equity, and leadership. She is “passionate” about mentorship, Dr. Carvajal said, and has understood “that URMs and women of color were not always getting [the mentorship they need to be successful].”
 

Guiding future leaders

Ivonne McLean, MD, assistant professor of family and community medicine at Icahn School of Medicine at Mount Sinai, New York, and an attending at a community health center in the Bronx, called Dr. Washington for advice a couple of years ago when she was considering her next career move.

Courtesy Society of Teachers of Family Medicine Foundation

“She took a genuine interest in me. She never said, this is what you should do. But the questions she asked and the examples she gave from her own life were incredibly helpful to me [in deciding to pursue a research fellowship] ... it was a pivotal conversation,” said Dr. McLean, associate director of a reproductive health fellowship and a research fellow in a New York State–funded program.

“From a lived experience angle, she also told me, here are some of the challenges you’ll have as a woman of color, and here are some of the ways you can approach that,” she said.

Dr. Carvajal, also a URM family physician, credits Dr. Washington’s mentorship with the development of a day-long workshop – held before the annual Society of Teachers of Family Medicine (STFM) meeting – on the low and declining rates of Black males in medicine. “We’d planned it as a presentation, and [she heard of it and] helped us expand it,” she said, calling Dr. Washington “warm, welcoming, and encouraging.

“That work and collaboration with her and the others she brought [into the process] have resulted in publications and more presentations and strategy building for diversifying the workforce,” said Dr. Carvajal, assistant professor, director of reproductive health education in family medicine, and codirector of the research section, all in the department of family and community medicine at the University of Maryland, Baltimore.

STFM involvement

Dr. Washington, who says that all or almost all of her mentees are now leaders in their academic institutions and communities, has been instrumental in developing STFM’s mentoring programming and in facilitating the organization’s multifaceted URM Initiative.

She has been active in STFM since the start of her academic career, and in 2009, while serving as assistant program director for the residency program in which she’d trained, she joined two other African American women, Monique Y. Davis-Smith, MD, and Joedrecka Brown-Speights, MD, in cochairing the society’s Group on Minority and Multicultural Health.

It was in this space, that Dr. Washington said she “heard people’s stories of being in major academic institutions and not feeling supported, not being given roadmaps to success, not getting assistance with publishing, or just kind of feeling like an outsider ... of not being pulled in.” Hispanic and African American females, in particular, “were feeling marginalized,” she said.

In 2018, having co-led development of the STFM Quality Mentoring Program for URM faculty, Dr. Washington was asked to join the STFM Foundation and subsequently led the STFM Foundation’s fundraising campaign for a new URM Initiative. She exceeded her goal, increasing support for URM participation in meetings and activities, and then participated in an STFM steering committee to create broader and longer-lasting support for URM faculty, community teachers, and medical students and residents going into academic family medicine.

Increasing the percentage of URM family medicine faculty in leadership positions – and raising awareness of structural barriers to achievement – is one of the current pillars of the URM Initiative.
 

Navigating the ‘minority tax’

As part of her mentoring, Dr. Washington helps URM physicians navigate the minority tax – a term referring to the uncompensated citizenship tasks that are more often assigned to Black and other URM physicians than to White physicians, and that take time away from scholarship, further perpetuating inequities.

Courtesy Society of Teahcers of Family Medicine Foundation

“Some of our young faculty members find themselves thrust into being the diversity and inclusion leaders in their institutions at a level at which they feel little power and little buy-in from [leadership],” she noted.

A commentary written by Dr. Washington and several colleagues on the minority tax as it impacts women – and the need to build a “tax shelter” to make academic medicine a more just environment for URM women – was published earlier this year in the Journal of Women’s Health.

She also answers e-mails and fields phone calls from young URM faculty who are mulling career moves and facing other familiar challenges.

Physicians who are URM, and African American physicians in particular, tend to “get pulled into the [often underserved] communities, into the patient care and community service areas,” Dr. Washington explained. “But unless you convert these projects into scholarship and publications, and unless you serve on a national committee outside of your institution, you’re not going to be promoted.”

Dr. Washington helps junior faculty envision themselves 5-plus years down the road, find what she calls scholarly “passion projects,” and prepare themselves for their next steps.

She helps her mentees navigate other parts of the continuum of unconscious bias and racism as well, from microaggressions from colleagues to overt discrimination from patients.

“I spend countless minutes fielding texts and phone calls from those who need support,” she wrote in a blog post. “They are a constant reminder that I must continue to speak up when I get the opportunity to do so.”
 

A journey through family medicine, and through bias and racism

Dr. Washington’s early days in medicine included graduating from Meharry Medical College in 1983 and the Mountainside Family Practice Residency Program in 1990. Following 6 years of working in a private practice in rural Maryland, she moved to academia, spending 6 years at East Tennessee State University and 4 years at the UMDNJ–New Jersey Medical School in Newark as an assistant professor of family medicine.

As had happened in rural Maryland, bias and racism have too often lurked during her career as a physician.

“I grew up in Alabama so I was pretty much ready to deal with racism in the South,” Dr. Washington said. “What I was not ready for was coming to the Northeast and seeing that you’re marginalized because you’re not invited into the room. Or if you do go into spaces when you’re the only one, you often don’t feel as welcomed as you thought you might be.”

Her ideas and contributions were too often dismissed, she wrote in a 2020 blog entry posted on her LinkedIn page. And during contract negotiations, “I was not aware of all the information that my White colleagues had. They had the advantage of inside information.”

Dr. Washington says that “it took a village” to make her who she is today: teachers in her segregated schools in Alabama, one of her college professors, her best friend in medical school – and STFM, “where the list [of her own mentors] is long.”

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

Based on significant progression-free survival (PFS) benefits shown in the phase 3 TULIP trial, trastuzumab duocarmazine (SYD985) may provide a new treatment option among HER2-positive metastatic breast cancer patients, according to Cristina Saura, MD, head of the breast cancer program at Vall d’Hebron University Hospital, Barcelona. Dr. Saura presented the results of the TULIP trial (abstract LBA15) on Sept. 19 at the 2021 European Society for Medical Oncology Congress.

Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate that consists of trastuzumab and a drug containing duocarmycin. Its three-way mechanism of action includes uptake of the antibody-drug conjugate by internalization and intracellular release of duocarmycin with two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.

While one physician described the results as encouraging, another said the treatment is not nearly ready for primetime.

“It is encouraging to observe clinically meaningful and potentially practice changing progression-free survival improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, Massachusetts General Hospital, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years including T-DXd, neratinib, tucatinib, and margetuximab. Trastuzumab duocarmazine could eventually be another option.”

Fatima Cardoso, MD, director of the breast cancer unit at the Breast Cancer Research Foundation, New York, said: “At this time there is only a minor 2-month difference in progression-free survival and a nonsignificant overall difference. With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
 

Two or more prior therapies for metastatic breast cancer

TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to trastuzumab duocarmazine (1.2 mg/kg every 21 days, 291 patients) or physician’s choice (146 patients) of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.

Longer PFS with trastuzumab duocarmazine

Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed PFS was significantly longer in the trastuzumab duocarmazine group at 7.0 months versus 4.9 months for physicians choice treatment (hazard ratio, 0.64; 95% confidence interval, 0.49-0.84; P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for trastuzumab duocarmazine over physician’s choice across all categories (except for Eastern Cooperative Oncology Group status 2). Analysis of PFS by investigators showed a similar benefit for trastuzumab duocarmazine (6.9 months vs. 4.6 months; HR, 0.60; P < .001).

A first look at median overall survival showed a nonsignificant advantage for trastuzumab duocarmazine (20.4 months vs. 16.3 months (HR, 0.83; 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for trastuzumab duocarmazine and 29.5% for physician’s choice with reductions in target lesion measurement at 70.2% and 32.2% for trastuzumab duocarmazine and physician’s choice, respectively. The clinical benefit rates were 38.5% for trastuzumab duocarmazine and 32.2% for physician’s choice.
 

Ocular toxicity

Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for trastuzumab duocarmazine were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with trastuzumab duocarmazine, including two grade 5 events.

Eye toxicity led to discontinuations in 20.8% of trastuzumab duocarmazine patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of trastuzumab duocarmazine patients. Six fatalities (2.1%) were reported in the trastuzumab duocarmazine group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.

Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.

TULIP was funded by Byondis. Dr. Saura disclosed numerous financial interests including support from AstraZeneca and Daiichi Sankyo.

COVID vaccination rates among pregnant people remain low, despite data that shows the vaccines can prevent the high risk of severe disease during pregnancy.

About 30% of pregnant people are vaccinated, according to the latest CDC data, with only 18% obtaining a dose during pregnancy. Health officials have been tracking the timing of vaccination before and during pregnancy.

The vaccination rates are even lower among pregnant Black people, CDC data shows. About 15% are fully vaccinated, compared with 25% of pregnant Hispanic and Latino people, 34% of pregnant White people, and 46% of pregnant Asian people.

“This puts them at severe risk of severe disease from COVID-19,” Rochelle Walensky, MD, the CDC director, said during a news briefing with the White House COVID-19 Response Team.

“We know that pregnant women are at increased risk of severe disease, of hospitalization and ventilation,” she said. “They’re also at increased risk for adverse events to their baby.”

Those who give birth while infected with COVID-19 had “significantly higher rates” of intensive care unit admission, intubation, ventilation, and death, according to a recent study published in JAMA Network Open.

Dr. Walensky said on Sept. 28 that studies show COVID-19 vaccines can be taken at any time while pregnant or breastfeeding. She noted that the vaccines are safe for both mothers and their babies.

“We’ve actually seen that some antibody from the vaccine traverses [the placenta] to the baby and, in fact, could potentially protect the baby,” she said.

Public health officials say the low vaccination rates can be attributed to caution around the time of pregnancy, concern for the baby, barriers to health care, and misinformation promoted online.

“Pregnancy is a precious time. It’s also a time that a lot of women have fear,” Pam Oliver, MD, an obstetrics and gynecology doctor and executive vice president of North Carolina’s Novant Health, told USA Today.

“It is natural to have questions,” she said. “So, let’s talk about what we know, let’s put it in perspective.”

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

COVID vaccination rates among pregnant people remain low, despite data that shows the vaccines can prevent the high risk of severe disease during pregnancy.

About 30% of pregnant people are vaccinated, according to the latest CDC data, with only 18% obtaining a dose during pregnancy. Health officials have been tracking the timing of vaccination before and during pregnancy.

The vaccination rates are even lower among pregnant Black people, CDC data shows. About 15% are fully vaccinated, compared with 25% of pregnant Hispanic and Latino people, 34% of pregnant White people, and 46% of pregnant Asian people.

“This puts them at severe risk of severe disease from COVID-19,” Rochelle Walensky, MD, the CDC director, said during a news briefing with the White House COVID-19 Response Team.

“We know that pregnant women are at increased risk of severe disease, of hospitalization and ventilation,” she said. “They’re also at increased risk for adverse events to their baby.”

Those who give birth while infected with COVID-19 had “significantly higher rates” of intensive care unit admission, intubation, ventilation, and death, according to a recent study published in JAMA Network Open.

Dr. Walensky said on Sept. 28 that studies show COVID-19 vaccines can be taken at any time while pregnant or breastfeeding. She noted that the vaccines are safe for both mothers and their babies.

“We’ve actually seen that some antibody from the vaccine traverses [the placenta] to the baby and, in fact, could potentially protect the baby,” she said.

Public health officials say the low vaccination rates can be attributed to caution around the time of pregnancy, concern for the baby, barriers to health care, and misinformation promoted online.

“Pregnancy is a precious time. It’s also a time that a lot of women have fear,” Pam Oliver, MD, an obstetrics and gynecology doctor and executive vice president of North Carolina’s Novant Health, told USA Today.

“It is natural to have questions,” she said. “So, let’s talk about what we know, let’s put it in perspective.”

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

COVID vaccination rates among pregnant people remain low, despite data that shows the vaccines can prevent the high risk of severe disease during pregnancy.

About 30% of pregnant people are vaccinated, according to the latest CDC data, with only 18% obtaining a dose during pregnancy. Health officials have been tracking the timing of vaccination before and during pregnancy.

The vaccination rates are even lower among pregnant Black people, CDC data shows. About 15% are fully vaccinated, compared with 25% of pregnant Hispanic and Latino people, 34% of pregnant White people, and 46% of pregnant Asian people.

“This puts them at severe risk of severe disease from COVID-19,” Rochelle Walensky, MD, the CDC director, said during a news briefing with the White House COVID-19 Response Team.

“We know that pregnant women are at increased risk of severe disease, of hospitalization and ventilation,” she said. “They’re also at increased risk for adverse events to their baby.”

Those who give birth while infected with COVID-19 had “significantly higher rates” of intensive care unit admission, intubation, ventilation, and death, according to a recent study published in JAMA Network Open.

Dr. Walensky said on Sept. 28 that studies show COVID-19 vaccines can be taken at any time while pregnant or breastfeeding. She noted that the vaccines are safe for both mothers and their babies.

“We’ve actually seen that some antibody from the vaccine traverses [the placenta] to the baby and, in fact, could potentially protect the baby,” she said.

Public health officials say the low vaccination rates can be attributed to caution around the time of pregnancy, concern for the baby, barriers to health care, and misinformation promoted online.

“Pregnancy is a precious time. It’s also a time that a lot of women have fear,” Pam Oliver, MD, an obstetrics and gynecology doctor and executive vice president of North Carolina’s Novant Health, told USA Today.

“It is natural to have questions,” she said. “So, let’s talk about what we know, let’s put it in perspective.”

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

The U.S. Food and Drug Administration has granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen/Genmab) for the treatment of adult patients with recurrent or metastatic cervical cancer who have experienced disease progression on or after chemotherapy.

There is currently no standard option for these patients. The mainstay of therapy in this setting is monotherapy with chemotherapy, but the benefit-risk profiles are poor, and overall response rates (ORRs) are less than 15%.

In the clinical trial that led to the accelerated approval, tisotumab vedotin-tftv yielded an ORR of 24%, which an expert not connected with the trial said was “impressive.”

“Tivdak’s approval as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement.

Tisotumab vedotin is an antibody–drug conjugate: A human monoclonal antibody directed against tissue factor, which is highly expressed on many solid tumors, is attached to the microtubule-disrupting agent monomethyl auristatin E.
 

Details of clinical trial data

The accelerated approval was based on the results of the innovaTV 204, an open-label, multicenter, single-arm clinical trial, which was published online on April 9 in The Lancet Oncology, as reported at the time.

The trial included 101 women with recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer whose disease had progressed with or after doublet chemotherapy with bevacizumab (if eligible by local standards) and who had received two or fewer previous systemic regimens for recurrent or metastatic disease.

All patients received tisotumab vendotin intravenously at a dose of 2.0 mg/kg (up to a maximum of 200 mg) once every 3 weeks until disease progression or unacceptable toxicity.

The confirmed ORR was 24% and included seven (7%) complete responses and 17 (17%) partial responses.

The disease control rate was 72%, and the median duration of response was 8.3 months. The median progression-free survival was 4.2 months; the 6-month progression-free survival rate was 30%.

Median overall survival (OS) was 12.1 months. OS rates were 79% at 6 months and 51% at 12 months.

Overall, the safety profile with tisotumab vedotin was manageable, the trialists reported. The most common treatment-related adverse events were alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (26%), and dry eye (23%). Adverse events of grade 3 or higher were reported by 28% of patients and included neutropenia (3%), fatigue (2%), ulcerative keratitis (2%), and peripheral neuropathies (2%). One patient died as a result of septic shock that was considered by the investigators to be related to therapy.

The new product labeling includes a boxed warning for ocular toxicity. It notes that tisotumab vedotin “caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration.” It recommends that clinicians conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated and that patients adhere to premedication and required eye care before, during, and after infusion.
 

Confirmatory trial underway

Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

The confirmatory trial for tisotumab vedotin is already underway: The global phase 3 innovaTV 301 trial began in January 2021. It will compare tisotumab vendotin to chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) for patients with recurrent or metastatic cervical cancer who have received one or two prior lines of systemic therapy.

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

The U.S. Food and Drug Administration has granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen/Genmab) for the treatment of adult patients with recurrent or metastatic cervical cancer who have experienced disease progression on or after chemotherapy.

There is currently no standard option for these patients. The mainstay of therapy in this setting is monotherapy with chemotherapy, but the benefit-risk profiles are poor, and overall response rates (ORRs) are less than 15%.

In the clinical trial that led to the accelerated approval, tisotumab vedotin-tftv yielded an ORR of 24%, which an expert not connected with the trial said was “impressive.”

“Tivdak’s approval as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement.

Tisotumab vedotin is an antibody–drug conjugate: A human monoclonal antibody directed against tissue factor, which is highly expressed on many solid tumors, is attached to the microtubule-disrupting agent monomethyl auristatin E.
 

Details of clinical trial data

The accelerated approval was based on the results of the innovaTV 204, an open-label, multicenter, single-arm clinical trial, which was published online on April 9 in The Lancet Oncology, as reported at the time.

The trial included 101 women with recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer whose disease had progressed with or after doublet chemotherapy with bevacizumab (if eligible by local standards) and who had received two or fewer previous systemic regimens for recurrent or metastatic disease.

All patients received tisotumab vendotin intravenously at a dose of 2.0 mg/kg (up to a maximum of 200 mg) once every 3 weeks until disease progression or unacceptable toxicity.

The confirmed ORR was 24% and included seven (7%) complete responses and 17 (17%) partial responses.

The disease control rate was 72%, and the median duration of response was 8.3 months. The median progression-free survival was 4.2 months; the 6-month progression-free survival rate was 30%.

Median overall survival (OS) was 12.1 months. OS rates were 79% at 6 months and 51% at 12 months.

Overall, the safety profile with tisotumab vedotin was manageable, the trialists reported. The most common treatment-related adverse events were alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (26%), and dry eye (23%). Adverse events of grade 3 or higher were reported by 28% of patients and included neutropenia (3%), fatigue (2%), ulcerative keratitis (2%), and peripheral neuropathies (2%). One patient died as a result of septic shock that was considered by the investigators to be related to therapy.

The new product labeling includes a boxed warning for ocular toxicity. It notes that tisotumab vedotin “caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration.” It recommends that clinicians conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated and that patients adhere to premedication and required eye care before, during, and after infusion.
 

Confirmatory trial underway

Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

The confirmatory trial for tisotumab vedotin is already underway: The global phase 3 innovaTV 301 trial began in January 2021. It will compare tisotumab vendotin to chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) for patients with recurrent or metastatic cervical cancer who have received one or two prior lines of systemic therapy.

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

The U.S. Food and Drug Administration has granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen/Genmab) for the treatment of adult patients with recurrent or metastatic cervical cancer who have experienced disease progression on or after chemotherapy.

There is currently no standard option for these patients. The mainstay of therapy in this setting is monotherapy with chemotherapy, but the benefit-risk profiles are poor, and overall response rates (ORRs) are less than 15%.

In the clinical trial that led to the accelerated approval, tisotumab vedotin-tftv yielded an ORR of 24%, which an expert not connected with the trial said was “impressive.”

“Tivdak’s approval as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” Jan van de Winkel, PhD, chief executive officer of Genmab, said in a statement.

Tisotumab vedotin is an antibody–drug conjugate: A human monoclonal antibody directed against tissue factor, which is highly expressed on many solid tumors, is attached to the microtubule-disrupting agent monomethyl auristatin E.
 

Details of clinical trial data

The accelerated approval was based on the results of the innovaTV 204, an open-label, multicenter, single-arm clinical trial, which was published online on April 9 in The Lancet Oncology, as reported at the time.

The trial included 101 women with recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer whose disease had progressed with or after doublet chemotherapy with bevacizumab (if eligible by local standards) and who had received two or fewer previous systemic regimens for recurrent or metastatic disease.

All patients received tisotumab vendotin intravenously at a dose of 2.0 mg/kg (up to a maximum of 200 mg) once every 3 weeks until disease progression or unacceptable toxicity.

The confirmed ORR was 24% and included seven (7%) complete responses and 17 (17%) partial responses.

The disease control rate was 72%, and the median duration of response was 8.3 months. The median progression-free survival was 4.2 months; the 6-month progression-free survival rate was 30%.

Median overall survival (OS) was 12.1 months. OS rates were 79% at 6 months and 51% at 12 months.

Overall, the safety profile with tisotumab vedotin was manageable, the trialists reported. The most common treatment-related adverse events were alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (26%), and dry eye (23%). Adverse events of grade 3 or higher were reported by 28% of patients and included neutropenia (3%), fatigue (2%), ulcerative keratitis (2%), and peripheral neuropathies (2%). One patient died as a result of septic shock that was considered by the investigators to be related to therapy.

The new product labeling includes a boxed warning for ocular toxicity. It notes that tisotumab vedotin “caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration.” It recommends that clinicians conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated and that patients adhere to premedication and required eye care before, during, and after infusion.
 

Confirmatory trial underway

Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

The confirmatory trial for tisotumab vedotin is already underway: The global phase 3 innovaTV 301 trial began in January 2021. It will compare tisotumab vendotin to chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) for patients with recurrent or metastatic cervical cancer who have received one or two prior lines of systemic therapy.

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

Women who have taken hormone replacement therapy for menopausal symptoms will be relieved by findings from a large British case-control study reporting no overall increased risk of dementia as long as exposure is not long term.

Publishing results online Sept. 29 in BMJ, ( Yana Vinogradova, PhD, a senior research fellow at the University of Nottingham (England), and colleagues made this observation after conducting nested case-control studies involving more than 700,000 women in two U.K. primary care databases. The investigators undertook the study to clarify disparate findings over the past 2 decades on dementia risk associated with menopausal hormone replacement,

“The findings show that menopausal hormone therapy, or MHT, is generally safe for women who require it,” Dr. Vinogradova said in an interview. “A small risk association was found for future development of Alzheimer’s disease increasing with the length of menopausal hormone treatment.” This finding applied only to combined treatments of estrogen plus progestin and became measurable only after long-term use of 5 years or more. “These risk associations, only for long-term use of MHT, are in line with findings related to breast cancer risk,” she said.

The findings also align with previous biological speculations that estrogen combined with progestin may have a harmful effect on the aging brain, she added, “but we also cannot completely rule out other possible factors from our study. For example, some women who were in fact suffering from early signs of Alzheimer’s disease similar to menopausal symptoms may have continued with their menopausal therapy for longer than other women.”

Concerns about the risk of dementia with MHT date back to 2003 when data from the Women’s Health Initiative Memory Study showed that incidence of all-cause dementia doubled in women age 65 years and older after treatment with conjugated equine estrogens and medroxyprogesterone acetate for an average of 4 years. More recently, Finnish research has yielded conflicting data about risks.

The study

The investigators used two U.K. primary care databases (QResearch and CPRD) to analyze MHT prescriptions for 118,501 women age 55 and older diagnosed with dementia between 1998 and 2020 and 497,416 female controls matched by age and general practice, but with no record of dementia.

The cohort was older: mean age of cases was 83.5 years and mean duration of treatment was 16 years for an average age of 67.7 at first captured prescription, considerably later than when most women begin MHT. Relevant factors such as family history, smoking, alcohol consumption, preexisting conditions, and other prescribed drugs were taken into account.

Overall, 16,291 (14%) dementia cases and 68,726 (14%) controls had been exposed to MHT in the period up to 3 years before diagnosis.

After adjusting for potentially confounding factors, the researchers found no overall associations between hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Within the subgroup of women younger than 80 years who had been taking estrogen-only therapy for 10 years or more, a slightly decreased risk of dementia emerged: odds ratio, 0.85; 95% confidence interval, 0.76-0.94.

However, an analysis of dementia cases with a diagnosis specifically of Alzheimer’s disease showed a slight increase in risk associated with estrogen-progestin therapy. Increased risks of developing specifically Alzheimer’s disease emerged in those who had used combination therapy for 5-9 years (OR, 1.11; 95% CI, 1.04-1.20) and also for 10 years or more (OR, 1.19; 95% CI, 1.06-1.33). This risk rose gradually with each year of exposure, reaching an average 11% increased risk for use from 5-9 years and an average 19% for use 10 years or more – equivalent to, respectively, five and seven extra cases per 10,000 woman-years.

According to Jill M. Rabin, MD, a professor at the Feinstein Institutes for Medical Research and an ob.gyn. with Northwell Health in Manhasset, N.Y., the findings make sense for two reasons. “First, there are other health issues noted in women taking long-term combination hormonal therapy such as an increased risk of breast cancer,” she said in an interview. “Second, progesterone is recommended for women who have retained their uterus in order to counteract the potential effects of estrogen on the uterine lining causing possible overgrowth. There are systemic effects however of progesterone, as it counteracts estrogen, potentially decreasing its benefit on the neurological system.”

She added that this analysis is synchronous with other biological studies demonstrating possible neuroprotective effects of estrogen on the brain, especially among younger women. “The vascular system in the newly menopausal female is noted to have less endothelial and intimal thickening, better blood flow and oxygenation, and in general less vascular damage. Estrogen in these relatively younger, newly menopausal women may help to stabilize the vasculature as well as the neurologic system. On the other hand, estrogen therapy over the age of 80 may be delivered to a neurovasculature damaged with age and time, may be somewhat less beneficial.” Older women also have fewer estrogen receptors and, in general, other medical comorbidities.

According to the authors, the findings will be helpful to policy-makers, doctors, and patients when making choices about hormone therapy.

In an accompanying editorial, two U.S. researchers called the findings reassuring. Pauline M. Maki, PhD, of the University of Illinois at Chicago, and JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health in Boston, however, pointed out that the current study with its older cohort and older age at MHT initiation could not address the important issue of the “timing hypothesis” – namely, that earlier initiation of hormone therapy might confer greater protection against Alzheimer’s disease, compared with later use.

And while the current observations do not change the recommendation that MHT should not be used to prevent dementia, they are helpful for providers to put dementia findings in context for patients. “The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they wrote.

This study was funded by the U.K. National Institute for Health Research School for Primary Care Research.

Coauthor Dr. Julia Hippisley-Cox is a director of QResearch, EMIS Health, which supplies the QResearch database used for this work, and is a founder and shareholder of ClinRisk., which produces software to implement clinical risk algorithms.

Women who have taken hormone replacement therapy for menopausal symptoms will be relieved by findings from a large British case-control study reporting no overall increased risk of dementia as long as exposure is not long term.

Publishing results online Sept. 29 in BMJ, ( Yana Vinogradova, PhD, a senior research fellow at the University of Nottingham (England), and colleagues made this observation after conducting nested case-control studies involving more than 700,000 women in two U.K. primary care databases. The investigators undertook the study to clarify disparate findings over the past 2 decades on dementia risk associated with menopausal hormone replacement,

“The findings show that menopausal hormone therapy, or MHT, is generally safe for women who require it,” Dr. Vinogradova said in an interview. “A small risk association was found for future development of Alzheimer’s disease increasing with the length of menopausal hormone treatment.” This finding applied only to combined treatments of estrogen plus progestin and became measurable only after long-term use of 5 years or more. “These risk associations, only for long-term use of MHT, are in line with findings related to breast cancer risk,” she said.

The findings also align with previous biological speculations that estrogen combined with progestin may have a harmful effect on the aging brain, she added, “but we also cannot completely rule out other possible factors from our study. For example, some women who were in fact suffering from early signs of Alzheimer’s disease similar to menopausal symptoms may have continued with their menopausal therapy for longer than other women.”

Concerns about the risk of dementia with MHT date back to 2003 when data from the Women’s Health Initiative Memory Study showed that incidence of all-cause dementia doubled in women age 65 years and older after treatment with conjugated equine estrogens and medroxyprogesterone acetate for an average of 4 years. More recently, Finnish research has yielded conflicting data about risks.

The study

The investigators used two U.K. primary care databases (QResearch and CPRD) to analyze MHT prescriptions for 118,501 women age 55 and older diagnosed with dementia between 1998 and 2020 and 497,416 female controls matched by age and general practice, but with no record of dementia.

The cohort was older: mean age of cases was 83.5 years and mean duration of treatment was 16 years for an average age of 67.7 at first captured prescription, considerably later than when most women begin MHT. Relevant factors such as family history, smoking, alcohol consumption, preexisting conditions, and other prescribed drugs were taken into account.

Overall, 16,291 (14%) dementia cases and 68,726 (14%) controls had been exposed to MHT in the period up to 3 years before diagnosis.

After adjusting for potentially confounding factors, the researchers found no overall associations between hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Within the subgroup of women younger than 80 years who had been taking estrogen-only therapy for 10 years or more, a slightly decreased risk of dementia emerged: odds ratio, 0.85; 95% confidence interval, 0.76-0.94.

However, an analysis of dementia cases with a diagnosis specifically of Alzheimer’s disease showed a slight increase in risk associated with estrogen-progestin therapy. Increased risks of developing specifically Alzheimer’s disease emerged in those who had used combination therapy for 5-9 years (OR, 1.11; 95% CI, 1.04-1.20) and also for 10 years or more (OR, 1.19; 95% CI, 1.06-1.33). This risk rose gradually with each year of exposure, reaching an average 11% increased risk for use from 5-9 years and an average 19% for use 10 years or more – equivalent to, respectively, five and seven extra cases per 10,000 woman-years.

According to Jill M. Rabin, MD, a professor at the Feinstein Institutes for Medical Research and an ob.gyn. with Northwell Health in Manhasset, N.Y., the findings make sense for two reasons. “First, there are other health issues noted in women taking long-term combination hormonal therapy such as an increased risk of breast cancer,” she said in an interview. “Second, progesterone is recommended for women who have retained their uterus in order to counteract the potential effects of estrogen on the uterine lining causing possible overgrowth. There are systemic effects however of progesterone, as it counteracts estrogen, potentially decreasing its benefit on the neurological system.”

She added that this analysis is synchronous with other biological studies demonstrating possible neuroprotective effects of estrogen on the brain, especially among younger women. “The vascular system in the newly menopausal female is noted to have less endothelial and intimal thickening, better blood flow and oxygenation, and in general less vascular damage. Estrogen in these relatively younger, newly menopausal women may help to stabilize the vasculature as well as the neurologic system. On the other hand, estrogen therapy over the age of 80 may be delivered to a neurovasculature damaged with age and time, may be somewhat less beneficial.” Older women also have fewer estrogen receptors and, in general, other medical comorbidities.

According to the authors, the findings will be helpful to policy-makers, doctors, and patients when making choices about hormone therapy.

In an accompanying editorial, two U.S. researchers called the findings reassuring. Pauline M. Maki, PhD, of the University of Illinois at Chicago, and JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health in Boston, however, pointed out that the current study with its older cohort and older age at MHT initiation could not address the important issue of the “timing hypothesis” – namely, that earlier initiation of hormone therapy might confer greater protection against Alzheimer’s disease, compared with later use.

And while the current observations do not change the recommendation that MHT should not be used to prevent dementia, they are helpful for providers to put dementia findings in context for patients. “The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they wrote.

This study was funded by the U.K. National Institute for Health Research School for Primary Care Research.

Coauthor Dr. Julia Hippisley-Cox is a director of QResearch, EMIS Health, which supplies the QResearch database used for this work, and is a founder and shareholder of ClinRisk., which produces software to implement clinical risk algorithms.

Women who have taken hormone replacement therapy for menopausal symptoms will be relieved by findings from a large British case-control study reporting no overall increased risk of dementia as long as exposure is not long term.

Publishing results online Sept. 29 in BMJ, ( Yana Vinogradova, PhD, a senior research fellow at the University of Nottingham (England), and colleagues made this observation after conducting nested case-control studies involving more than 700,000 women in two U.K. primary care databases. The investigators undertook the study to clarify disparate findings over the past 2 decades on dementia risk associated with menopausal hormone replacement,

“The findings show that menopausal hormone therapy, or MHT, is generally safe for women who require it,” Dr. Vinogradova said in an interview. “A small risk association was found for future development of Alzheimer’s disease increasing with the length of menopausal hormone treatment.” This finding applied only to combined treatments of estrogen plus progestin and became measurable only after long-term use of 5 years or more. “These risk associations, only for long-term use of MHT, are in line with findings related to breast cancer risk,” she said.

The findings also align with previous biological speculations that estrogen combined with progestin may have a harmful effect on the aging brain, she added, “but we also cannot completely rule out other possible factors from our study. For example, some women who were in fact suffering from early signs of Alzheimer’s disease similar to menopausal symptoms may have continued with their menopausal therapy for longer than other women.”

Concerns about the risk of dementia with MHT date back to 2003 when data from the Women’s Health Initiative Memory Study showed that incidence of all-cause dementia doubled in women age 65 years and older after treatment with conjugated equine estrogens and medroxyprogesterone acetate for an average of 4 years. More recently, Finnish research has yielded conflicting data about risks.

The study

The investigators used two U.K. primary care databases (QResearch and CPRD) to analyze MHT prescriptions for 118,501 women age 55 and older diagnosed with dementia between 1998 and 2020 and 497,416 female controls matched by age and general practice, but with no record of dementia.

The cohort was older: mean age of cases was 83.5 years and mean duration of treatment was 16 years for an average age of 67.7 at first captured prescription, considerably later than when most women begin MHT. Relevant factors such as family history, smoking, alcohol consumption, preexisting conditions, and other prescribed drugs were taken into account.

Overall, 16,291 (14%) dementia cases and 68,726 (14%) controls had been exposed to MHT in the period up to 3 years before diagnosis.

After adjusting for potentially confounding factors, the researchers found no overall associations between hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Within the subgroup of women younger than 80 years who had been taking estrogen-only therapy for 10 years or more, a slightly decreased risk of dementia emerged: odds ratio, 0.85; 95% confidence interval, 0.76-0.94.

However, an analysis of dementia cases with a diagnosis specifically of Alzheimer’s disease showed a slight increase in risk associated with estrogen-progestin therapy. Increased risks of developing specifically Alzheimer’s disease emerged in those who had used combination therapy for 5-9 years (OR, 1.11; 95% CI, 1.04-1.20) and also for 10 years or more (OR, 1.19; 95% CI, 1.06-1.33). This risk rose gradually with each year of exposure, reaching an average 11% increased risk for use from 5-9 years and an average 19% for use 10 years or more – equivalent to, respectively, five and seven extra cases per 10,000 woman-years.

According to Jill M. Rabin, MD, a professor at the Feinstein Institutes for Medical Research and an ob.gyn. with Northwell Health in Manhasset, N.Y., the findings make sense for two reasons. “First, there are other health issues noted in women taking long-term combination hormonal therapy such as an increased risk of breast cancer,” she said in an interview. “Second, progesterone is recommended for women who have retained their uterus in order to counteract the potential effects of estrogen on the uterine lining causing possible overgrowth. There are systemic effects however of progesterone, as it counteracts estrogen, potentially decreasing its benefit on the neurological system.”

She added that this analysis is synchronous with other biological studies demonstrating possible neuroprotective effects of estrogen on the brain, especially among younger women. “The vascular system in the newly menopausal female is noted to have less endothelial and intimal thickening, better blood flow and oxygenation, and in general less vascular damage. Estrogen in these relatively younger, newly menopausal women may help to stabilize the vasculature as well as the neurologic system. On the other hand, estrogen therapy over the age of 80 may be delivered to a neurovasculature damaged with age and time, may be somewhat less beneficial.” Older women also have fewer estrogen receptors and, in general, other medical comorbidities.

According to the authors, the findings will be helpful to policy-makers, doctors, and patients when making choices about hormone therapy.

In an accompanying editorial, two U.S. researchers called the findings reassuring. Pauline M. Maki, PhD, of the University of Illinois at Chicago, and JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health in Boston, however, pointed out that the current study with its older cohort and older age at MHT initiation could not address the important issue of the “timing hypothesis” – namely, that earlier initiation of hormone therapy might confer greater protection against Alzheimer’s disease, compared with later use.

And while the current observations do not change the recommendation that MHT should not be used to prevent dementia, they are helpful for providers to put dementia findings in context for patients. “The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they wrote.

This study was funded by the U.K. National Institute for Health Research School for Primary Care Research.

Coauthor Dr. Julia Hippisley-Cox is a director of QResearch, EMIS Health, which supplies the QResearch database used for this work, and is a founder and shareholder of ClinRisk., which produces software to implement clinical risk algorithms.