Sharon Worcester

April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”

Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.

ACOG

Facing hard numbers, harder conversations

The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.

Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.

The rate for non-Hispanic black women was 37 per 100,000 live births.

Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.

“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”

However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.

In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”

In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.

“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”

That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.

A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.

“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.

In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.

A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.

Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.

Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.

The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.

This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.

ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.

But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.

Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.

She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”

“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.

“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”

That was in 2011.

Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).

“I think we really set the stage for these discussions,” she said.
 

Addressing equity to enact change

The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.

Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.

“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.

She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.

The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.

“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.

More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.

“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.

Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.

“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.

The work started through these initiatives will continue because there is much left to be done, she said.

Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.

Hearing implicit bias from patients’ perspective

Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.

“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”

Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.

Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.

Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”

He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.

“Maybe they would have done something,” he said.

Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.

Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.

The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).

The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).

Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.

In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.

Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.

“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.

“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”

He stressed that his words aren’t “an indictment of the profession.”

“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
 

Fixing systems, finding solutions

Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.

“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”

But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.

“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.

“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.

The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.

“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.

Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.


We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.

[email protected]

April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”

Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.

ACOG

Facing hard numbers, harder conversations

The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.

Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.

The rate for non-Hispanic black women was 37 per 100,000 live births.

Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.

“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”

However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.

In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”

In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.

“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”

That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.

A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.

“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.

In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.

A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.

Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.

Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.

The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.

This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.

ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.

But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.

Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.

She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”

“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.

“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”

That was in 2011.

Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).

“I think we really set the stage for these discussions,” she said.
 

Addressing equity to enact change

The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.

Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.

“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.

She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.

The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.

“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.

More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.

“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.

Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.

“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.

The work started through these initiatives will continue because there is much left to be done, she said.

Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.

Hearing implicit bias from patients’ perspective

Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.

“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”

Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.

Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.

Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”

He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.

“Maybe they would have done something,” he said.

Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.

Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.

The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).

The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).

Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.

In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.

Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.

“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.

“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”

He stressed that his words aren’t “an indictment of the profession.”

“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
 

Fixing systems, finding solutions

Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.

“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”

But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.

“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.

“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.

The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.

“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.

Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.


We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.

[email protected]

April 11-17 marked the third annual national Black Maternal Health Week, an event launched in 2017 by the Atlanta-based Black Mamas Matter Alliance (BMMA), in part to “deepen the national conversation about black maternal health.”

Around the same time, emerging data showing higher mortality rates among black patients versus patients of other races with COVID-19 opened similar dialogue fraught with questions about what might explain the disturbing health disparities.

ACOG

Facing hard numbers, harder conversations

The U.S. maternal mortality rate in 2018 was 17 per 100,000 live births – the highest of any similarly wealthy industrialized nation, the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) reported in January. That’s a striking statistic in its own right. Perhaps more striking is the breakdown by race.

Hispanic women had the lowest maternal mortality rate at 12 per 100,000 live births, followed by non-Hispanic white women at 15.

The rate for non-Hispanic black women was 37 per 100,000 live births.

Numerous factors contribute to these disparities. Among those listed by the American College of Obstetricians and Gynecologists’ chief executive officer Maureen G. Phipps, MD, in a press statement on the NCHS data, are care access issues, lack of standardization of care, bias, and racism. All of these must be addressed if the disparities in maternal and other areas of care are to be eliminated, according to Dr. Phipps.

“The NCHS data confirmed what we have known from other data sources: The rate of maternal deaths for non-Hispanic black women is substantially higher than the rates for non-Hispanic white women,” she wrote. “Continued efforts to improve the standardization of data and review processes related to U.S. maternal mortality are a necessary step to achieving the goal of eliminating disparities and preventable maternal mortality.”

However, such efforts frequently encounter roadblocks constructed by the reluctance among “many academics, policy makers, scientists, elected officials, journalists, and others responsible for defining and responding to the public discourse” to identify racism as a root cause of health disparities, according to Zinzi D. Bailey, ScD, former director of research and evaluation for the New York City Department of Health and Mental Hygiene, and colleagues.

In the third of a three-part conceptual report in The Lancet, entitled America: Equity and Equality in Health, Dr. Bailey and colleagues argued that advancing health equity requires a focus on structural racism – which they defined as “the totality of ways in which societies foster racial discrimination via mutually reinforcing inequitable systems (e.g., in housing, education, employment, earning, benefits, credit, media, healthcare, and criminal justice, etc.) that in turn reinforce discriminatory beliefs, values, and distribution of resources.”

In their series, the authors peeled back layer upon layer of sociological and political contributors to structural racism throughout history, revealing how each laid a foundation for health inequity over time. They particularly home in on health care quality and access.

“Interpersonal racism, bias, and discrimination in healthcare settings can directly affect health through poor health care,” they wrote, noting that “almost 15 years ago, the Institute of Medicine report entitled Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, documented systematic and pervasive bias in the treatment of people of color resulting in substandard care.”

That report concluded that “bias, stereotyping, prejudice, and clinical uncertainty on the part of healthcare providers” likely play a role in the continuation of health disparities. More recent data – including the NCHS maternal mortality data – show an ongoing crisis.

A study of 210 experienced primary care providers and 190 community members in the Denver area, for example, found substantial evidence of implicit bias against both Latino and African American patients. The authors defined implicit bias as “unintentional and even unconscious” negative evaluation of one group and its members relative to another that is expressed implicitly, such as through negative nonverbal behavior.

“Activated by situational cues (e.g., a person’s skin color), implicit bias can quickly and unknowingly exert its influence on perception, memory, and behavior,” they wrote.

In their study, Implicit Association Test and self-report measures of bias showed similar rates of implicit bias among the providers and community members, with only a slight weakening of ethnic/racial bias among providers after adjustment for background characteristics, which suggests “a wider societal problem,” they said.

A specific example of how implicit bias can manifest was described in a 2016 report addressing the well-documented under-treatment of pain among black versus white patients. Kelly M. Hoffman, PhD, and colleagues demonstrated that a substantial number of individuals with at least some medical training endorse false beliefs regarding biological differences between black and white patients. For example, 25% of 28 white residents surveyed agreed black individuals have thicker skin, and 4% believed black individuals have faster blood coagulation and less sensitivity in their nerve endings.

Those who more strongly endorsed such erroneous beliefs were more likely to underestimate and undertreat pain among black patients, the authors found.

Another study, which underscored the insidiousness of structural racism, was reported in Science. The authors identified significant racial bias in an algorithm widely used by health systems, insurers, and practitioners to allocate health care resources for patients with complex health needs. The algorithm, which affects millions of patients, uses predictions of future health care costs rather than future illness to determine who should receive extra medical care.

The problem is that unequal care access for black patients skews lower the foundational cost data used for making those predictions. Correcting the algorithm would increase the percentage of black patients receiving additional medical help from 17.7% to 46.5%, the authors concluded.

This evidence of persistent racism and bias in medicine, however, doesn’t mean progress is lacking.

ACOG has partnered with numerous other organizations to promote awareness and change, including through legislation. A recent win was the enactment of the Preventing Maternal Deaths Act of 2018, a bipartisan bill designed to promote and support maternal mortality review committees in every state. A major focus of BMMA’s Black Maternal Health Week was the Black Maternal Health Momnibus Act of 2020, a nine-bill package introduced in March to comprehensively address the crisis.

But efforts like these, whether they aim to elucidate the contributors to health disparities or to directly target structural and overt racism and root out implicit bias in medical care, are nothing new. As Dr. Bailey and colleagues noted, a challenge is getting the message across because efforts to avoid tough conversations around these topics are nothing new, either.

Dr. Gee attested to that during a maternal mortality panel discussion at the 2019 ACOG meeting where she spoke about the resistance she encountered in 2016 when she was appointed secretary of the Louisiana Health Department and worked to make racism and bias a foundational part of the discussion on improving maternal and fetal outcomes.

She established the first Office of Health Equity in the state – and the first in the nation to not only require measurement outcomes by race but also explicitly address racial bias at the outset. The goal wasn’t just to talk about it but to “plan for addressing equity in every single aspect of what we do with ... our case equity action teams.”

“At our first maternal mortality quality meetings we insisted on focusing on equity at the very outset, and we had people that left when we started talking about racism,” she said, noting that others said it was “too political” to discuss during an election year or that equity was something to address later.

“We said no. We insisted on it, and I think that was very important because all ships don’t rise with the tide, not with health disparities,” she said, recounting an earlier experience when she led the Louisiana Birth Outcomes Initiative: “I asked to have a brown-bag focused on racism at the department so we could talk about the impact of implicit bias on decision making, and I was told that I was a Yankee who didn’t understand the South and that racism didn’t really exist here, and what did I know about it – and I couldn’t have the brown-bag.”

That was in 2011.

Fast-forward to April 24, 2020. As Dr. Gee shared her perspective on addressing racism and bias in medicine, she was preparing for a call regarding the racial disparities in COVID-19 outcomes – the first health equity action sanctioned by Louisiana Governor John Bel Edwards (D).

“I think we really set the stage for these discussions,” she said.
 

Addressing equity to enact change

The efforts in Louisiana also set the stage for better maternal outcomes. At the 2019 ACOG meeting where she spoke as part of the President’s Panel, Dr. Gee said Louisiana had the highest maternal mortality rates in the nation. The NCHC data released in January, however, suggest that may no longer be the case.

Inconsistencies in how the latest and prior data were reported, including in how maternal mortality was defined, make direct comparison impossible. But in the latest report, Louisiana ranked seventh among states with available data.

“Ninety percent of the deliveries in the state happen at hospitals that we worked with,” Dr. Gee said, highlighting the reach of the efforts to improve outcomes there.

She also described a recent case involving an anemic patient whose bleeding risk was identified early thanks to the programs put in place. That enabled early preparation in the event of complications.

The patient experienced a massive hemorrhage, but the preparation, including having units of blood on hand in case of such an emergency, saved her life.

“So we clearly have not just data, but individual stories of people whose lives have been saved by this work,” she said.

More tangible data on maternal morbidity further show that the efforts in the state are making a difference, Dr. Gillispie said, citing preliminary outcomes data from the Pregnancy-Associated Mortality Review launched in 2018.

“We started with an initial goal of reducing severe maternal morbidity related to hypertension and hemorrhage by 20%, as well as reducing the black/white disparity gap by Mother’s Day 2020,” she said.

Final analyses have been delayed because of COVID-19, but early assessments showed a reduction in the disparity gap, she said, again highlighting the importance of focusing on equity.

“Definitely from the standpoint of the Quality Collaborative side ... we’ve been working with our facilities to make them aware of what implicit bias is, helping them to also do the Harvard Implicit Bias Test so they can figure out what their own biases are, start working to acknowledge them and address them, and start working to fight against letting that bias change how they treat individuals,” Dr. Gillispie said.

The work started through these initiatives will continue because there is much left to be done, she said.

Indeed, the surprised reactions in recent weeks to the reports of disparities in COVID-19 outcomes further underscore that reality, and the maternal mortality statistics – with use of the voices of those directly affected by structural and overt racism and bias in maternal care as a megaphone – speak for themselves.

Hearing implicit bias from patients’ perspective

Just ask Timoria McQueen Saba, a black woman who nearly died from a postpartum hemorrhage in 2010. At ACOG 2019, she spoke about how she had to switch ob.gyns. three times during her first pregnancy because she felt she had not received quality care – one doctor neglected to tell her she had placenta previa. She also experienced excessive wait times at prenatal appointments and had been on the receiving end of microaggressions and degrading questions such as “Are you still married?” and “Is your husband your baby’s father?” – and these are all things her white friends who recommended those physicians never experienced, she said.

“The health care system has just sometimes beaten people down so much, just like the world has – people of color, especially – to where you’re dismissed, your concerns are invalidated,” she said. “Some doctors don’t even think black people feel pain [or that] our pain is less.”

Mrs. Saba also spoke about how her health care “improved a billion percent” when her white husband accompanied her to appointments.

Just ask Charles S. Johnson IV, whose wife Kira Dixon Johnson died in 2016 during surgery for postpartum bleeding complications – after he and other family members spent 10 hours pleading for help for her.

Speaking at the ACOG panel discussion with Mrs. Saba, Mr. Johnson described “a clear disconnect” between the medical staff at the hospital and the way they viewed and valued Kira. He shared his frustration in wanting to advocate for his wife, but knowing that, as an African American male, he risked being seen as a threat and removed from the hospital if he didn’t stay calm, if he “tapped into those natural instincts as a man and a husband who wants to just protect his family.”

He fought back emotions, struggling to get the words out, saying that’s what haunts him and keeps him up at night – wondering if he should have “fought harder, grabbed the doctor by the collar, raised his voice, slammed on the counter.

“Maybe they would have done something,” he said.

Such experiences cross all socioeconomic boundaries. Ask U.S. Track and Field Olympic gold medalist Allyson Felix, who testified at a U.S. House Ways and Means Committee hearing on May 16, 2019 after developing severe preeclampsia that threatened her life and that of her baby. Ask tennis champion Serena Williams, who demanded assessment for pulmonary embolism following the birth of her child; she knew the signs, but her health care providers initially dismissed her concerns.

Their experiences aren’t just anecdotal. Data consistently show how racism and bias affect patient treatment and outcomes. Dr. Gee, for example, shared findings from a retrospective assessment of 47 confirmed pregnancy-related deaths in Louisiana between 2011 and 2016 that looked specifically at whether the deaths could potentially have been prevented if blood was given sooner, cardiomyopathy was recognized sooner, hypertension was treated on time, or other changes were made to care.

The answer was “Yes” in 9% of cases involving white patients – and in 59% of cases involving black patients (odds ratio, 14.6).

The study, reported in February in Obstetrics & Gynecology, showed that 27 of the deaths (58%) occurred at level III or IV birth facilities and that those deaths were not less likely than those at level I or II facilities to be categorized as preventable (OR, 2.0).

Findings from the Giving Voice to Mothers study, published in Reproductive Health in 2019, showed how mistreatment during childbirth might contribute to such outcomes.

In an online cross-sectional survey of more than 2,100 U.S. women, one in six reported at least one type of mistreatment, such as loss of autonomy, being yelled at or threatened, being ignored or having requests for help ignored, Saraswathi Vedam, SciD, of the Birth Place Lab at the University of British Columbia, Vancouver, and colleagues reported.

Race was among the factors associated with likelihood of mistreatment, and the rates of mistreatment for women of color were consistently higher – even when looking at interactions between race and other characteristics, such as socioeconomic status (SES). For example, 27.2% of women of color with low SES, compared with 18.7% of white women with low SES, reported mistreatment. Having a partner who was black, regardless of maternal race, was also associated with an increased rate of mistreatment, the authors found.

“I often get the question, ‘Do you think Kira would be alive if she was white,’ ” Mr. Johnson said. “The first way I respond to that question is [by saying that] the simple fact that you have to ask me is a problem.

“When this first happened, I was in so much pain that I couldn’t process the fact that something so egregious and outrageous happened to my wife because of the color of her skin, but as I began to process and really think about it and unpack this scenario, I have to be really frank ... do I think that she would have sat there for 10 hours while we begged and pleaded? Absolutely not.”

He stressed that his words aren’t “an indictment of the profession.”

“This is not an indictment saying that all people are racist or prejudiced,” he said. “But here’s the reality: If you are in this profession, if you are responsible for the well-being of patients and their families, and you are not able to see them in the same way that you see your mother, your wife, your sister, you have two options – you need to find something else to do or you need to take steps to get better.”
 

Fixing systems, finding solutions

Dr. Gee acknowledged the work that physicians need to do to help improve outcomes.

“The average time we give a patient to talk is 11 seconds before we interrupt them,” she said, as one example. “We have to recognize that.”

But efforts to improve outcomes shouldn’t just focus on changing physician behavior, she said.

“We really need to focus, as has the U.K. – very effectively – on using midwives, doulas, other health care professionals as complements to physicians to make sure that we have women-centered birth experiences.

“So, instead of just blaming the doctors, I think we need to change the system,” Dr. Gee emphasized.

The disruptions in health systems caused by COVID-19 present a unique opportunity to do that, she said. There is now an opportunity to build them back.

“We have a chance to build the systems back, and when we do so, we ought to build them back correcting for implicit bias and some of the systemic issues that lead to poor outcomes for people of color in our country,” she said.

Solutions proposed by Dr. Gee and others include more diversity in the workforce, more inclusion of patient advocates in maternal care, development of culturally appropriate literacy and numeracy communications, measurement by race (and action on the outcomes), standardization of care, and development of new ways to improve care access.


We will focus more specifically on these solutions in Part 2 of this article in our maternal mortality series. Previous articles in the series are available at mdedge.com/obgyn/maternal-mortality.

[email protected]

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

[email protected]

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

[email protected]

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

A minimally invasive multicancer blood test used with standard-of-care screening is safe, effective, and feasible for use in routine clinical care, according to interim findings from a large, prospective study.

The DETECT-A blood test, an early version of the CancerSEEK test currently in development, effectively guided patient management in real time, in some cases leading to diagnosis of early cancer and potentially curative surgery in asymptomatic women with no history of cancer.

Nickolas Papadopoulos, PhD, of Johns Hopkins Medicine in Baltimore, reported these findings at the AACR virtual meeting I. The findings were simultaneously published in Science.

The study enrolled 10,006 women, aged 65-75 years, with no prior cancer diagnosis. After exclusion and loss to follow-up, 9,911 women remained.

There were 26 patients who had cancer detected by the DETECT-A blood test, 15 of whom underwent follow-up PET-CT imaging and 9 of whom underwent surgical excision. An additional 24 cancers were detected by standard screening, and 46 were detected by other means.

The positive predictive value of the blood test was 19%. When the blood test was combined with imaging, the positive predictive value was 41%.
 

Improving upon standard screening

“Standard-of-care screening [was used] for three different organs: breast, lung, and colon. It was more sensitive for breast cancer,” Dr. Papadopoulos noted. “Blood testing, though, identified cancer in 10 different organs.”

In fact, the DETECT-A blood test detected 14 of 45 cancers in 7 organs for which no standard screening test is available.

In addition, 12 cancers in 3 organs (breast, lung, and colon) were first detected by DETECT-A rather than by standard screening. This increased the sensitivity of cancer detection from 47% with standard screening alone to 71% with standard screening plus blood testing.

“More important, 65% [of the cancers detected by blood test] were localized or regional, which have higher chance of successful treatment with intent to cure,” Dr. Papadopoulos said.

DETECT-A covers regions of 16 commonly mutated genes and 9 proteins known to be associated with cancer. In this study, 57% of cancers were detected by mutations.
 

Safety and additional screening

DETECT-A also proved safe, “without incurring a large number of futile invasive follow-up tests,” Dr. Papadopoulos said.

In fact, only 1% of patients without cancer underwent PET-CT imaging, and only 0.22% underwent a “futile” invasive follow-up procedure.

Three surgeries occurred in patients who were counted as false-positives, but the surgeries were determined to be indicated, Dr. Papadopoulos said. He explained that one was for large colonic polyps with high-grade dysplasia that could not be removed endoscopically, one was for an in situ carcinoma of the appendix, and one was for a 10-cm ovarian lesion that was found to be a mucinous cystadenoma.

The investigators also analyzed whether the availability of a “liquid biopsy” test like DETECT-A would inadvertently reduce patients’ use of standard screening and found that it did not. Mammography screening habits after receiving the baseline DETECT-A blood test did not differ significantly from those prior to study enrollment.

These findings are important because early detection is a key factor in reducing cancer-specific morbidity and mortality, and although minimally invasive screening tests, including liquid biopsies like DETECT-A, hold great promise, prospective clinical studies of these new methods are needed to ensure that the anticipated benefits outweigh the potential risks, Dr. Papadopoulos explained.

“The problem is that most cancers are detected at advanced stages when they are difficult to treat,” he said. “The earlier cancer is detected, the greater the chance of successful treatment.”
 

Unanswered questions and future studies

This study demonstrates that it is feasible for a minimally invasive blood test to safely detect multiple cancer types in patients without a history of cancer and to enable treatment with curative intent, at least in a subset of individuals, Dr. Papadopoulos said. He added that the findings also inform the design of future randomized trials “to establish clinical utility, cost-effectiveness, and benefit-to-risk ratio of future tests.”

Further studies will also be required to determine the clinical validity and utility of the strategy of using liquid biopsy as a complement to standard-of-care screening, Dr. Papadopoulos said.

Invited discussant David G. Huntsman, MD, of the University of British Columbia in Vancouver, applauded the investigators, saying this study serves to “move the field forward.” However, it still isn’t clear how sensitivity and negative predictive value will be determined and what the optimal testing schedule is.

“This is a prospective study that will provide the data on how this assay will be used [and] whether it should be used going forward,” Dr. Huntsman said, noting that the “much bigger and more important question” is whether it improves survival.

Cost-effectiveness will also be critical, he said.

This research was supported by The Marcus Foundation, Lustgarten Foundation for Pancreatic Cancer Research, The Virginia and D.K. Ludwig Fund for Cancer Research, The Sol Goldman Center for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, the Rolfe Foundation, The Conrad R. Hilton Foundation, The John Templeton Foundation, Burroughs Wellcome Career Award For Medical Scientists, and grants/contracts from the National Institutes of Health.

Dr. Papadopoulos disclosed relationships with Thrive Earlier Detection Inc., PGDx Inc., NeoPhore, Cage Pharma, and other companies. Dr. Huntsman is a founder, shareholder, and chief medical officer for Contextual Genomics.

[email protected]

SOURCE: Papadopoulos N et al. AACR 2020, Abstract CT022; Lennon AM et al. Science. 2020 Apr 28. pii: eabb9601. doi: 10.1126/science.abb9601.

Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.

The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.

The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).

In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).

“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.

However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
 

Final overall survival

At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.

The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)

The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”

Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.

Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.

In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.

“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.

She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
 

Quality of life and safety

Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.

The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.

The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).

At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.

Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.

Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.

She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
 

Jury’s still out

Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.

She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.

“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”

Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.

The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.

[email protected]

SOURCE: Litton J et al., AACR 20, Abstract CT071.

Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.

The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.

The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).

In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).

“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.

However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
 

Final overall survival

At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.

The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)

The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”

Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.

Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.

In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.

“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.

She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
 

Quality of life and safety

Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.

The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.

The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).

At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.

Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.

Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.

She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
 

Jury’s still out

Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.

She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.

“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”

Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.

The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.

[email protected]

SOURCE: Litton J et al., AACR 20, Abstract CT071.

Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.

The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.

The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).

In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).

“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.

However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
 

Final overall survival

At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.

The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)

The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”

Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.

Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.

In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.

“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.

She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
 

Quality of life and safety

Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.

The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.

The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).

At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.

Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.

Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.

She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
 

Jury’s still out

Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.

She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.

“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”

Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.

The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.

[email protected]

SOURCE: Litton J et al., AACR 20, Abstract CT071.

Enrollment in a supportive oncodermatology program was associated with improved quality of life in patients who experienced dermatologic effects from cancer therapy, according to a cross-sectional survey of participants.

The average quality of life score prior to program participation in 34 adult patients enrolled in the George Washington University Supportive Oncodermatology Clinic who responded to the survey was 6.5, indicating a moderate effect of their dermatologic symptoms on quality of life. After the beginning of treatment, the average score declined significantly to 3.8, indicating a small effect of the symptoms on quality of life, Leora Aizman, a medical student at George Washington University, Washington, and colleagues reported in the Journal of Drugs in Dermatology.

“On average, [quality of life] total scores were significantly reduced by 2.7 points after joining the supportive oncodermatology clinic,” the authors wrote.

Decreases were seen across all quality of life categories, including physical symptoms, embarrassment, clothes, social/leisure, work/school, and close relationships; the only score that didn’t decrease significantly was for physical symptoms of itch, pain, or soreness (1.43 vs. 1.1 before and after therapy), whereas the category that showed the greatest difference was embarrassment about the dermatologic condition (1.57 vs. 0.83 before and after therapy).

As for satisfaction with the program, the average participant satisfaction score was 4.15, indicating satisfaction with the program. The lowest – an average of 3.67, indicating neutral to satisfied – was related to the effects of the program on treatment adherence.

Survey respondents were adults aged over 18 years who received dermatologic care between the opening of the clinic in May 2017 and Nov. 1, 2019. The online survey included questions adapted from the Dermatology Life Quality Index and Patient Satisfaction Questionnaire.

The findings, though limited by the potential for recall bias and other factors inherent in a survey-based study, suggest that participation in a comprehensive, supportive program could be of benefit for cancer patients experiencing dermatologic conditions from cancer treatment, the authors wrote, explaining that such conditions can be disabling and are associated with negative psychosocial effects. In fact, more than half of all cancer patients experience treatment interruption because of such events.

The findings also underscore the importance of a close partnerships between dermatologists and oncologists as nearly 90% of the surveyed patients were referred to the clinic by their oncologist, the authors wrote. However, the uncertainty that survey respondents experienced with respect to the effects of program participation on treatment adherence highlights a need for further study.

“Our results highlight that supportive oncodermatology interventions improve the psychosocial wellness of patients but require further research on evidence-based preventive and active management strategies,” they wrote.

Additionally, more work is needed to “optimize treatment of secondary toxicities and allow for the continuation of life-prolonging anticancer therapy,” they noted, adding that “prospective, multicenter studies on the management of [dermatologic adverse events] are critical to better understand the effectiveness of these clinics.”

This study was funded by a La Roche–Posay grant. Ms. Aizman reported having no disclosures. One coauthor reported relationships involving consulting and/or honoraria with several companies, including La Roche–Posay.

[email protected]

SOURCE: Aizman L et al. J Drugs Dermatol. 2020 Apr 17. doi: 10.36849/JDD.2020.5040.

Enrollment in a supportive oncodermatology program was associated with improved quality of life in patients who experienced dermatologic effects from cancer therapy, according to a cross-sectional survey of participants.

The average quality of life score prior to program participation in 34 adult patients enrolled in the George Washington University Supportive Oncodermatology Clinic who responded to the survey was 6.5, indicating a moderate effect of their dermatologic symptoms on quality of life. After the beginning of treatment, the average score declined significantly to 3.8, indicating a small effect of the symptoms on quality of life, Leora Aizman, a medical student at George Washington University, Washington, and colleagues reported in the Journal of Drugs in Dermatology.

“On average, [quality of life] total scores were significantly reduced by 2.7 points after joining the supportive oncodermatology clinic,” the authors wrote.

Decreases were seen across all quality of life categories, including physical symptoms, embarrassment, clothes, social/leisure, work/school, and close relationships; the only score that didn’t decrease significantly was for physical symptoms of itch, pain, or soreness (1.43 vs. 1.1 before and after therapy), whereas the category that showed the greatest difference was embarrassment about the dermatologic condition (1.57 vs. 0.83 before and after therapy).

As for satisfaction with the program, the average participant satisfaction score was 4.15, indicating satisfaction with the program. The lowest – an average of 3.67, indicating neutral to satisfied – was related to the effects of the program on treatment adherence.

Survey respondents were adults aged over 18 years who received dermatologic care between the opening of the clinic in May 2017 and Nov. 1, 2019. The online survey included questions adapted from the Dermatology Life Quality Index and Patient Satisfaction Questionnaire.

The findings, though limited by the potential for recall bias and other factors inherent in a survey-based study, suggest that participation in a comprehensive, supportive program could be of benefit for cancer patients experiencing dermatologic conditions from cancer treatment, the authors wrote, explaining that such conditions can be disabling and are associated with negative psychosocial effects. In fact, more than half of all cancer patients experience treatment interruption because of such events.

The findings also underscore the importance of a close partnerships between dermatologists and oncologists as nearly 90% of the surveyed patients were referred to the clinic by their oncologist, the authors wrote. However, the uncertainty that survey respondents experienced with respect to the effects of program participation on treatment adherence highlights a need for further study.

“Our results highlight that supportive oncodermatology interventions improve the psychosocial wellness of patients but require further research on evidence-based preventive and active management strategies,” they wrote.

Additionally, more work is needed to “optimize treatment of secondary toxicities and allow for the continuation of life-prolonging anticancer therapy,” they noted, adding that “prospective, multicenter studies on the management of [dermatologic adverse events] are critical to better understand the effectiveness of these clinics.”

This study was funded by a La Roche–Posay grant. Ms. Aizman reported having no disclosures. One coauthor reported relationships involving consulting and/or honoraria with several companies, including La Roche–Posay.

[email protected]

SOURCE: Aizman L et al. J Drugs Dermatol. 2020 Apr 17. doi: 10.36849/JDD.2020.5040.

Enrollment in a supportive oncodermatology program was associated with improved quality of life in patients who experienced dermatologic effects from cancer therapy, according to a cross-sectional survey of participants.

The average quality of life score prior to program participation in 34 adult patients enrolled in the George Washington University Supportive Oncodermatology Clinic who responded to the survey was 6.5, indicating a moderate effect of their dermatologic symptoms on quality of life. After the beginning of treatment, the average score declined significantly to 3.8, indicating a small effect of the symptoms on quality of life, Leora Aizman, a medical student at George Washington University, Washington, and colleagues reported in the Journal of Drugs in Dermatology.

“On average, [quality of life] total scores were significantly reduced by 2.7 points after joining the supportive oncodermatology clinic,” the authors wrote.

Decreases were seen across all quality of life categories, including physical symptoms, embarrassment, clothes, social/leisure, work/school, and close relationships; the only score that didn’t decrease significantly was for physical symptoms of itch, pain, or soreness (1.43 vs. 1.1 before and after therapy), whereas the category that showed the greatest difference was embarrassment about the dermatologic condition (1.57 vs. 0.83 before and after therapy).

As for satisfaction with the program, the average participant satisfaction score was 4.15, indicating satisfaction with the program. The lowest – an average of 3.67, indicating neutral to satisfied – was related to the effects of the program on treatment adherence.

Survey respondents were adults aged over 18 years who received dermatologic care between the opening of the clinic in May 2017 and Nov. 1, 2019. The online survey included questions adapted from the Dermatology Life Quality Index and Patient Satisfaction Questionnaire.

The findings, though limited by the potential for recall bias and other factors inherent in a survey-based study, suggest that participation in a comprehensive, supportive program could be of benefit for cancer patients experiencing dermatologic conditions from cancer treatment, the authors wrote, explaining that such conditions can be disabling and are associated with negative psychosocial effects. In fact, more than half of all cancer patients experience treatment interruption because of such events.

The findings also underscore the importance of a close partnerships between dermatologists and oncologists as nearly 90% of the surveyed patients were referred to the clinic by their oncologist, the authors wrote. However, the uncertainty that survey respondents experienced with respect to the effects of program participation on treatment adherence highlights a need for further study.

“Our results highlight that supportive oncodermatology interventions improve the psychosocial wellness of patients but require further research on evidence-based preventive and active management strategies,” they wrote.

Additionally, more work is needed to “optimize treatment of secondary toxicities and allow for the continuation of life-prolonging anticancer therapy,” they noted, adding that “prospective, multicenter studies on the management of [dermatologic adverse events] are critical to better understand the effectiveness of these clinics.”

This study was funded by a La Roche–Posay grant. Ms. Aizman reported having no disclosures. One coauthor reported relationships involving consulting and/or honoraria with several companies, including La Roche–Posay.

[email protected]

SOURCE: Aizman L et al. J Drugs Dermatol. 2020 Apr 17. doi: 10.36849/JDD.2020.5040.

The Food and Drug Administration has expanded the indication for ibrutinib (Imbruvica) to allow its combination with rituximab for frontline treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults.

The approval, announced April 21, was based on findings from the randomized, controlled, open-label, phase 3 E1912 trial of 529 patients, which demonstrated significantly improved progression-free survival (PFS) among those who received ibrutinib plus rituximab, compared with those who received fludarabine, cyclophosphamide, and rituximab (FCR) (87% vs. 75%; hazard ratio, 0.34). Median PFS was not reached in either arm after a median follow-up of 37 months.

E1912 was the first study to show superiority of a chemotherapy-free regimen over FCR chemoimmunotherapy, considered the gold standard for newly diagnosed CLL and SLL for the past 2 decades.

The recommended dosage for the newly approved combination is a once-daily 420-mg dose of ibrutinib taken with a glass of water, with rituximab initiation in the second cycle at doses of 50 mg/m2 on day 1, 325 mg/m2 on day 2, and 500 mg/m2 on days 1-5 of subsequent cycles for a total of six cycles.

This approval marks the 11th for ibrutinib across six disease areas, and its 6th in CLL.

[email protected]

The Food and Drug Administration has expanded the indication for ibrutinib (Imbruvica) to allow its combination with rituximab for frontline treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults.

The approval, announced April 21, was based on findings from the randomized, controlled, open-label, phase 3 E1912 trial of 529 patients, which demonstrated significantly improved progression-free survival (PFS) among those who received ibrutinib plus rituximab, compared with those who received fludarabine, cyclophosphamide, and rituximab (FCR) (87% vs. 75%; hazard ratio, 0.34). Median PFS was not reached in either arm after a median follow-up of 37 months.

E1912 was the first study to show superiority of a chemotherapy-free regimen over FCR chemoimmunotherapy, considered the gold standard for newly diagnosed CLL and SLL for the past 2 decades.

The recommended dosage for the newly approved combination is a once-daily 420-mg dose of ibrutinib taken with a glass of water, with rituximab initiation in the second cycle at doses of 50 mg/m2 on day 1, 325 mg/m2 on day 2, and 500 mg/m2 on days 1-5 of subsequent cycles for a total of six cycles.

This approval marks the 11th for ibrutinib across six disease areas, and its 6th in CLL.

[email protected]

The Food and Drug Administration has expanded the indication for ibrutinib (Imbruvica) to allow its combination with rituximab for frontline treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults.

The approval, announced April 21, was based on findings from the randomized, controlled, open-label, phase 3 E1912 trial of 529 patients, which demonstrated significantly improved progression-free survival (PFS) among those who received ibrutinib plus rituximab, compared with those who received fludarabine, cyclophosphamide, and rituximab (FCR) (87% vs. 75%; hazard ratio, 0.34). Median PFS was not reached in either arm after a median follow-up of 37 months.

E1912 was the first study to show superiority of a chemotherapy-free regimen over FCR chemoimmunotherapy, considered the gold standard for newly diagnosed CLL and SLL for the past 2 decades.

The recommended dosage for the newly approved combination is a once-daily 420-mg dose of ibrutinib taken with a glass of water, with rituximab initiation in the second cycle at doses of 50 mg/m2 on day 1, 325 mg/m2 on day 2, and 500 mg/m2 on days 1-5 of subsequent cycles for a total of six cycles.

This approval marks the 11th for ibrutinib across six disease areas, and its 6th in CLL.

[email protected]

Lung cancer patients should be prioritized for COVID-19 testing, according to an editorial published in Annals of Oncology.

In fact, treatment recommendations should call for baseline COVID-19 testing for all patients with lung cancer, Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan, Italy, and colleagues argued in the editorial.

“While all types of malignancies seem to be associated with high COVID-19 prevalence, morbidity, and mortality, lung cancer represents a specific scenario of cumulative risk factors for COVID-19 complications,” the authors wrote.

“[Lung cancer patients] are at a uniquely escalated risk of complications from COVID-19 due to the common features of smoking history, respiratory and cardiac disease, advanced age, and often predisposing risks from treatment, such as lung surgery and immunosuppressive chemotherapy,” said Howard (Jack) West, MD, of City of Hope Comprehensive Cancer Center in Duarte, Calif., who was not involved in the editorial.

“They also routinely experience a cough as well as chest imaging that may overlap between their underlying lung cancer, possible side effects of treatment, and potential COVID-19, leading to troubling ambiguity that can only be addressed by proactive and widespread testing of patients with lung cancer at the earliest opportunity and as a very high priority,” Dr. West added.

Dr. Passaro and colleagues’ editorial outlined these and other issues that suggest a need to prioritize testing in lung cancer patients.

Disease characteristics, treatment, and imaging

Lung cancer patients may have “defective pulmonary architecture,” such as mechanical obstruction from a tumor or previous lung surgery, that predisposes them to infection and can increase the risk of cytokine release. This is a concern because massive cytokine release during SARS-CoV-2 infection “has been postulated to be the major step in leading to the development of ARDS [acute respiratory distress syndrome],” Dr. Passaro and colleagues wrote.

The authors also argued that similar clinical symptoms among lung cancer patients and those with COVID-19 – such as cough, fever, and dyspnea – underscore the need for an accurate screening model to allow for early COVID-19 detection and potentially improve outcomes.

Similarly, lung cancer patients and COVID-19 patients may have overlapping findings on imaging. The radiologic effects of some common treatments for lung cancer can lead to the same kind of ground glass opacities and other findings seen in COVID-19 patients. Therefore, the authors predict an increase in “COVID-19-suspicious imaging, even in the absence of new symptoms” in the coming weeks.

Another issue to consider is the frequent use of corticosteroids in cancer patients. Corticosteroids may be harmful when used for COVID-19–related acute respiratory distress syndrome and could mask early symptoms of infection. Therefore, routine COVID-19 testing in patients receiving steroids may be warranted, according to Dr. Passaro and colleagues.

In addition, immunosuppression associated with cancer treatment “may impose specific consideration on the schedule and dose of cytotoxic chemotherapy for lung cancer patients in epidemic areas,” the authors wrote.

Increasing awareness: A registry and guidelines

“In the era of COVID-19, the optimal management of patients with lung cancer remains unknown, and the oncology community should have increased awareness to prevent the emergence of an increase in cancer-related and infectious mortality,” Dr. Passaro and colleagues wrote.

To that end, a novel global registry (TERAVOLT) has been launched and is collecting data worldwide with an aim of developing a tailored risk assessment strategy for lung cancer patients. The authors noted that developing international consensus with respect to COVID-19 testing in lung cancer is essential for achieving that goal.

The European Society for Medical Oncology recently released guidelines for treating lung cancer patients during the COVID-19 pandemic, but those guidelines do not include recommendations on COVID-19 testing.

“Baseline SARS-CoV-2 testing for all patients affected by lung cancer should be recommended,” Dr. Passaro and colleagues wrote. “In addition, for those patients with a negative swab test and new ground glass opacities detected on CT scan, with or without new respiratory symptoms, bronchoscopy should be considered to increase testing sensitivity.”

This work was partially supported by the Italian Ministry of Health. The authors reported having no relevant conflicts of interest. Dr. West is a regular correspondent for Medscape, which is owned by the same parent company as MDedge.

[email protected]

SOURCE: Passaro A et al. Annals of Oncology. doi: 10.1016/j.annonc.2020.04.002.

Lung cancer patients should be prioritized for COVID-19 testing, according to an editorial published in Annals of Oncology.

In fact, treatment recommendations should call for baseline COVID-19 testing for all patients with lung cancer, Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan, Italy, and colleagues argued in the editorial.

“While all types of malignancies seem to be associated with high COVID-19 prevalence, morbidity, and mortality, lung cancer represents a specific scenario of cumulative risk factors for COVID-19 complications,” the authors wrote.

“[Lung cancer patients] are at a uniquely escalated risk of complications from COVID-19 due to the common features of smoking history, respiratory and cardiac disease, advanced age, and often predisposing risks from treatment, such as lung surgery and immunosuppressive chemotherapy,” said Howard (Jack) West, MD, of City of Hope Comprehensive Cancer Center in Duarte, Calif., who was not involved in the editorial.

“They also routinely experience a cough as well as chest imaging that may overlap between their underlying lung cancer, possible side effects of treatment, and potential COVID-19, leading to troubling ambiguity that can only be addressed by proactive and widespread testing of patients with lung cancer at the earliest opportunity and as a very high priority,” Dr. West added.

Dr. Passaro and colleagues’ editorial outlined these and other issues that suggest a need to prioritize testing in lung cancer patients.

Disease characteristics, treatment, and imaging

Lung cancer patients may have “defective pulmonary architecture,” such as mechanical obstruction from a tumor or previous lung surgery, that predisposes them to infection and can increase the risk of cytokine release. This is a concern because massive cytokine release during SARS-CoV-2 infection “has been postulated to be the major step in leading to the development of ARDS [acute respiratory distress syndrome],” Dr. Passaro and colleagues wrote.

The authors also argued that similar clinical symptoms among lung cancer patients and those with COVID-19 – such as cough, fever, and dyspnea – underscore the need for an accurate screening model to allow for early COVID-19 detection and potentially improve outcomes.

Similarly, lung cancer patients and COVID-19 patients may have overlapping findings on imaging. The radiologic effects of some common treatments for lung cancer can lead to the same kind of ground glass opacities and other findings seen in COVID-19 patients. Therefore, the authors predict an increase in “COVID-19-suspicious imaging, even in the absence of new symptoms” in the coming weeks.

Another issue to consider is the frequent use of corticosteroids in cancer patients. Corticosteroids may be harmful when used for COVID-19–related acute respiratory distress syndrome and could mask early symptoms of infection. Therefore, routine COVID-19 testing in patients receiving steroids may be warranted, according to Dr. Passaro and colleagues.

In addition, immunosuppression associated with cancer treatment “may impose specific consideration on the schedule and dose of cytotoxic chemotherapy for lung cancer patients in epidemic areas,” the authors wrote.

Increasing awareness: A registry and guidelines

“In the era of COVID-19, the optimal management of patients with lung cancer remains unknown, and the oncology community should have increased awareness to prevent the emergence of an increase in cancer-related and infectious mortality,” Dr. Passaro and colleagues wrote.

To that end, a novel global registry (TERAVOLT) has been launched and is collecting data worldwide with an aim of developing a tailored risk assessment strategy for lung cancer patients. The authors noted that developing international consensus with respect to COVID-19 testing in lung cancer is essential for achieving that goal.

The European Society for Medical Oncology recently released guidelines for treating lung cancer patients during the COVID-19 pandemic, but those guidelines do not include recommendations on COVID-19 testing.

“Baseline SARS-CoV-2 testing for all patients affected by lung cancer should be recommended,” Dr. Passaro and colleagues wrote. “In addition, for those patients with a negative swab test and new ground glass opacities detected on CT scan, with or without new respiratory symptoms, bronchoscopy should be considered to increase testing sensitivity.”

This work was partially supported by the Italian Ministry of Health. The authors reported having no relevant conflicts of interest. Dr. West is a regular correspondent for Medscape, which is owned by the same parent company as MDedge.

[email protected]

SOURCE: Passaro A et al. Annals of Oncology. doi: 10.1016/j.annonc.2020.04.002.

Lung cancer patients should be prioritized for COVID-19 testing, according to an editorial published in Annals of Oncology.

In fact, treatment recommendations should call for baseline COVID-19 testing for all patients with lung cancer, Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan, Italy, and colleagues argued in the editorial.

“While all types of malignancies seem to be associated with high COVID-19 prevalence, morbidity, and mortality, lung cancer represents a specific scenario of cumulative risk factors for COVID-19 complications,” the authors wrote.

“[Lung cancer patients] are at a uniquely escalated risk of complications from COVID-19 due to the common features of smoking history, respiratory and cardiac disease, advanced age, and often predisposing risks from treatment, such as lung surgery and immunosuppressive chemotherapy,” said Howard (Jack) West, MD, of City of Hope Comprehensive Cancer Center in Duarte, Calif., who was not involved in the editorial.

“They also routinely experience a cough as well as chest imaging that may overlap between their underlying lung cancer, possible side effects of treatment, and potential COVID-19, leading to troubling ambiguity that can only be addressed by proactive and widespread testing of patients with lung cancer at the earliest opportunity and as a very high priority,” Dr. West added.

Dr. Passaro and colleagues’ editorial outlined these and other issues that suggest a need to prioritize testing in lung cancer patients.

Disease characteristics, treatment, and imaging

Lung cancer patients may have “defective pulmonary architecture,” such as mechanical obstruction from a tumor or previous lung surgery, that predisposes them to infection and can increase the risk of cytokine release. This is a concern because massive cytokine release during SARS-CoV-2 infection “has been postulated to be the major step in leading to the development of ARDS [acute respiratory distress syndrome],” Dr. Passaro and colleagues wrote.

The authors also argued that similar clinical symptoms among lung cancer patients and those with COVID-19 – such as cough, fever, and dyspnea – underscore the need for an accurate screening model to allow for early COVID-19 detection and potentially improve outcomes.

Similarly, lung cancer patients and COVID-19 patients may have overlapping findings on imaging. The radiologic effects of some common treatments for lung cancer can lead to the same kind of ground glass opacities and other findings seen in COVID-19 patients. Therefore, the authors predict an increase in “COVID-19-suspicious imaging, even in the absence of new symptoms” in the coming weeks.

Another issue to consider is the frequent use of corticosteroids in cancer patients. Corticosteroids may be harmful when used for COVID-19–related acute respiratory distress syndrome and could mask early symptoms of infection. Therefore, routine COVID-19 testing in patients receiving steroids may be warranted, according to Dr. Passaro and colleagues.

In addition, immunosuppression associated with cancer treatment “may impose specific consideration on the schedule and dose of cytotoxic chemotherapy for lung cancer patients in epidemic areas,” the authors wrote.

Increasing awareness: A registry and guidelines

“In the era of COVID-19, the optimal management of patients with lung cancer remains unknown, and the oncology community should have increased awareness to prevent the emergence of an increase in cancer-related and infectious mortality,” Dr. Passaro and colleagues wrote.

To that end, a novel global registry (TERAVOLT) has been launched and is collecting data worldwide with an aim of developing a tailored risk assessment strategy for lung cancer patients. The authors noted that developing international consensus with respect to COVID-19 testing in lung cancer is essential for achieving that goal.

The European Society for Medical Oncology recently released guidelines for treating lung cancer patients during the COVID-19 pandemic, but those guidelines do not include recommendations on COVID-19 testing.

“Baseline SARS-CoV-2 testing for all patients affected by lung cancer should be recommended,” Dr. Passaro and colleagues wrote. “In addition, for those patients with a negative swab test and new ground glass opacities detected on CT scan, with or without new respiratory symptoms, bronchoscopy should be considered to increase testing sensitivity.”

This work was partially supported by the Italian Ministry of Health. The authors reported having no relevant conflicts of interest. Dr. West is a regular correspondent for Medscape, which is owned by the same parent company as MDedge.

[email protected]

SOURCE: Passaro A et al. Annals of Oncology. doi: 10.1016/j.annonc.2020.04.002.

For Luanne Freer, MD, an expert in high-altitude pulmonary edema (HAPE) and founder and director of Everest ER, a nonprofit seasonal clinic at the Mt. Everest base camp in Nepal (elevation, 17,600 ft), a sudden flurry of messages and questions she received about a possible COVID-19/HAPE link was startling.

Courtesy Rowie Ververis

“That’s why it kind of poked me in the eye,” she said, referencing her extensive experience treating HAPE, which she described as a pressure-related phenomenon. “My goodness, they are so completely different.”

Dr. Freer, an emergency physician, reached out to several pulmonary intensivists with experience treating both HAPE and COVID-19 to gauge their reactions, and within 36 hours, they had drafted their response. In the commentary, published in High Altitude Medicine & Biology, the clinicians note that the comparison between HAPE and COVID-19 is potentially risky.

“As a group of physicians who have in some cases cared for patients with COVID-19 and in all cases cared for patients with HAPE and studied its pathophysiology and management, we feel it important to correct this misconception, as continued amplification of this message could have adverse effects on management of these patients,” they wrote.

The suggestion that COVID-19 lung injury sometimes looks more like HAPE than like acute respiratory distress syndrome (ARDS) appeared in a journal review article in late March and was put forth by medical professionals on social media where it gained traction in recent weeks and was amplified in multiple media outlets, including this one.

“With COVID, we don’t understand everything that’s going on, but we know for sure it’s an inflammatory process – not a pressure-related problem,” Dr. Freer said. “I thought ... this could be so dangerous to load the medicines that we use when we’re treating HAPE onto patients with COVID-19.”

The pathophysiological mechanisms in HAPE are different than those in other respiratory syndromes, including those associated with COVID-19, said Andrew M. Luks, MD, of the UW Medicine, Seattle, and the first author on the commentary.

“HAPE is a noncardiogenic form of pulmonary edema, as are ARDS due to bacteria or viral pneumonia, re-expansion pulmonary edema, immersion pulmonary edema, negative pressure pulmonary edema, and neurogenic pulmonary edema,” Dr. Luks, Dr. Freer, and colleagues wrote in the commentary, explaining that all of these entities cause varying degrees of hypoxemia and diffuse bilateral opacities on chest imaging. “Importantly, in all of these cases, edema accumulates in the interstitial and alveolar spaces of the lung as a result of imbalance in Starling forces.”

A difference between these entities, however, is “the mechanism by which that imbalance develops,” they noted.

The excessive and uneven hypoxic pulmonary vasoconstriction that leads to a marked increase in pulmonary artery pressure, subsequent lung overperfusion, increased pulmonary capillary hydrostatic pressure, and leakage of fluid from the vascular space into the alveolar space as seen in HAPE, is a “fundamentally different phenomenon than what is seen in COVID-19-related ARDS, which involves viral-mediated inflammatory responses as the primary pathophysiological mechanism,” they added.

The authors described several other differences between the conditions, ultimately noting that “understanding the distinction between the pathophysiological mechanisms of these entities is critical for patient management.”

In HAPE, supplemental oxygen alone may be sufficient; in COVID-19, it may improve hypoxemia but won’t resolve the underlying inflammation or injury, they explained, adding that “only good supportive care including mechanical ventilation, quite often for long periods of time, allows some patients to survive until their disease resolves.”

Further, HAPE can be prevented or treated with pulmonary vasodilators such a nifedipine or sildenafil, which decrease pulmonary artery pressure and, as a result lower pulmonary capillary hydrostatic pressure, they said.

Use of such medications for COVID-19 might decrease pulmonary artery pressure and improve right ventricular function in COVID-19, but “by releasing hypoxic pulmonary vasoconstriction and increasing perfusion to nonventilated regions of the lung, they could also worsen ventilation-perfusion mismatch” and thereby worsen hypoxemia, they explained, adding that the treatments can also cause or worsen hypotension.

Efforts to share observations and experience are important in medicine, but sometimes, as in this circumstance, “they get out there, spread around – like a brushfire almost – and get [unwarranted] face validity,” Dr. Luks said, noting that in response to information circulating about COVID-19 and HAPE, he has already heard medical professionals floating the idea of treating COVID-19 with treatments used for HAPE.

It’s true that some COVID-19 lung injury cases are behaving differently than typical ARDS, he said, adding that presentation can vary.

“But trying to equate HAPE and COVID-19 is just wrong,” he said. “HAPE and COVID-19 may share several features ...but those are features that are shared by a lot of different forms of respiratory failure.”

In a recent video interview, WebMD’s chief medical officer John Whyte, MD, spoke with a New York City physician trained in critical care and emergency medicine, Cameron Kyle-Sidell, MD, who raised the need to consider different respiratory protocols for COVID-19, noting that standard protocols were falling short in many cases.

“What we’re seeing ... is something unusual, it’s something that we are not used to,” Dr. Kyle-Sidell of Maimonides Medical Center said in that interview, stressing that the presentation differed from that seen in typical ARDS. “The patterns I was seeing did not make sense.”

Like others, he noted that COVID-19 patients were presenting with illness that clinically looked more like HAPE, but that the pathophysiology is not necessary similar to HAPE.

At around the same time, Luciano Gattinoni, MD, of the Medical University of Göttingen in Germany and colleagues, published a letter to the editor in the American Journal of Respiratory and Critical Care Medicine stressing that the ARDS presentation in COVID-19 patients is atypical and requires a patient physiology–driven treatment approach, rather than a standard protocol–driven approach. Dr. Gattinoni and colleagues suggested that instead of high positive end-expiratory pressure (PEEP), physicians should consider the lowest possible PEEP and gentle ventilation.

Dr. Luks agreed that “some patients with COVID-19 do not have the same physiologic derangements that we see in a lot of other people with ARDS.”

“[Dr. Gattinoni] is making the point that we need to treat these people differently ... and I think that’s a valid point, and honestly, that’s a point that applied even before COVID-19,” he said. “Most of the things that we see in clinical practice – there’s a lot of heterogeneity between patients, and you have to be prepared to tailor your therapy in light of the differences that you’re picking up from your observations at the bedside and other data that you’re getting on the patient.”

The main concern Dr. Luks and his coauthors wanted to convey, they said, is making sure that the anecdotal experiences and observations of clinicians struggling to find answers don’t spiral out of control without proper vetting, thereby leading to patient harm.

“In this challenging time, we must identify the best means to care for these critically ill patients. That approach should be grounded in sound pulmonary physiology, clinical experience and, when available, evidence from clinical studies,” they concluded.

Dr. Luks and Dr. Freer reported having no financial disclosures.

[email protected]

For Luanne Freer, MD, an expert in high-altitude pulmonary edema (HAPE) and founder and director of Everest ER, a nonprofit seasonal clinic at the Mt. Everest base camp in Nepal (elevation, 17,600 ft), a sudden flurry of messages and questions she received about a possible COVID-19/HAPE link was startling.

Courtesy Rowie Ververis

“That’s why it kind of poked me in the eye,” she said, referencing her extensive experience treating HAPE, which she described as a pressure-related phenomenon. “My goodness, they are so completely different.”

Dr. Freer, an emergency physician, reached out to several pulmonary intensivists with experience treating both HAPE and COVID-19 to gauge their reactions, and within 36 hours, they had drafted their response. In the commentary, published in High Altitude Medicine & Biology, the clinicians note that the comparison between HAPE and COVID-19 is potentially risky.

“As a group of physicians who have in some cases cared for patients with COVID-19 and in all cases cared for patients with HAPE and studied its pathophysiology and management, we feel it important to correct this misconception, as continued amplification of this message could have adverse effects on management of these patients,” they wrote.

The suggestion that COVID-19 lung injury sometimes looks more like HAPE than like acute respiratory distress syndrome (ARDS) appeared in a journal review article in late March and was put forth by medical professionals on social media where it gained traction in recent weeks and was amplified in multiple media outlets, including this one.

“With COVID, we don’t understand everything that’s going on, but we know for sure it’s an inflammatory process – not a pressure-related problem,” Dr. Freer said. “I thought ... this could be so dangerous to load the medicines that we use when we’re treating HAPE onto patients with COVID-19.”

The pathophysiological mechanisms in HAPE are different than those in other respiratory syndromes, including those associated with COVID-19, said Andrew M. Luks, MD, of the UW Medicine, Seattle, and the first author on the commentary.

“HAPE is a noncardiogenic form of pulmonary edema, as are ARDS due to bacteria or viral pneumonia, re-expansion pulmonary edema, immersion pulmonary edema, negative pressure pulmonary edema, and neurogenic pulmonary edema,” Dr. Luks, Dr. Freer, and colleagues wrote in the commentary, explaining that all of these entities cause varying degrees of hypoxemia and diffuse bilateral opacities on chest imaging. “Importantly, in all of these cases, edema accumulates in the interstitial and alveolar spaces of the lung as a result of imbalance in Starling forces.”

A difference between these entities, however, is “the mechanism by which that imbalance develops,” they noted.

The excessive and uneven hypoxic pulmonary vasoconstriction that leads to a marked increase in pulmonary artery pressure, subsequent lung overperfusion, increased pulmonary capillary hydrostatic pressure, and leakage of fluid from the vascular space into the alveolar space as seen in HAPE, is a “fundamentally different phenomenon than what is seen in COVID-19-related ARDS, which involves viral-mediated inflammatory responses as the primary pathophysiological mechanism,” they added.

The authors described several other differences between the conditions, ultimately noting that “understanding the distinction between the pathophysiological mechanisms of these entities is critical for patient management.”

In HAPE, supplemental oxygen alone may be sufficient; in COVID-19, it may improve hypoxemia but won’t resolve the underlying inflammation or injury, they explained, adding that “only good supportive care including mechanical ventilation, quite often for long periods of time, allows some patients to survive until their disease resolves.”

Further, HAPE can be prevented or treated with pulmonary vasodilators such a nifedipine or sildenafil, which decrease pulmonary artery pressure and, as a result lower pulmonary capillary hydrostatic pressure, they said.

Use of such medications for COVID-19 might decrease pulmonary artery pressure and improve right ventricular function in COVID-19, but “by releasing hypoxic pulmonary vasoconstriction and increasing perfusion to nonventilated regions of the lung, they could also worsen ventilation-perfusion mismatch” and thereby worsen hypoxemia, they explained, adding that the treatments can also cause or worsen hypotension.

Efforts to share observations and experience are important in medicine, but sometimes, as in this circumstance, “they get out there, spread around – like a brushfire almost – and get [unwarranted] face validity,” Dr. Luks said, noting that in response to information circulating about COVID-19 and HAPE, he has already heard medical professionals floating the idea of treating COVID-19 with treatments used for HAPE.

It’s true that some COVID-19 lung injury cases are behaving differently than typical ARDS, he said, adding that presentation can vary.

“But trying to equate HAPE and COVID-19 is just wrong,” he said. “HAPE and COVID-19 may share several features ...but those are features that are shared by a lot of different forms of respiratory failure.”

In a recent video interview, WebMD’s chief medical officer John Whyte, MD, spoke with a New York City physician trained in critical care and emergency medicine, Cameron Kyle-Sidell, MD, who raised the need to consider different respiratory protocols for COVID-19, noting that standard protocols were falling short in many cases.

“What we’re seeing ... is something unusual, it’s something that we are not used to,” Dr. Kyle-Sidell of Maimonides Medical Center said in that interview, stressing that the presentation differed from that seen in typical ARDS. “The patterns I was seeing did not make sense.”

Like others, he noted that COVID-19 patients were presenting with illness that clinically looked more like HAPE, but that the pathophysiology is not necessary similar to HAPE.

At around the same time, Luciano Gattinoni, MD, of the Medical University of Göttingen in Germany and colleagues, published a letter to the editor in the American Journal of Respiratory and Critical Care Medicine stressing that the ARDS presentation in COVID-19 patients is atypical and requires a patient physiology–driven treatment approach, rather than a standard protocol–driven approach. Dr. Gattinoni and colleagues suggested that instead of high positive end-expiratory pressure (PEEP), physicians should consider the lowest possible PEEP and gentle ventilation.

Dr. Luks agreed that “some patients with COVID-19 do not have the same physiologic derangements that we see in a lot of other people with ARDS.”

“[Dr. Gattinoni] is making the point that we need to treat these people differently ... and I think that’s a valid point, and honestly, that’s a point that applied even before COVID-19,” he said. “Most of the things that we see in clinical practice – there’s a lot of heterogeneity between patients, and you have to be prepared to tailor your therapy in light of the differences that you’re picking up from your observations at the bedside and other data that you’re getting on the patient.”

The main concern Dr. Luks and his coauthors wanted to convey, they said, is making sure that the anecdotal experiences and observations of clinicians struggling to find answers don’t spiral out of control without proper vetting, thereby leading to patient harm.

“In this challenging time, we must identify the best means to care for these critically ill patients. That approach should be grounded in sound pulmonary physiology, clinical experience and, when available, evidence from clinical studies,” they concluded.

Dr. Luks and Dr. Freer reported having no financial disclosures.

[email protected]

For Luanne Freer, MD, an expert in high-altitude pulmonary edema (HAPE) and founder and director of Everest ER, a nonprofit seasonal clinic at the Mt. Everest base camp in Nepal (elevation, 17,600 ft), a sudden flurry of messages and questions she received about a possible COVID-19/HAPE link was startling.

Courtesy Rowie Ververis

“That’s why it kind of poked me in the eye,” she said, referencing her extensive experience treating HAPE, which she described as a pressure-related phenomenon. “My goodness, they are so completely different.”

Dr. Freer, an emergency physician, reached out to several pulmonary intensivists with experience treating both HAPE and COVID-19 to gauge their reactions, and within 36 hours, they had drafted their response. In the commentary, published in High Altitude Medicine & Biology, the clinicians note that the comparison between HAPE and COVID-19 is potentially risky.

“As a group of physicians who have in some cases cared for patients with COVID-19 and in all cases cared for patients with HAPE and studied its pathophysiology and management, we feel it important to correct this misconception, as continued amplification of this message could have adverse effects on management of these patients,” they wrote.

The suggestion that COVID-19 lung injury sometimes looks more like HAPE than like acute respiratory distress syndrome (ARDS) appeared in a journal review article in late March and was put forth by medical professionals on social media where it gained traction in recent weeks and was amplified in multiple media outlets, including this one.

“With COVID, we don’t understand everything that’s going on, but we know for sure it’s an inflammatory process – not a pressure-related problem,” Dr. Freer said. “I thought ... this could be so dangerous to load the medicines that we use when we’re treating HAPE onto patients with COVID-19.”

The pathophysiological mechanisms in HAPE are different than those in other respiratory syndromes, including those associated with COVID-19, said Andrew M. Luks, MD, of the UW Medicine, Seattle, and the first author on the commentary.

“HAPE is a noncardiogenic form of pulmonary edema, as are ARDS due to bacteria or viral pneumonia, re-expansion pulmonary edema, immersion pulmonary edema, negative pressure pulmonary edema, and neurogenic pulmonary edema,” Dr. Luks, Dr. Freer, and colleagues wrote in the commentary, explaining that all of these entities cause varying degrees of hypoxemia and diffuse bilateral opacities on chest imaging. “Importantly, in all of these cases, edema accumulates in the interstitial and alveolar spaces of the lung as a result of imbalance in Starling forces.”

A difference between these entities, however, is “the mechanism by which that imbalance develops,” they noted.

The excessive and uneven hypoxic pulmonary vasoconstriction that leads to a marked increase in pulmonary artery pressure, subsequent lung overperfusion, increased pulmonary capillary hydrostatic pressure, and leakage of fluid from the vascular space into the alveolar space as seen in HAPE, is a “fundamentally different phenomenon than what is seen in COVID-19-related ARDS, which involves viral-mediated inflammatory responses as the primary pathophysiological mechanism,” they added.

The authors described several other differences between the conditions, ultimately noting that “understanding the distinction between the pathophysiological mechanisms of these entities is critical for patient management.”

In HAPE, supplemental oxygen alone may be sufficient; in COVID-19, it may improve hypoxemia but won’t resolve the underlying inflammation or injury, they explained, adding that “only good supportive care including mechanical ventilation, quite often for long periods of time, allows some patients to survive until their disease resolves.”

Further, HAPE can be prevented or treated with pulmonary vasodilators such a nifedipine or sildenafil, which decrease pulmonary artery pressure and, as a result lower pulmonary capillary hydrostatic pressure, they said.

Use of such medications for COVID-19 might decrease pulmonary artery pressure and improve right ventricular function in COVID-19, but “by releasing hypoxic pulmonary vasoconstriction and increasing perfusion to nonventilated regions of the lung, they could also worsen ventilation-perfusion mismatch” and thereby worsen hypoxemia, they explained, adding that the treatments can also cause or worsen hypotension.

Efforts to share observations and experience are important in medicine, but sometimes, as in this circumstance, “they get out there, spread around – like a brushfire almost – and get [unwarranted] face validity,” Dr. Luks said, noting that in response to information circulating about COVID-19 and HAPE, he has already heard medical professionals floating the idea of treating COVID-19 with treatments used for HAPE.

It’s true that some COVID-19 lung injury cases are behaving differently than typical ARDS, he said, adding that presentation can vary.

“But trying to equate HAPE and COVID-19 is just wrong,” he said. “HAPE and COVID-19 may share several features ...but those are features that are shared by a lot of different forms of respiratory failure.”

In a recent video interview, WebMD’s chief medical officer John Whyte, MD, spoke with a New York City physician trained in critical care and emergency medicine, Cameron Kyle-Sidell, MD, who raised the need to consider different respiratory protocols for COVID-19, noting that standard protocols were falling short in many cases.

“What we’re seeing ... is something unusual, it’s something that we are not used to,” Dr. Kyle-Sidell of Maimonides Medical Center said in that interview, stressing that the presentation differed from that seen in typical ARDS. “The patterns I was seeing did not make sense.”

Like others, he noted that COVID-19 patients were presenting with illness that clinically looked more like HAPE, but that the pathophysiology is not necessary similar to HAPE.

At around the same time, Luciano Gattinoni, MD, of the Medical University of Göttingen in Germany and colleagues, published a letter to the editor in the American Journal of Respiratory and Critical Care Medicine stressing that the ARDS presentation in COVID-19 patients is atypical and requires a patient physiology–driven treatment approach, rather than a standard protocol–driven approach. Dr. Gattinoni and colleagues suggested that instead of high positive end-expiratory pressure (PEEP), physicians should consider the lowest possible PEEP and gentle ventilation.

Dr. Luks agreed that “some patients with COVID-19 do not have the same physiologic derangements that we see in a lot of other people with ARDS.”

“[Dr. Gattinoni] is making the point that we need to treat these people differently ... and I think that’s a valid point, and honestly, that’s a point that applied even before COVID-19,” he said. “Most of the things that we see in clinical practice – there’s a lot of heterogeneity between patients, and you have to be prepared to tailor your therapy in light of the differences that you’re picking up from your observations at the bedside and other data that you’re getting on the patient.”

The main concern Dr. Luks and his coauthors wanted to convey, they said, is making sure that the anecdotal experiences and observations of clinicians struggling to find answers don’t spiral out of control without proper vetting, thereby leading to patient harm.

“In this challenging time, we must identify the best means to care for these critically ill patients. That approach should be grounded in sound pulmonary physiology, clinical experience and, when available, evidence from clinical studies,” they concluded.

Dr. Luks and Dr. Freer reported having no financial disclosures.

[email protected]

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

[email protected]

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

[email protected]

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

ORLANDO – Combination pepinemab and avelumab is well tolerated and shows antitumor activity in patients with advanced non–small cell lung cancer (NSCLC) who progressed on prior treatment, according to interim results from a phase 1b/2 trial.

Sharon Worcester/MDedge News

Treatment with pepinemab, an anti–semaphorin 4D antibody, and avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, produced disease control rates of 59% in immunotherapy-resistant patients and 81% in immunotherapy-naive patients.

Michael Rahman Shafique, MD, of Moffitt Cancer Center in Tampa, Fla., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.

The CLASSICAL-Lung trial initially enrolled 12 immunotherapy-naive patients with stage IIIb/IV NSCLC into a dose-escalation phase that examined pepinemab at doses of 5, 10, and 20 mg/kg along with 10 mg/kg of avelumab every 2 weeks.

Then, the trial enrolled 50 stage IIIb/IV patients – including 18 immunotherapy-naive patients and 32 who failed prior immunotherapy – into a phase 2 dose-expansion phase.

The 10 mg/kg pepinemab dose and 10 mg/kg avelumab dose were selected for the expansion phase based on the dose-escalation results, Dr. Shafique said. He explained that all three doses were safe, but “we were saturating the target at the 10-mg dose.”
 

Efficacy and safety

“In general, the safety data were encouraging,” Dr. Shafique said. “This was a very well-tolerated combination with no concerning safety signals. The most common adverse events were grade 1 and grade 2 fatigue, chills, pyrexia, and no grade 5 events attributable to the combination were reported.”

In the efficacy analysis, there were 29 evaluable patients who received pepinemab and avelumab after progressing on prior immunotherapy and were followed for at least 6 months. Two of these patients experienced a confirmed partial response (PR), and 15 had stable disease, for a disease control rate of 59%. Five patients had durable clinical benefit lasting at least 23 weeks, and three remained on active treatment at last follow-up, including one who had been on treatment for more than a year.

Of 21 evaluable immunotherapy-naive patients followed for at least 6 months, 5 experienced a confirmed PR, and 12 had stable disease, for a disease control rate of 81%. Three patients had clinical benefit lasting at least a year, and two remained on study and continued to receive treatment at last follow-up.

Pre- and on-treatment biopsies performed on the same lesion about 5 weeks apart demonstrated “a pretty drastic reduction in viable tumor,” Dr. Shafique noted.

“Even in patients with stable disease, many of them had absent tumor on these repeat, on-treatment biopsies,” he said, also noting that CD8-positive T-cell density increased in most tumors following treatment in patients who had a PR or stable disease, and the levels appeared to correspond with response.
 

Mechanism of action

Despite advances in immunotherapy, NSCLC patients often are refractory or acquire resistance to currently available agents, but semaphorin 4D “seems to shift the balance in the microenvironment to one of myeloid-induced immune suppression and generally a protumor, if you will, microenvironment,” Dr. Shafique said.

“Blockade of semaphorin 4D with pepinemab, we think, helps relieve this suppressive environment and actually seems to stimulate infiltration of T cells and improve T-cell activity in these tumors,” he added. He went on to explain that the mechanism of action is believed to generally be through suppression of myeloid cell trafficking to the tumor and myeloid cell cytokine secretion.

Further, and more importantly for cancer immunotherapy, preclinical models suggest that anti–semaphorin 4D antibodies are synergistic with various checkpoint inhibitors, including the PD-L1 inhibitor avelumab and others, Dr. Shafique said.

Indeed, these early CLASSICAL-Lung trial findings “do support the mechanism of action being reversing this myeloid-induced suppression in the microenvironment and improving T-cell infiltration and activity,” and they support a potential benefit of combining anti–semaphorin 4D antibodies and checkpoint inhibition in advanced NSCLC after progression on prior therapy, Dr. Shafique added.

Sharon Worcester/MDedge News

Invited discussant Timothy A. Yap, MBBS, of the University of Texas MD Anderson Cancer Center in Houston, said that “inhibition of [semaphorin 4D] promotes functional immune infiltration into the [tumor microenvironment] and, therefore, is a rational way of inhibiting tumor progression” in NSCLC and other cancers.

The CLASSICAL-Lung trial “didn’t escalate all the way to the [maximum tolerated dose] but did demonstrate durable on-treatment increases in CD8-positive T-cell infiltration, including in 79% of patients with low or null PD-L1 expression, as proof of mechanism,” Dr. Yap said, noting the responses in both immunotherapy-naive and immunotherapy-resistant patients.

“So I guess the key question will be, ‘Is this an active combination in NSCLC?’ ” Dr. Yap said. “In my opinion, yes it is, but is it going to be enough to take it past registration?”
 

Next steps

As next steps for the investigators, Dr. Yap suggested looking at a more specific population of PD-L1–low or –null immunotherapy-resistant NSCLC patients, considering adding a chemotherapy agent to the pepinemab/avelumab combination, or perhaps going “straight to a randomized phase 2/3 trial [comparing the combination with] pembrolizumab.”

“The investigators should also consider other tumor types beyond non–small cell lung cancer with this particular combination,” he said.

The preclinical data with respect to the anti–semaphorin 4D antibody suggest that study in combination with other agents, such as anti–CTLA-4 agents or anti-LAG3 agents, is also warranted, Dr. Yap added, noting that triplet combinations might also be worth investigating.

The CLASSICAL-Lung trial is funded by Vaccinex and Merck. Dr. Shafique reported a consulting or advisory role with GlaxoSmithKline. Dr. Yap reported relationships with numerous pharmaceutical companies, including Merck. MD Anderson’s Institute of Applied Cancer Science, where Dr. Yap serves as medical director, has a commercial interest in DNA damage response inhibitors and other inhibitors.

[email protected]

SOURCE: Shafique MR et al. ASCO-SITC 2020, Abstract 75.

Nearly 700 women died from pregnancy-related complications in the United States in 2018, and almost a third of those deaths were associated with cardiovascular disease, according to the latest data from the Centers for Disease Control and Prevention.

Strikingly, studies suggest that up to half of cardiovascular disease–related maternal deaths are preventable, yet CVD remains the leading cause of maternal morbidity and mortality – and the incidence has been rising steadily for 2 decades.

The American College of Obstetricians and Gynecologists says that acquired heart disease is the likely culprit in the rise in incidence of maternal mortality as women enter pregnancy with an increasingly heavy burden of CVD risk factors, including older age, obesity, diabetes, and hypertension.

“They are entering pregnancy while already at risk, and that has led to an increase in morbidity and mortality during pregnancy,” Renee Patrice Bullock-Palmer, MD, a cardiologist and director of the Women’s Heart Center at Deborah Heart and Lung Center in Browns Mills, N.J., explained in an interview. “Unfortunately, among developed countries, the U.S. has the highest rates of maternal morbidity and mortality, and that’s shocking.”

It’s a problem that requires collaboration between obstetricians, cardiologists, and others involved in the care of pregnant women, she said.
 

The data and the depth of the crisis

The maternal mortality rate in 1987 – the year the CDC’s Pregnancy Mortality Surveillance System was implemented – was 7.2 per 100,000 live births. The rate in 2016 was more than double that at 16.9, and the rate in 2018, the most recent year for which data are available, was 17.4 – and significant racial and ethnic disparities in those rates have persisted over time.

In an August 2019 article published on the American Heart Association website, Dr. Bullock-Palmer addressed the cardiovascular state of health for pregnant women and the role of the cardiologists in their care, noting that there is a “role for increased collaboration between the cardiologist and the obstetrician with regards to a pregnancy heart team.”

“It is vital that mothers who are at increased risk for CVD or have established CVD be referred to a cardiologist for cardiovascular assessment and management,” she wrote, adding it is important to raise awareness among ob.gyns. and to improve cardiologists’ recognition of women at risk when they present for care for the first time.

These referrals should be made in the antepartum and early postpartum period, she said in an interview. More attention also must be paid to racial and ethnic disparities, and the role of cardiologists in addressing these disparities.

The CDC has emphasized racial and ethnic disparities in maternal mortality, noting in a 2019 Morbidity and Mortality Weekly report that, compared with white women, black and American Indian/Alaskan Native women aged over 30 years have a 300%-400% higher rate of pregnancy-related deaths (Morb Mortal Wkly Rep. 2019 Sep 6;68[35]:762-5).

With regard to disparities, Dr. Bullock-Palmer said the causes are multifold and may be related to a higher prevalence of CVD risk factors like obesity and hypertension in non-Hispanic black women.

“There may also be limited access to adequate postpartum care in this patient population,” she wrote, adding that some attention has been paid to addressing disparities, but that “there is a lot of work left to be done in resolving these inequities in maternal health care.”

Partnerships across specialties will help in addressing most of the factors associated with CVD and maternal death, she said.

The urgent need for these partnerships is underscored by the latest findings on CVD-related complications in pregnancy. A study published in March 2020 in the Journal of the American College of Cardiology, for example, looked specifically at the incidence of serious cardiac events (SCEs) in pregnant women with heart disease, and whether the events were preventable.

In a prospective cohort of 1,315 pregnancies among women with heart disease, Birgit Pfaller, MD, of the University of Toronto Pregnancy and Heart Disease Research Program, and colleagues found that SCEs occurred in 3.6% of cases (47 women) – most often during the antepartum period – that 49% were preventable, and that 74% were related to provider management factors.

The most common SCEs were cardiac death or arrest, heart failure, arrhythmias, and urgent intervention, and they were more likely to occur in women with acquired heart disease, severe aortic or mitral stenosis, mechanical valves, and systemic ventricular dysfunction. Adverse fetal and neonatal outcomes more than doubled in cases involving SCEs, compared with those without (62% vs. 29%), and adverse obstetric events occurred most often in women with severe preeclampsia.

“The majority of the preventable events occurred due to provider management factors, including: failure to identify the patient condition prior to pregnancy, failure to identify the patient as high risk, late recognition in cardiac deterioration, delay in treatment/intervention, inappropriate treatment, and lack of preconception counseling,” Melinda Davis, MD, of the University of Michigan, Ann Arbor, wrote in a summary and editorial published in the Journal of the American College of Cardiology.

Some preventable events were attributable to patient failure to seek care, noncompliance with care recommendations, and lack of access to care, Dr. Davis noted.

“These findings suggest that provider training, patient education, and health care advocacy are all important interventions to improve outcomes among pregnant women,” she wrote, adding that “the development of multidisciplinary cardio-obstetric clinics at tertiary care centers may also be helpful.”

Dr. Bullock-Palmer added the need for greater risk-prediction tools to the list, explaining that these are needed to assess CVD risk in the prenatal, antenatal, and postnatal period.

“The recently concluded Cardiac Disease in Pregnancy [CARPREG II] study indicated that there were 10 predictors that could be utilized to asses maternal CVD risk,” she noted.

The CARPREG II authors identified five general predictors (prior cardiac events or arrhythmias, poor functional class or cyanosis, high-risk valve disease/left ventricular outflow tract obstruction, systemic ventricular dysfunction, no prior cardiac interventions), four lesion-specific predictors (mechanical valves, high-risk aortopathies, pulmonary hypertension, coronary artery disease), and one delivery-of-care predictor (late pregnancy assessment), and incorporated them into a risk index.

“It is hopeful that these new initiatives will assist providers in improving their ability to appropriately risk stratify women,” Dr. Bullock-Palmer said.

 

Ongoing efforts

Efforts also are ongoing to develop the types of cardio-obstetric clinics mentioned by Dr. Davis and to establish collaborations and “pregnancy heart teams” as attention is increasingly focused on the U.S. maternal mortality crisis.

In fact, such teams are a cornerstone of ACOG’s guidance on pregnancy and heart disease. In May 2019 the college released a Practice Bulletin with 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period.

Pregnant women and postpartum women with known or suspected CVD should undergo evaluation by a “pregnancy heart team that includes a cardiologist and maternal-fetal medicine subspecialist, or both, and other subspecialists as necessary,” according to the bulletin.

In a recent interview, Lisa Hollier, MD, immediate past president of ACOG and an instrumental figure in the push to better address maternal mortality – and in particular the cardiovascular contributors to the crisis – said she is “seeing a strengthening of that” with numerous organizations establishing pregnancy health teams.

Dr. Bullock-Palmer said she also is seeing progress, and added that collaboration should be prioritized even in the absence of dedicated pregnancy heart teams and clinics.

“Heart disease in pregnancy requires a multidisciplinary approach. You can’t just see the patient from the cardiac perspective – you also have to interact and team up with the obstetrician who is handling the pregnancy,” she said, adding that, without a dedicated team, coordination takes more effort, but is imperative for improving outcomes. “You have to collaborate at times when it is beyond the expertise of the institution or the physician; you have to know when to refer these higher-risk patients, particularly women with adult congenital heart disease.”

This referral should occur early – preferably in the antenatal period, she added.

The most important thing, however, is “recognizing these women ... even before the pregnancy,” Dr. Bullock-Palmer said, explaining that this can facilitate the necessary management – and in some cases, postponement – of pregnancy for women whose cardiac issues need to be addressed first.

Among other efforts to address maternal mortality are several programs developed by ACOG, and the Heart Outcomes in Pregnancy: Expectations for Mom and Baby Registry (HOPE) project of the Saint Luke’s Health System in Kansas.

“Hopefully the [HOPE] research collaborative ... which aims to address key clinical questions surrounding the preconception period, antenatal care, delivery planning and outcomes, and long-term postpartum care and outcomes of women will help to address the knowledge gaps and disparities in the care of women with heart disease in pregnancy,” Dr. Bullock-Palmer wrote in her article.

CVD-related risks in the post partum

Dr. Bullock-Palmer has particular concern for postpartum follow-up, given the increased risk for future heart disease among women with CVD-related pregnancy complications and the heightened risk of certain CVD-related events in the postpartum period.

That’s a component of the crisis that also was addressed during a press briefing at the 2019 ACOG annual meeting when the Pregnancy and Heart Disease Practice Bulletin was released.

Sharon Worcester/MDedge News

James Martin, MD, chair of ACOG’s Pregnancy and Heart Disease Task Force and a past ACOG president, explained during the briefing that CVD-related risks may accelerate and persist in the days and weeks after delivery, underscoring the need for follow-up and postpartum care.

Cardiomyopathy is a particular concern during this time – it’s the major cause of maternal mortality after 42 days, he noted. An emphasis on postpartum care also is especially important given that some data suggest up to 40% of women don’t return for that care.

“That is a very sad statistic and perhaps it reflects on our need to change payment models so that physicians and patients realize the importance of coming back for continuing care, because this really may be the end of pregnancy, but it is the beginning of the rest of their life,” he said. “And if they have cardiovascular disease or the risk factors ... they are going to possibly become worse over the course of their lifetime.”

[email protected]

Nearly 700 women died from pregnancy-related complications in the United States in 2018, and almost a third of those deaths were associated with cardiovascular disease, according to the latest data from the Centers for Disease Control and Prevention.

Strikingly, studies suggest that up to half of cardiovascular disease–related maternal deaths are preventable, yet CVD remains the leading cause of maternal morbidity and mortality – and the incidence has been rising steadily for 2 decades.

The American College of Obstetricians and Gynecologists says that acquired heart disease is the likely culprit in the rise in incidence of maternal mortality as women enter pregnancy with an increasingly heavy burden of CVD risk factors, including older age, obesity, diabetes, and hypertension.

“They are entering pregnancy while already at risk, and that has led to an increase in morbidity and mortality during pregnancy,” Renee Patrice Bullock-Palmer, MD, a cardiologist and director of the Women’s Heart Center at Deborah Heart and Lung Center in Browns Mills, N.J., explained in an interview. “Unfortunately, among developed countries, the U.S. has the highest rates of maternal morbidity and mortality, and that’s shocking.”

It’s a problem that requires collaboration between obstetricians, cardiologists, and others involved in the care of pregnant women, she said.
 

The data and the depth of the crisis

The maternal mortality rate in 1987 – the year the CDC’s Pregnancy Mortality Surveillance System was implemented – was 7.2 per 100,000 live births. The rate in 2016 was more than double that at 16.9, and the rate in 2018, the most recent year for which data are available, was 17.4 – and significant racial and ethnic disparities in those rates have persisted over time.

In an August 2019 article published on the American Heart Association website, Dr. Bullock-Palmer addressed the cardiovascular state of health for pregnant women and the role of the cardiologists in their care, noting that there is a “role for increased collaboration between the cardiologist and the obstetrician with regards to a pregnancy heart team.”

“It is vital that mothers who are at increased risk for CVD or have established CVD be referred to a cardiologist for cardiovascular assessment and management,” she wrote, adding it is important to raise awareness among ob.gyns. and to improve cardiologists’ recognition of women at risk when they present for care for the first time.

These referrals should be made in the antepartum and early postpartum period, she said in an interview. More attention also must be paid to racial and ethnic disparities, and the role of cardiologists in addressing these disparities.

The CDC has emphasized racial and ethnic disparities in maternal mortality, noting in a 2019 Morbidity and Mortality Weekly report that, compared with white women, black and American Indian/Alaskan Native women aged over 30 years have a 300%-400% higher rate of pregnancy-related deaths (Morb Mortal Wkly Rep. 2019 Sep 6;68[35]:762-5).

With regard to disparities, Dr. Bullock-Palmer said the causes are multifold and may be related to a higher prevalence of CVD risk factors like obesity and hypertension in non-Hispanic black women.

“There may also be limited access to adequate postpartum care in this patient population,” she wrote, adding that some attention has been paid to addressing disparities, but that “there is a lot of work left to be done in resolving these inequities in maternal health care.”

Partnerships across specialties will help in addressing most of the factors associated with CVD and maternal death, she said.

The urgent need for these partnerships is underscored by the latest findings on CVD-related complications in pregnancy. A study published in March 2020 in the Journal of the American College of Cardiology, for example, looked specifically at the incidence of serious cardiac events (SCEs) in pregnant women with heart disease, and whether the events were preventable.

In a prospective cohort of 1,315 pregnancies among women with heart disease, Birgit Pfaller, MD, of the University of Toronto Pregnancy and Heart Disease Research Program, and colleagues found that SCEs occurred in 3.6% of cases (47 women) – most often during the antepartum period – that 49% were preventable, and that 74% were related to provider management factors.

The most common SCEs were cardiac death or arrest, heart failure, arrhythmias, and urgent intervention, and they were more likely to occur in women with acquired heart disease, severe aortic or mitral stenosis, mechanical valves, and systemic ventricular dysfunction. Adverse fetal and neonatal outcomes more than doubled in cases involving SCEs, compared with those without (62% vs. 29%), and adverse obstetric events occurred most often in women with severe preeclampsia.

“The majority of the preventable events occurred due to provider management factors, including: failure to identify the patient condition prior to pregnancy, failure to identify the patient as high risk, late recognition in cardiac deterioration, delay in treatment/intervention, inappropriate treatment, and lack of preconception counseling,” Melinda Davis, MD, of the University of Michigan, Ann Arbor, wrote in a summary and editorial published in the Journal of the American College of Cardiology.

Some preventable events were attributable to patient failure to seek care, noncompliance with care recommendations, and lack of access to care, Dr. Davis noted.

“These findings suggest that provider training, patient education, and health care advocacy are all important interventions to improve outcomes among pregnant women,” she wrote, adding that “the development of multidisciplinary cardio-obstetric clinics at tertiary care centers may also be helpful.”

Dr. Bullock-Palmer added the need for greater risk-prediction tools to the list, explaining that these are needed to assess CVD risk in the prenatal, antenatal, and postnatal period.

“The recently concluded Cardiac Disease in Pregnancy [CARPREG II] study indicated that there were 10 predictors that could be utilized to asses maternal CVD risk,” she noted.

The CARPREG II authors identified five general predictors (prior cardiac events or arrhythmias, poor functional class or cyanosis, high-risk valve disease/left ventricular outflow tract obstruction, systemic ventricular dysfunction, no prior cardiac interventions), four lesion-specific predictors (mechanical valves, high-risk aortopathies, pulmonary hypertension, coronary artery disease), and one delivery-of-care predictor (late pregnancy assessment), and incorporated them into a risk index.

“It is hopeful that these new initiatives will assist providers in improving their ability to appropriately risk stratify women,” Dr. Bullock-Palmer said.

 

Ongoing efforts

Efforts also are ongoing to develop the types of cardio-obstetric clinics mentioned by Dr. Davis and to establish collaborations and “pregnancy heart teams” as attention is increasingly focused on the U.S. maternal mortality crisis.

In fact, such teams are a cornerstone of ACOG’s guidance on pregnancy and heart disease. In May 2019 the college released a Practice Bulletin with 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period.

Pregnant women and postpartum women with known or suspected CVD should undergo evaluation by a “pregnancy heart team that includes a cardiologist and maternal-fetal medicine subspecialist, or both, and other subspecialists as necessary,” according to the bulletin.

In a recent interview, Lisa Hollier, MD, immediate past president of ACOG and an instrumental figure in the push to better address maternal mortality – and in particular the cardiovascular contributors to the crisis – said she is “seeing a strengthening of that” with numerous organizations establishing pregnancy health teams.

Dr. Bullock-Palmer said she also is seeing progress, and added that collaboration should be prioritized even in the absence of dedicated pregnancy heart teams and clinics.

“Heart disease in pregnancy requires a multidisciplinary approach. You can’t just see the patient from the cardiac perspective – you also have to interact and team up with the obstetrician who is handling the pregnancy,” she said, adding that, without a dedicated team, coordination takes more effort, but is imperative for improving outcomes. “You have to collaborate at times when it is beyond the expertise of the institution or the physician; you have to know when to refer these higher-risk patients, particularly women with adult congenital heart disease.”

This referral should occur early – preferably in the antenatal period, she added.

The most important thing, however, is “recognizing these women ... even before the pregnancy,” Dr. Bullock-Palmer said, explaining that this can facilitate the necessary management – and in some cases, postponement – of pregnancy for women whose cardiac issues need to be addressed first.

Among other efforts to address maternal mortality are several programs developed by ACOG, and the Heart Outcomes in Pregnancy: Expectations for Mom and Baby Registry (HOPE) project of the Saint Luke’s Health System in Kansas.

“Hopefully the [HOPE] research collaborative ... which aims to address key clinical questions surrounding the preconception period, antenatal care, delivery planning and outcomes, and long-term postpartum care and outcomes of women will help to address the knowledge gaps and disparities in the care of women with heart disease in pregnancy,” Dr. Bullock-Palmer wrote in her article.

CVD-related risks in the post partum

Dr. Bullock-Palmer has particular concern for postpartum follow-up, given the increased risk for future heart disease among women with CVD-related pregnancy complications and the heightened risk of certain CVD-related events in the postpartum period.

That’s a component of the crisis that also was addressed during a press briefing at the 2019 ACOG annual meeting when the Pregnancy and Heart Disease Practice Bulletin was released.

Sharon Worcester/MDedge News

James Martin, MD, chair of ACOG’s Pregnancy and Heart Disease Task Force and a past ACOG president, explained during the briefing that CVD-related risks may accelerate and persist in the days and weeks after delivery, underscoring the need for follow-up and postpartum care.

Cardiomyopathy is a particular concern during this time – it’s the major cause of maternal mortality after 42 days, he noted. An emphasis on postpartum care also is especially important given that some data suggest up to 40% of women don’t return for that care.

“That is a very sad statistic and perhaps it reflects on our need to change payment models so that physicians and patients realize the importance of coming back for continuing care, because this really may be the end of pregnancy, but it is the beginning of the rest of their life,” he said. “And if they have cardiovascular disease or the risk factors ... they are going to possibly become worse over the course of their lifetime.”

[email protected]

Nearly 700 women died from pregnancy-related complications in the United States in 2018, and almost a third of those deaths were associated with cardiovascular disease, according to the latest data from the Centers for Disease Control and Prevention.

Strikingly, studies suggest that up to half of cardiovascular disease–related maternal deaths are preventable, yet CVD remains the leading cause of maternal morbidity and mortality – and the incidence has been rising steadily for 2 decades.

The American College of Obstetricians and Gynecologists says that acquired heart disease is the likely culprit in the rise in incidence of maternal mortality as women enter pregnancy with an increasingly heavy burden of CVD risk factors, including older age, obesity, diabetes, and hypertension.

“They are entering pregnancy while already at risk, and that has led to an increase in morbidity and mortality during pregnancy,” Renee Patrice Bullock-Palmer, MD, a cardiologist and director of the Women’s Heart Center at Deborah Heart and Lung Center in Browns Mills, N.J., explained in an interview. “Unfortunately, among developed countries, the U.S. has the highest rates of maternal morbidity and mortality, and that’s shocking.”

It’s a problem that requires collaboration between obstetricians, cardiologists, and others involved in the care of pregnant women, she said.
 

The data and the depth of the crisis

The maternal mortality rate in 1987 – the year the CDC’s Pregnancy Mortality Surveillance System was implemented – was 7.2 per 100,000 live births. The rate in 2016 was more than double that at 16.9, and the rate in 2018, the most recent year for which data are available, was 17.4 – and significant racial and ethnic disparities in those rates have persisted over time.

In an August 2019 article published on the American Heart Association website, Dr. Bullock-Palmer addressed the cardiovascular state of health for pregnant women and the role of the cardiologists in their care, noting that there is a “role for increased collaboration between the cardiologist and the obstetrician with regards to a pregnancy heart team.”

“It is vital that mothers who are at increased risk for CVD or have established CVD be referred to a cardiologist for cardiovascular assessment and management,” she wrote, adding it is important to raise awareness among ob.gyns. and to improve cardiologists’ recognition of women at risk when they present for care for the first time.

These referrals should be made in the antepartum and early postpartum period, she said in an interview. More attention also must be paid to racial and ethnic disparities, and the role of cardiologists in addressing these disparities.

The CDC has emphasized racial and ethnic disparities in maternal mortality, noting in a 2019 Morbidity and Mortality Weekly report that, compared with white women, black and American Indian/Alaskan Native women aged over 30 years have a 300%-400% higher rate of pregnancy-related deaths (Morb Mortal Wkly Rep. 2019 Sep 6;68[35]:762-5).

With regard to disparities, Dr. Bullock-Palmer said the causes are multifold and may be related to a higher prevalence of CVD risk factors like obesity and hypertension in non-Hispanic black women.

“There may also be limited access to adequate postpartum care in this patient population,” she wrote, adding that some attention has been paid to addressing disparities, but that “there is a lot of work left to be done in resolving these inequities in maternal health care.”

Partnerships across specialties will help in addressing most of the factors associated with CVD and maternal death, she said.

The urgent need for these partnerships is underscored by the latest findings on CVD-related complications in pregnancy. A study published in March 2020 in the Journal of the American College of Cardiology, for example, looked specifically at the incidence of serious cardiac events (SCEs) in pregnant women with heart disease, and whether the events were preventable.

In a prospective cohort of 1,315 pregnancies among women with heart disease, Birgit Pfaller, MD, of the University of Toronto Pregnancy and Heart Disease Research Program, and colleagues found that SCEs occurred in 3.6% of cases (47 women) – most often during the antepartum period – that 49% were preventable, and that 74% were related to provider management factors.

The most common SCEs were cardiac death or arrest, heart failure, arrhythmias, and urgent intervention, and they were more likely to occur in women with acquired heart disease, severe aortic or mitral stenosis, mechanical valves, and systemic ventricular dysfunction. Adverse fetal and neonatal outcomes more than doubled in cases involving SCEs, compared with those without (62% vs. 29%), and adverse obstetric events occurred most often in women with severe preeclampsia.

“The majority of the preventable events occurred due to provider management factors, including: failure to identify the patient condition prior to pregnancy, failure to identify the patient as high risk, late recognition in cardiac deterioration, delay in treatment/intervention, inappropriate treatment, and lack of preconception counseling,” Melinda Davis, MD, of the University of Michigan, Ann Arbor, wrote in a summary and editorial published in the Journal of the American College of Cardiology.

Some preventable events were attributable to patient failure to seek care, noncompliance with care recommendations, and lack of access to care, Dr. Davis noted.

“These findings suggest that provider training, patient education, and health care advocacy are all important interventions to improve outcomes among pregnant women,” she wrote, adding that “the development of multidisciplinary cardio-obstetric clinics at tertiary care centers may also be helpful.”

Dr. Bullock-Palmer added the need for greater risk-prediction tools to the list, explaining that these are needed to assess CVD risk in the prenatal, antenatal, and postnatal period.

“The recently concluded Cardiac Disease in Pregnancy [CARPREG II] study indicated that there were 10 predictors that could be utilized to asses maternal CVD risk,” she noted.

The CARPREG II authors identified five general predictors (prior cardiac events or arrhythmias, poor functional class or cyanosis, high-risk valve disease/left ventricular outflow tract obstruction, systemic ventricular dysfunction, no prior cardiac interventions), four lesion-specific predictors (mechanical valves, high-risk aortopathies, pulmonary hypertension, coronary artery disease), and one delivery-of-care predictor (late pregnancy assessment), and incorporated them into a risk index.

“It is hopeful that these new initiatives will assist providers in improving their ability to appropriately risk stratify women,” Dr. Bullock-Palmer said.

 

Ongoing efforts

Efforts also are ongoing to develop the types of cardio-obstetric clinics mentioned by Dr. Davis and to establish collaborations and “pregnancy heart teams” as attention is increasingly focused on the U.S. maternal mortality crisis.

In fact, such teams are a cornerstone of ACOG’s guidance on pregnancy and heart disease. In May 2019 the college released a Practice Bulletin with 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period.

Pregnant women and postpartum women with known or suspected CVD should undergo evaluation by a “pregnancy heart team that includes a cardiologist and maternal-fetal medicine subspecialist, or both, and other subspecialists as necessary,” according to the bulletin.

In a recent interview, Lisa Hollier, MD, immediate past president of ACOG and an instrumental figure in the push to better address maternal mortality – and in particular the cardiovascular contributors to the crisis – said she is “seeing a strengthening of that” with numerous organizations establishing pregnancy health teams.

Dr. Bullock-Palmer said she also is seeing progress, and added that collaboration should be prioritized even in the absence of dedicated pregnancy heart teams and clinics.

“Heart disease in pregnancy requires a multidisciplinary approach. You can’t just see the patient from the cardiac perspective – you also have to interact and team up with the obstetrician who is handling the pregnancy,” she said, adding that, without a dedicated team, coordination takes more effort, but is imperative for improving outcomes. “You have to collaborate at times when it is beyond the expertise of the institution or the physician; you have to know when to refer these higher-risk patients, particularly women with adult congenital heart disease.”

This referral should occur early – preferably in the antenatal period, she added.

The most important thing, however, is “recognizing these women ... even before the pregnancy,” Dr. Bullock-Palmer said, explaining that this can facilitate the necessary management – and in some cases, postponement – of pregnancy for women whose cardiac issues need to be addressed first.

Among other efforts to address maternal mortality are several programs developed by ACOG, and the Heart Outcomes in Pregnancy: Expectations for Mom and Baby Registry (HOPE) project of the Saint Luke’s Health System in Kansas.

“Hopefully the [HOPE] research collaborative ... which aims to address key clinical questions surrounding the preconception period, antenatal care, delivery planning and outcomes, and long-term postpartum care and outcomes of women will help to address the knowledge gaps and disparities in the care of women with heart disease in pregnancy,” Dr. Bullock-Palmer wrote in her article.

CVD-related risks in the post partum

Dr. Bullock-Palmer has particular concern for postpartum follow-up, given the increased risk for future heart disease among women with CVD-related pregnancy complications and the heightened risk of certain CVD-related events in the postpartum period.

That’s a component of the crisis that also was addressed during a press briefing at the 2019 ACOG annual meeting when the Pregnancy and Heart Disease Practice Bulletin was released.

Sharon Worcester/MDedge News

James Martin, MD, chair of ACOG’s Pregnancy and Heart Disease Task Force and a past ACOG president, explained during the briefing that CVD-related risks may accelerate and persist in the days and weeks after delivery, underscoring the need for follow-up and postpartum care.

Cardiomyopathy is a particular concern during this time – it’s the major cause of maternal mortality after 42 days, he noted. An emphasis on postpartum care also is especially important given that some data suggest up to 40% of women don’t return for that care.

“That is a very sad statistic and perhaps it reflects on our need to change payment models so that physicians and patients realize the importance of coming back for continuing care, because this really may be the end of pregnancy, but it is the beginning of the rest of their life,” he said. “And if they have cardiovascular disease or the risk factors ... they are going to possibly become worse over the course of their lifetime.”

[email protected]

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

[email protected]

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

[email protected]

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.

Adding trastuzumab to carboplatin/paclitaxel improved survival in patients with advanced or recurrent HER2/Neu-positive uterine serous carcinoma (USC), according to an updated analysis from a phase 2 trial.

Dr Amanda Nickles Fader

At a median follow-up of 25.9 months, the median progression-free survival (PFS) was 12.9 months in patients who received trastuzumab plus carboplatin/paclitaxel and 8.0 months in patients who received only carboplatin/paclitaxel. The median overall survival (OS) was 29.6 months and 24.4 months, respectively.

Amanda Nickles Fader, MD, of Johns Hopkins Medicine, Baltimore, and colleagues reported these findings in an abstract that was slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Confirmed benefit

The phase 2 trial was designed to assess whether trastuzumab, a humanized monoclonal antibody that targets HER2/neu – a growth factor receptor found in almost all USC cases and overexpressed in 30% of cases – would improve survival in patients with USC, Dr. Nickles Fader explained in an interview. She noted that trastuzumab has been shown to provide benefit in breast cancer patients with HER2/neu overexpression.

“[U]terine serous carcinoma ... is a very aggressive high-grade endometrial cancer subtype that is associated with really poor clinical outcomes and significant mortality,” Dr. Nickles Fader said. “It represents fewer than 10% of all uterine cancer cases, but it actually accounts for a disproportionate 40% of all deaths from uterine cancer.”

The overall survival among USC patients is about 45%, compared with 91% for more common lower-grade types of uterine cancers, she added.

“The conventional treatments for uterine serous carcinoma include surgery and then chemotherapy, but we’ve only really gotten so far by using a sort of one-size-fits-all treatment philosophy,” Dr. Nickles Fader said.

Based on preliminary findings from the current trial (J Clin Oncol. 2018 Jul 10;36[20]:2044-51), trastuzumab plus carboplatin/paclitaxel is now recognized as an alternative standard in treating advanced or recurrent HER2/Neu-positive USC, and this updated analysis confirms the benefits of adding trastuzumab, she said.
 

PFS, OS, and toxicity

There were 58 evaluable patients with primary stage III-IV or recurrent USC who were randomized to receive six cycles of carboplatin/paclitaxel alone or in combination with intravenous trastuzumab given until toxicity or progression.

The median PFS at a median follow-up of 25.9 months “very significantly favored” the trastuzumab arm, Dr. Nickles Fader said. The median PFS was 12.9 months in the trastuzumab arm and 8.0 months in the carboplatin/paclitaxel arm (hazard ratio, 0.46; P = .005).

In the 41 patients undergoing primary treatment, the median PFS was 17.7 months in the trastuzumab arm and 9.3 months in the control arm (HR, 0.44; P = .015). In the 17 patients with recurrent disease, the median PFS was 9.2 months and 7.0 months, respectively (HR, 0.12; P = .004).

“We were very pleased to see that there was also an overall survival benefit of about 5 months in the trastuzumab arm, compared to the control arm,” Dr. Nickles Fader said. The median OS was 29.6 months and 24.4 months, respectively (HR, 0.58; P = .046).

The PFS and OS benefit was “particularly striking” in the stage III-IV patients, according to Dr. Nickles Fader and colleagues. In this subgroup, the median OS was not reached in the trastuzumab arm, and it was 25.4 months in the control arm (HR, 0.49; P = .041).

Long-term toxicity did not differ between the treatment arms.
 

Applications and next steps

“The take-home message here is women should be tested if they have this subtype,” Dr. Nickles Fader said. “If they’re newly diagnosed, they should be tested for the HER2/neu receptor, and if [it is overexpressed] and they have advanced disease, we do recommend treatment with not only the conventional treatment, but with trastuzumab added to that, because that’s where we saw the most benefit.”

This is the only trial that has ever shown a major PFS and OS difference with combination targeted therapy and conventional chemotherapy in USC, Dr. Nickles Fader noted.

“So it was really exciting to see that,” she said, adding that a “much larger cooperative group trial” is being designed by the National Cancer Institute and NRG Oncology Group to look at this approach in HER2-positive, advanced-stage uterine cancers. The trial will include patients with USC, but it will extend to other uterine cancer types as well.

“We’re looking at different combinations of anti-HER2 therapies to sort of validate the results of this trial, but also to study this in other tumors that are HER2 positive,” Dr. Nickles Fader explained.

She also stressed the importance of addressing racial disparities in survival among women with USC, as African American women have higher rates of USC and related mortality than do other groups.

“It’s going to be important to look at not only molecular targets and improving survival but also racial inequalities and potentially epigenetics to really improve survival across the board,” Dr. Nickles Fader said.

She reported having no disclosures. The trial was sponsored by Yale University in collaboration with Genentech.

[email protected]

SOURCE: Nickles Fader A et al. SGO 2020, Abstract 12.