Ob.Gyn. News

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.

The benefit of adding capivasertib to fulvestrant was also seen in patients with previous exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and in patients with liver metastases, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.

“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
 

AKT alterations

Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.

Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.

In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.

The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
 

Results

The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).

In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).

An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.

An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.

Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.

Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.

There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).

The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.

Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.
 

‘Clinically relevant benefit’

Invited discussant Fabrice André, MD, PhD, of Gustave Roussy Cancer Center in Villejuif, France, noted that the CAPItello-291 study is one of the first randomized trials enriched with patients whose tumors are resistant to CDK4/6 inhibitors.

“What are the take-home messages? First, there is a clinically relevant benefit in the overall population and in the PIK3CA mutant/AKT/PTEN altered population,” he said.

He noted that the exploratory analysis showed a small clinical benefit with an impressive hazard ratio but broad confidence interval in patients with biomarker-negative tumors, and noted that the study lacked either circulating tumor DNA analysis or exploration of other mechanisms of AKT pathway alteration.

The study was funded by AstraZeneca. Dr. Turner has served on the advisory board for AstraZeneca, and his institution has received research funding from the company. Dr. Andre disclosed fees to his hospital on his behalf from AstraZeneca, Daiichi Sankyo, Sanofi, Pfizer, Lilly, and Roche.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

San Antonio – A 16-gene molecular signature may identify patients with breast cancer who are at risk for locoregional recurrence, as well as those who can be safely spared from breast radiation following breast-conserving surgery, an international team of investigators said.

In combined data from three independent randomized trials grouped into a meta-analysis, patients who had low scores on the messenger RNA–based signature, dubbed “Profile for the Omission of Local Adjuvant Radiotherapy” (POLAR), derived only minimal benefit from radiotherapy following breast-conserving surgery. In contrast, patients with high POLAR scores had significant clinical benefit from adjuvant radiotherapy, reported Per Karlsson, MD, chief physician with the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg (Sweden). Dr. Karlsson reported his findings at the San Antonio Breast Cancer Symposium.

“To our knowledge, POLAR is the first genomic classifier that is not only prognostic but also predictive of radiotherapy benefit, showing a significant interaction between radiotherapy and the classifier,” he said. “These important retrospective findings warrant further investigation, including in contemporary clinical studies.”

Investigators with the Swedish SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy), the Scottish Conservation (radiotherapy) Trial (SCT), and a trial from the Princess Margaret Cancer Hospital in Toronto, collaborated on improving and validating the POLAR signature, which was originally developed for use in the SweBCG91RT trial in patients with lymph node–negative breast cancer who underwent breast-conserving surgery. The patients were randomized to whole breast irradiation or no radiotherapy.

To develop the signature, researchers collected tumor blocks from 1,004 patients, and extracted RNA from the samples. Gene expression data were obtained from primary tumors of 764 patients. The subset of 597 patients with estrogen receptor–positive, HER2-negative tumors (ER+/HER2–) who did not receive systemic therapy were divided into a training set with 243 patients, and a validation cohort with 354 patients.

They identified a total of 16 genes involved in cellular proliferation and immune response, and then validated the signature using retrospective data from three clinical trials of patients randomized to radiotherapy or no radiation following breast-conserving surgery.

Of 623 patients with node-negative ER+/HER2– tumors who were included in the meta-analysis, 429 patients were found to have high POLAR scores. These patients benefited from adjuvant radiation therapy after breast-conserving surgery with a 10-year cumulative incidence of low risk of locoregional recurrence ranging from 15% to 26% for those who were not treated with radiation therapy, compared with only 4%-11% percent for those who received radiation therapy (hazard ratio, 0.37; P < .001).

In contrast, among the 194 patients whose tumors had POLAR low scores, there was no apparent benefit from radiation therapy with a nonsignificant HR of 0.92 (P = .832).

In Cox proportional hazard models for time to locoregional recurrences for 309 patients who did not undergo radiation, POLAR scores were significantly prognostic for recurrence, with a HR of 1.53 (P < .001) in univariable analysis, and 1.43 (P = .005) in multivariable analysis controlling for age, tumor size, tumor grade and molecular groupings.
 

New modalities may make findings less relevant

Alphonse Taghian, MD, PhD, a breast radiation oncologist with Mass General Cancer Center, Boston, who was not involved in the study, said there have been major changes in radiation therapy since the studies used for development of the POLAR signature were performed. For example, the Scottish Conservation Trial ran from 1985 to 1991, while the SweBCGR91RT trial and Princess Margaret trial were both conducted in the 1990s.

He noted that patients in those studies would likely experience more morbidities from radiation than patients treated with more recent modalities such as intensity modulated radiation therapy, and that patients treated 30 years ago would have to put up with lengthy fractionation schedules that required daily trips to the hospital over as long as 6 weeks, whereas a majority of patients can now be treated with hypofractionated radiation that can be performed in a much shorter time and with minimal comorbidities.

He acknowledged, however, that “it will help to have a signature proved, confirmed, or validated retrospectively with a different set of data.”

Dr. Taghian also said that it would be helpful to have more data about the age of patients, because omitting radiation is more common for elderly patients than it is for younger patients.

“It will maybe be beneficial to look at this signature in patients that we think might not need radiation,” he said.

The study was supported by the Swedish Cancer Society, Swedish Research Council, King Gustav 5 Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences. Dr. Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX. Dr. Taghian reported having no relevant disclosures.

Endometrial receptivity testing (ERT) did not increase the chances of achieving live birth in patients undergoing in vitro fertilization.

The study was promoted by widespread use of the tests in reproductive medicine and earlier conflicting studies regarding its effectiveness. The procedure, in which doctors extract cells from a woman’s endometrial lining in an effort to determine the best day to perform in vitro fertilization, requires a biopsy, can take a month to generate results, and costs up to $1,000.

But the new study, published online December 6 in the Journal of the American Medical Association, found that embryo transfer based on the timing of ERT was no better than that based on the standard protocol.

“Endometrial receptivity testing ended up not being beneficial in the population of interest, a good-prognosis IVF patient population,” said Nicole Doyle, MD, PhD, of Shady Grove Fertility, in Arlington, Va., who led the study. “For this particular patient population I would not recommend ERT based on the results of the trial.”

“Unfortunately, as is our history in reproductive medicine, we may embrace technology prematurely given patient desperation and physician eagerness to improve pregnancy outcomes,” said Mark P. Trolice, MD, director of the IVF Center in Orlando, who was not involved in the new research.

The double-blind, randomized clinical trial enrolled 726 women treated at Dr. Doyle’s clinic between May 2018 and September 2020.

All the women underwent ERT. Of those who received adjusted progesterone exposure after the test, live birth occurred in 58.5% of transfers (223 of 381). Among those in a control group who did not have their progesterone adjusted after ERT and underwent IVF on a standardized schedule, 61.9% of transfers (239 of 386) resulted in live birth, according to the researchers.

The differences in rates of clinical (77.2% vs. 79.5% [95% confidence interval, −10.4% to 2.4%]) and biochemical pregnancy (68.8% vs. 72.8% [95% CI, −8.2% to 3.5%]) were not statistically significant between the two groups, Dr. Doyle and her colleagues reported.

Women who experienced recurrent implantation failure (RIF), defined as more than two failed embryo transfers, were excluded from the study. “We can’t assess the benefit of an endometrial receptivity testing in this particular patient population,” Dr. Doyle said.

However, she noted that the number of women who undergo RIF is “a very small fraction of all IVF patients, less than 5%.” Of those, half are expected to have embryos that are not suitable for implantation, Dr. Doyle said.

As a result, she said, “it’s really only about 2.5% of IVF patients for which we don’t yet have an answer regarding the utility of ERT.”

Dr. Trolice, also a professor at the University of Central Florida, Orlando, expressed certainty that the “one-size-fits-all approach” for ERT has been disproven by the study’s failure to find a benefit from the procedure in women with a “good prognosis.” But, he added, whether ERT is of value in a subset of patients, such as those with recurrent implantation failure, remains “a question of vital importance.”

Dr. Doyle and Dr. Trolice reported no relevant financial relationships.

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

Endometrial receptivity testing (ERT) did not increase the chances of achieving live birth in patients undergoing in vitro fertilization.

The study was promoted by widespread use of the tests in reproductive medicine and earlier conflicting studies regarding its effectiveness. The procedure, in which doctors extract cells from a woman’s endometrial lining in an effort to determine the best day to perform in vitro fertilization, requires a biopsy, can take a month to generate results, and costs up to $1,000.

But the new study, published online December 6 in the Journal of the American Medical Association, found that embryo transfer based on the timing of ERT was no better than that based on the standard protocol.

“Endometrial receptivity testing ended up not being beneficial in the population of interest, a good-prognosis IVF patient population,” said Nicole Doyle, MD, PhD, of Shady Grove Fertility, in Arlington, Va., who led the study. “For this particular patient population I would not recommend ERT based on the results of the trial.”

“Unfortunately, as is our history in reproductive medicine, we may embrace technology prematurely given patient desperation and physician eagerness to improve pregnancy outcomes,” said Mark P. Trolice, MD, director of the IVF Center in Orlando, who was not involved in the new research.

The double-blind, randomized clinical trial enrolled 726 women treated at Dr. Doyle’s clinic between May 2018 and September 2020.

All the women underwent ERT. Of those who received adjusted progesterone exposure after the test, live birth occurred in 58.5% of transfers (223 of 381). Among those in a control group who did not have their progesterone adjusted after ERT and underwent IVF on a standardized schedule, 61.9% of transfers (239 of 386) resulted in live birth, according to the researchers.

The differences in rates of clinical (77.2% vs. 79.5% [95% confidence interval, −10.4% to 2.4%]) and biochemical pregnancy (68.8% vs. 72.8% [95% CI, −8.2% to 3.5%]) were not statistically significant between the two groups, Dr. Doyle and her colleagues reported.

Women who experienced recurrent implantation failure (RIF), defined as more than two failed embryo transfers, were excluded from the study. “We can’t assess the benefit of an endometrial receptivity testing in this particular patient population,” Dr. Doyle said.

However, she noted that the number of women who undergo RIF is “a very small fraction of all IVF patients, less than 5%.” Of those, half are expected to have embryos that are not suitable for implantation, Dr. Doyle said.

As a result, she said, “it’s really only about 2.5% of IVF patients for which we don’t yet have an answer regarding the utility of ERT.”

Dr. Trolice, also a professor at the University of Central Florida, Orlando, expressed certainty that the “one-size-fits-all approach” for ERT has been disproven by the study’s failure to find a benefit from the procedure in women with a “good prognosis.” But, he added, whether ERT is of value in a subset of patients, such as those with recurrent implantation failure, remains “a question of vital importance.”

Dr. Doyle and Dr. Trolice reported no relevant financial relationships.

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

Endometrial receptivity testing (ERT) did not increase the chances of achieving live birth in patients undergoing in vitro fertilization.

The study was promoted by widespread use of the tests in reproductive medicine and earlier conflicting studies regarding its effectiveness. The procedure, in which doctors extract cells from a woman’s endometrial lining in an effort to determine the best day to perform in vitro fertilization, requires a biopsy, can take a month to generate results, and costs up to $1,000.

But the new study, published online December 6 in the Journal of the American Medical Association, found that embryo transfer based on the timing of ERT was no better than that based on the standard protocol.

“Endometrial receptivity testing ended up not being beneficial in the population of interest, a good-prognosis IVF patient population,” said Nicole Doyle, MD, PhD, of Shady Grove Fertility, in Arlington, Va., who led the study. “For this particular patient population I would not recommend ERT based on the results of the trial.”

“Unfortunately, as is our history in reproductive medicine, we may embrace technology prematurely given patient desperation and physician eagerness to improve pregnancy outcomes,” said Mark P. Trolice, MD, director of the IVF Center in Orlando, who was not involved in the new research.

The double-blind, randomized clinical trial enrolled 726 women treated at Dr. Doyle’s clinic between May 2018 and September 2020.

All the women underwent ERT. Of those who received adjusted progesterone exposure after the test, live birth occurred in 58.5% of transfers (223 of 381). Among those in a control group who did not have their progesterone adjusted after ERT and underwent IVF on a standardized schedule, 61.9% of transfers (239 of 386) resulted in live birth, according to the researchers.

The differences in rates of clinical (77.2% vs. 79.5% [95% confidence interval, −10.4% to 2.4%]) and biochemical pregnancy (68.8% vs. 72.8% [95% CI, −8.2% to 3.5%]) were not statistically significant between the two groups, Dr. Doyle and her colleagues reported.

Women who experienced recurrent implantation failure (RIF), defined as more than two failed embryo transfers, were excluded from the study. “We can’t assess the benefit of an endometrial receptivity testing in this particular patient population,” Dr. Doyle said.

However, she noted that the number of women who undergo RIF is “a very small fraction of all IVF patients, less than 5%.” Of those, half are expected to have embryos that are not suitable for implantation, Dr. Doyle said.

As a result, she said, “it’s really only about 2.5% of IVF patients for which we don’t yet have an answer regarding the utility of ERT.”

Dr. Trolice, also a professor at the University of Central Florida, Orlando, expressed certainty that the “one-size-fits-all approach” for ERT has been disproven by the study’s failure to find a benefit from the procedure in women with a “good prognosis.” But, he added, whether ERT is of value in a subset of patients, such as those with recurrent implantation failure, remains “a question of vital importance.”

Dr. Doyle and Dr. Trolice reported no relevant financial relationships.

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

Interventional cardiologist Richard B. Zelman, MD, has filed a lawsuit against Cape Cod Hospital, Cape Cod Healthcare Inc., and its chief executive officer Michael K. Lauf, alleging that he was fired and maligned after raising concerns about poorly performed surgeries and poor ethical practices at the hospital.

Dr. Zelman, from Barnstable, Mass., has been affiliated with Cape Cod Hospital in Hyannis, Mass., for more than 30 years. He helped found the hospital’s Heart and Vascular Institute and has served as its medical director since 2018.

In his lawsuit filed Dec. 6, Dr. Zelman alleges that the defendants, under Mr. Lauf’s leadership, “placed profit above all else, including by prioritizing revenue generation over patient safety and public health.”

Dr. Zelman says the defendants supported him “to the extent his actions were profitable.”

Yet, when he raised patient safety concerns that harmed that bottom line, Dr. Zelman says the defendants retaliated against him, including by threatening his career and reputation and unlawfully terminating his employment with the hospital.

The complaint notes Dr. Zelman is bringing this action “to recover damages for violations of the Massachusetts Healthcare Provider Whistleblower Statute ... as well as for breach of contract and common law claims.”

Dr. Zelman’s complaint alleges the defendants refused to adequately address the “dangerous care and violations of the professional standards of practice” that he reported, “resulting in harmful and tragic consequences.”

It also alleges Mr. Lauf restricted the use of a cerebral protection device used in patients undergoing transcatheter aortic-valve replacement (TAVR) deemed to be at high risk for periprocedural stroke to only those patients whose insurance reimbursed at higher rates.

Dr. Zelman says he objected to this prohibition “in accordance with his contractual and ethical obligations to ensure treatment of patients without regard to their ability to pay.”

Dr. Zelman’s lawsuit further alleges that Mr. Lauf launched a “trumped-up” and “baseless, biased, and retaliatory sham” investigation against him.

In a statement sent to the Boston Globe, Cape Cod Hospital denied Dr. Zelman’s claims that the cardiologist was retaliated against for raising patient safety issues, or that the hospital didn’t take action to improve cardiac care at the facility.
 

Voiced concerns

In a statement sent to this news organization, Dr. Zelman, now in private practice, said, “Over the past 25 years, I have been instrumental in bringing advanced cardiac care to Cape Cod. My commitment has always been to delivering the same quality outcomes and safety as the academic centers in Boston.

“Unfortunately, over the past 5 years, there has been inadequate oversight by the hospital administration and problems have occurred that in my opinion have led to serious patient consequences,” Dr. Zelman stated.

He said he has “voiced concerns over several years and they have been ignored.”

He added that Cape Cod Hospital offered him a million-dollar contract as long as he agreed to immediately issue a written statement endorsing the quality and safety of the cardiac surgical program that no longer exists.

“No amount of money was going to buy my silence,” Dr. Zelman told this news organization.

In his lawsuit, Dr. Zelman is seeking an undisclosed amount in damages, including back and front pay, lost benefits, physical and emotional distress, and attorneys’ fees.

This news organization reached out to Cape Cod Hospital for comment but has not yet received a response.

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

Interventional cardiologist Richard B. Zelman, MD, has filed a lawsuit against Cape Cod Hospital, Cape Cod Healthcare Inc., and its chief executive officer Michael K. Lauf, alleging that he was fired and maligned after raising concerns about poorly performed surgeries and poor ethical practices at the hospital.

Dr. Zelman, from Barnstable, Mass., has been affiliated with Cape Cod Hospital in Hyannis, Mass., for more than 30 years. He helped found the hospital’s Heart and Vascular Institute and has served as its medical director since 2018.

In his lawsuit filed Dec. 6, Dr. Zelman alleges that the defendants, under Mr. Lauf’s leadership, “placed profit above all else, including by prioritizing revenue generation over patient safety and public health.”

Dr. Zelman says the defendants supported him “to the extent his actions were profitable.”

Yet, when he raised patient safety concerns that harmed that bottom line, Dr. Zelman says the defendants retaliated against him, including by threatening his career and reputation and unlawfully terminating his employment with the hospital.

The complaint notes Dr. Zelman is bringing this action “to recover damages for violations of the Massachusetts Healthcare Provider Whistleblower Statute ... as well as for breach of contract and common law claims.”

Dr. Zelman’s complaint alleges the defendants refused to adequately address the “dangerous care and violations of the professional standards of practice” that he reported, “resulting in harmful and tragic consequences.”

It also alleges Mr. Lauf restricted the use of a cerebral protection device used in patients undergoing transcatheter aortic-valve replacement (TAVR) deemed to be at high risk for periprocedural stroke to only those patients whose insurance reimbursed at higher rates.

Dr. Zelman says he objected to this prohibition “in accordance with his contractual and ethical obligations to ensure treatment of patients without regard to their ability to pay.”

Dr. Zelman’s lawsuit further alleges that Mr. Lauf launched a “trumped-up” and “baseless, biased, and retaliatory sham” investigation against him.

In a statement sent to the Boston Globe, Cape Cod Hospital denied Dr. Zelman’s claims that the cardiologist was retaliated against for raising patient safety issues, or that the hospital didn’t take action to improve cardiac care at the facility.
 

Voiced concerns

In a statement sent to this news organization, Dr. Zelman, now in private practice, said, “Over the past 25 years, I have been instrumental in bringing advanced cardiac care to Cape Cod. My commitment has always been to delivering the same quality outcomes and safety as the academic centers in Boston.

“Unfortunately, over the past 5 years, there has been inadequate oversight by the hospital administration and problems have occurred that in my opinion have led to serious patient consequences,” Dr. Zelman stated.

He said he has “voiced concerns over several years and they have been ignored.”

He added that Cape Cod Hospital offered him a million-dollar contract as long as he agreed to immediately issue a written statement endorsing the quality and safety of the cardiac surgical program that no longer exists.

“No amount of money was going to buy my silence,” Dr. Zelman told this news organization.

In his lawsuit, Dr. Zelman is seeking an undisclosed amount in damages, including back and front pay, lost benefits, physical and emotional distress, and attorneys’ fees.

This news organization reached out to Cape Cod Hospital for comment but has not yet received a response.

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

Interventional cardiologist Richard B. Zelman, MD, has filed a lawsuit against Cape Cod Hospital, Cape Cod Healthcare Inc., and its chief executive officer Michael K. Lauf, alleging that he was fired and maligned after raising concerns about poorly performed surgeries and poor ethical practices at the hospital.

Dr. Zelman, from Barnstable, Mass., has been affiliated with Cape Cod Hospital in Hyannis, Mass., for more than 30 years. He helped found the hospital’s Heart and Vascular Institute and has served as its medical director since 2018.

In his lawsuit filed Dec. 6, Dr. Zelman alleges that the defendants, under Mr. Lauf’s leadership, “placed profit above all else, including by prioritizing revenue generation over patient safety and public health.”

Dr. Zelman says the defendants supported him “to the extent his actions were profitable.”

Yet, when he raised patient safety concerns that harmed that bottom line, Dr. Zelman says the defendants retaliated against him, including by threatening his career and reputation and unlawfully terminating his employment with the hospital.

The complaint notes Dr. Zelman is bringing this action “to recover damages for violations of the Massachusetts Healthcare Provider Whistleblower Statute ... as well as for breach of contract and common law claims.”

Dr. Zelman’s complaint alleges the defendants refused to adequately address the “dangerous care and violations of the professional standards of practice” that he reported, “resulting in harmful and tragic consequences.”

It also alleges Mr. Lauf restricted the use of a cerebral protection device used in patients undergoing transcatheter aortic-valve replacement (TAVR) deemed to be at high risk for periprocedural stroke to only those patients whose insurance reimbursed at higher rates.

Dr. Zelman says he objected to this prohibition “in accordance with his contractual and ethical obligations to ensure treatment of patients without regard to their ability to pay.”

Dr. Zelman’s lawsuit further alleges that Mr. Lauf launched a “trumped-up” and “baseless, biased, and retaliatory sham” investigation against him.

In a statement sent to the Boston Globe, Cape Cod Hospital denied Dr. Zelman’s claims that the cardiologist was retaliated against for raising patient safety issues, or that the hospital didn’t take action to improve cardiac care at the facility.
 

Voiced concerns

In a statement sent to this news organization, Dr. Zelman, now in private practice, said, “Over the past 25 years, I have been instrumental in bringing advanced cardiac care to Cape Cod. My commitment has always been to delivering the same quality outcomes and safety as the academic centers in Boston.

“Unfortunately, over the past 5 years, there has been inadequate oversight by the hospital administration and problems have occurred that in my opinion have led to serious patient consequences,” Dr. Zelman stated.

He said he has “voiced concerns over several years and they have been ignored.”

He added that Cape Cod Hospital offered him a million-dollar contract as long as he agreed to immediately issue a written statement endorsing the quality and safety of the cardiac surgical program that no longer exists.

“No amount of money was going to buy my silence,” Dr. Zelman told this news organization.

In his lawsuit, Dr. Zelman is seeking an undisclosed amount in damages, including back and front pay, lost benefits, physical and emotional distress, and attorneys’ fees.

This news organization reached out to Cape Cod Hospital for comment but has not yet received a response.

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

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.

These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.

“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”

To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.

Sixteen of the 33 women had clinically significant mood disturbances. Compared with the other participants, these 16 women had significant upregulation of genes driving inflammatory pathways and significantly reduced activation of genes associated with viral response.

“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
 

Findings draw skepticism

“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.

In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.

“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”

Only prospective studies can answer these questions, she said.

Dr. Nicoloro-SantaBarbara agreed that further research is needed.

“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”

The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.

Two years ago, Ashley Hingston had a miscarriage. The 35-year-old Floridian and her husband had been going through in vitro fertilization when they received the news no one wants to get, but which many in their position reflexively expect: “You are going to lose the pregnancy.” 

On the other end of the line was Ms. Hingston’s physician, who offered her advice and comfort to ease the pain of the bad news.

“I was a complete wreck and could barely even talk,” Ms. Hingston recalled. “But I think my doctor knew what I was asking, and she was doing the best to answer the questions I had: Why did this happen? What does this mean? And she sat and listened to me.”

An estimated 2% of babies born in the United States each year are the result of IVF, according to 2019 data from the Centers for Disease Control and Prevention. The process is often emotionally, physically, and economically taxing for patients. According to the CDC, the chance a pregnancy will be successful through IVF is 21.3%. Consequently, doctors often find themselves the bearers of bad news.

But interaction with a care team or a string of nurses and providers, rather than a physician, is the norm for IVF patients, according to Aimee Eyvazzadeh, MD, a specialist in infertility and reproductive endocrinology in San Ramon, Calif.

“Patients see a doctor for all of 10 minutes and then they are handed off to a care team who don’t know their whole story,” she said.

For Dr. Eyvazzadeh and other health care professionals, physicians must improve the ways they share bad news, and how they divide tasks with care teams.

Personalized care works best

Providing personalized care will improve how IVF patients respond to bad news, according to Dr. Eyvazzadeh and others.

“When people have gone through so much trauma, anything you say to them, sometimes they can’t process it very well, so they have to see the information in different ways,” she told this news organization. “After each phone call, I’ll actually type up a summary for them, with links and articles for them to read, so they are directed in a way that I think is healthy so they aren’t pulled into a rabbit hole.”

Dr. Eyvazzadeh said she encourages her patients to seek counseling during IVF treatment, and even pays for their initial psychiatric consultation. Not many doctors do this, she noted.

“Taking the time to allow the patient to process the bad news is vital,” said Linda Kim, PhD, a psychiatrist at Moon Mental Health, to whom Dr. Eyvazzadeh refers couples. Sometimes, several calls are necessary.

“Rather than thinking of the conversation as a linear process, consider it a sphere of processing,” Dr. Kim said. “The patient may need space to grieve, may ask many questions, may need to clarify what happened, or may need to vent and release frustration. This is space that the patient needs to process the bad news.” (See below for more tips on how to share bad news with your patients.)

Many care teams are skilled in delivering bad news to patients, according to Liz Grill, PsyD, a psychologist at Weill Cornell Medicine, New York. The challenge for them is ensuring new nurses and clinicians continue to have empathy training, she said.

“You want to make sure clinicians are building relationships, and empathy. Whether there is a protocol to build that level of empathy, or if they have their own innate ability to build empathy, it’s about communicating in the right way,” Dr. Grill told this news organization.

But Mark Trolice, MD, a reproductive endocrinologist and infertility specialist at the University of Central Florida, Orlando, agreed that nurses should not deliver bad news, even if they have the expertise and the compassion to do so.

“It’s the doctor’s responsibility to make that call. It’s a very difficult call and it puts an unnecessary burden on your care team to be making these calls all the time,” Dr. Trolice said. “I feel the patient wants to hear from the physician who oversaw their cycle and did the procedure and embryo transfer. It shows a tremendous amount of responsibility and commitment on the part of the physician.”

Dr. Trolice also recommended clinicians refer to the HEART (Hearing, Empathy, Apology, Response, and Thanks) guidelines to ensure proper conversations with patients about bad news.

“You give the patient time to process the information and ask questions, and then we schedule another time to talk about plans going forward,” he said.

“Patients can feel powerless and not in control of what is happening, or even over their own bodies,” Dr. Kim added. “To counteract this, it can be helpful to outline projected steps as much as possible.”

For Dr. Eyvazzadeh, caring for an IVF patient is a matter of knowing your strengths.

Providing links to web resources, recommending an organic diet, and sending them to support groups (see below) are helpful, she said. “For some people, their strength isn’t engaging with patients on the same level that I do. But I still feel like there are ways that we can still make the patients feel cared for without being extreme.”

Tips on how to share bad news with patients

A guide often cited by clinicians when delivering bad news is the Buckman Six Step Protocol:

• Get the physical context right.
• Find out how much the patient knows.
• Find out how much the patient wants to know.
• Share the information.
• Respond to the patient’s feelings.
• Plan and follow through.

Linda Kim, PhD, notes that patient preference in receiving bad news is often culturally mediated. She recommends asking patients how they would want to receive bad news, especially in during IVF process, where there can be many challenges over the course of treatment. Dr. Kim also recommends these steps:

• Get as much information in advance as possible and ask your patient directly how they want bad news. When you are meeting a patient and their families for the first time, and they are filling out their intake paperwork or health forms, you may consider adding a section on “What is your preferred method of communication?” And after that, you might add, “What is the best way to tell you challenging or difficult news? Would you prefer to be by yourself or with a loved one? Please elaborate any additional preferences.” Everyone is different, and it can be helpful to hear from the patient directly how they would like to receive bad news. It will not only meet them where they are during a difficult time, it will also demonstrate to the patient that you are respecting their preferences and involving those preferences in the process.
• Try to leave enough time for a difficult conversation with a patient. Even better is if a clinician can prepare a patient that there is some disappointing or difficult news to share.
• Finally, offer discussion on next steps. It never hurts to ask the patient directly when they are ready to discuss next steps. This may take a few hours, a few days, or even a few months or longer.

Social media as support

Monica Wunderman, a patient of Dr. Eyvazzadeh’s since 2020, began her own social media campaign on Instagram to find support and give support to women experiencing IVF.

“I started scrolling and liking posts, and a girl reached out to me to ask if I needed help” in the form of emotional support, she recalls.

Instagram became a haven for Ms. Wunderman to share information, experiences, and support with others. It also allowed her to create a network of support and meet other women, like Ashley Hingston, going through similar struggles.

Ms. Wunderman has been through four rounds of IVF so far. Three were completely unsuccessful; the last ended in miscarriage. Although she and her husband are trying again with a surrogate, the uncertainty remains. And she feels the health care system should be offering her – and the other would-be parents she has met online – more support.

“We place such importance as a society on growing families,” she says. “But then we do very little to support those who want them and struggle.”

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

Two years ago, Ashley Hingston had a miscarriage. The 35-year-old Floridian and her husband had been going through in vitro fertilization when they received the news no one wants to get, but which many in their position reflexively expect: “You are going to lose the pregnancy.” 

On the other end of the line was Ms. Hingston’s physician, who offered her advice and comfort to ease the pain of the bad news.

“I was a complete wreck and could barely even talk,” Ms. Hingston recalled. “But I think my doctor knew what I was asking, and she was doing the best to answer the questions I had: Why did this happen? What does this mean? And she sat and listened to me.”

An estimated 2% of babies born in the United States each year are the result of IVF, according to 2019 data from the Centers for Disease Control and Prevention. The process is often emotionally, physically, and economically taxing for patients. According to the CDC, the chance a pregnancy will be successful through IVF is 21.3%. Consequently, doctors often find themselves the bearers of bad news.

But interaction with a care team or a string of nurses and providers, rather than a physician, is the norm for IVF patients, according to Aimee Eyvazzadeh, MD, a specialist in infertility and reproductive endocrinology in San Ramon, Calif.

“Patients see a doctor for all of 10 minutes and then they are handed off to a care team who don’t know their whole story,” she said.

For Dr. Eyvazzadeh and other health care professionals, physicians must improve the ways they share bad news, and how they divide tasks with care teams.

Personalized care works best

Providing personalized care will improve how IVF patients respond to bad news, according to Dr. Eyvazzadeh and others.

“When people have gone through so much trauma, anything you say to them, sometimes they can’t process it very well, so they have to see the information in different ways,” she told this news organization. “After each phone call, I’ll actually type up a summary for them, with links and articles for them to read, so they are directed in a way that I think is healthy so they aren’t pulled into a rabbit hole.”

Dr. Eyvazzadeh said she encourages her patients to seek counseling during IVF treatment, and even pays for their initial psychiatric consultation. Not many doctors do this, she noted.

“Taking the time to allow the patient to process the bad news is vital,” said Linda Kim, PhD, a psychiatrist at Moon Mental Health, to whom Dr. Eyvazzadeh refers couples. Sometimes, several calls are necessary.

“Rather than thinking of the conversation as a linear process, consider it a sphere of processing,” Dr. Kim said. “The patient may need space to grieve, may ask many questions, may need to clarify what happened, or may need to vent and release frustration. This is space that the patient needs to process the bad news.” (See below for more tips on how to share bad news with your patients.)

Many care teams are skilled in delivering bad news to patients, according to Liz Grill, PsyD, a psychologist at Weill Cornell Medicine, New York. The challenge for them is ensuring new nurses and clinicians continue to have empathy training, she said.

“You want to make sure clinicians are building relationships, and empathy. Whether there is a protocol to build that level of empathy, or if they have their own innate ability to build empathy, it’s about communicating in the right way,” Dr. Grill told this news organization.

But Mark Trolice, MD, a reproductive endocrinologist and infertility specialist at the University of Central Florida, Orlando, agreed that nurses should not deliver bad news, even if they have the expertise and the compassion to do so.

“It’s the doctor’s responsibility to make that call. It’s a very difficult call and it puts an unnecessary burden on your care team to be making these calls all the time,” Dr. Trolice said. “I feel the patient wants to hear from the physician who oversaw their cycle and did the procedure and embryo transfer. It shows a tremendous amount of responsibility and commitment on the part of the physician.”

Dr. Trolice also recommended clinicians refer to the HEART (Hearing, Empathy, Apology, Response, and Thanks) guidelines to ensure proper conversations with patients about bad news.

“You give the patient time to process the information and ask questions, and then we schedule another time to talk about plans going forward,” he said.

“Patients can feel powerless and not in control of what is happening, or even over their own bodies,” Dr. Kim added. “To counteract this, it can be helpful to outline projected steps as much as possible.”

For Dr. Eyvazzadeh, caring for an IVF patient is a matter of knowing your strengths.

Providing links to web resources, recommending an organic diet, and sending them to support groups (see below) are helpful, she said. “For some people, their strength isn’t engaging with patients on the same level that I do. But I still feel like there are ways that we can still make the patients feel cared for without being extreme.”

Tips on how to share bad news with patients

A guide often cited by clinicians when delivering bad news is the Buckman Six Step Protocol:

• Get the physical context right.
• Find out how much the patient knows.
• Find out how much the patient wants to know.
• Share the information.
• Respond to the patient’s feelings.
• Plan and follow through.

Linda Kim, PhD, notes that patient preference in receiving bad news is often culturally mediated. She recommends asking patients how they would want to receive bad news, especially in during IVF process, where there can be many challenges over the course of treatment. Dr. Kim also recommends these steps:

• Get as much information in advance as possible and ask your patient directly how they want bad news. When you are meeting a patient and their families for the first time, and they are filling out their intake paperwork or health forms, you may consider adding a section on “What is your preferred method of communication?” And after that, you might add, “What is the best way to tell you challenging or difficult news? Would you prefer to be by yourself or with a loved one? Please elaborate any additional preferences.” Everyone is different, and it can be helpful to hear from the patient directly how they would like to receive bad news. It will not only meet them where they are during a difficult time, it will also demonstrate to the patient that you are respecting their preferences and involving those preferences in the process.
• Try to leave enough time for a difficult conversation with a patient. Even better is if a clinician can prepare a patient that there is some disappointing or difficult news to share.
• Finally, offer discussion on next steps. It never hurts to ask the patient directly when they are ready to discuss next steps. This may take a few hours, a few days, or even a few months or longer.

Social media as support

Monica Wunderman, a patient of Dr. Eyvazzadeh’s since 2020, began her own social media campaign on Instagram to find support and give support to women experiencing IVF.

“I started scrolling and liking posts, and a girl reached out to me to ask if I needed help” in the form of emotional support, she recalls.

Instagram became a haven for Ms. Wunderman to share information, experiences, and support with others. It also allowed her to create a network of support and meet other women, like Ashley Hingston, going through similar struggles.

Ms. Wunderman has been through four rounds of IVF so far. Three were completely unsuccessful; the last ended in miscarriage. Although she and her husband are trying again with a surrogate, the uncertainty remains. And she feels the health care system should be offering her – and the other would-be parents she has met online – more support.

“We place such importance as a society on growing families,” she says. “But then we do very little to support those who want them and struggle.”

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

Two years ago, Ashley Hingston had a miscarriage. The 35-year-old Floridian and her husband had been going through in vitro fertilization when they received the news no one wants to get, but which many in their position reflexively expect: “You are going to lose the pregnancy.” 

On the other end of the line was Ms. Hingston’s physician, who offered her advice and comfort to ease the pain of the bad news.

“I was a complete wreck and could barely even talk,” Ms. Hingston recalled. “But I think my doctor knew what I was asking, and she was doing the best to answer the questions I had: Why did this happen? What does this mean? And she sat and listened to me.”

An estimated 2% of babies born in the United States each year are the result of IVF, according to 2019 data from the Centers for Disease Control and Prevention. The process is often emotionally, physically, and economically taxing for patients. According to the CDC, the chance a pregnancy will be successful through IVF is 21.3%. Consequently, doctors often find themselves the bearers of bad news.

But interaction with a care team or a string of nurses and providers, rather than a physician, is the norm for IVF patients, according to Aimee Eyvazzadeh, MD, a specialist in infertility and reproductive endocrinology in San Ramon, Calif.

“Patients see a doctor for all of 10 minutes and then they are handed off to a care team who don’t know their whole story,” she said.

For Dr. Eyvazzadeh and other health care professionals, physicians must improve the ways they share bad news, and how they divide tasks with care teams.

Personalized care works best

Providing personalized care will improve how IVF patients respond to bad news, according to Dr. Eyvazzadeh and others.

“When people have gone through so much trauma, anything you say to them, sometimes they can’t process it very well, so they have to see the information in different ways,” she told this news organization. “After each phone call, I’ll actually type up a summary for them, with links and articles for them to read, so they are directed in a way that I think is healthy so they aren’t pulled into a rabbit hole.”

Dr. Eyvazzadeh said she encourages her patients to seek counseling during IVF treatment, and even pays for their initial psychiatric consultation. Not many doctors do this, she noted.

“Taking the time to allow the patient to process the bad news is vital,” said Linda Kim, PhD, a psychiatrist at Moon Mental Health, to whom Dr. Eyvazzadeh refers couples. Sometimes, several calls are necessary.

“Rather than thinking of the conversation as a linear process, consider it a sphere of processing,” Dr. Kim said. “The patient may need space to grieve, may ask many questions, may need to clarify what happened, or may need to vent and release frustration. This is space that the patient needs to process the bad news.” (See below for more tips on how to share bad news with your patients.)

Many care teams are skilled in delivering bad news to patients, according to Liz Grill, PsyD, a psychologist at Weill Cornell Medicine, New York. The challenge for them is ensuring new nurses and clinicians continue to have empathy training, she said.

“You want to make sure clinicians are building relationships, and empathy. Whether there is a protocol to build that level of empathy, or if they have their own innate ability to build empathy, it’s about communicating in the right way,” Dr. Grill told this news organization.

But Mark Trolice, MD, a reproductive endocrinologist and infertility specialist at the University of Central Florida, Orlando, agreed that nurses should not deliver bad news, even if they have the expertise and the compassion to do so.

“It’s the doctor’s responsibility to make that call. It’s a very difficult call and it puts an unnecessary burden on your care team to be making these calls all the time,” Dr. Trolice said. “I feel the patient wants to hear from the physician who oversaw their cycle and did the procedure and embryo transfer. It shows a tremendous amount of responsibility and commitment on the part of the physician.”

Dr. Trolice also recommended clinicians refer to the HEART (Hearing, Empathy, Apology, Response, and Thanks) guidelines to ensure proper conversations with patients about bad news.

“You give the patient time to process the information and ask questions, and then we schedule another time to talk about plans going forward,” he said.

“Patients can feel powerless and not in control of what is happening, or even over their own bodies,” Dr. Kim added. “To counteract this, it can be helpful to outline projected steps as much as possible.”

For Dr. Eyvazzadeh, caring for an IVF patient is a matter of knowing your strengths.

Providing links to web resources, recommending an organic diet, and sending them to support groups (see below) are helpful, she said. “For some people, their strength isn’t engaging with patients on the same level that I do. But I still feel like there are ways that we can still make the patients feel cared for without being extreme.”

Tips on how to share bad news with patients

A guide often cited by clinicians when delivering bad news is the Buckman Six Step Protocol:

• Get the physical context right.
• Find out how much the patient knows.
• Find out how much the patient wants to know.
• Share the information.
• Respond to the patient’s feelings.
• Plan and follow through.

Linda Kim, PhD, notes that patient preference in receiving bad news is often culturally mediated. She recommends asking patients how they would want to receive bad news, especially in during IVF process, where there can be many challenges over the course of treatment. Dr. Kim also recommends these steps:

• Get as much information in advance as possible and ask your patient directly how they want bad news. When you are meeting a patient and their families for the first time, and they are filling out their intake paperwork or health forms, you may consider adding a section on “What is your preferred method of communication?” And after that, you might add, “What is the best way to tell you challenging or difficult news? Would you prefer to be by yourself or with a loved one? Please elaborate any additional preferences.” Everyone is different, and it can be helpful to hear from the patient directly how they would like to receive bad news. It will not only meet them where they are during a difficult time, it will also demonstrate to the patient that you are respecting their preferences and involving those preferences in the process.
• Try to leave enough time for a difficult conversation with a patient. Even better is if a clinician can prepare a patient that there is some disappointing or difficult news to share.
• Finally, offer discussion on next steps. It never hurts to ask the patient directly when they are ready to discuss next steps. This may take a few hours, a few days, or even a few months or longer.

Social media as support

Monica Wunderman, a patient of Dr. Eyvazzadeh’s since 2020, began her own social media campaign on Instagram to find support and give support to women experiencing IVF.

“I started scrolling and liking posts, and a girl reached out to me to ask if I needed help” in the form of emotional support, she recalls.

Instagram became a haven for Ms. Wunderman to share information, experiences, and support with others. It also allowed her to create a network of support and meet other women, like Ashley Hingston, going through similar struggles.

Ms. Wunderman has been through four rounds of IVF so far. Three were completely unsuccessful; the last ended in miscarriage. Although she and her husband are trying again with a surrogate, the uncertainty remains. And she feels the health care system should be offering her – and the other would-be parents she has met online – more support.

“We place such importance as a society on growing families,” she says. “But then we do very little to support those who want them and struggle.”

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

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

Lawmakers in several conservative-led states – including Montana, Wyoming, Missouri, and Mississippi – are expected to consider proposals to provide a year of continuous health coverage to new mothers enrolled in Medicaid.

Medicaid beneficiaries nationwide are guaranteed continuous postpartum coverage during the ongoing covid-19 public health emergency. But momentum has been building for states to extend the default 60-day required coverage period ahead of the emergency’s eventual end. Approximately 42% of births nationwide are covered under Medicaid, the federal-state health insurance program for low-income people, and extending postpartum coverage aims to reduce the risk of pregnancy-related deaths and illnesses by ensuring that new mothers’ medical care isn’t interrupted.

The push comes as a provision in the American Rescue Plan Act makes extending postpartum Medicaid coverage easier because states no longer need to apply for a waiver. A renewed focus on maternal health amid high U.S. maternal mortality rates also is driving the proposals, as is the expectation that more women will need postpartum care as state abortion bans proliferate in the wake of the U.S. Supreme Court’s decision to eliminate federal protections.

Thirty-five states and Washington have already extended, or plan to extend, postpartum eligibility in their Medicaid programs. That number includes Texas and Wisconsin, which did not implement the ARPA provision but have proposed limited extensions of 6 months and 90 days, respectively.

The 15 states that limit postpartum Medicaid eligibility to 60 days are predominantly a swath of Republican-led states that stretch from the Mountain West to the South. But that could change when legislative sessions start in the new year.

In Montana, Republican Gov. Greg Gianforte and Department of Public Health and Human Services Director Charlie Brereton included 12-month postpartum eligibility in the governor’s proposed state budget. It would cost $9.2 million in federal and state funding over the next 2 years, according to the proposal, with the federal government covering nearly 70%.

A 2021 U.S. Department of Health and Human Services report estimated about 2,000 women in Montana would benefit from the change. State health department spokesperson Jon Ebelt said state officials’ estimate is half that number. The reason for the disparity was not immediately clear.

Mr. Brereton considers the “extension of coverage for new mothers to be a pro-life, pro-family reform,” Mr. Ebelt said.

To become law, the proposal must be approved by state lawmakers once the legislative session begins in January. It has already received enthusiastic support from the senior Democrat on the committee that oversees the health department’s budget. “Continuous eligibility for women after they have a baby is really important,” said state Rep. Mary Caferro during the Children’s Legislative Forum in Helena on Nov. 30.

The top Republican on the committee, state Rep.-elect Bob Keenan, said he hasn’t dug in on the governor’s budget proposal but added that he plans to survey his fellow lawmakers and health care providers on the postpartum extension. “I wouldn’t dare venture a guess as to its acceptance,” he said.

Nationwide, more than 1 in 5 mothers whose pregnancies were covered by Medicaid lose their insurance within 6 months of giving birth, and 1 in 3 pregnancy-related deaths happen between a week and a year after a birth occurs, according to federal health officials.

The United States had the highest overall maternal mortality rate, by far, among wealthy nations in 2020, at 23.8 deaths per 100,000 births, according to a report by the Commonwealth Fund, a foundation that supports research focused on health care issues. The rate for Black women in the United States is even higher, 55.3 deaths.

“Many maternal deaths result from missed or delayed opportunities for treatment,” the report said.

The maternal mortality rate in Montana is not publicly available because the Centers for Disease Control and Prevention suppressed the state data in 2020 “due to reliability and confidentiality restrictions.” Mr. Ebelt, the state health department spokesperson, could not provide a rate before this article’s publication.

Annie Glover, a senior research scientist for the University of Montana’s Rural Institute for Inclusive Communities, said the governor’s proposal to extend postpartum Medicaid coverage could make a significant difference in improving overall maternal health in Montana. The university was awarded a federal grant this year for such efforts, particularly to lower the mortality rate among Native Americans, and Ms. Glover said the state measure could further reduce rates.

“The reason really has to do with maintaining access to care during this very critical period,” Ms. Glover said. That goes for helping mothers with postpartum depression, as well as medical conditions like high blood pressure that require follow-ups with a physician well after delivery, she said.

In Wyoming, a legislative committee voted 6-5 in August to introduce a bill in the next session; dissenters cited the cost and their reluctance to further entangle the state in federal government programs.

About a third of Wyoming births are covered by Medicaid, and state officials estimate about 1,250 women would benefit from the change.

Postpartum eligibility bills are also expected to be taken up by legislators in Missouri and Mississippi, two states that have previously grappled with the issue. Both states have outlawed most abortions since the U.S. Supreme Court lifted federal protections in June, and Mississippi leaders have said additional postpartum care is needed because of the thousands of additional births expected as a result of the state’s ban.

A proposed coverage expansion died in the Mississippi House last session, but Lt. Gov. Delbert Hosemann said the Senate will revive the measure, according to Mississippi Today.

Last year, federal officials approved a Medicaid waiver for Missouri that allows the state to extend postpartum eligibility. But state officials delayed implementing the change to determine how enrollment would be affected by Missouri voters’ decision in August 2020 to expand Medicaid eligibility to more people. The delay prompted a bill to be filed last session that would have extended postpartum coverage by a year. That measure died, but a state lawmaker has pre-filed a bill that will bring back the debate in the upcoming session.

In Idaho, a children’s advocacy group said it will press lawmakers to approve a postpartum eligibility extension, among other measures, after the state banned nearly all abortions this year.
 

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

Lawmakers in several conservative-led states – including Montana, Wyoming, Missouri, and Mississippi – are expected to consider proposals to provide a year of continuous health coverage to new mothers enrolled in Medicaid.

Medicaid beneficiaries nationwide are guaranteed continuous postpartum coverage during the ongoing covid-19 public health emergency. But momentum has been building for states to extend the default 60-day required coverage period ahead of the emergency’s eventual end. Approximately 42% of births nationwide are covered under Medicaid, the federal-state health insurance program for low-income people, and extending postpartum coverage aims to reduce the risk of pregnancy-related deaths and illnesses by ensuring that new mothers’ medical care isn’t interrupted.

The push comes as a provision in the American Rescue Plan Act makes extending postpartum Medicaid coverage easier because states no longer need to apply for a waiver. A renewed focus on maternal health amid high U.S. maternal mortality rates also is driving the proposals, as is the expectation that more women will need postpartum care as state abortion bans proliferate in the wake of the U.S. Supreme Court’s decision to eliminate federal protections.

Thirty-five states and Washington have already extended, or plan to extend, postpartum eligibility in their Medicaid programs. That number includes Texas and Wisconsin, which did not implement the ARPA provision but have proposed limited extensions of 6 months and 90 days, respectively.

The 15 states that limit postpartum Medicaid eligibility to 60 days are predominantly a swath of Republican-led states that stretch from the Mountain West to the South. But that could change when legislative sessions start in the new year.

In Montana, Republican Gov. Greg Gianforte and Department of Public Health and Human Services Director Charlie Brereton included 12-month postpartum eligibility in the governor’s proposed state budget. It would cost $9.2 million in federal and state funding over the next 2 years, according to the proposal, with the federal government covering nearly 70%.

A 2021 U.S. Department of Health and Human Services report estimated about 2,000 women in Montana would benefit from the change. State health department spokesperson Jon Ebelt said state officials’ estimate is half that number. The reason for the disparity was not immediately clear.

Mr. Brereton considers the “extension of coverage for new mothers to be a pro-life, pro-family reform,” Mr. Ebelt said.

To become law, the proposal must be approved by state lawmakers once the legislative session begins in January. It has already received enthusiastic support from the senior Democrat on the committee that oversees the health department’s budget. “Continuous eligibility for women after they have a baby is really important,” said state Rep. Mary Caferro during the Children’s Legislative Forum in Helena on Nov. 30.

The top Republican on the committee, state Rep.-elect Bob Keenan, said he hasn’t dug in on the governor’s budget proposal but added that he plans to survey his fellow lawmakers and health care providers on the postpartum extension. “I wouldn’t dare venture a guess as to its acceptance,” he said.

Nationwide, more than 1 in 5 mothers whose pregnancies were covered by Medicaid lose their insurance within 6 months of giving birth, and 1 in 3 pregnancy-related deaths happen between a week and a year after a birth occurs, according to federal health officials.

The United States had the highest overall maternal mortality rate, by far, among wealthy nations in 2020, at 23.8 deaths per 100,000 births, according to a report by the Commonwealth Fund, a foundation that supports research focused on health care issues. The rate for Black women in the United States is even higher, 55.3 deaths.

“Many maternal deaths result from missed or delayed opportunities for treatment,” the report said.

The maternal mortality rate in Montana is not publicly available because the Centers for Disease Control and Prevention suppressed the state data in 2020 “due to reliability and confidentiality restrictions.” Mr. Ebelt, the state health department spokesperson, could not provide a rate before this article’s publication.

Annie Glover, a senior research scientist for the University of Montana’s Rural Institute for Inclusive Communities, said the governor’s proposal to extend postpartum Medicaid coverage could make a significant difference in improving overall maternal health in Montana. The university was awarded a federal grant this year for such efforts, particularly to lower the mortality rate among Native Americans, and Ms. Glover said the state measure could further reduce rates.

“The reason really has to do with maintaining access to care during this very critical period,” Ms. Glover said. That goes for helping mothers with postpartum depression, as well as medical conditions like high blood pressure that require follow-ups with a physician well after delivery, she said.

In Wyoming, a legislative committee voted 6-5 in August to introduce a bill in the next session; dissenters cited the cost and their reluctance to further entangle the state in federal government programs.

About a third of Wyoming births are covered by Medicaid, and state officials estimate about 1,250 women would benefit from the change.

Postpartum eligibility bills are also expected to be taken up by legislators in Missouri and Mississippi, two states that have previously grappled with the issue. Both states have outlawed most abortions since the U.S. Supreme Court lifted federal protections in June, and Mississippi leaders have said additional postpartum care is needed because of the thousands of additional births expected as a result of the state’s ban.

A proposed coverage expansion died in the Mississippi House last session, but Lt. Gov. Delbert Hosemann said the Senate will revive the measure, according to Mississippi Today.

Last year, federal officials approved a Medicaid waiver for Missouri that allows the state to extend postpartum eligibility. But state officials delayed implementing the change to determine how enrollment would be affected by Missouri voters’ decision in August 2020 to expand Medicaid eligibility to more people. The delay prompted a bill to be filed last session that would have extended postpartum coverage by a year. That measure died, but a state lawmaker has pre-filed a bill that will bring back the debate in the upcoming session.

In Idaho, a children’s advocacy group said it will press lawmakers to approve a postpartum eligibility extension, among other measures, after the state banned nearly all abortions this year.