Breast Cancer

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.

Standard adjuvant chemotherapy remained superior to capecitabine in older patients with early breast cancer, according to long-term follow-up results from a randomized study.

“We previously reported the primary analysis after a median follow-up of 2.4 years,” wrote Hyman B. Muss, MD, of the University of North Carolina, Chapel Hill, and his colleagues in Journal of Clinical Oncology.

“We now assess the risks and benefits of treatment after a median follow-up time of 11.4 years,” they said.

The Cancer and Leukemia Group B 49907 trial included 633 women aged 65 years and over with early breast cancer. Study patients were randomly assigned to receive either standard adjuvant chemotherapy (either cyclophosphamide and doxorubicin, methotrexate and fluorouracil, or cyclophosphamide) or capecitabine.

The study was designed to evaluate noninferiority of capecitabine versus standard chemotherapy. The primary outcome measured was recurrence-free survival (RFS); overall survival (OS) was included as a secondary endpoint.

After analysis, the researchers reported that the 10-year RFS rates were 56% with standard chemotherapy versus 50% with capecitabine (hazard ratio, 0.80; P = .03).

In addition, the breast cancer–specific survival rates were 88% and 82% in patients treated with standard chemotherapy, compared with capecitabine, respectively (hazard ratio, 0.62; P = .03). OS rates were 62% and 56% in the same groups (HR, 0.84; P = .16).

“With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease,” Dr. Muss and his colleagues wrote.

The researchers acknowledged that the presence of comorbidities in this older population may diminish overall survival benefits.

“Optimally, we must increase the number of older patients in cancer clinical trials to have accurate data on outcomes, especially toxicity, for newer agents,” they concluded.

The study was funded by the National Cancer Institute of the National Institutes of Health. The authors reported financial affiliations with Boehringer Ingelheim, Celgene, Genentech, Novartis, Puma Biotechnology, Pfizer, Sanofi, Seattle Genetics, and several others.

SOURCE: Muss HB et al. J Clin Oncol. 2019 Jul 24. doi: 10.1200/JCO.19.00647.

Among women with breast cancer, risk of death is more than twice as high for those who are childhood cancer survivors than for those in whom this cancer is their first, found a retrospective cohort study. However, the excess deaths are mainly from comorbidities related to previous therapies.

Breast cancer is among the leading subsequent malignancies in adult survivors of pediatric cancers, note the investigators, who were led by Chaya S. Moskowitz, PhD, of the department of epidemiology and biostatistics at Memorial Sloan Kettering Cancer Center in New York. But outcomes after this diagnosis are not well characterized.

The investigators used the Childhood Cancer Survivor Study to identify 274 female 5-year survivors of cancer diagnosed before age 21 years who received a subsequent breast cancer diagnosis at a median age of 38 years. They then used Surveillance, Epidemiology, and End Results data to identify a control group of 1,095 female patients with de novo breast cancer matched on age, race, stage, and year of breast cancer diagnosis.

The 10-year overall survival was 73% among the childhood cancer survivors, investigators reported in the Journal of Clinical Oncology.

Compared with the control women whose breast cancer was their first cancer, the women with breast cancer who were childhood cancer survivors had an elevated risk of death from any cause (hazard ratio, 2.2) that persisted after analyses were adjusted for receipt of chemotherapy and radiation therapy (HR, 2.4). In addition, findings were similar in analyses restricted to women with ductal carcinoma in situ and women with stage 1-3 breast cancer.

The childhood cancer survivors had a modestly elevated risk of dying from breast cancer (HR, 1.3) but a sharply elevated risk of dying from other health-related causes, including other subsequent malignancies and cardiovascular or pulmonary disease often related to previous therapies (HR, 5.5).

In addition, the childhood cancer survivors had a higher cumulative incidence of diagnosis of second asynchronous breast cancers a year or more later, relative to the women in whom breast cancer was their first cancer (P less than .001). The 5-year cumulative incidence was 8.0% among the childhood cancer survivors and just 2.7% among the control women.

“Although BC [breast cancer]-specific mortality was modestly higher in childhood cancer survivors, deaths attributable to health conditions other than BC seem to be the driving force in the elevated all-cause mortality,” Dr. Moskowitz and colleagues wrote.

“To change the dismal outcomes of these women, our results suggest that it is imperative that at the time of a secondary BC diagnosis, they have a comprehensive evaluation that extends beyond a singular focus of the BC,” they concluded. “This should include an assessment of existing cardiopulmonary disease and a plan for future cancer screening to optimize the management of comorbidities and cardiopulmonary disease and prolong the lifespan of these survivors.”

Dr. Moskowitz reported that she has a consulting or advisory role with Bioclinica. The study was supported by the National Cancer Institute, a Memorial Sloan Kettering Cancer Center Core grant, the Meg Berté Owen Foundation, and the American Lebanese Syrian Associated Charities.

SOURCE: Moskowitz CS et al. J Clin Oncol. 2019 Jul 1. doi: 10.1200/JCO.18.02219.

Among women with breast cancer, risk of death is more than twice as high for those who are childhood cancer survivors than for those in whom this cancer is their first, found a retrospective cohort study. However, the excess deaths are mainly from comorbidities related to previous therapies.

Breast cancer is among the leading subsequent malignancies in adult survivors of pediatric cancers, note the investigators, who were led by Chaya S. Moskowitz, PhD, of the department of epidemiology and biostatistics at Memorial Sloan Kettering Cancer Center in New York. But outcomes after this diagnosis are not well characterized.

The investigators used the Childhood Cancer Survivor Study to identify 274 female 5-year survivors of cancer diagnosed before age 21 years who received a subsequent breast cancer diagnosis at a median age of 38 years. They then used Surveillance, Epidemiology, and End Results data to identify a control group of 1,095 female patients with de novo breast cancer matched on age, race, stage, and year of breast cancer diagnosis.

The 10-year overall survival was 73% among the childhood cancer survivors, investigators reported in the Journal of Clinical Oncology.

Compared with the control women whose breast cancer was their first cancer, the women with breast cancer who were childhood cancer survivors had an elevated risk of death from any cause (hazard ratio, 2.2) that persisted after analyses were adjusted for receipt of chemotherapy and radiation therapy (HR, 2.4). In addition, findings were similar in analyses restricted to women with ductal carcinoma in situ and women with stage 1-3 breast cancer.

The childhood cancer survivors had a modestly elevated risk of dying from breast cancer (HR, 1.3) but a sharply elevated risk of dying from other health-related causes, including other subsequent malignancies and cardiovascular or pulmonary disease often related to previous therapies (HR, 5.5).

In addition, the childhood cancer survivors had a higher cumulative incidence of diagnosis of second asynchronous breast cancers a year or more later, relative to the women in whom breast cancer was their first cancer (P less than .001). The 5-year cumulative incidence was 8.0% among the childhood cancer survivors and just 2.7% among the control women.

“Although BC [breast cancer]-specific mortality was modestly higher in childhood cancer survivors, deaths attributable to health conditions other than BC seem to be the driving force in the elevated all-cause mortality,” Dr. Moskowitz and colleagues wrote.

“To change the dismal outcomes of these women, our results suggest that it is imperative that at the time of a secondary BC diagnosis, they have a comprehensive evaluation that extends beyond a singular focus of the BC,” they concluded. “This should include an assessment of existing cardiopulmonary disease and a plan for future cancer screening to optimize the management of comorbidities and cardiopulmonary disease and prolong the lifespan of these survivors.”

Dr. Moskowitz reported that she has a consulting or advisory role with Bioclinica. The study was supported by the National Cancer Institute, a Memorial Sloan Kettering Cancer Center Core grant, the Meg Berté Owen Foundation, and the American Lebanese Syrian Associated Charities.

SOURCE: Moskowitz CS et al. J Clin Oncol. 2019 Jul 1. doi: 10.1200/JCO.18.02219.

Among women with breast cancer, risk of death is more than twice as high for those who are childhood cancer survivors than for those in whom this cancer is their first, found a retrospective cohort study. However, the excess deaths are mainly from comorbidities related to previous therapies.

Breast cancer is among the leading subsequent malignancies in adult survivors of pediatric cancers, note the investigators, who were led by Chaya S. Moskowitz, PhD, of the department of epidemiology and biostatistics at Memorial Sloan Kettering Cancer Center in New York. But outcomes after this diagnosis are not well characterized.

The investigators used the Childhood Cancer Survivor Study to identify 274 female 5-year survivors of cancer diagnosed before age 21 years who received a subsequent breast cancer diagnosis at a median age of 38 years. They then used Surveillance, Epidemiology, and End Results data to identify a control group of 1,095 female patients with de novo breast cancer matched on age, race, stage, and year of breast cancer diagnosis.

The 10-year overall survival was 73% among the childhood cancer survivors, investigators reported in the Journal of Clinical Oncology.

Compared with the control women whose breast cancer was their first cancer, the women with breast cancer who were childhood cancer survivors had an elevated risk of death from any cause (hazard ratio, 2.2) that persisted after analyses were adjusted for receipt of chemotherapy and radiation therapy (HR, 2.4). In addition, findings were similar in analyses restricted to women with ductal carcinoma in situ and women with stage 1-3 breast cancer.

The childhood cancer survivors had a modestly elevated risk of dying from breast cancer (HR, 1.3) but a sharply elevated risk of dying from other health-related causes, including other subsequent malignancies and cardiovascular or pulmonary disease often related to previous therapies (HR, 5.5).

In addition, the childhood cancer survivors had a higher cumulative incidence of diagnosis of second asynchronous breast cancers a year or more later, relative to the women in whom breast cancer was their first cancer (P less than .001). The 5-year cumulative incidence was 8.0% among the childhood cancer survivors and just 2.7% among the control women.

“Although BC [breast cancer]-specific mortality was modestly higher in childhood cancer survivors, deaths attributable to health conditions other than BC seem to be the driving force in the elevated all-cause mortality,” Dr. Moskowitz and colleagues wrote.

“To change the dismal outcomes of these women, our results suggest that it is imperative that at the time of a secondary BC diagnosis, they have a comprehensive evaluation that extends beyond a singular focus of the BC,” they concluded. “This should include an assessment of existing cardiopulmonary disease and a plan for future cancer screening to optimize the management of comorbidities and cardiopulmonary disease and prolong the lifespan of these survivors.”

Dr. Moskowitz reported that she has a consulting or advisory role with Bioclinica. The study was supported by the National Cancer Institute, a Memorial Sloan Kettering Cancer Center Core grant, the Meg Berté Owen Foundation, and the American Lebanese Syrian Associated Charities.

SOURCE: Moskowitz CS et al. J Clin Oncol. 2019 Jul 1. doi: 10.1200/JCO.18.02219.

Odds of triple-negative breast cancer (TNBC) are elevated for minority women and younger women, results of a nationwide cross-sectional cohort study of more than a million breast cancer cases confirm.

Previous studies have suggested certain sociodemographic groups are disproportionately affected by TNBC, but have been limited by the population studied, size, and characteristics assessed, note the investigators, who were led by Lia C. Scott, PhD, MPH, of the division of epidemiology and biostatistics at the School of Public Health, Georgia State University, Atlanta. “It is imperative that cancer research identify factors that drive disparities and focus on prevention,” they wrote in Cancer.

Dr. Scott and coinvestigators used the United States Cancer Statistics database to identify 1,151,724 cases of breast cancer diagnosed during 2010-2014 in 39 states having the necessary data. TNBC accounted for roughly 8.4% of all cases.

In unadjusted analyses using non-Hispanic white women as the comparator, odds of TNBC were significantly higher for non-Hispanic black women (odds ratio, 2.27), Hispanic women (OR, 1.22), and American Indian/Alaska Native women (OR, 1.26). On the other hand, odds were lower for Asian women (OR, 0.92).

By age group, compared with women 50-64 years old, women younger than 40 years were most likely to have the TNBC phenotype (OR, 1.95), while women aged 75 or older were least likely (OR, 0.75). Odds of TNBC were also significantly elevated for women whose cancer was diagnosed at stage III or higher (OR, 1.69) or at stage IV (OR, 1.47).

Findings were essentially the same in analyses simultaneously adjusted for age, race, and stage.

“The results of the current study demonstrated that there is a significant burden of disease in TNBC diagnosed among women of color, specifically non-Hispanic black women, and younger women,” Dr. Scott and coinvestigators write. “Given the large sample size and geospatial coverage of the data, these results are somewhat different from and also more generalizable, compared with data from previous studies.”

“With the advent and availability of more comprehensive cancer data, such as the United States Cancer Statistics database, it is important that we continue to explore disparities in order to better inform practice and policy around screenable cancers like breast cancer,” she further commented in a statement. “We hope that this update on the epidemiology of triple-negative breast cancer can provide a basis to further explore contributing factors in future research.”

Dr. Scott disclosed that she received a Dissertation Training Grant (F31-Diversity) from the National Institutes of Health. The study was funded by the National Institute on Minority Health and Health Disparities of the National Institutes of Health; the Centers for Disease Control and Prevention’s National Program of Cancer Registries contributed funds to cover the standard research data center fees for researchers conducting analyses under approved research projects.

SOURCE: Scott LC et al. Cancer. 2019 Jul 8. doi: 10.1002/cncr.32207.

Odds of triple-negative breast cancer (TNBC) are elevated for minority women and younger women, results of a nationwide cross-sectional cohort study of more than a million breast cancer cases confirm.

Previous studies have suggested certain sociodemographic groups are disproportionately affected by TNBC, but have been limited by the population studied, size, and characteristics assessed, note the investigators, who were led by Lia C. Scott, PhD, MPH, of the division of epidemiology and biostatistics at the School of Public Health, Georgia State University, Atlanta. “It is imperative that cancer research identify factors that drive disparities and focus on prevention,” they wrote in Cancer.

Dr. Scott and coinvestigators used the United States Cancer Statistics database to identify 1,151,724 cases of breast cancer diagnosed during 2010-2014 in 39 states having the necessary data. TNBC accounted for roughly 8.4% of all cases.

In unadjusted analyses using non-Hispanic white women as the comparator, odds of TNBC were significantly higher for non-Hispanic black women (odds ratio, 2.27), Hispanic women (OR, 1.22), and American Indian/Alaska Native women (OR, 1.26). On the other hand, odds were lower for Asian women (OR, 0.92).

By age group, compared with women 50-64 years old, women younger than 40 years were most likely to have the TNBC phenotype (OR, 1.95), while women aged 75 or older were least likely (OR, 0.75). Odds of TNBC were also significantly elevated for women whose cancer was diagnosed at stage III or higher (OR, 1.69) or at stage IV (OR, 1.47).

Findings were essentially the same in analyses simultaneously adjusted for age, race, and stage.

“The results of the current study demonstrated that there is a significant burden of disease in TNBC diagnosed among women of color, specifically non-Hispanic black women, and younger women,” Dr. Scott and coinvestigators write. “Given the large sample size and geospatial coverage of the data, these results are somewhat different from and also more generalizable, compared with data from previous studies.”

“With the advent and availability of more comprehensive cancer data, such as the United States Cancer Statistics database, it is important that we continue to explore disparities in order to better inform practice and policy around screenable cancers like breast cancer,” she further commented in a statement. “We hope that this update on the epidemiology of triple-negative breast cancer can provide a basis to further explore contributing factors in future research.”

Dr. Scott disclosed that she received a Dissertation Training Grant (F31-Diversity) from the National Institutes of Health. The study was funded by the National Institute on Minority Health and Health Disparities of the National Institutes of Health; the Centers for Disease Control and Prevention’s National Program of Cancer Registries contributed funds to cover the standard research data center fees for researchers conducting analyses under approved research projects.

SOURCE: Scott LC et al. Cancer. 2019 Jul 8. doi: 10.1002/cncr.32207.

Odds of triple-negative breast cancer (TNBC) are elevated for minority women and younger women, results of a nationwide cross-sectional cohort study of more than a million breast cancer cases confirm.

Previous studies have suggested certain sociodemographic groups are disproportionately affected by TNBC, but have been limited by the population studied, size, and characteristics assessed, note the investigators, who were led by Lia C. Scott, PhD, MPH, of the division of epidemiology and biostatistics at the School of Public Health, Georgia State University, Atlanta. “It is imperative that cancer research identify factors that drive disparities and focus on prevention,” they wrote in Cancer.

Dr. Scott and coinvestigators used the United States Cancer Statistics database to identify 1,151,724 cases of breast cancer diagnosed during 2010-2014 in 39 states having the necessary data. TNBC accounted for roughly 8.4% of all cases.

In unadjusted analyses using non-Hispanic white women as the comparator, odds of TNBC were significantly higher for non-Hispanic black women (odds ratio, 2.27), Hispanic women (OR, 1.22), and American Indian/Alaska Native women (OR, 1.26). On the other hand, odds were lower for Asian women (OR, 0.92).

By age group, compared with women 50-64 years old, women younger than 40 years were most likely to have the TNBC phenotype (OR, 1.95), while women aged 75 or older were least likely (OR, 0.75). Odds of TNBC were also significantly elevated for women whose cancer was diagnosed at stage III or higher (OR, 1.69) or at stage IV (OR, 1.47).

Findings were essentially the same in analyses simultaneously adjusted for age, race, and stage.

“The results of the current study demonstrated that there is a significant burden of disease in TNBC diagnosed among women of color, specifically non-Hispanic black women, and younger women,” Dr. Scott and coinvestigators write. “Given the large sample size and geospatial coverage of the data, these results are somewhat different from and also more generalizable, compared with data from previous studies.”

“With the advent and availability of more comprehensive cancer data, such as the United States Cancer Statistics database, it is important that we continue to explore disparities in order to better inform practice and policy around screenable cancers like breast cancer,” she further commented in a statement. “We hope that this update on the epidemiology of triple-negative breast cancer can provide a basis to further explore contributing factors in future research.”

Dr. Scott disclosed that she received a Dissertation Training Grant (F31-Diversity) from the National Institutes of Health. The study was funded by the National Institute on Minority Health and Health Disparities of the National Institutes of Health; the Centers for Disease Control and Prevention’s National Program of Cancer Registries contributed funds to cover the standard research data center fees for researchers conducting analyses under approved research projects.

SOURCE: Scott LC et al. Cancer. 2019 Jul 8. doi: 10.1002/cncr.32207.

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

Breast density should be a factor in assessing breast cancer risk and recommending supplemental imaging, but not the primary factor, according to a study of women who were screened for the disease.

Dr. Cecil Fox/National Cancer Institute

“Counseling strategies that identified women for supplemental imaging based on breast density and BCSC 5-year risk were more efficient compared with strategies based on age and density or density alone,” wrote Karla Kerlikowske, MD, of the Department of Veterans Affairs, and her coauthors. The study was published in JAMA Internal Medicine.

To assess breast cancer risk and strategies for recommending supplemental screening, the researchers assembled a cohort of 638,856 women aged 40 to 74 years who received mammograms at Breast Cancer Surveillance Consortium (BCSC) facilities from Jan. 3, 2005, to Dec. 31, 2014. Participants were identified as high risk via combinations of Breast Imaging Reporting and Data System (BI-RADS) breast density, BCSC 5-year breast cancer risk, and age.

Women with dense breasts made up 47% of those screened, and 60% of those with advanced cancers. Low advanced cancer rates (less than .61 per 1,000 mammograms) occurred in 34.5% of women with dense breasts, while high advanced cancer rates (greater than or equal to .61 cases per 1,000 mammograms) occurred in women with heterogeneously dense breasts and a 5-year risk of 2.5% or higher (6.0% of screened women) and those with extremely dense breasts and a 5-year risk of 1.0% or higher (6.5% of screened women).

In a hypothetical cohort of 100,000 women, supplemental imaging for all 47,012 women with dense breasts would mean a ratio of 1,866 supplemental imaging discussions per potential advanced breast cancer prevented. If imaging was considered based on a combination of density plus BCSC 5-year risk, the number of women screened would be reduced to 12,506 and the ratio would become 1,097 supplemental imaging discussions per potential advanced cancer prevented.

The coauthors acknowledged their study’s limitations, including their lack of ability to determine if women at high risk of advanced cancer would benefit from supplemental screening. In addition, they were unable to evaluate digital breast tomosynthesis outcomes, though they noted that, to their knowledge, “no published evidence indicates that advanced cancer rates differ for digital mammography vs. tomosynthesis according to breast density.”

The study was funded by the Patient-Centered Outcomes Research Institute, the Breast Cancer Surveillance Consortium, the National Cancer Institute, the Agency for Health Research and Quality, and the Lake Champlain Cancer Research Organization. The authors reported several potential conflicts of interest, including being members of various working groups, advisory boards, committees, task forces, and panels.

SOURCE: Kerlikowske K et al. JAMA Intern Med. 2019 Jul 1. doi:10.1001/jamainternmed.2019.1758 .

Breast density should be a factor in assessing breast cancer risk and recommending supplemental imaging, but not the primary factor, according to a study of women who were screened for the disease.

Dr. Cecil Fox/National Cancer Institute

“Counseling strategies that identified women for supplemental imaging based on breast density and BCSC 5-year risk were more efficient compared with strategies based on age and density or density alone,” wrote Karla Kerlikowske, MD, of the Department of Veterans Affairs, and her coauthors. The study was published in JAMA Internal Medicine.

To assess breast cancer risk and strategies for recommending supplemental screening, the researchers assembled a cohort of 638,856 women aged 40 to 74 years who received mammograms at Breast Cancer Surveillance Consortium (BCSC) facilities from Jan. 3, 2005, to Dec. 31, 2014. Participants were identified as high risk via combinations of Breast Imaging Reporting and Data System (BI-RADS) breast density, BCSC 5-year breast cancer risk, and age.

Women with dense breasts made up 47% of those screened, and 60% of those with advanced cancers. Low advanced cancer rates (less than .61 per 1,000 mammograms) occurred in 34.5% of women with dense breasts, while high advanced cancer rates (greater than or equal to .61 cases per 1,000 mammograms) occurred in women with heterogeneously dense breasts and a 5-year risk of 2.5% or higher (6.0% of screened women) and those with extremely dense breasts and a 5-year risk of 1.0% or higher (6.5% of screened women).

In a hypothetical cohort of 100,000 women, supplemental imaging for all 47,012 women with dense breasts would mean a ratio of 1,866 supplemental imaging discussions per potential advanced breast cancer prevented. If imaging was considered based on a combination of density plus BCSC 5-year risk, the number of women screened would be reduced to 12,506 and the ratio would become 1,097 supplemental imaging discussions per potential advanced cancer prevented.

The coauthors acknowledged their study’s limitations, including their lack of ability to determine if women at high risk of advanced cancer would benefit from supplemental screening. In addition, they were unable to evaluate digital breast tomosynthesis outcomes, though they noted that, to their knowledge, “no published evidence indicates that advanced cancer rates differ for digital mammography vs. tomosynthesis according to breast density.”

The study was funded by the Patient-Centered Outcomes Research Institute, the Breast Cancer Surveillance Consortium, the National Cancer Institute, the Agency for Health Research and Quality, and the Lake Champlain Cancer Research Organization. The authors reported several potential conflicts of interest, including being members of various working groups, advisory boards, committees, task forces, and panels.

SOURCE: Kerlikowske K et al. JAMA Intern Med. 2019 Jul 1. doi:10.1001/jamainternmed.2019.1758 .

Breast density should be a factor in assessing breast cancer risk and recommending supplemental imaging, but not the primary factor, according to a study of women who were screened for the disease.

Dr. Cecil Fox/National Cancer Institute

“Counseling strategies that identified women for supplemental imaging based on breast density and BCSC 5-year risk were more efficient compared with strategies based on age and density or density alone,” wrote Karla Kerlikowske, MD, of the Department of Veterans Affairs, and her coauthors. The study was published in JAMA Internal Medicine.

To assess breast cancer risk and strategies for recommending supplemental screening, the researchers assembled a cohort of 638,856 women aged 40 to 74 years who received mammograms at Breast Cancer Surveillance Consortium (BCSC) facilities from Jan. 3, 2005, to Dec. 31, 2014. Participants were identified as high risk via combinations of Breast Imaging Reporting and Data System (BI-RADS) breast density, BCSC 5-year breast cancer risk, and age.

Women with dense breasts made up 47% of those screened, and 60% of those with advanced cancers. Low advanced cancer rates (less than .61 per 1,000 mammograms) occurred in 34.5% of women with dense breasts, while high advanced cancer rates (greater than or equal to .61 cases per 1,000 mammograms) occurred in women with heterogeneously dense breasts and a 5-year risk of 2.5% or higher (6.0% of screened women) and those with extremely dense breasts and a 5-year risk of 1.0% or higher (6.5% of screened women).

In a hypothetical cohort of 100,000 women, supplemental imaging for all 47,012 women with dense breasts would mean a ratio of 1,866 supplemental imaging discussions per potential advanced breast cancer prevented. If imaging was considered based on a combination of density plus BCSC 5-year risk, the number of women screened would be reduced to 12,506 and the ratio would become 1,097 supplemental imaging discussions per potential advanced cancer prevented.

The coauthors acknowledged their study’s limitations, including their lack of ability to determine if women at high risk of advanced cancer would benefit from supplemental screening. In addition, they were unable to evaluate digital breast tomosynthesis outcomes, though they noted that, to their knowledge, “no published evidence indicates that advanced cancer rates differ for digital mammography vs. tomosynthesis according to breast density.”

The study was funded by the Patient-Centered Outcomes Research Institute, the Breast Cancer Surveillance Consortium, the National Cancer Institute, the Agency for Health Research and Quality, and the Lake Champlain Cancer Research Organization. The authors reported several potential conflicts of interest, including being members of various working groups, advisory boards, committees, task forces, and panels.

SOURCE: Kerlikowske K et al. JAMA Intern Med. 2019 Jul 1. doi:10.1001/jamainternmed.2019.1758 .

Postmenopausal breast cancer survivors are at greater risk for cardiovascular disease than are their peers without breast cancer, according to a new study of nearly 300 women.

Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.

In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.

Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.

Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).

In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.

The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.

However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.

“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.

The researchers had no financial conflicts to disclose.

SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.

Postmenopausal breast cancer survivors are at greater risk for cardiovascular disease than are their peers without breast cancer, according to a new study of nearly 300 women.

Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.

In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.

Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.

Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).

In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.

The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.

However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.

“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.

The researchers had no financial conflicts to disclose.

SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.

Postmenopausal breast cancer survivors are at greater risk for cardiovascular disease than are their peers without breast cancer, according to a new study of nearly 300 women.

Previous studies have shown that cardiovascular risk is greater among postmenopausal women treated for breast cancer compared with those without cancer, but specific risk factors have not been well studied, wrote Daniel de Araujo Brito Buttros, MD, of Paulista State University, Sao Paulo, Brazil, and colleagues.

In a study published in Menopause, the researchers evaluated several CVD risk factors in 96 postmenopausal women with breast cancer and 192 women without breast cancer, including metabolic syndrome, subclinical atherosclerosis, and heat shock proteins (HSP) 60 and 70.

Overall, breast cancer patients had significantly higher HSP60 levels and lower HSP70 levels than those of their cancer-free peers. These two proteins have an antagonistic relationship in cardiovascular disease, with HSP60 considered a risk factor for CVD, and HSP70 considered a protective factor. Average HSP60 levels for the breast cancer and control groups were 35 ng/mL and 10.8 ng/mL, respectively; average HSP70 levels were 0.5 ng/mL and 1.3 ng/mL, respectively.

Both diabetes and metabolic syndrome were significantly more common among breast cancer patients vs. controls (19.8% vs. 6.8% and 54.2% vs. 30.7%, respectively). Carotid artery plaque also was more common in breast cancer patients vs. controls (19.8% vs. 9.4%, respectively, P = 0.013).

In addition, systolic and diastolic blood pressure levels were significantly higher among the breast cancer patients, as were triglycerides and glucose.

The findings were limited by several factors including the cross-sectional design that could not prove a causal relationship between CVD risk and breast cancer, the researchers noted.

However, the results demonstrate the increased CVD risk for breast cancer patients, and “[therefore], women diagnosed with breast cancer might receive multidisciplinary care, including cardiology consultation at the time of breast cancer diagnosis and also during oncologic follow-up visits,” they said.

“Heart disease appears more commonly in women treated for breast cancer because of the toxicities of chemotherapy, radiation therapy, and use of aromatase inhibitors, which lower estrogen. Heart-healthy lifestyle modifications will decrease both the risk of recurrent breast cancer and the risk of developing heart disease,” JoAnn Pinkerton, MD, executive director of the North American Menopause Society, said in a statement. “Women should schedule a cardiology consultation when breast cancer is diagnosed and continue with ongoing follow-up after cancer treatments are completed,” she emphasized.

The researchers had no financial conflicts to disclose.

SOURCE: Buttros DAB et al. Menopause. 2019. doi: 10.1097/GME.0000000000001348.

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.

NEOSTAR in NSCLC

With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.

Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).

Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
 

What this means in practice

Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.

If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.

PREDIX in HER2-positive breast cancer

As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.

Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.

In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.

PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.

What this means in practice

Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.

Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.

NEOSTAR in NSCLC

With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.

Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).

Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
 

What this means in practice

Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.

If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.

PREDIX in HER2-positive breast cancer

As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.

Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.

In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.

PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.

What this means in practice

Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.

Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two “chemo-free” neoadjuvant studies reported at the annual meeting of the American Society of Clinical Oncology. One summarizes the potential utility of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) patients who are – or can become – candidates for curative resection and the other highlights the potential utility of neoadjuvant trastuzumab emtansine (T-DM1) for HER2-positive breast cancer patients.

NEOSTAR in NSCLC

With the accumulation of comorbid conditions in an aging population, we all see NSCLC patients who are potential candidates for curative surgery, but for whom we have concerns about standard preoperative chemotherapy plus or minus radiation. At ASCO 2019, abstracts 8503 (atezolizumab, the LCMC3 trial) and 8504 (nivolumab plus or minus ipilimumab, NEOSTAR) addressed the neoadjuvant use of ICIs. I will focus on NEOSTAR, because the major pathologic response (mPR) rate – reduction in viable tumor cells to 10% or less – was higher with the combination of nivolumab plus ipilimumab in NEOSTAR than with single agent nivolumab or atezolizumab in the NEOSTAR or LCMC3 trials, respectively.

Briefly, 44 patients with stage I-IIIA NSCLC were randomized to nivolumab plus or minus ipilimumab. In total, 93% completed 6 weeks of neoadjuvant therapy and 89% were resected. The mPR rate was 33% with nivolumab plus ipilimumab (about twice as high as with nivolumab alone in NEOSTAR or atezolizumab in LCMC3).

Among resected patients, nivolumab plus ipilimumab had a 44% mPR rate and a pathologic complete response rate of 38%. Although RECIST (Response Evaluation Criteria in Solid Tumors) responses were more likely in patients who had an mPR, 11% of patients had radiographic “nodal immune flare” because of noncaseating granulomas in regional (or nonregional) nodes. Elevated baseline programmed death-ligand 1 was associated with a higher rate of mPR. Surgical complications seemed similar to expectations – 1 bronchopleural fistula and 8 air leaks among the 39 resected patients.
 

What this means in practice

Although the mPR endpoint has no validated association with survival and the studies were relatively small, neoadjuvant use of ICIs in patients for whom tolerance to standard chemotherapy plus or minus radiation might be problematic is attractive – especially in view of the reality of an approximately 50% relapse rate after surgical resection with standard therapy.

If I had a potential candidate for neoadjuvant ICI therapy – especially one with a high proportion of cells with PD-L1 or someone with an equivocal distant metastasis on a preoperative PET-CT – I would consider using an ICI as given in LCMC3 or NEOSTAR.

PREDIX in HER2-positive breast cancer

As Mark Pegram, MD, of Stanford (Calif.) University suggested in his discussion at the local/regional/adjuvant breast cancer session at ASCO 2019, the goal of HER2-targeted therapy was originally that it could replace – not supplement – the use of cytotoxic chemotherapy.

Abstracts 500 (the KRISTINE trial: neoadjuvant T-DM1 plus pertuzumab vs. docetaxel, carboplatin, and trastuzumab plus pertuzumab); 501 (the PREDIX study: T-DM1 vs. docetaxel plus trastuzumab plus pertuzumab [DTP] for six cycles); and 502 (HER2 heterogeneity as a predictor of response) addressed the potential for the antibody-drug conjugate to replace standard preoperative cytotoxic chemotherapy plus HER2-targeting.

In PREDIX, it was anticipated that toxicity would be lower with T-DM1 than with DTP – and it was, with better quality of life scores. The authors found a pathologic complete response rate of 45% among 98 participants with stage IIA-IIIA HER2-positive breast cancer, with higher rates among hormone receptor–negative than hormone receptor–positive patients, as expected.

PREDIX patients were allowed to switch from T-DM1 to DTP for progression, lack of clinical/radiographic response, or toxicity. More than twice as many patients switched from DTP to T-DM1 than vice versa for progression or lack of response.

What this means in practice

Although neither DTP nor T-DM1 are National Comprehensive Cancer Network guideline-endorsed neoadjuvant regimens at present, the KRISTINE and PREDIX trials and Abstract 502 advance the discussion about further personalizing therapy for HER2-amplified breast cancer with high HER2 copy number and lack of intratumor heterogeneity for HER2. They also raise questions about de-escalating therapy for patients with good prognosis and HER2-positive cancers, and the creative use of T-DM1 in the neoadjuvant setting.

Neoadjuvant T-DM1 may not be standard of care yet, but watch this space.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

A novel multiorgan body-on-a-chip system shows promise to improve the preclinical evaluation of various anticancer therapies, investigators report.

C.W. McAleer et al. Science Translational Medicine (2019)

“Initially, organ-on-a-chip systems were designed for specific applications with limited ability for reconfiguration and typically with cells from a single organ,” wrote Christopher W. McAleer, PhD, of Hesperos Inc., Orlando, and colleagues. Their report is in Science Translational Medicine.

“To address these issues, a reconfigurable body-on-a-chip system was developed with the capacity to house multiple organ-like tissue constructs,” the authors explained.

The researchers used two different system configurations to evaluate the off-target organ toxicities, metabolism, and efficacy of diclofenac and imatinib (system 1), in addition to tamoxifen (system 2). Both therapies were combined with verapamil in the study.

In system 1, cancer-derived bone marrow cells were cultured with primary hepatocytes, and were analyzed for anti-leukemic activity. In this configuration, both imatinib and diclofenac showed cytostatic activity on cancer progression in the bone marrow cells.

“Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%,” the researchers wrote.

System 2 included a wide variety of cell-lines, including primary hepatocytes, induced pluripotent stem cell-derived cardiomyocytes, a multidrug-resistant vulva cancer line, and a non-multidrug-resistant breast cancer line.

In this configuration, tamoxifen monotherapy and tamoxifen coadministered with verapamil resulted in off-target cardiac toxicities, but did not alter cell viability.

“These systems demonstrate the utility of a human cell–based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites,” Dr. McAleer and colleagues wrote.

The researchers acknowledged that the dosing parameters used in the model were acute. As a result, chronic, low-dose treatment strategies may reflect clinical conditions more accurately.

“These systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies,” they concluded.

The study was supported by Hesperos Internal Development funds, the NIH, and Roche. The authors reported financial affiliations with Hesperos and Roche.

SOURCE: McAleer CW et al. Sci Transl Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav1386.

A novel multiorgan body-on-a-chip system shows promise to improve the preclinical evaluation of various anticancer therapies, investigators report.

C.W. McAleer et al. Science Translational Medicine (2019)

“Initially, organ-on-a-chip systems were designed for specific applications with limited ability for reconfiguration and typically with cells from a single organ,” wrote Christopher W. McAleer, PhD, of Hesperos Inc., Orlando, and colleagues. Their report is in Science Translational Medicine.

“To address these issues, a reconfigurable body-on-a-chip system was developed with the capacity to house multiple organ-like tissue constructs,” the authors explained.

The researchers used two different system configurations to evaluate the off-target organ toxicities, metabolism, and efficacy of diclofenac and imatinib (system 1), in addition to tamoxifen (system 2). Both therapies were combined with verapamil in the study.

In system 1, cancer-derived bone marrow cells were cultured with primary hepatocytes, and were analyzed for anti-leukemic activity. In this configuration, both imatinib and diclofenac showed cytostatic activity on cancer progression in the bone marrow cells.

“Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%,” the researchers wrote.

System 2 included a wide variety of cell-lines, including primary hepatocytes, induced pluripotent stem cell-derived cardiomyocytes, a multidrug-resistant vulva cancer line, and a non-multidrug-resistant breast cancer line.

In this configuration, tamoxifen monotherapy and tamoxifen coadministered with verapamil resulted in off-target cardiac toxicities, but did not alter cell viability.

“These systems demonstrate the utility of a human cell–based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites,” Dr. McAleer and colleagues wrote.

The researchers acknowledged that the dosing parameters used in the model were acute. As a result, chronic, low-dose treatment strategies may reflect clinical conditions more accurately.

“These systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies,” they concluded.

The study was supported by Hesperos Internal Development funds, the NIH, and Roche. The authors reported financial affiliations with Hesperos and Roche.

SOURCE: McAleer CW et al. Sci Transl Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav1386.

A novel multiorgan body-on-a-chip system shows promise to improve the preclinical evaluation of various anticancer therapies, investigators report.

C.W. McAleer et al. Science Translational Medicine (2019)

“Initially, organ-on-a-chip systems were designed for specific applications with limited ability for reconfiguration and typically with cells from a single organ,” wrote Christopher W. McAleer, PhD, of Hesperos Inc., Orlando, and colleagues. Their report is in Science Translational Medicine.

“To address these issues, a reconfigurable body-on-a-chip system was developed with the capacity to house multiple organ-like tissue constructs,” the authors explained.

The researchers used two different system configurations to evaluate the off-target organ toxicities, metabolism, and efficacy of diclofenac and imatinib (system 1), in addition to tamoxifen (system 2). Both therapies were combined with verapamil in the study.

In system 1, cancer-derived bone marrow cells were cultured with primary hepatocytes, and were analyzed for anti-leukemic activity. In this configuration, both imatinib and diclofenac showed cytostatic activity on cancer progression in the bone marrow cells.

“Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%,” the researchers wrote.

System 2 included a wide variety of cell-lines, including primary hepatocytes, induced pluripotent stem cell-derived cardiomyocytes, a multidrug-resistant vulva cancer line, and a non-multidrug-resistant breast cancer line.

In this configuration, tamoxifen monotherapy and tamoxifen coadministered with verapamil resulted in off-target cardiac toxicities, but did not alter cell viability.

“These systems demonstrate the utility of a human cell–based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites,” Dr. McAleer and colleagues wrote.

The researchers acknowledged that the dosing parameters used in the model were acute. As a result, chronic, low-dose treatment strategies may reflect clinical conditions more accurately.

“These systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies,” they concluded.

The study was supported by Hesperos Internal Development funds, the NIH, and Roche. The authors reported financial affiliations with Hesperos and Roche.

SOURCE: McAleer CW et al. Sci Transl Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav1386.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.