Neil Osterweil

Among Asian women with hormone receptor–positive/human epidermal growth factor receptor-2 (HER2)–negative metastatic breast cancer that is resistant to endocrine therapy, a combination of palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with a significant improvement in progression-free survival (PFS), reported investigators from the PALOMA-3 trial.

A preplanned subgroup analysis of 102 pre- and postmenopausal women from Japan, South Korea, and Taiwan who were enrolled in the trial showed that median PFS for 71 women assigned to palbociclib and fulvestrant had not been reached at the trial end. In contrast, median PFS among 31 patients assigned to placebo and fulvestrant was 5.8 months (hazard ratio, 0.485; P = .0065), reported Hiroji Iwata, MD, PhD, of the Aichi Cancer Center Hospital in Nagoya, Japan, and his colleagues.

“Overall, palbociclib plus fulvestrant seems to be a reasonable treatment option in Asians with HR-positive/HER2-negative metastatic breast cancer that has progressed on prior endocrine therapy,” they wrote in the Journal of Global Oncology (2017 Apr 11. doi: 10.1200/JGO.2016.008318).

PALOMA-3 was a multinational randomized double-blind, placebo-controlled phase III trial comparing a combination of fulvestrant, a selective estrogen receptor downregulator, and palbociclib, a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) with fulvestrant plus placebo in 521 women with HR-positive/HER2-negative advanced breast cancer.

The trial was halted early for efficacy of the combination. The final overall analysis, published in April 2016 in The Lancet Oncology, showed that the combination significantly improved PFS, compared with fulvestrant and placebo, regardless of the patients’ degree of endocrine resistance, level of hormone receptor expression level, or PIK3CA mutational status.

Dr. Iwata and his associates noted that breast cancer is generally diagnosed at a younger age among Asian women (median, 45-50 years vs. 55-60 years among Western women) and that differences in genetic backgrounds may influence drug metabolism, resulting in potential differences in efficacy and adverse event profiles.

Among patients treated with palbociclib, the most common grade 3 or higher adverse events were neutropenia in 92%, compared with none in the placebo arm, and leukopenia in 29% vs. 0%. In contrast, grade 3/4 neutropenia occurred in 58% of non-Asian patients treated with the combination and 0.7% of non-Asian controls. Leukopenia rates were similar between Asian and non-Asian populations, however.

Comparisons of mean trough concentrations across subgroups showed that palbociclib exposures among Asians and non-Asians were similar. Patient reported outcomes were also similar between the groups, except for significantly more dyspnea among patients who received palbociclib (P = .05).

“This study adds to the limited body of literature assessing a CDK4/6 inhibitor in Asians and represents the largest patient experience with palbociclib in Asians. The present findings show that palbociclib plus fulvestrant improved PFS in Asians with HR-positive/HER2-negative [metastatic breast cancer] who experienced progression on prior endocrine therapy and that the safety profile of palbociclib plus fulvestrant in Asians was generally consistent with that observed in non-Asians. Together, these findings suggest that palbociclib is beneficial in patients who have not previously received endocrine therapy and in Asians and non-Asians who experienced relapse or progression during prior endocrine therapy,” they wrote.

The PALOMA-3 trial was supported by Pfizer. Dr. Iwata disclosed consultations with Chugai Pharma, Eisai, and AstraZeneca. Several coauthors are Pfizer employees and shareholders.

Among Asian women with hormone receptor–positive/human epidermal growth factor receptor-2 (HER2)–negative metastatic breast cancer that is resistant to endocrine therapy, a combination of palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with a significant improvement in progression-free survival (PFS), reported investigators from the PALOMA-3 trial.

A preplanned subgroup analysis of 102 pre- and postmenopausal women from Japan, South Korea, and Taiwan who were enrolled in the trial showed that median PFS for 71 women assigned to palbociclib and fulvestrant had not been reached at the trial end. In contrast, median PFS among 31 patients assigned to placebo and fulvestrant was 5.8 months (hazard ratio, 0.485; P = .0065), reported Hiroji Iwata, MD, PhD, of the Aichi Cancer Center Hospital in Nagoya, Japan, and his colleagues.

“Overall, palbociclib plus fulvestrant seems to be a reasonable treatment option in Asians with HR-positive/HER2-negative metastatic breast cancer that has progressed on prior endocrine therapy,” they wrote in the Journal of Global Oncology (2017 Apr 11. doi: 10.1200/JGO.2016.008318).

PALOMA-3 was a multinational randomized double-blind, placebo-controlled phase III trial comparing a combination of fulvestrant, a selective estrogen receptor downregulator, and palbociclib, a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) with fulvestrant plus placebo in 521 women with HR-positive/HER2-negative advanced breast cancer.

The trial was halted early for efficacy of the combination. The final overall analysis, published in April 2016 in The Lancet Oncology, showed that the combination significantly improved PFS, compared with fulvestrant and placebo, regardless of the patients’ degree of endocrine resistance, level of hormone receptor expression level, or PIK3CA mutational status.

Dr. Iwata and his associates noted that breast cancer is generally diagnosed at a younger age among Asian women (median, 45-50 years vs. 55-60 years among Western women) and that differences in genetic backgrounds may influence drug metabolism, resulting in potential differences in efficacy and adverse event profiles.

Among patients treated with palbociclib, the most common grade 3 or higher adverse events were neutropenia in 92%, compared with none in the placebo arm, and leukopenia in 29% vs. 0%. In contrast, grade 3/4 neutropenia occurred in 58% of non-Asian patients treated with the combination and 0.7% of non-Asian controls. Leukopenia rates were similar between Asian and non-Asian populations, however.

Comparisons of mean trough concentrations across subgroups showed that palbociclib exposures among Asians and non-Asians were similar. Patient reported outcomes were also similar between the groups, except for significantly more dyspnea among patients who received palbociclib (P = .05).

“This study adds to the limited body of literature assessing a CDK4/6 inhibitor in Asians and represents the largest patient experience with palbociclib in Asians. The present findings show that palbociclib plus fulvestrant improved PFS in Asians with HR-positive/HER2-negative [metastatic breast cancer] who experienced progression on prior endocrine therapy and that the safety profile of palbociclib plus fulvestrant in Asians was generally consistent with that observed in non-Asians. Together, these findings suggest that palbociclib is beneficial in patients who have not previously received endocrine therapy and in Asians and non-Asians who experienced relapse or progression during prior endocrine therapy,” they wrote.

The PALOMA-3 trial was supported by Pfizer. Dr. Iwata disclosed consultations with Chugai Pharma, Eisai, and AstraZeneca. Several coauthors are Pfizer employees and shareholders.

Among Asian women with hormone receptor–positive/human epidermal growth factor receptor-2 (HER2)–negative metastatic breast cancer that is resistant to endocrine therapy, a combination of palbociclib (Ibrance) and fulvestrant (Faslodex) was associated with a significant improvement in progression-free survival (PFS), reported investigators from the PALOMA-3 trial.

A preplanned subgroup analysis of 102 pre- and postmenopausal women from Japan, South Korea, and Taiwan who were enrolled in the trial showed that median PFS for 71 women assigned to palbociclib and fulvestrant had not been reached at the trial end. In contrast, median PFS among 31 patients assigned to placebo and fulvestrant was 5.8 months (hazard ratio, 0.485; P = .0065), reported Hiroji Iwata, MD, PhD, of the Aichi Cancer Center Hospital in Nagoya, Japan, and his colleagues.

“Overall, palbociclib plus fulvestrant seems to be a reasonable treatment option in Asians with HR-positive/HER2-negative metastatic breast cancer that has progressed on prior endocrine therapy,” they wrote in the Journal of Global Oncology (2017 Apr 11. doi: 10.1200/JGO.2016.008318).

PALOMA-3 was a multinational randomized double-blind, placebo-controlled phase III trial comparing a combination of fulvestrant, a selective estrogen receptor downregulator, and palbociclib, a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) with fulvestrant plus placebo in 521 women with HR-positive/HER2-negative advanced breast cancer.

The trial was halted early for efficacy of the combination. The final overall analysis, published in April 2016 in The Lancet Oncology, showed that the combination significantly improved PFS, compared with fulvestrant and placebo, regardless of the patients’ degree of endocrine resistance, level of hormone receptor expression level, or PIK3CA mutational status.

Dr. Iwata and his associates noted that breast cancer is generally diagnosed at a younger age among Asian women (median, 45-50 years vs. 55-60 years among Western women) and that differences in genetic backgrounds may influence drug metabolism, resulting in potential differences in efficacy and adverse event profiles.

Among patients treated with palbociclib, the most common grade 3 or higher adverse events were neutropenia in 92%, compared with none in the placebo arm, and leukopenia in 29% vs. 0%. In contrast, grade 3/4 neutropenia occurred in 58% of non-Asian patients treated with the combination and 0.7% of non-Asian controls. Leukopenia rates were similar between Asian and non-Asian populations, however.

Comparisons of mean trough concentrations across subgroups showed that palbociclib exposures among Asians and non-Asians were similar. Patient reported outcomes were also similar between the groups, except for significantly more dyspnea among patients who received palbociclib (P = .05).

“This study adds to the limited body of literature assessing a CDK4/6 inhibitor in Asians and represents the largest patient experience with palbociclib in Asians. The present findings show that palbociclib plus fulvestrant improved PFS in Asians with HR-positive/HER2-negative [metastatic breast cancer] who experienced progression on prior endocrine therapy and that the safety profile of palbociclib plus fulvestrant in Asians was generally consistent with that observed in non-Asians. Together, these findings suggest that palbociclib is beneficial in patients who have not previously received endocrine therapy and in Asians and non-Asians who experienced relapse or progression during prior endocrine therapy,” they wrote.

The PALOMA-3 trial was supported by Pfizer. Dr. Iwata disclosed consultations with Chugai Pharma, Eisai, and AstraZeneca. Several coauthors are Pfizer employees and shareholders.

Even at the end of life, nonwhite patients with ovarian cancer are more likely to receive suboptimal care.

That’s the finding of investigators who looked at Medicare-enrolled patients with end-stage ovarian cancer in Texas. They found that compared with white patients, nonwhites were less likely to be enrolled in or die in hospice, more likely to be admitted to an intensive care unit, more likely to have an emergency department visit, and more likely to be subjected to some kind of putatively life-extending intervention.

“More investigation is needed to determine not only how to best reduce the overall number of patients with ovarian cancer who receive aggressive and invasive care but also how to lessen the disparity of who receives more aggressive and invasive care. With regard to end-of-life care for patients with ovarian cancer, less may be more,” wrote Jolyn S. Taylor, MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues (J Clin Oncol. 2017 April 7 doi: 10.1200/JCO.2016.70.2894).

Quality-of-care recommendations from the American Society of Clinical Oncology Quality Oncology Practice Initiative, Physician Consortium for Performance Improvement, and National Quality Forum call on clinicians to recognize that excessive or aggressive end-of-life interventions can have a negative effect on the quality of life for patients with limited life expectancy, the authors noted.

“Although changes have occurred over the last decade leading to increased hospice use by patients with ovarian cancer before death, many patients still receive intensive and invasive care in the last month of life. Similar to other disease sites, patients of minority race and ethnicity and lower socioeconomic status who have ovarian cancer have been reported to have less hospice use and more intensive end-of-life care,” the researchers wrote.

To see whether these disparities still existed, the investigators examined Texas Cancer Registry–Medicare data on patients who died from ovarian cancer from 2000 to 2012 who had least 13 months of continuous Medicare coverage before their deaths. They looked for specific measures of end-of-life care quality, including chemotherapy use within 2 weeks of death, ICU admission in the last month of life, and emergency department visits, hospital admissions, or invasive or life-extending procedures, all during the last 30 days of a patient’s life.

Of the 3,666 patients studied, 2,819 (77%) were white, 553 (15%) were Hispanic, 256 (7%) were black, and 38 (1%) were classified as “other.”

In multivariate regression models adjusted for year of death, age at death, time from diagnosis to death, Charlson comorbidity index score, disease stage at diagnosis, educational and poverty level by census tract, and geography (rural versus urban), the researchers found that both black and Hispanic patients were significantly less likely than were white patients to enroll in and die in hospice, with odds ratios (OR) of 0.66 for black patients (P = .004), and 0.76 for Hispanics (P = .01).

Black but not Hispanic patients were more likely to have had more than one emergency department visit within 30 days of death (OR 2.20, P less than .001), or a life-extending procedure (OR 2.13, P less than .001). Hispanic but not black patients were more likely to have been admitted to an ICU within a month of death (OR 1.37, P = .02).

The study was supported by grants from the Cancer Prevention & Research Institute of Texas, National Institutes of Health, National Cancer Institute, and Duncan Family Institute.

Even at the end of life, nonwhite patients with ovarian cancer are more likely to receive suboptimal care.

That’s the finding of investigators who looked at Medicare-enrolled patients with end-stage ovarian cancer in Texas. They found that compared with white patients, nonwhites were less likely to be enrolled in or die in hospice, more likely to be admitted to an intensive care unit, more likely to have an emergency department visit, and more likely to be subjected to some kind of putatively life-extending intervention.

“More investigation is needed to determine not only how to best reduce the overall number of patients with ovarian cancer who receive aggressive and invasive care but also how to lessen the disparity of who receives more aggressive and invasive care. With regard to end-of-life care for patients with ovarian cancer, less may be more,” wrote Jolyn S. Taylor, MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues (J Clin Oncol. 2017 April 7 doi: 10.1200/JCO.2016.70.2894).

Quality-of-care recommendations from the American Society of Clinical Oncology Quality Oncology Practice Initiative, Physician Consortium for Performance Improvement, and National Quality Forum call on clinicians to recognize that excessive or aggressive end-of-life interventions can have a negative effect on the quality of life for patients with limited life expectancy, the authors noted.

“Although changes have occurred over the last decade leading to increased hospice use by patients with ovarian cancer before death, many patients still receive intensive and invasive care in the last month of life. Similar to other disease sites, patients of minority race and ethnicity and lower socioeconomic status who have ovarian cancer have been reported to have less hospice use and more intensive end-of-life care,” the researchers wrote.

To see whether these disparities still existed, the investigators examined Texas Cancer Registry–Medicare data on patients who died from ovarian cancer from 2000 to 2012 who had least 13 months of continuous Medicare coverage before their deaths. They looked for specific measures of end-of-life care quality, including chemotherapy use within 2 weeks of death, ICU admission in the last month of life, and emergency department visits, hospital admissions, or invasive or life-extending procedures, all during the last 30 days of a patient’s life.

Of the 3,666 patients studied, 2,819 (77%) were white, 553 (15%) were Hispanic, 256 (7%) were black, and 38 (1%) were classified as “other.”

In multivariate regression models adjusted for year of death, age at death, time from diagnosis to death, Charlson comorbidity index score, disease stage at diagnosis, educational and poverty level by census tract, and geography (rural versus urban), the researchers found that both black and Hispanic patients were significantly less likely than were white patients to enroll in and die in hospice, with odds ratios (OR) of 0.66 for black patients (P = .004), and 0.76 for Hispanics (P = .01).

Black but not Hispanic patients were more likely to have had more than one emergency department visit within 30 days of death (OR 2.20, P less than .001), or a life-extending procedure (OR 2.13, P less than .001). Hispanic but not black patients were more likely to have been admitted to an ICU within a month of death (OR 1.37, P = .02).

The study was supported by grants from the Cancer Prevention & Research Institute of Texas, National Institutes of Health, National Cancer Institute, and Duncan Family Institute.

Even at the end of life, nonwhite patients with ovarian cancer are more likely to receive suboptimal care.

That’s the finding of investigators who looked at Medicare-enrolled patients with end-stage ovarian cancer in Texas. They found that compared with white patients, nonwhites were less likely to be enrolled in or die in hospice, more likely to be admitted to an intensive care unit, more likely to have an emergency department visit, and more likely to be subjected to some kind of putatively life-extending intervention.

“More investigation is needed to determine not only how to best reduce the overall number of patients with ovarian cancer who receive aggressive and invasive care but also how to lessen the disparity of who receives more aggressive and invasive care. With regard to end-of-life care for patients with ovarian cancer, less may be more,” wrote Jolyn S. Taylor, MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues (J Clin Oncol. 2017 April 7 doi: 10.1200/JCO.2016.70.2894).

Quality-of-care recommendations from the American Society of Clinical Oncology Quality Oncology Practice Initiative, Physician Consortium for Performance Improvement, and National Quality Forum call on clinicians to recognize that excessive or aggressive end-of-life interventions can have a negative effect on the quality of life for patients with limited life expectancy, the authors noted.

“Although changes have occurred over the last decade leading to increased hospice use by patients with ovarian cancer before death, many patients still receive intensive and invasive care in the last month of life. Similar to other disease sites, patients of minority race and ethnicity and lower socioeconomic status who have ovarian cancer have been reported to have less hospice use and more intensive end-of-life care,” the researchers wrote.

To see whether these disparities still existed, the investigators examined Texas Cancer Registry–Medicare data on patients who died from ovarian cancer from 2000 to 2012 who had least 13 months of continuous Medicare coverage before their deaths. They looked for specific measures of end-of-life care quality, including chemotherapy use within 2 weeks of death, ICU admission in the last month of life, and emergency department visits, hospital admissions, or invasive or life-extending procedures, all during the last 30 days of a patient’s life.

Of the 3,666 patients studied, 2,819 (77%) were white, 553 (15%) were Hispanic, 256 (7%) were black, and 38 (1%) were classified as “other.”

In multivariate regression models adjusted for year of death, age at death, time from diagnosis to death, Charlson comorbidity index score, disease stage at diagnosis, educational and poverty level by census tract, and geography (rural versus urban), the researchers found that both black and Hispanic patients were significantly less likely than were white patients to enroll in and die in hospice, with odds ratios (OR) of 0.66 for black patients (P = .004), and 0.76 for Hispanics (P = .01).

Black but not Hispanic patients were more likely to have had more than one emergency department visit within 30 days of death (OR 2.20, P less than .001), or a life-extending procedure (OR 2.13, P less than .001). Hispanic but not black patients were more likely to have been admitted to an ICU within a month of death (OR 1.37, P = .02).

The study was supported by grants from the Cancer Prevention & Research Institute of Texas, National Institutes of Health, National Cancer Institute, and Duncan Family Institute.

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.

Some genetic variants included in commercially available gene panels for breast cancer susceptibility matter a great deal, while others appear to be irrelevant or of uncertain significance, investigators suggested.

Among 65,057 women with breast cancer who were tested for germline mutations with one of nine different gene panels in a case-control study, testing confirmed that some known genes were associated with a two- to sevenfold greater risk for breast cancer, while other candidate genes were not associated with any increase in risk, according to Fergus J. Couch, PhD, from the Mayo Clinic in Rochester, Minn., and his colleagues.

“Although the risks presented herein may not be generalizable to all mutation carriers, they are highly relevant to those with clinical histories suggestive of hereditary breast cancer predisposition,” they wrote in JAMA Oncology.

It is well known that pathogenic variants in BRCA1 and BRCA2 increase a woman’s lifetime risk for breast cancer, but the level of risk conferred by other genes included in multigene test panels for hereditary cancers is less well documented, the investigators noted.

To better quantify risks associated with germline variants in cancer predisposition genes, the investigators took a retrospective look at 65,057 breast cancer patients who were tested for germline mutations, and examined associations between breast cancer and pathogenic variants in 16 panel genes in a subsample of 38,326 white patients, whose cases were compared with those of 26,911 controls of non-Finn European background from the Exome Aggregation Consortium data set. Variants in BRCA1, BRCA2, and genes associated with known breast-cancer syndromes (CDH1, PTEN, and TP53) were excluded from the analysis.

They identified variants in five genes as being associated with high or moderate increases in risk for breast cancer. The genes, with the associated odds ratios for breast cancer, are PALB2 (OR, 7.46), RAD51D (OR, 3.07), ATM (OR, 2.78), BARD1 (OR, 2.16), and CHEK2 (OR, 1.48). All associations were significant as shown by confidence intervals.

Variants of other genes included in hereditary panels, however, were not associated with increased breast cancer risk. These included the ovarian cancer risk genes BRIP1 and RAD51C; the MRN (Mre11-Rad50-Nbs1) complex genes MRE11A, RAD50, and NBN; the mismatch repair genes MLH1 and PMS2; and the tumor suppressor protein-coding gene NF1.

In an accompanying editorial, Elias I. Obeid, MD, MPH, and his colleagues from the Fox Chase Cancer Center in Philadelphia commented that “the incorporation of moderate-risk genes into multigene panel tests risks generating information that may not be clinically relevant and at times could be misleading to patients and their families.”

“We are in immediate need of well-designed studies to provide further clarification of risk estimates for low-penetrance and moderate-risk genes, as well as expanded guidelines on how to best manage these risks over the lifetime of the patient,” they continued.

The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation, and was sponsored by Ambry Genetics. Six of the coauthors are current or former employees of Ambry. Couch and his colleagues reported no conflicts of interest.

MIAMI BEACH – The Food and Drug Administration has accepted pathological complete response rate (pCR) as a surrogate endpoint for disease-free and overall survival in clinical trials for neoadjuvant therapy of breast cancer.

Yet the specimen collection and histopathologic methods used to measure pCR have differed considerably across major neoadjuvant trials for breast cancer, said Michael F. Press, MD, PhD, of the USC/Norris Comprehensive Cancer Center at the University of California, Los Angeles.

In a video interview conducted at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, Dr. Press outlined the problems associated with a lack of standardization of outcomes measures, and described how residual cancer burden may be a more effective, validated measures for comparing outcomes across clinical trials.

MIAMI BEACH – The Food and Drug Administration has accepted pathological complete response rate (pCR) as a surrogate endpoint for disease-free and overall survival in clinical trials for neoadjuvant therapy of breast cancer.

Yet the specimen collection and histopathologic methods used to measure pCR have differed considerably across major neoadjuvant trials for breast cancer, said Michael F. Press, MD, PhD, of the USC/Norris Comprehensive Cancer Center at the University of California, Los Angeles.

In a video interview conducted at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, Dr. Press outlined the problems associated with a lack of standardization of outcomes measures, and described how residual cancer burden may be a more effective, validated measures for comparing outcomes across clinical trials.

MIAMI BEACH – The Food and Drug Administration has accepted pathological complete response rate (pCR) as a surrogate endpoint for disease-free and overall survival in clinical trials for neoadjuvant therapy of breast cancer.

Yet the specimen collection and histopathologic methods used to measure pCR have differed considerably across major neoadjuvant trials for breast cancer, said Michael F. Press, MD, PhD, of the USC/Norris Comprehensive Cancer Center at the University of California, Los Angeles.

In a video interview conducted at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, Dr. Press outlined the problems associated with a lack of standardization of outcomes measures, and described how residual cancer burden may be a more effective, validated measures for comparing outcomes across clinical trials.

MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.

Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.

MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.

Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.

MIAMI BEACH – The remarkable progress seen with immune checkpoint inhibitors in metastatic melanoma, non–small-cell lung cancer, and other tumors has yet to be replicated in breast cancer, but it’s early days yet, and breast cancer researchers need more time before the ultimate clinical benefits of immunotherapy in breast cancer can be ascertained, said Adam M. Brufsky, MD, PhD, of the University of Pittsburgh.

Early studies with inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 in patients with advanced triple-negative breast cancer have yielded only minimal response rates to date, but it it’s far too early to give up on the concept, Dr. Brufsky cautioned at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, he discussed the challenges of treating breast cancers, which may be less immunogenic and have a lower tumor mutational burden than other malignancies that respond more readily to PD-1 inhibition. Several large, phase III clinical trials of checkpoint inhibitors combined with cytotoxic chemotherapy are underway, he said, and those eventual findings may shed light on the optimal approach to using immunotherapy to treat patients with refractory metastatic breast cancers.

MIAMI BEACH – Breast tumors positive for the human epidermal growth factor receptor-2 (HER2) comprise only about 20% of all breast cancers, but for patients with HER2-positive disease, neoadjuvant therapy with trastuzumab (Herceptin) was and is a game changer, improving pathological complete response rates and long-term disease-free and overall survival rates, Debu Tripathy, MD, said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In the nearly 2 decades that have passed since the approval of trastuzumab, clinicians have learned how best to use HER2 inhibitors, how to weigh the relative risks and benefits of anti-HER2 therapy in patients who may be at risk for cardiotoxicities such as heart failure, and what combination regimens work best with HER2 inhibitors in early-stage disease.

In a video interview, Dr. Tripathy, professor and chair of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, discusses current clinical considerations for the use of trastuzumab and pertuzumab (Perjeta) in the neoadjuvant and adjuvant settings, investigational targeted therapies and immunotherapeutic strategies, and recently released clinical trial data showing a significant increase in disease-free survival for patients treated with dual HER2-blockade compared with HER2 monotherapy.

MIAMI BEACH – Breast tumors positive for the human epidermal growth factor receptor-2 (HER2) comprise only about 20% of all breast cancers, but for patients with HER2-positive disease, neoadjuvant therapy with trastuzumab (Herceptin) was and is a game changer, improving pathological complete response rates and long-term disease-free and overall survival rates, Debu Tripathy, MD, said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In the nearly 2 decades that have passed since the approval of trastuzumab, clinicians have learned how best to use HER2 inhibitors, how to weigh the relative risks and benefits of anti-HER2 therapy in patients who may be at risk for cardiotoxicities such as heart failure, and what combination regimens work best with HER2 inhibitors in early-stage disease.

In a video interview, Dr. Tripathy, professor and chair of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, discusses current clinical considerations for the use of trastuzumab and pertuzumab (Perjeta) in the neoadjuvant and adjuvant settings, investigational targeted therapies and immunotherapeutic strategies, and recently released clinical trial data showing a significant increase in disease-free survival for patients treated with dual HER2-blockade compared with HER2 monotherapy.

MIAMI BEACH – Breast tumors positive for the human epidermal growth factor receptor-2 (HER2) comprise only about 20% of all breast cancers, but for patients with HER2-positive disease, neoadjuvant therapy with trastuzumab (Herceptin) was and is a game changer, improving pathological complete response rates and long-term disease-free and overall survival rates, Debu Tripathy, MD, said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In the nearly 2 decades that have passed since the approval of trastuzumab, clinicians have learned how best to use HER2 inhibitors, how to weigh the relative risks and benefits of anti-HER2 therapy in patients who may be at risk for cardiotoxicities such as heart failure, and what combination regimens work best with HER2 inhibitors in early-stage disease.

In a video interview, Dr. Tripathy, professor and chair of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, discusses current clinical considerations for the use of trastuzumab and pertuzumab (Perjeta) in the neoadjuvant and adjuvant settings, investigational targeted therapies and immunotherapeutic strategies, and recently released clinical trial data showing a significant increase in disease-free survival for patients treated with dual HER2-blockade compared with HER2 monotherapy.

MIAMI BEACH – Randomized clinical trials are the gold standard for evidence-based medicine, but only about 5% of patients are enrolled. The majority of patients who are being treated for diseases such as breast cancer are ineligible for trials due to advanced age, poor performance, comorbidities, or other factors, noted Mohammad Jahanzeb, MD, professor of hematology/oncology at the University of Miami.

In contrast, studies using data from prospective registries provide valuable insights for investigators into diseases of real patients in real-world settings. Registry studies serve as a “living laboratory” that can help inform clinical practice, generate new clinical questions, and optimize clinical trial designs, he said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, Dr. Jahanzeb described the benefits of large patient registries and studies based on their data, including the registerHER and SystHERs observational registries of women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

MIAMI BEACH – Randomized clinical trials are the gold standard for evidence-based medicine, but only about 5% of patients are enrolled. The majority of patients who are being treated for diseases such as breast cancer are ineligible for trials due to advanced age, poor performance, comorbidities, or other factors, noted Mohammad Jahanzeb, MD, professor of hematology/oncology at the University of Miami.

In contrast, studies using data from prospective registries provide valuable insights for investigators into diseases of real patients in real-world settings. Registry studies serve as a “living laboratory” that can help inform clinical practice, generate new clinical questions, and optimize clinical trial designs, he said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, Dr. Jahanzeb described the benefits of large patient registries and studies based on their data, including the registerHER and SystHERs observational registries of women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

MIAMI BEACH – Randomized clinical trials are the gold standard for evidence-based medicine, but only about 5% of patients are enrolled. The majority of patients who are being treated for diseases such as breast cancer are ineligible for trials due to advanced age, poor performance, comorbidities, or other factors, noted Mohammad Jahanzeb, MD, professor of hematology/oncology at the University of Miami.

In contrast, studies using data from prospective registries provide valuable insights for investigators into diseases of real patients in real-world settings. Registry studies serve as a “living laboratory” that can help inform clinical practice, generate new clinical questions, and optimize clinical trial designs, he said at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource.

In a video interview, Dr. Jahanzeb described the benefits of large patient registries and studies based on their data, including the registerHER and SystHERs observational registries of women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

MIAMI BEACH – Unquestionably, the advent of human epidermal growth factor receptor-2 (HER2) inhibitors has dramatically improved long-term outcomes in patients with HER2-positive breast cancer.

But the benefits of therapy with the HER2-inhibitor trastuzumab (Herceptin) must be weighed against its potential for causing or exacerbating cardiomyopathy, especially when combined with anthracyclines such as doxorubicin that are associated with increased risk for late cardiotoxicity, said Sara Hurvitz, MD, director of the Breast Cancer Clinical Research Program at the David Geffen School of Medicine at UCLA in Santa Monica, Calif.

In a video interview, Dr. Hurvitz discussed strategies under development for identifying and evaluating biomarkers and cardiac imaging studies that could help to identify patients at highest risk for long-term cardiotoxicity, as well as alternative therapeutic regimens that eliminate the need for anthracyclines.

Dr. Hurvitz disclosed grants/research support from Amgen, Bayer, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Pfizer, Roche, Biomarin, Merrimack, OBI Pharma, Puma Biotechnology, Dignitana, Medivation, Lilly and Novartis, and travel reimbursement from Lilly, Novartis, and OBI Pharma.

MIAMI BEACH – Unquestionably, the advent of human epidermal growth factor receptor-2 (HER2) inhibitors has dramatically improved long-term outcomes in patients with HER2-positive breast cancer.

But the benefits of therapy with the HER2-inhibitor trastuzumab (Herceptin) must be weighed against its potential for causing or exacerbating cardiomyopathy, especially when combined with anthracyclines such as doxorubicin that are associated with increased risk for late cardiotoxicity, said Sara Hurvitz, MD, director of the Breast Cancer Clinical Research Program at the David Geffen School of Medicine at UCLA in Santa Monica, Calif.

In a video interview, Dr. Hurvitz discussed strategies under development for identifying and evaluating biomarkers and cardiac imaging studies that could help to identify patients at highest risk for long-term cardiotoxicity, as well as alternative therapeutic regimens that eliminate the need for anthracyclines.

Dr. Hurvitz disclosed grants/research support from Amgen, Bayer, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Pfizer, Roche, Biomarin, Merrimack, OBI Pharma, Puma Biotechnology, Dignitana, Medivation, Lilly and Novartis, and travel reimbursement from Lilly, Novartis, and OBI Pharma.

MIAMI BEACH – Unquestionably, the advent of human epidermal growth factor receptor-2 (HER2) inhibitors has dramatically improved long-term outcomes in patients with HER2-positive breast cancer.

But the benefits of therapy with the HER2-inhibitor trastuzumab (Herceptin) must be weighed against its potential for causing or exacerbating cardiomyopathy, especially when combined with anthracyclines such as doxorubicin that are associated with increased risk for late cardiotoxicity, said Sara Hurvitz, MD, director of the Breast Cancer Clinical Research Program at the David Geffen School of Medicine at UCLA in Santa Monica, Calif.

In a video interview, Dr. Hurvitz discussed strategies under development for identifying and evaluating biomarkers and cardiac imaging studies that could help to identify patients at highest risk for long-term cardiotoxicity, as well as alternative therapeutic regimens that eliminate the need for anthracyclines.

Dr. Hurvitz disclosed grants/research support from Amgen, Bayer, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Pfizer, Roche, Biomarin, Merrimack, OBI Pharma, Puma Biotechnology, Dignitana, Medivation, Lilly and Novartis, and travel reimbursement from Lilly, Novartis, and OBI Pharma.

MIAMI BEACH – Hormonal ablation is a mainstay of therapy for women with hormone receptor–positive breast cancer. A significant proportion of patients, however, are either initially refractory to hormonal therapy or acquire resistance to it over time.

The difficulty for patients with breast cancer and for the physicians who treat them is that there are no simple answers to the question of which patients can continue to benefit from endocrine monotherapy. Are there adequate biomarkers for optimal follow-on therapy when a patient experiences disease progression, and what is the optimal sequence of targeted therapy with endocrine inhibitors, disrupters, or other agents?

In a video interview at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, William J. Gradishar, MD, of Northwestern University, Chicago, discusses strategies for combating resistance to endocrine ablative therapy, and describes how new therapies and new treatment strategies are being incorporated into National Comprehensive Cancer Network breast cancer guidelines.

Dr. Gradishar reported having no clinical disclosures.

MIAMI BEACH – Hormonal ablation is a mainstay of therapy for women with hormone receptor–positive breast cancer. A significant proportion of patients, however, are either initially refractory to hormonal therapy or acquire resistance to it over time.

The difficulty for patients with breast cancer and for the physicians who treat them is that there are no simple answers to the question of which patients can continue to benefit from endocrine monotherapy. Are there adequate biomarkers for optimal follow-on therapy when a patient experiences disease progression, and what is the optimal sequence of targeted therapy with endocrine inhibitors, disrupters, or other agents?

In a video interview at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, William J. Gradishar, MD, of Northwestern University, Chicago, discusses strategies for combating resistance to endocrine ablative therapy, and describes how new therapies and new treatment strategies are being incorporated into National Comprehensive Cancer Network breast cancer guidelines.

Dr. Gradishar reported having no clinical disclosures.

MIAMI BEACH – Hormonal ablation is a mainstay of therapy for women with hormone receptor–positive breast cancer. A significant proportion of patients, however, are either initially refractory to hormonal therapy or acquire resistance to it over time.

The difficulty for patients with breast cancer and for the physicians who treat them is that there are no simple answers to the question of which patients can continue to benefit from endocrine monotherapy. Are there adequate biomarkers for optimal follow-on therapy when a patient experiences disease progression, and what is the optimal sequence of targeted therapy with endocrine inhibitors, disrupters, or other agents?

In a video interview at the annual Miami Breast Cancer Conference, held by Physicians’ Education Resource, William J. Gradishar, MD, of Northwestern University, Chicago, discusses strategies for combating resistance to endocrine ablative therapy, and describes how new therapies and new treatment strategies are being incorporated into National Comprehensive Cancer Network breast cancer guidelines.

Dr. Gradishar reported having no clinical disclosures.

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

op@frontlinemedcom.com

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

op@frontlinemedcom.com

ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.

High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.

Tumor-induced immune suppression

Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.

“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.

In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.

“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
 

Higher levels correlate with outcomes

To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.

They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.

The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.

They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.

Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.

They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).

They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.

“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
 

‘A little bit curious’

Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.

op@frontlinemedcom.com