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Short-HER trial: DFS is similar, cardiac toxicity lower with short trastuzumab course
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
AT ASCO 2017
Key clinical point:
Major finding: The 5-year disease-free survival rates were 87.5% and 85.4% with 9 weeks, vs. 1 year, of trastuzumab (HR, 1.15).
Data source: The phase III Short-HER study of 1,253 patients.
Disclosures: The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
VIDEO: NCI estimation of MBC numbers a start, but more is needed
CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.
A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.
“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.
A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.
“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.
A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.
“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Metastatic Trial Search links MBC patients to relevant trials
CHICAGO – Metastatic Trial Search was launched in 2015 by ClinicalTrials.org to make it easier for patients with metastatic breast cancer to consider clinical trials as a routine option as they are making treatment decisions with their physicians.
In a video interview, Shirley A. Mertz, JD, president of the Metastatic Breast Cancer Network, describes the tool, the mixed response from physicians, the barriers to trial participation still faced by patients, and the tweaked version 2.0 of the search tool, expected to launch by the end of this year.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Metastatic Trial Search was launched in 2015 by ClinicalTrials.org to make it easier for patients with metastatic breast cancer to consider clinical trials as a routine option as they are making treatment decisions with their physicians.
In a video interview, Shirley A. Mertz, JD, president of the Metastatic Breast Cancer Network, describes the tool, the mixed response from physicians, the barriers to trial participation still faced by patients, and the tweaked version 2.0 of the search tool, expected to launch by the end of this year.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Metastatic Trial Search was launched in 2015 by ClinicalTrials.org to make it easier for patients with metastatic breast cancer to consider clinical trials as a routine option as they are making treatment decisions with their physicians.
In a video interview, Shirley A. Mertz, JD, president of the Metastatic Breast Cancer Network, describes the tool, the mixed response from physicians, the barriers to trial participation still faced by patients, and the tweaked version 2.0 of the search tool, expected to launch by the end of this year.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
OlympiAD’s positive results spell good news for olaparib in breast cancer
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
CHICAGO – The oral PARP inhibitor olaparib likely offers a new treatment option for patients with BRCA-related HER2-negative metastatic breast cancer, according to results of the randomized phase III OlympiAD trial reported at the annual meeting of the American Society of Clinical Oncology.
Inhibitors of PARP, or poly(ADP-ribose) polymerase, exploit defective DNA repair due to BRCA mutations, lead author Mark E. Robson, MD, clinic director of the clinical genetics service and medical oncologist at Memorial Sloan Kettering Cancer Center in New York, noted in a press briefing.
“PARP inhibitors have already been approved for the treatment of ovarian cancer in patients with mutations of BRCA1 or BRCA2, and recently in other circumstances. And there have been a couple of small studies that have suggested that breast cancer in BRCA mutation carriers could also be responsive to PARP inhibitors,” he said.
“This is the first phase III study that’s shown an advantage of a PARP inhibitor over standard-of-care chemotherapy in breast cancer patients with BRCA mutations,” Dr. Robson commented. “It was generally well tolerated, with less than 5% of patients discontinuing treatment for toxicity, and a lower rate of grade 3 or worse side effects.”
“It is our opinion that olaparib could be an effective treatment option for women with BRCA mutations who have metastatic HER2-negative breast cancer, including importantly women with BRCA mutations in triple-negative disease,” he concluded.
Findings going forward
Although the trial was positive, the absolute difference in progression-free survival was just 2.8 months, and the curves converged over time, raising questions about potentially more efficacious PARP inhibitors or strategies for getting greater benefit out of olaparib.
“There are three PARP inhibitors in the developmental stage in breast cancer, and there are noncomparative trials and no really good ways to make a decision about which one is better,” Dr. Robson commented.
Several strategies are being explored for enhancing the benefit of these drugs, he continued. “One is combining it with a conventional chemotherapy agent, which is hard to do because of overlapping bone marrow toxicity, so it’s tough to get full doses of chemotherapy and full doses of PARP inhibitor in. Another is to combine it with other targeted agents that interact with components of the DNA damage repair pathway … and there are certainly combination therapy trials that are underway. And then third is … a combination of olaparib with an immuno-oncology agent.”
Additionally, some studies are evaluating expansion of PARP inhibitors to populations such as patients with triple-negative breast cancer who do not have an identifiable BRCA mutation, on the assumption that they have similar, somatic DNA defects that might be susceptible to this class of agents, according to Dr. Robson.
“The studies have been small and at least the initial ones have not been particularly encouraging,” he said. “But as mentioned, combination approaches now are being evaluated as a way to potentially ‘soup up’ the effect in a broader group of patients.”
Expert perspective
The OlympiAD trial represents a “major step forward in breast cancer” in terms of both translational medicine and precision medicine, according to ASCO President Daniel F. Hayes, MD, FACP, FASCO.
Trials moving olaparib into earlier metastatic settings and possibly even the adjuvant setting will likely be conducted in the next year or 2, speculated Dr. Hayes, who is also clinical director of the breast oncology program and Stuart B. Padnos Professor in Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Potential issues of long-term toxicity, such as secondary leukemias, will need to be kept in mind, especially if olaparib is moved to the curative treatment setting, he cautioned. And a better understanding of resistance (as suggested by the converging progression-free survival curves) and how to overcome it will be key. “That goes back to using it in different ways, clever ways, perhaps combining it with other sorts of therapies,” he said.
Study details
OlympiAD, which was funded by AstraZeneca, enrolled patients with HER2-negative metastatic breast cancer and a centrally confirmed germline (inherited) BRCA mutation who had received anthracyclines and taxanes, and up to two lines of chemotherapy for metastases.
They were randomized 2:1 to open-label treatment with either olaparib (300 mg., twice daily) or single-agent chemotherapy of the treating physician’s choice among three options (capecitabine, eribulin, or vinorelbine). A tablet formulation and dose of olaparib were used that differ from the currently approved capsule formulation and dose to reduce pill burden, Dr. Robson noted.
The patients were about equally split between BRCA1 and BRCA2 mutations, and between hormone receptor–positive disease and triple-negative disease, he reported. The majority (71%) had received chemotherapy for metastases, and a sizable minority (28%) had received prior platinum in the (neo)adjuvant or metastatic setting.
With a median follow-up of about 14.5 months, median progression-free survival assessed by central radiologic review was 7.0 months with olaparib and 4.2 months with chemotherapy (hazard ratio, 0.58; P = .0009).
The median time to investigator-reported second progression or death was also longer with olaparib (13.2 vs. 9.3 months; HR, 0.57; P = .0033).
Median overall survival was about 19-20 months in each group and not significantly different in an interim analysis.
The olaparib group had lower rates of grade 3 or worse adverse events (36.6% vs. 50.5%) and treatment discontinuation because of adverse events (4.9% vs. 7.7%).
The main adverse event of any grade with olaparib was nausea, which was usually mild; only about a quarter of affected patients required antiemetics, according to Dr. Robson. Patients also commonly experienced anemia, requiring transfusion in some cases, and fatigue.
Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; rand receives research funding (institutional) from AstraZeneca, Abbvie, Myriad Genetics, Biomarin, Medivation, and Tesaro.
AT ASCO 2017
Key clinical point:
Major finding: Progression-free survival was superior with olaparib as compared with standard single-agent chemotherapy (7.0 vs. 4.2 months; hazard ratio, 0.58; P = .0009).
Data source: An open-label randomized phase III trial among 302 patients with HER2-negative metastatic breast cancer and a germline BRCA mutation (OlympiAD trial).
Disclosures: Dr. Robson disclosed that he has a consulting or advisory role with McKesson and AstraZeneca; receives honoraria, travel, accommodations, and/or expenses from AstraZeneca; and receives research funding (institutional) from AstraZeneca, AbbVie, Myriad Genetics, Biomarin, Medivation, and Tesaro. The trial was funded by AstraZeneca.
VIDEO: Pertuzumab prolongs disease-free survival in HER2+ early breast cancer
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Survival improves when cancer patients self-report symptoms
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
AT THE 2017 ASCO ANNUAL MEETING
Key clinical point:
Major finding: Median overall survival was 31.2, vs. 26 months, with self-reporting of symptoms, vs. usual care.
Data source: A randomized controlled clinical trial of 766 patients.
Disclosures: This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
VIDEO: Routine genomic testing identifies actionable alterations in 52% of tumors
CHICAGO –
Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).
“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Many patients either were too sick to receive the recommended treatment or died before they could be treated, Dr. Tredan said in a video interview.
Of the patients who did receive targeted treatment, over 60% received mTOR inhibitors. The next most common therapies were multitarget tyrosine kinase receptor (TKR)–inhibiting/antiangiogenic therapies, received by about one-third of patients. Fewer than one in five patients received any other therapies. Tumor types were colorectal, gynecological, breast, head and neck carcinomas, sarcomas, and brain tumors.
A new randomized clinical study, profiLER 2, is planned. The new study will pit a 315-gene commercial test against the 69-gene test used in profiLER 1, to see whether casting a wider net yields more targets for therapy.
Still, knowing that a treatment might help is useful only if the patient can actually receive the drug, said Dr. Tredan. “What we want is more molecular targeted agent initiation, so we need to have larger screening programs, but we need also to have access to novel targeted agents.”
Dr. Tredan reported financial relationships with Bayer, GlaxoSmithKline, and Novartis.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO –
Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).
“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Many patients either were too sick to receive the recommended treatment or died before they could be treated, Dr. Tredan said in a video interview.
Of the patients who did receive targeted treatment, over 60% received mTOR inhibitors. The next most common therapies were multitarget tyrosine kinase receptor (TKR)–inhibiting/antiangiogenic therapies, received by about one-third of patients. Fewer than one in five patients received any other therapies. Tumor types were colorectal, gynecological, breast, head and neck carcinomas, sarcomas, and brain tumors.
A new randomized clinical study, profiLER 2, is planned. The new study will pit a 315-gene commercial test against the 69-gene test used in profiLER 1, to see whether casting a wider net yields more targets for therapy.
Still, knowing that a treatment might help is useful only if the patient can actually receive the drug, said Dr. Tredan. “What we want is more molecular targeted agent initiation, so we need to have larger screening programs, but we need also to have access to novel targeted agents.”
Dr. Tredan reported financial relationships with Bayer, GlaxoSmithKline, and Novartis.
koakes@frontlinemedcom.com
On Twitter @karioakes
CHICAGO –
Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).
“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Many patients either were too sick to receive the recommended treatment or died before they could be treated, Dr. Tredan said in a video interview.
Of the patients who did receive targeted treatment, over 60% received mTOR inhibitors. The next most common therapies were multitarget tyrosine kinase receptor (TKR)–inhibiting/antiangiogenic therapies, received by about one-third of patients. Fewer than one in five patients received any other therapies. Tumor types were colorectal, gynecological, breast, head and neck carcinomas, sarcomas, and brain tumors.
A new randomized clinical study, profiLER 2, is planned. The new study will pit a 315-gene commercial test against the 69-gene test used in profiLER 1, to see whether casting a wider net yields more targets for therapy.
Still, knowing that a treatment might help is useful only if the patient can actually receive the drug, said Dr. Tredan. “What we want is more molecular targeted agent initiation, so we need to have larger screening programs, but we need also to have access to novel targeted agents.”
Dr. Tredan reported financial relationships with Bayer, GlaxoSmithKline, and Novartis.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT ASCO 2017
Immune-agonist combo has activity against several tumor types
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
Biomarker predicts prolonged depression in breast cancer patients
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
SAN FRANCISCO – Nearly 40% of breast cancer patients experience prolonged depression lasting for at least 16 months after diagnosis of their malignancy; those at increased risk may be identifiable in a timely way by their exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy, according to Kate R. Kuhlman, PhD.
“There are several psychological interventions that mitigate depressive symptoms and psychologic distress in women with breast cancer. This time period immediately following cancer diagnosis and surgery may be the optimal time to intervene,” said Dr. Kuhlman, a psychologist at the University of California, Los Angeles.
She presented a prospective study of 135 women with breast cancer who collected saliva samples for analysis of hypothalamic-pituitary-adrenal axis functioning on 3 consecutive days after their primary surgery but prior to starting adjuvant therapy. Samples were obtained on each of the 3 days upon awakening, 30 minutes later, 8 hours later, and at bedtime. The women also completed the Center for Epidemiologic Studies Depression Scale (CES-D) then and again 6 months after completing their breast cancer treatment.
At baseline, 45 of the 135 women scored 16 points or higher out of a possible 60 on the 20-question CES-D, indicative of clinically significant depression. Hypothalamic-pituitary-adrenal axis functioning wasn’t associated with depressive symptoms at that time. Importantly, however, one measure of baseline HPA axis functioning – the cortisol awakening response – proved to be associated with an increase in depressive symptoms over time, Dr. Kuhlman reported.
In a multivariate analysis adjusted for age, breast cancer stage, type of surgery, and forms of adjuvant therapy, a 1-standard-deviation increase above the mean in baseline cortisol awakening response was associated with a 6-point increase in CES-D score at follow-up 6 months after completion of breast cancer therapy. This association was seen only in the 90 women without significant depressive symptoms at baseline. And that’s exactly the population where a predictive biologic marker for future depression is most needed, Dr. Kuhlman said at the annual conference of the Anxiety and Depression Association of America.
“The people at highest risk of depressive symptoms in the future are the ones who have the most symptoms now. They’re easy to identify. We have good reliable measures. But then there are also people at risk whom we would miss by using those measures because they don’t have high symptoms right now,” the psychologist explained.
She and her coinvestigators zeroed in on cortisol awakening response as a potential biomarker of increased future risk of depression because it reflects the adrenal gland’s sensitivity to adrenocorticotropic hormone and the gland’s ability to signal the pituitary to produce cortisol. This action is triggered when people go from sleep to awakening.
The next steps in this research are to confirm these novel findings and hunt for an alternative marker of adrenal sensitivity to adrenocorticotropic hormone that’s simpler than sending a waking saliva sample off to a laboratory.
This ongoing longitudinal study is funded by the National Cancer Institute. Dr. Kuhlman reported having no relevant financial conflicts.
AT ANXIETY AND DEPRESSION CONFERENCE 2017
Key clinical point:
Major finding: Nondepressed breast cancer patients whose saliva samples show an exaggerated cortisol awakening response when measured after surgery but before adjuvant therapy are at increased risk for developing prolonged depression as treatment progresses.
Data source: A prospective longitudinal study of 135 women with breast cancer.
Disclosures: This ongoing study is funded by the National Cancer Institute. The presenter reported having no relevant financial conflicts.
Test goes wide and deep to detect free tumor DNA in blood
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.
AT ASCO 2017
Key clinical point: High-intensity sequencing of plasma samples appears capable of detecting actionable tumor mutations in a large proportion of samples.
Major finding: In 89% of patients with advanced cancers, genetic variants were identified in both tumor samples and circulating free DNA testing.
Data source: Prospective study of tissue and plasma samples from 124 patients with non–small cell lung cancer or metastatic breast and prostate cancers.
Disclosures: The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.