The study provides proof of principle that targeting the proteasome may prevent and/or delay the emergence of acquired resistance to endocrine therapy with fulvestrant.
—Kerin B. Adelson, MD
Highlighted here are summaries of four abstracts presented at the 2014 San Antonio Breast Cancer Symposium: They focus on the EPO-ANE-3010 clinical trial of epoetin alfa (Epogen, Procrit) in anemic patients with metastatic breast cancer, a New York Cancer Consortium trial of fulvestrant (Faslodex) and bortezomib (Velcade) in hormone receptor–positive metastatic breast cancer, the use of a 25-gene hereditary cancer panel, and the BEACON trial of etirinotecan pegol in patients with metastatic breast cancer.
Risks Associated With Epoetin Alfa Confirmed
The use of epoetin alfa led to increased mortality and tumor progression in metastatic breast cancer patients who were evaluated in the U. S. Food and Drug Administration (FDA)-mandated EPO-ANE-3010 trial, based on safety concerns that arose with erythropoiesis-stimulating agents in 2002.1
“The results were consistent with the black box warning. We had hoped for better,” said Brian Leyland-Jones, MD, of the Avera Medical Group Oncology and Hematology in Sioux Falls, South Dakota.
The recommendation remains, he said, that epoetin alfa should only be used for chemotherapy-related anemia in patients where cure is not the anticipated outcome.
For the management of anemia in the first or second line of chemotherapy in metastatic breast cancer, “transfusion would be the preferred approach,” he emphasized.
EPO-ANE-3010, which began in 2004, enrolled 2,100 patients with metastatic breast cancer and a hemoglobin level ≤ 11 g/dL. Patients underwent chemotherapy and were randomized to receive standard supportive care or supportive care plus epoetin alfa 40,000 IU weekly.
“The primary endpoint of progression-free survival, per investigator-determined progressive disease, did not meet the protocol-defined noninferiority criteria of 1.15,” Dr. Leyland-Jones announced. A 9% increased risk in disease progression or death and a 6% increased risk in death were observed, although overall survival data are not yet mature.
The median progression-free survival was 7.4 months with epoetin alfa (95% confidence interval [CI] = 6.9–7.6) and 7.5 months in the control arm (95% CI = 7.1–7.6, hazard ratio [HR] = 1.089). For the epoetin alpha and control arms, respectively, the median time to tumor progression was 7.5 months (95% CI = 7.4–7.9) and 7.5 months (95% CI = 7.4–8.0, HR = 1.094), respectively. At cutoff, the median overall survival was 17.2 months (95% CI = 16.1–18.5) and 17.4 months (95% CI = 16.0–18.9, HR = 1.057), respectively.
“The separation of the time to disease progression Kaplan-Meier curves was completely unanticipated,” Dr. Leyland-Jones commented. “The progression-free survival and time to progression curves separated after about 12 months and overall survival after about 18 months. The difference is driven by 30% of patients who were progression-free at 12 months. There do not appear to be any factors that explain the divergence.”
Transfusion rates were low in both groups—11.4% with standard care vs 5.8% with epoetin alfa —although epoetin alfa did reduce the need by 51% (P < .001). Thrombotic vascular events were infrequent, 1.4% vs 2.8%, respectively, “although they were serious when they occurred,” he said. Grade ≥ 3 adverse events were similar in both groups.
Fulvestrant Plus Bortezomib
In the randomized phase II New York Cancer Consortium NCI Trial 8457, the addition of bortezomib to fulvestrant significantly reduced the rate of disease progression (HR = 0.73, P = .06) and significantly improved the 12-month progression-free survival, from 14% to 28% (P = .03) in treatment-refractory patients [note: P < .1 for significance), reported Kerin B. Adelson, MD, of Yale University School of Medicine, New Haven, Connecticut.2
Bortezomib did not, however, improve progression-free survival at 6 months or median progression-free survival. “We estimated the median progression-free survival in the fulvestrant-alone arm would be 5.4 months. The observed median of 2.7 months suggests a more hormone-resistant population than expected, and this may have impacted our median progression-free survival calculations.”
The study enrolled 118 women with estrogen receptor–positive metastatic breast cancer resistant to aromatase inhibitors. Patients were randomly assigned to receive fulvestrant (500 mg) alone or with bortezomib (1.6 mg/m2).
Almost half the fulvestrant arm crossed over to the combination. In this group, the clinical benefit (progression-free for ≥ 24 weeks) was observed in 18%. Five patients had a longer progression-free survival after crossover than they did on fulvestrant alone.
The doublet increased nausea, diarrhea, and neuropathy, but there was little grade 3 and no grade 4 toxicity due to treatment, suggesting the regimen is well tolerated.
“The study provides proof of principle that targeting the proteasome may prevent and/or delay the emergence of acquired resistance to endocrine therapy with fulvestrant,” Dr. Adelson suggested.
25-Gene Panel Offers More Thorough Screening
Use of a 25-gene gene panel in community oncology practices could greatly increase the detection of hereditary breast cancer mutations, according to a study by US Oncology investigators.3
In their study, the 25-gene hereditary cancer panel increased the identification of deleterious mutations by almost 70% over testing for hereditary breast and ovarian cancer or Lynch syndrome alone, reported Sami Diab, MD, of Rocky Mountain Care Centers and Colorado Integrative Care in Aurora.
“We found that almost 10% of high-risk patients had a mutation that could have been causing their cancer. If we limited our testing to the BRCA genes or Lynch syndrome genes, we would have identified only 60%. There are 40% of patients with other genes that could be identified,” Dr. Diab said.
The 25-gene panel, which is based on next-generation sequencing, targets 8 cancers: breast, ovarian, colorectal, endometrial, pancreatic, melanoma, prostate, and stomach. The panel assays for mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, CDKN2A, CDK4, PALB2, CHEK2, SMAD4, BMPR1A, STK11, TP53, CHD1, PTEN, ATM, NBN, BARD1, BRIP1, RAD51C, and RAD51D.
U.S. Oncology clinicians performed the test on 997 individuals, of whom 773 (77.5%) had a personal history of at least one of the eight panel cancers. Almost all met the National Comprehensive Cancer Network guidelines for testing for hereditary breast and ovarian cancer, Lynch syndrome, or both.
The test identified 83 mutations in 79 patients. Of those with a personal history of cancer, 72 (9.3%) had a pathogenic mutation. Mutations were identified in 15 different genes. Only 59% of these genes were among the six genes that are included in single-syndrome hereditary breast and ovarian cancer (BRCA1, BRCA2) and Lynch syndrome (MSH6, MLH1, MSH2, PMS2) testing, Dr. Diab reported.
“A significant portion of mutations were found in genes not traditionally associated with hereditary breast and ovarian cancer or Lynch syndrome,” he said.
The next step is to better understand the clinical spectrum of the deleterious mutations identified in this 25-gene panel in order to provide appropriate screening recommendations.
Novel Topo-1 Inhibitor
The international phase III BEACON trial will evaluate a novel topoisomerase 1 inhibitor, etirinotecan pegol, in patients with previously treated metastatic breast cancer and target-specific biomarkers in circulating tumor cells, according to Edith Perez, MD, of the Mayo Clinic in Jacksonville, Florida.4
Topoisomerase 1 is a nuclear enzyme that plays an essential role in DNA replication, transcription, recombination, and repair. Etirinotecan pegol is a long-acting topoisomerase 1 inhibitor designed for prolonged tumor cell exposure.
In a previous phase II trial of 70 patients, the response rate to etirinotecan pegol was 29%, the median progression-free survival was 4.7 months, and the median overall survival was 10.3 months. Based on these results, the phase III BEACON trial was designed; it will compare single-agent etirinotecan pegol with physicians’ choice of treatment in 852 previously treated patients. Patients must have received an anthracycline, taxane, and capecitabine, “so they are truly refractory patients,” she said.
One of the exciting aspects of the trial is that it is biomarker-driven, Dr. Perez emphasized. The investigators will analyze circulating tumor cells obtained at baseline and throughout treatment and correlate these findings with clinical outcomes. BEACON is employing the ApoStream system for isolation of circulating tumor cells. This technique, which is based on dielectrophoresis and microfluidic technology and is antibody-independent, reportedly yields higher numbers of circulating tumor cells than the first-generation EpCAM-dependent methods.
“We were happy to have access to novel technology that can detect many more circulating tumor cells than EpCAM-dependent technology,” she said.
Top-line results—the endpoint being overall survival—are expected in the first quarter of 2015. ■
Disclosure: Dr. Leyland-Jones has served as a consultant for Genentech, Roche, Bristol-Myers Squibb, Janssen, Xoma, Genta, NewBiotics, GlaxoSmithKline, and Hospira. He also has contracts with Roche, AstraZeneca, Insmed, Arius, and Nanocarrier. Dr. Adelson is a speaker for Genomic Health. Drs. Diab and Perez reported no potential conflicts of interest.
1. Leyland-Jones B, Bondarenko I, Nemsadze G, et al: A randomized, open-label, multicenter, phase 3 study of epoetin alfa plus standard supportive care versus standard supportive care in anemic patients with metastatic breast cancer receiving standard chemotherapy. 2014 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 12, 2014.
2. Adelson KB, Ramaswamy B, Sparano JA, et al: Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York Cancer Consortium trial. 2014 San Antonio Breast Cancer Symposium. Abstract S6-03. Presented December 12, 2014.
3. Diab S, Rodriguez P, Leininger A, et al: Experience in the community oncology practice with a 25-gene hereditary cancer panel. 2014 San Antonio Breast Cancer Symposium. Abstract P1-03-03. Presented December 10, 2014.
4. Perez EA, Caygill K, Hannah AL, et al: Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study. 2014 San Antonio Breast Cancer Symposium. Abstract P3-10-03. Presented December 11, 2014.