Commercial biomarkers that guide clinical decisions in breast cancer appeared on the market just over a decade ago. In April, researchers unveiled long-awaited, prospective phase III results for the European market leader: a 70-gene assay called Mammaprint. The new data show that many patients whom the assay identified as having low risk of recurrence can safely avoid chemotherapy. Researchers presented the results at the American Association for Cancer Research’s annual meeting in New Orleans.
The U.S. Food and Drug Administration approved Mammaprint in 2007, citing evidence that it could predict whether a woman’s breast cancer is likely to return within 5–10 years. Published a year earlier in JNCI, the evidence came from a study of 302 women diagnosed with node-negative, stage T1–T2 breast cancer between 1980 and 1998 who hadn’t received adjuvant systemic therapy. The authors concluded that Mammaprint adds independent prognostic information and identifies women with a low risk of metastases and death more reliably than clinical factors such as age, tumor size, and tumor grade. But that retrospective early study relied on frozen tumor samples for genetic analysis. Despite FDA approval, many U.S. experts were therefore unconvinced that Mammaprint should play a role in chemotherapy treatment decisions. Indeed, in updated clinical practice guidelines published last February, the American Society of Clinical Oncology (ASCO) recommended against using Mammaprint for that purpose. ASCO panelists claimed they couldn’t determine whether the assay identifies women for whom chemotherapy is likely to be ineffective. But they also wrote that they were awaiting results from MINDACT, the prospective phase III trial sponsored by the Brussels-based European Organisation for Research and Treatment of Cancer (EORTC).
According to Lyndsay N. Harris, M.D., chair of the ASCO Breast Cancer Guidelines Advisory Group and director of the Breast Cancer Program at Case Western Reserve University School of Medicine in Cleveland, the data appear to offer “level 1 evidence that the 70-gene assay is associated with improved patient outcomes.” However, ASCO panelists still need to review the published MINDACT data before possibly revising their decision against it, she said. Those data are expected later this year.
The ASCO guidelines approved five molecular assays in various stages of development. The guidelines limited recommended uses to women with hormone receptor (HR)–positive, HER2-negative, node-negative breast cancer. Many such women have low risks of incurable recurrence after treatment with surgery, radiation, or hormonal therapy. Chemotherapy can reduce that risk by an additional 30%, but it also produces potentially life-threatening toxic effects in 2%–3% of otherwise healthy women. Whether chemotherapy’s added benefits justify the potential harm to low-risk patients often isn’t clear. Therefore, clinicians are turning to molecular assays for new insights.
[Some 94% of patients in which Mammaprint predicated a low recurrence risk had metastasis-free survival at 5 years regardless of whether they underwent chemotherapy.] “That’s the fundamental message. This is the group for which Mammaprint could be most helpful.”
The test with the longest history, the 21-gene Oncotype DX assay (among those ASCO recommended), classifies risk of recurrence as low, medium, high. A massive National Cancer Institute–sponsored study, the TAILORx trial, is evaluating Oncotype DX. That study recently published data showing that 98% of women in the low-risk group remained free of distant metastases 5 years after hormonal therapy. Researchers generally agree that high-risk women need chemotherapy. But whether chemotherapy benefits the roughly 60% of patients in the medium-risk category remains an open question. Therefore, TAILORx randomized medium-risk patients to treatment with either hormonal therapy alone or hormonal therapy plus chemotherapy. Those results are not yet available. But according to Nancy Davidson, M.D., professor of oncology at the University of Pittsburgh Cancer Institute, the results should eventually offer information to help predict how treatment decisions informed by molecular screening influence survival.
Oncotype DX and Mammaprint both address similar needs, but their gene signatures are dissimilar. The former measures genes associated with the estrogen receptor and HER2 pathways, whereas the latter measures genes involved in tumor proliferation, metastasis, angiogenesis, and other disease processes. Moreover, whereas Oncotype DX groups risk into three categories, Mammaprint describes risks as only high or low.
The MINDACT trial evaluated nearly 7,000 patients in two ways. Researchers both used Mammaprint to genetically screen patients’ tumors and assessed patients with Adjuvant! Online, a tool that uses clinical criteria such as age and tumor size to predict breast cancer recurrence. Often, patients deemed high risk by Mammaprint were likewise deemed high risk by Adjuvant Online! and vice versa. However, in about 1,500 patients, Mammaprint predicted low recurrence risk, whereas Adjuvant! Online predicted the opposite. According to Martine Piccart, M.D., Ph.D., professor of oncology at the University of Brussels in Belgium and MINDACT’s principal investigator, 94% of patients in that discordant group still had metastasis-free survival at 5 years regardless of whether they underwent chemotherapy.“That’s the fundamental message. Piccart said. This is the group for which Mammaprint could be most helpful.”
Unlike TAILORx, which enrolled only women with HR-positive, HER-negative, node-negative disease, MINDACT combined those groups. About 10% of enrolled patients were HER2 positive, 12% were HR negative, and 20% had one to three positive nodes. Jan Bogaerts, Ph.D., a statistician and methodology director at EORTC , said investigators adopted that approach because they wanted the trial to more broadly represent women with breast cancer (though approximately 80% of women so diagnosed are HR positive). According to Harold Burstein, M.D., Ph.D., associate professor of medicine at Harvard Medical School in Boston, the hope was “that you could take a more unselected group of patients and use genetic tumor screening to find out who needs chemotherapy and who doesn’t.” But because MINDACT included so few of these other groups, Burstein said, the study’s relevance to them was limited at best. “MINDACT covers the same terrain as the other tests,” Burstein said.
Piccart said that Oncotype DX is so broadly used in the United States that clinicians here might not change habits. “However, we now have a very robust demonstration that the 70-gene signal is powerful, and I’m confident that ASCO leaders will agree and revise their recommendation,” she said.
According to Harris, the final outcome will hinge on the published data. “We have to look at that and be convinced that it shows clinical utility,” she said.