MINDACT Study Supports Gene Signature Test in Predicting Chemotherapy Efficacy in Breast Cancer

A 70-gene signature test (MammaPrint) appears to accurately predict which women with early-stage breast cancer will benefit from chemotherapy and who can safely forego it. The 70-gene signature was found to be superior to clinical-pathologic features in providing prognostic and predictive information about patients’ tumors in the phase 3 MINDACT study.

The MINDACT Trial

“We decided to conduct this study because as breast cancer doctors we were very well aware that we were overtreating women with early breast cancer,” explained Martine J. Piccart, MD, PhD, Director of the Department of Medicine, Jules Border Institute, and Co-Founder of the Breast International Group (BIG), in Brussels, Belgium.

“Because the disease becomes so much harder to treat once it has metastasized, we try very hard to control it before that happens,” she explained. However, in some cases, zealously treating a localized tumor to prevent metastasis may lead to overtreatment.

MINDACT included 6693 women who underwent surgery for early-stage breast cancer. The initial study design called only for patients with node-negative disease to be enrolled, but the protocol was subsequently amended to allow women with as many as 3 positive axillary nodes after the gene signature was validated in such patients.

Every patient was evaluated by a clinical-pathologic prognostic model and the 70-gene signature. Clinical low risk was defined as an estimated 10-year disease-specific survival of 88% without chemotherapy or endocrine therapy for estrogen receptor (ER)-positive disease, or 92% for ER-negative disease.

The 2745 patients in MINDACT with low-risk disease determined through both methods did not receive chemotherapy, and all 1806 patients who were identified as having high-risk disease by both methods received chemotherapy. The 2142 patients (23% of the sample) who had discordant results (high by one method, low by the other) were randomized to chemotherapy or no chemotherapy on the basis of either clinical-pathologic or 70-gene signature results. The primary end point of the trial was 5-year distant metastasis-free survival (DMFS).

Patients who were determined to be high risk by clinical-pathologic features but low risk by the 70-gene assay had a 5-year DMFS of 94.4% without chemotherapy compared with 95.9% with chemotherapy, a difference that was not significant (hazard ratio, 0.78; P = .267). In patients with a low clinical-pathologic risk but high genetic risk, the 5-year DMFS rate was 95% versus 96% with or without chemotherapy, respectively.

In women with early-stage disease who were at high clinical risk and low genomic risk for recurrence, withholding chemotherapy based on the results of the 70-gene signature test led to a 5-year DMFS rate that was statistically equivalent to that in women who received chemotherapy.

“Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy,” Dr Piccart and colleagues concluded. The implication is that many women diagnosed at an early stage with specific types of breast cancer may be able to safely avoid chemotherapy.

Little Progress in 15 Years?: MINDACT Findings Debated

Although the findings of the MINDACT study for clinical practice appear to be conclusive, they were debated at the recent 2017 Miami Breast Cancer Conference.

Adam M. Brufsky, MD, PhD, FACP, Associate Chief, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, PA, said “MINDACT is clearly practice-changing. Something we need to start thinking about is that maybe we are overtreating a subset of [patients with] HER2-positive, early-stage breast cancer.”

Among those not swayed by the MINDACT data was Norman Wolmark, MD, Professor of Surgery, Temple University School of Medicine, Pittsburgh, PA. “I liked it when it first came out in 2002,” Dr Wolmark said of the 70-gene signature. “I must say that I like it considerably less after the MINDACT data.”

The aim of MINDACT, he said, was not to predict benefit from chemotherapy but to demonstrate that patients with high clinical risk but low genomic risk based on the 70-gene assay have a favorable outcome (DMFS >92%) to justify not treating them with chemotherapy. “If that’s the case, why did you need a randomized prospective trial if that’s all you’re powered to show? You could have done a single-arm trial and said that the DMFS is greater than 92% and you’re done,” Dr Wolmark said.

Dr Wolmark went on to say that the future lies in liquid biopsies or next-generation sequencing rather than gene signature assays, which have been in clinical practice for 15 years since Oncotype DX hit the market.