The 70-Gene Signature as an Aid to Treatment Decisions in Early Breast Cancer

Published - Written by Ramya Ramaswami, M.B.B.S., M.R.C.P., M.P.H.

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“Your cancer has been successfully removed with surgery, but there may be a role for chemotherapy to protect you in the future.” This message is expressed by oncologists in consulting rooms all over the world. In women with early-stage breast cancer, adjuvant chemotherapy may be offered as an insurance policy against cancer recurrence. Risk of recurrence can be estimated based on algorithms using patient and tumor characteristics, but following these algorithms can lead to overtreatment by exposing some patients to the toxicity of combination chemotherapy, without the benefit.

Genomic testing of tumors may provide greater accuracy in predicting risk of recurrence. However, genomic test results may conflict with existing conventional methods of risk stratification, and it is uncertain whether patients whose clinical and tumor characteristics suggest higher risk of recurrence but whose genomic tumor features suggest lower risk would benefit from adjuvant chemotherapy.

In a study published in this week’s NEJM, Cardoso and colleagues evaluated the role of a genomic testing tool in discordant cases. The study was part of the international multicentre, prospective, randomized-controlled MINDACT trial (Microarray in Node negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy). The MINDACT trial compared risk assessment based on the 70-gene-signature assay (MammaPrint®) to assessment with standard clinical-pathological criteria (modified version of Adjuvant!Online) to direct use of adjuvant chemotherapy in 6693 patients with early breast cancer (median age, 55 years); 79% of patients were node negative and 88% had estrogen-receptor/progesterone-receptor–positive breast cancer. Patients were divided into four groups based on clinical-pathological (C) and genomic (G) risk assessments: high C/ high G (n=1806), low C/low G (n=2745), high C/ low G (n=1550) and low C/high G (n=592).

Patients with high C/high G assessments were treated with chemotherapy and those with low C/ low G risk assessments did not receive chemotherapy. The study focussed on the discordant subset of 1550 patients with high C/low G risk. Patients from this group and those with low C/high G risk were randomized to either clinical or genetic risk assignments to determine if they should receive or forego adjuvant chemotherapy. The primary endpoint was to assess whether the distant metastasis-free 5-year survival exceeds 92% in the high C/low G risk group randomized to forgo chemotherapy. Investigators also compared distant metastasis-free 5-year survival rates in patients in the high C/low G risk group who did and did not receive chemotherapy.

In the high C/low G risk group randomized to omit chemotherapy, the primary endpoint was met as the distant metastasis-free 5-year survival was 94.7% (95% confidence interval (CI), 92.5–96.2%). There was a 1.5 percentage point difference in the distant metastasis-free 5-year survival favoring chemotherapy in the high C/low G risk group. However, this secondary analysis was underpowered and not statistically significant (adjusted hazard ratio 0.78, 95% CI: 0.50-1.21, P=0.267).

Of note, among patients with low clinical risk of recurrence, the genetic test provided no added benefit.  Patients with low C had similar outcomes whether they had high or low genetic risk.

In the accompanying editorial, Dr. Clifford A. Hudis and Dr. Maura Dickler consider the significance of a 1.5 percentage-point difference in distant metastasis-free 5-year survival in two women of different ages, priorities, and high clinical risk. They explain, “This difference does not precisely exclude a benefit that clinicians and patients might find meaningful.” The findings of this trial should be helpful in informing decisions about genetic testing of tumors and adjuvant chemotherapy. Despite these technological advances, patients will require careful discussion with their oncologist to determine their next steps.

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Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.

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