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Expert Critique

FROM THE ASCO Reading Room

Sawsan Rashdan, MD Assistant Professor UT Southwestern Medical Center

The MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study showed that a significant proportion of women with early-stage hormone receptor (HR)-positive breast cancer could safely avoid chemotherapy by applying the 70-gene assay (MammaPrint). This test, as the study shows, can provide prognostic information on the risk of distant recurrence based on the intrinsic molecular subtype from the RNA expression profile.

The results of the MINDACT study are certainly impressive; however, it is unclear at this point whether the 70-gene assay could replace the Oncotype DX test to determine the benefit of adjuvant chemotherapy in patients with early-stage hormone-positive breast cancer. There are certainly some questions that need to be answered and explained in order to move forward with this in practice.

Full Critique

The clinical utility of breast cancer recurrence assays, such as the 70-gene signature (MammaPrint), appears to have been established with the completion of the (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) study, in which the authors concluded that a significant proportion of women with clinically high-risk but genomically low-risk early breast cancer could safely avoid chemotherapy by applying the 70-gene signature.

Gene expression signature testing to identify patients to receive adjuvant chemotherapy has become the standard of care for early-stage hormone receptor (HR)-positive breast cancer. MINDACT purports to show the superiority of the 70-gene assay to clinical-pathologic factors in providing both prognostic and predictive information about patients' tumors.

Breast cancer is heterogeneous, with many molecular subtypes. Those identified by pathologic subtyping are often reclassified when subjected to molecular subtyping, noted co-director of the University of Pittsburgh Comprehensive Breast Cancer Center, speaking at the 2017 Miami Breast Cancer Conference. The 70-gene signature can determine the intrinsic molecular subtype from the RNA expression profile, and classifies tumors into those with a good or poor prognosis based on the risk of distant recurrence at 5 and 10 years.

MINDACT enrolled 6,693 patients who underwent surgery for early breast cancer. Only patients with node-negative disease were to be enrolled per the initial study design, but the protocol was subsequently amended to allow women with as many as three positive axillary nodes after the gene signature was validated in such patients.

Every patient was evaluated by the clinicopathologic 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 2,745 patients with low-risk disease by both methods did not receive chemotherapy, and all 1,806 patients who were high risk by both methods received chemotherapy. The 2,142 patients (23% of the sample) with discordant results (high by one method, low by the other) were randomized to chemotherapy group or no chemotherapy on the basis of either the clinical result or the genomic result: "These were patients that we would normally consider to give chemotherapy to; 58% were >2 cm, 93% were grades 2 and 3, almost half had one to three lymph nodes positive, and all were hormone positive," said Brufsky. The primary endpoint was 5-year distant metastasis-free survival (DMFS).

Patients at high clinical/pathologic risk 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 (HR 0.78, P=0.267). In patients with a low clinical risk but high genetic risk, the 5-year DMFS was 95% to 96% with or without chemotherapy.

Among the 3,356 clinically high-risk patients, 46% were genomically low risk and could avoid chemotherapy without impairing outcome, Brufsky noted.

There was no statistical difference in DMFS between chemotherapy and no chemotherapy for genetically low-risk patients, even among the women with positive lymph nodes. "MINDACT is clearly practice changing. Something we need to start thinking about is that maybe we are overtreating a subset of HER2-positive early-stage breast cancer."

Little Progress in 15 Years?

Not among the believers, however, is , chairman of the National Surgical Adjuvant Breast and Bowel Project and senior medical director of the Allegheny Health Network Cancer Institute in Pittsburgh. He and Brufsky debated the issue at the Miami meeting in a "medical crossfire" session titled "What is the Clinical Utility of Commercially Available Breast Cancer Recurrence Assays?"

Wolmark maintained that the future lies in liquid biopsies or next-generation sequencing, rather than in gene-signature assays, which have been in clinical practice for 15 years ever since Oncotype DX hit the market -- "If we were really doing our job, something would have come along in 15 years to supplant it," he said.

Oncotype DX was "a tour de force" when introduced, demonstrating in multiple settings that a low recurrence score was associated with about a 99% rate of freedom from distant recurrence at 5 years, and that the entire benefit of adjuvant chemotherapy occurred in the roughly one fourth of patients with high recurrence scores.

With respect to the 70-gene signature, Wolmark said: "I liked it when it first came out in 2002, but I must say that I like it considerably less after the MINDACT data."

The aim of MINDACT, he reminded the audience, was not to predict a benefit from chemotherapy but rather to demonstrate that patients with a high clinical risk but a low genomic risk based on the MammaPrint 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."

Wolmark said that in parsing the MINDACT data, a benefit to chemotherapy on the DMFS endpoint in the genomically low-risk group was not out of the realm of possibility, with a P value of 0.11 and a hazard ratio of 0.65. On the endpoint of disease-free survival in this group, the difference in favor of chemotherapy was statistically significant.

In the clinically low-/genomic high-risk group, "you would expect there to be a benefit from chemotherapy, and there was none," he said. "The genomic high group that received no chemotherapy had a 5-year DMFS of 93.9%; the genomic low group (the favorable group), had a DMFS of 94.8%. There's no difference. I would suggest that the data from MINDACT show that the Agendia 70-gene assay is not only not predictive, it doesn't appear to be prognostic as well."