Fabrice André, MD, PhD

Fabrice André, MD, PhD, Director of Research and Professor of Medical Oncology at Institut Gustave Roussy, Villejuif, France, commented on the two studies that used the MammaPrint 70-gene signature to identify patients for de-escalation or escalation of endocrine therapy.^1,2

The push to de-escalate endocrine therapy, he said, is based on recent large studies showing that endocrine therapy has a “measurable, chronic, deleterious impact on quality of life.”³ MINDACT asked whether the 70-gene signature can identify patients who will have excellent outcomes and therefore could forgo adjuvant endocrine therapy. Investigators evaluated three different risk groups—ultra-low genomic risk, low but not ultra-low risk, and high genomic risk.

MINDACT Limitations

In the analysis presented by Dr. Cardozo, patients with ultra-low risk had better outcomes than those with low but not ultra-low risk (hazard ratio = 0.65, 95% confidence interval = 0.45–0.94). The study did not, however, assess whether this excellent outcome was attributable to MammaPrint itself, Dr. André pointed out.

“For this, the researchers should have looked at the added value as compared to standard molecular tools, including Ki67 and grade,” he suggested. “Most importantly, they should have compared the outcome in patients with low clinical risk/ultra-low genomic risk vs those with low clinical risk/low genomic risk (not ultra-low).”

A weakness of the study, he said, is that it did not explore the roles of local relapse and second cancers. Moreover, it lacked information as to why some patients did not receive adjuvant systemic therapy.

Dr. André concluded: “There are patients with low clinical risk and genomic ultra-low risk who have excellent outcomes. Nevertheless, the study does not provide information about the value of the genomic test to identify these patients…. And the sample size is too small to lead to changes in practice…. From my perspective, this is an important study that adds to the emerging data showing a subset of patients with low clinical risk/ultra-low MammaPrint [scores] who could be spared adjuvant endocrine therapy, but now we need to start prospective trials—optimally in a very selected population.”

Remaining Questions

Commenting on the overall issue of endocrine therapy de-escalation, Dr. André posed some questions:

• What is the threshold of benefit below which de-escalation is acceptable?
• Can patients be identified who derive the most benefit from de-escalation, such as those at risk of treatment-related toxicity?
• What is the best aim/endpoint of de-escalation? Distant metastasis? Disease-free survival?
• How should the magnitude of benefit be assessed in retrospective studies?
• Who are the patients who are cured without endocrine therapy?
• How can the population of patients cured with short-duration endocrine therapy be increased?

Comments on NSABP B-42

The study by Rastogi et al² evaluated the opposite—which patients are the best candidates for extended adjuvant endocrine therapy? This question was explored by applying MammaPrint to a subset of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-42 population.

“In this study, it’s important to emphasize that most of the events were second cancers or locoregional relapse; distant relapses were minimal contributors, meaning that when we talk about endocrine therapy beyond 5 years, we are talking about primary, secondary, and tertiary prevention. It’s very difficult to consider all these events with a single intervention,” he said.

Further complicating the ability to predict the benefit of extended endocrine therapy is that events occurring after 5 years of treatment can have multiple causes: the intrinsic biology of the primary tumor, molecular evolution within the tumor environment, compliance with treatment, prior treatment, staging of metastatic residual disease, and more. The challenge, he said, is that the identification of patients who will derive benefit from extended adjuvant endocrine therapy requires “the integration of all these parameters into a single predictor.” 

DISCLOSURE: Dr. André holds stock or other ownership interests in Pegacsy; has received institutional research funding from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, GlaxoSmithKline, Novartis, and Roche.

REFERENCES

1. Cardozo JL, Drukker C, Schmidt M, et al: Outcome of patients with an ultralow-risk 70-gene signature in the MINDACT trial. 2021 ASCO Annual Meeting. Abstract 500. Presented June 6, 2021.

2. Rastogi P, Bandos H, Lucas PC, et al: Utility of the 70-gene MammaPrint assay for prediction of benefit from extended letrozole therapy in the NRG Oncology/NSABP B-42 Trial. 2021 ASCO Annual Meeting. Abstract 502. Presented June 6, 2021.

3. Ferreira AR, Di Meglio A, Pistilli B, et al: Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: A prospective patient-reported outcomes analysis. Ann Oncol 30:1784-1795, 2019.