Checkpoint inhibition for early-stage hormone receptor-positive breast cancer

ABSTRACT

Introduction

Most patients with breast cancer have early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease. Even though the prognosis for most of these patients is good, there is a need to identify patients at risk for poor outcomes and to develop strategies to mitigate this risk.

Areas covered

The addition of immunotherapy to standard neoadjuvant chemotherapy represents a promising option for select patients with HR-positive early breast cancer. Three randomized clinical trials have shown favorable results to date. In this review, we discuss the findings of I-SPY2, CheckMate 7FL (NCT04109066), and KEYNOTE-756 (NCT03725059).

Expert opinion

Despite the promising results of these trials, there are unanswered questions that need to be considered before incorporating neo/adjuvant immunotherapy in the treatment paradigm of early-stage HR-positive breast cancer. One example of an unanswered question is patient selection. Because the regimens used in these protocols are associated with long-term toxicities, identifying the patients who are more likely to derive a benefit from these agents, such as through the use of biomarkers, is critical. A second example is the optimal integration of adjuvant therapies that improve invasive disease-free survival, such as abemaciclib and ribociclib, which are not safely administered concurrently with immunotherapy.

KEYWORDS:

• Breast cancer
• chemotherapy
• early stage
• HER2-negative
• hormone receptor-positive
• immune checkpoint inhibitor
• immunotherapy
• neoadjuvant
• PD-L1

Article highlights

• Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common subtype.

• Subgroups of patients with HR+ and HER2- breast cancers who have elevated tumor-infiltrating lymphocytes (TILs), such as genomically high-risk, high-grade, high Ki-67 tumors that may benefit from immunotherapy.

• I-SPY2, CheckMate 7FL (NCT04109066), and KEYNOTE-756 (NCT03725059) showed that the addition of an immune checkpoint inhibitor to neoadjuvant chemotherapy led to improved pathologic complete response rates for patients with high-grade or ER-low, high-risk HR-positive breast cancer.

• Early translational work suggests that the presence of stromal TILs and programmed cell death-ligand 1 (PD-L1) may further delineate those who may benefit.

• Understanding the optimal integration of adjuvant CDK4/6 inhibitors with immunotherapy strategies is essential, as these regimens are not safe when administered concurrently.

Declaration of interest

C Corti reports reimbursement for travel and lodging by Veracyte. The competing interests were outside the submitted work. SS declares research funding to their institution from Astra Zeneca, Eli Lilly, Relay, SEAGEN and Sermonix; and consulting fees from Foundation Medicine, AstraZeneca, Daiichi Sankyo, Eli Lilly, Pfizer, Incyclix, Relay, Gilead, Sermonix and Novartis. EA Mittendorf reports compensated service on scientific advisory boards for AstraZeneca, BioNTech, Exact Sciences (formerly Genomic Health), Merck, Moderna, Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; speakers honoraria and travel support from Merck Sharp & Dohme; and institutional research support from Roche/Genentech (via SU2C grant) and Gilead. She receives research funding from Susan Komen for the Cure for which she serves as a Scientific Advisor. She also reports uncompensated participation as a member of the American Society of Clinical Oncology Board of Directors. SM Tolaney reports consulting or advisory roles for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui U.S.A., Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, and Johnson & Johnson; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, OncoPep, and Jazz Pharmaceuticals; and travel support from Eli Lilly, Sanofi, Gilead, Jazz Pharmaceuticals, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

I Schlam and SM Tolaney were involved in the conception, design, and drafting of the paper. C Corti prepared tables and figures. I Schlam, C Corti, S Sammons, EA Mittendorf and SM Tolaney revised intellectual content and approved the final version of the document.

Acknowledgments

We thank Valerie Hope Goldstein for editing and submission assistance. She is a full-time employee of Dana-Farber Cancer Institute.

Additional information

Funding

This paper was not funded.