Guideline Update Addresses Treatments for HER2-Negative Advanced Breast Cancer

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In light of findings from multiple recent clinical trials in HER2-negative metastatic breast cancer, ASCO has revised its treatment recommendations to inform more evidence-based care for metastatic breast cancer.1

“This guideline update provides important clinical guidance about the new use of immune checkpoint inhibitors, antibody-drug conjugates, and [poly (ADP-ribose) polymerase (PARP)] inhibitors for the treatment of metastatic breast cancer,” said Beverly Moy, MD, MPH, of Massachusetts General Hospital Cancer Center, and guideline expert panel Co-Chair. “These are important and effective new treatments for breast cancer, and every clinician should be aware of recommendations for optimal usage.”

Beverly Moy, MD, MPH

Beverly Moy, MD, MPH

Since 2014, several important new therapies have become available based on robust evidence from numerous clinical trials. They include but are not limited to the BOLERO-6 and PEARL trials for hormone receptor–positive, HER2-negative metastatic breast cancer; the ASCENT and EMBRACE trials for triple-negative metastatic breast cancer; and the OlympiAD and EMBRACA trials for metastatic breast cancer associated with germline BRCA1/2 mutations. This focused update was developed to address both chemotherapy and targeted therapy for women with advanced, HER2-negative disease that is either endocrine-pretreated or hormone receptor–negative.

The guideline update is among the first from ASCO to use the Grading of Recommendations, Assessment, Development and Evaluations methodology for the evaluation of the quality of evidence, which ASCO adopted as standard guideline development practice in all possible cases in 2020. It also brings ASCO into alignment with other organizations, such as the World Health Organization and the United Kingdom’s National Institute for Health and Care Excellence.

Following the Evidence

Among the recommendations from the guideline update are that patients with triple-negative (ie, hormone receptor–negative and HER2-negative) metastatic breast cancer and expression of PD-L1 receive immune checkpoint inhibitor therapy combined with chemotherapy as first-line therapy. Patients with HER2-negative metastatic breast cancer who are PD-L1–negative, however, should generally receive single-agent chemotherapy unless life-threatening disease requires polychemotherapy.

Patients with triple-negative metastatic breast cancer who have received at least two prior therapies can be given the antibody-drug conjugate sacituzumab govitecan-hziy, which recently received approval from the U.S. Food and Drug Administration. 

Lisa A. Carey, MD

Lisa A. Carey, MD

“Antibody-drug conjugates are emerging very quickly as being important in multiple subtypes of breast cancer, so we see those being studied a lot more,” said Lisa A. Carey, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center, and guideline expert panel Co-Chair. “Sacituzumab govitecan is a key addition to triple-negative breast cancer therapy, and we anticipate [the approval of] other antibody-drug conjugates in the not-too-distant future.”

Instead of chemotherapy, the guideline recommends oral PARP inhibitors (ie, olaparib or talazoparib) for patients with triple-negative metastatic breast cancer who have germline BRCA1/2 mutations and who were previously treated with chemotherapy. Similarly, PARP inhibitors—rather than chemotherapy—are appropriate for patients with hormone receptor–positive metastatic breast cancer with germline BRCA1/2 mutations who are no longer benefiting from endocrine therapy. 

“For patients with hormone receptor–positive, HER2-negative metastatic breast cancer who are no longer responding to endocrine therapy and for whom chemotherapy is being considered, clinicians should offer single-agent chemotherapy rather than combination chemotherapy—although combination regimens may be offered for highly symptomatic or life-threatening disease,” Dr. Moy said. 

Finally, patients with hormone receptor–positive metastatic breast cancer who experienced disease progression on an endocrine agent may receive either endocrine therapy with or without targeted therapy or single-agent chemotherapy, with the choice based on individual patient and treatment variables and options. 

The Road Ahead

The update process also revealed notable gaps where current data are missing, inadequate, or unclear. For instance, evidence-based recommendations cannot be made as to the optimal time for transitioning a patient to hospice or best supportive care alone. Rather, the guideline advises clinicians to use shared decision-making by talking with patients as early in their cancer journey as possible about the integration of supportive care and, if needed, hospice services.

Additionally, the timing, application, and method (eg, tissue vs liquid biopsy) of next-generation sequencing in HER2-negative, hormone receptor–positive, and hormone receptor–negative breast tumors remains controversial. 

These and other unanswered questions underscore the importance of keeping pace with advances in the field and disseminating evidence-based recommendations as rapidly as possible.

“I think as treatments get more complicated and physicians in the community are needing to absorb more new data, these kinds of guidelines are enormously helpful in giving people an easy-to-access tool that takes into account the latest data,” Dr. Carey said. “Physicians can just go down the flow diagrams and feel comforted that they’re not missing something, and that can be really useful for people who take care of all types of cancers, because we are living in a very fast-changing world.” 


1. Moy B, Rumble RB, Come SE, et al: Chemo- and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor–negative: ASCO Guideline Update. J Clin Oncol. July 29, 2021 (early release online). 

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 30, 2021. All rights reserved.