Emerging Therapies Underscore Need for Genomic Testing in HR+/HER2– Breast Cancer

Kari Wisinski, MD

Potential treatment options such as the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu), as well as PI3K and AKT pathway inhibitors, have reenforced the need to conduct testing to guide treatment decisions in later lines of therapy for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, according to Kari Wisinski, MD.

“It has become clear that genomic testing has become the standard of care for patients with metastatic HR-positive/HER2-negative breast cancer to identify potential drivers of disease, as well as resistance mutations, and to lead to new treatments,” Wisinski shared in an interview with OncLive® following a State of the Science Summit™ (SOSS) on breast cancer, which she chaired. Wisinski is the Endowed Professor of Hematology and Oncology, chief of the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine, associate director of clinical research and co-lead of the Breast Cancer Disease Oriented Team, at the University of Wisconsin (UW) Carbone Cancer Center, in Madison.

In the interview, Wisinski highlighted the use of oral SERDs and CDK4/6 inhibitors in the treatment of patients with HR-positive/HER2-negative breast cancer, the growing role of antibody-drug conjugates (ADCs) across the breast cancer spectrum, and ongoing research taking place at Carbone Cancer Center.

OncLive: Could you expand on the development of oral SERDs and other agents for the treatment of patients with advanced HR-positive/HER2-negative breast cancer?

Wisinski: HR-positive breast cancer is the most common type of breast cancer that we see. Although we know that anti-estrogen treatments, along with CDK4/6 inhibitors, have significantly improved outcomes, after progression on CDK4/6 inhibitors in metastatic breast cancer, there continues to be an opportunity to target the HR pathway.

Multiple new agents have been tested in this setting, including the new oral SERD elacestrant, as well as several PI3K and AKT inhibitors, like alpelisib (Piqray) and capivasertib.

Elacestrant data from the phase 3 EMERALD study [NCT03778931] demonstrated improvement in progression-free survival [PFS], particularly in those patients who had an ESR1 mutation identified in their circulating tumor DNA [ctDNA].

We also talked about PI3K/AKT inhibitors, such as alpelisib, which we have had data on for several years, and we have some experience now [using] it after CDK4/6 inhibitors. Additionally, the capivasertib data also demonstrated some improvement in PFS in the post-CDK4/6 inhibitor setting.

What unmet needs remain to be addressed for patients with HR-positive/HER2-negative breast cancer?

One of the key challenges that we face is identifying what is driving resistance to first-line endocrine therapy in the metastatic setting. Is there a better tool to identify resistance mechanisms beyond mutations that are present? What might be driving the cancer growth at that time? [This could] help us select whether a patient should be treated with agents such as an oral SERD, a PI3K pathway inhibitor, or one of the targeted therapies for HER2-mutant disease.

Malinda West, MD, of UW Carbone Cancer Center, discussed endocrine-based therapy in HER2-negative breast cancer. What role could CDK4/6 inhibitors play in the adjuvant setting?

Dr West highlighted the role of the CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer, from first-line metastatic disease setting to studies conducted after prior exposure to CDK4/6 inhibitors in metastatic disease, as well as emerging data in the early-stage, adjuvant setting.

She highlighted the phase 3 monarchE trial [NCT03155997] data regarding adjuvant abemaciclib [Verzenio] and how that continues to demonstrate an improvement in [risk of] recurrence in patients with high-risk, early-stage disease. She also mentioned new data from the phase 3 NATALEE trial [NCT03701334], which demonstrated that [adjuvant] ribociclib [Kisqali] appears to reduce the risk of recurrence in early-stage disease.

Yee Chung Cheng, MD, of the Medical College of Wisconsin, highlighted ADCs in HER2-negative breast cancer. How has sacituzumab govitecan-hziy (Trodelvy) affected the treatment paradigm?

Dr Cheng highlighted the role of sacituzumab govitecan in both metastatic triple-negative breast cancer and HR-positive/HER2-negative breast cancer. In both of those settings, it has demonstrated improvement in outcomes.

Lubna Chaudhary, MD, MS, of the Medical College of Wisconsin, spoke to HER2-positive and HER2-low breast cancer. What role do ADCs have for this patient population?

Dr Chaudhary highlighted the emergence of fam-trastuzumab deruxtecan-nxki (Enhertu) as a new standard of care for both patients with HER2-positive advanced breast cancer in the second-line setting and beyond, and in patients who have HER2-low disease. The data she highlighted demonstrated that in patients with HER2-low disease, trastuzumab deruxtecan has improved both PFS and overall survival.

Dr Chaudhary also highlighted emerging data that are suggesting that patients with HER2–ultra low disease may even benefit from this agent.

Mark Burkard, MD, PhD, of UW Wisconsin Carbone Cancer Center, discussed novel targets in breast cancer. What is the importance of next-generation sequencing (NGS) in this population?

Dr Burkard highlighted the importance of routinely using NGS in all patients with metastatic breast cancer to aid in decisions about novel therapies that can be used to treat patients [who have been affected] by this disease.

Lastly, Marina Sharifi, MD, PhD, of UW Carbone Cancer Center, discussed ctDNA for detection of minimal residual disease (MRD). What is the potential for utilizing MRD in breast cancer?

Dr Sharifi spoke on some very intriguing work that's emerging on the role of monitoring ctDNA to identify MRD in patients after treatment of early-stage disease. This is very intriguing and interesting work, and this will likely shift the paradigm in breast cancer in the future. However, at this point in time, we still don't know whether intervening in patients with detectable MRD really changes outcomes.

Is there any ongoing research at the University of Wisconsin Carbone Cancer Center you’d like to highlight?

At the University of Wisconsin, we have an exciting new [phase 1] pilot study [NCT04174352] in which we are looking at higher doses of tamoxifen as a way to potentially overcome ESR1 mutations when they're present in patients with metastatic HR-positive/HER2-negative disease. We are using FES PET imaging to help us identify what might be an optimal dose of tamoxifen to overcome these resistance mutations.