clinical topic updates

The Importance of Next-Generation Sequencing in Guiding Therapy Selection

by Matthew P. Goetz, MD


Our understanding of the genetic and molecular alterations associated with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is improving. Next-generation sequencing (NGS) may help shed light on mechanisms of treatment resistance.

Expert Commentary

Matthew P. Goetz, MD

Consultant and Erivan K. Haub Family Professorship in Cancer Research Honoring Richard F. Emslander, M.D.
Division of Medical Oncology, Department of Oncology
Mayo Clinic
Professor of Oncology and Pharmacology
Mayo Clinic College of Medicine and Science
Rochester, MN

"In patients who are treated with aromatase inhibitors, acquired ESR1 mutations drive endocrine resistance and are a focal point for research into new approaches to hormone therapy.”

Matthew P. Goetz, MD

NGS has become a standard approach for the management of HR+/HER2- metastatic breast cancer (MBC). Approximately 30% to 40% of these patients exhibit a PIK3CA mutation. These tend to be truncal mutations, meaning that they are present from the start of the tumor's development. Additional mutations that are targetable include BRCA/PALB2 mutations (poly [ADP-ribose] polymerase inhibitors) and ESR1 mutations (elacestrant).

For patients with newly diagnosed estrogen receptor–positive (ER+)/HER2- MBC who are eligible to begin therapy with a CDK4/6 inhibitor and in whom a large survival benefit has been observed with ribociclib, a common question is: Should the presence or absence of a germline or somatic alteration alter the recommendation away from a CDK4/6 inhibitor in favor of a targeted approach such as alpelisib for PIK3CA-mutated disease or olaparib for BRCA-mutated disease? The answer is that there are no data suggesting that we should be substituting these targeted approaches for a CDK4/6 inhibitor. However, a critical question is determining whether we can identify biomarkers for patients at risk for primary endocrine resistance. For these individuals, targeted approaches against PI3K/AKT/mTOR and/or BRCA mutations may lead to better outcomes compared with those associated with CDK4/6 inhibitor therapy. 

For patients with a PIK3CA mutation, alpelisib, a selective inhibitor of PI3Kα, was tested in the phase 3 SOLAR-1 study and following a CDK4/6 inhibitor in the phase 2 BYLieve trial. In the SOLAR-1 trial, patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer that had progressed during or after treatment with endocrine therapy exhibited significantly longer progression-free survival (PFS) when they received alpelisib plus fulvestrant compared with placebo plus fulvestrant, with researchers reporting an estimated 35% lower risk of progression or death. In the BYLieve trial, the median PFS was 7.3 months.  

In the phase 3 CAPItello-291 trial, patients with endocrine-resistant ER+/HER2- breast cancer who had progressed on endocrine therapy were randomized to capivasertib, a pan-AKT inhibitor, plus fulvestrant vs fulvestrant alone. In this study, there were dual end points (ie, PFS overall and in the AKT-altered cohort). Capivasertib plus fulvestrant significantly improved PFS compared with fulvestrant alone, both overall and in the AKT-altered subset (PIK3CA, PTEN loss, or AKT mutations). Importantly, prior CDK4/6 inhibitor therapy was a stratification factor, and the benefit was seen in all subgroups, including those on prior CDK4/6 inhibitors.

In patients who are treated with aromatase inhibitors, acquired ESR1 mutations drive endocrine resistance and are a focal point for research into new approaches to hormone therapy. The recently US Food and Drug Administration–approved selective estrogen receptor degrader (SERD) elacestrant improved PFS compared with fulvestrant in patients with MBC with prior progression on a CDK4/6 inhibitor and an ESR1 mutation. Other SERDs, such as camizestrant, imlunestrant, giredestrant, and ARV-471, as well as the selective estrogen receptor modulator (SERM) lasofoxifene, have demonstrated preliminary evidence of antitumor activity in this same setting. Ongoing studies will be evaluating these novel SERDs and SERMs in combination with CDK4/6 inhibitors and other targeted approaches.  

Finally, NGS may also identify a variety of rare mutations, such as NTRK translocations. Moreover, tumor mutation burden identified by NGS may allow patients with HR+ breast cancer to be eligible for the drug pembrolizumab.


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