Dr Krishnamurthy on Treatment Sequencing Based on Mutation Status in HR+/HER2– Breast Cancer

Jairam Krishnamurthy, MD, FACP, associate professor, Division of Oncology & Hematology; codirector, Breast Cancer Program, the University of Nebraska Medical Center, discusses the use of mutation status to inform treatment sequencing decisions for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer following progression on a first-line CDK4/6 inhibitor.

The adverse effect profile of capivasertib (Truqap) appears most favorable compared with alpelisib (Piqray) based on current data, providing an attractive alternative therapeutic strategy, Krishnamurthy begins. In patients with ESR1 mutations, elacestrant (Orserdu) offers a targeted treatment; for those without targetable mutations, switching CDK4/6 inhibitors following progression on first-line treatment may still deliver meaningful outcomes, he details. The latter approach is supported by findings from the phase 2 MAINTAIN (NCT02632045) and phase 3 postMONARCH (NCT05169567) studies, which suggest that patients progressing on palbociclib may benefit from transitioning to second-line ribociclib or abemaciclib, Krishnamurthy reports.

In MAINTAIN, 86.5% of patients initially received palbociclib prior to being switched to either ribociclib with endocrine therapy or placebo with endocrine therapy, Krishnamurthy states. Similarly, in postMONARCH, 59% of patients previously treated with palbociclib transitioned to abemaciclib plus fulvestrant versus placebo plus fulvestrant. Together, these trials provide evidence that switching CDK4/6 inhibitors is viable in patients who have progressed on initial therapy and lack other targetable mutations, with an adjustment to the endocrine partner further enhancing treatment outcomes, Krishnamurthy emphasizes.

This decision-making hinges critically on next-generation sequencing (NGS), which should be integrated through platforms such as Tempus, FoundationOne, Caris, Guardant, or in-house tests, Krishnamurthy continues. Such genomic profiling assays allow for the identification of PIK3CA, PTEN, AKT, or ESR1 alterations and selection of the next most appropriate treatment. Without NGS insights, the presence of these mutations and, consequently, the next treatment step, would remain uncertain, he notes. Even in the absence of actionable mutations, evidence supports the rationale of switching between CDK4/6 inhibitors, making it a practical approach in progressive cases without targetable genetic profiles, Krishnamurthy concludes.