Dr Kalinsky on the Importance of Biomarker Testing in HR+/HER2-Negative Advanced Breast Cancer

“Given that we see ESR1 mutations [in] patients [whose] tumors…have progressed [on] an aromatase inhibitor, it is important to check for ESR1 mutations.”

Kevin Kalinsky, MD, MS, FASCO, director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University and professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, emphasized the importance of biomarker testing in guiding therapeutic decision-making for patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer.

At the time of disease progression—particularly after treatment with aromatase inhibitors—ESR1 mutations commonly emerge and serve as a key mechanism of acquired resistance, Kalinsky explained. Kalinsky further underscored the value of identifying ESR1 mutations early, given the availability of targeted therapies such as elacestrant (Orserdu) for patients with ESR1-mutant tumors. He noted that testing for ESR1 mutations can be clinically informative not only at progression but potentially earlier in the disease course.

Kalinsky also highlighted the relevance of alterations in the PI3K/AKT/PTEN pathway, which he noted are detected in approximately one-third of patients with HR-positive, HER2-negative breast cancer. These include mutations in PIK3CA, AKT, and loss-of-function alterations in PTEN. The therapeutic implications of identifying such alterations include the use of pathway-targeted agents such as alpelisib (Piqray) and capivasertib (Truqap), with capivasertib often favored due to its safety and tolerability profile, he explained.

Kalinsky highlighted data presented at the 2025 ASCO Annual Meeting, including findings from the phase 3 INAVO120 trial (NCT04191499), which showed the first overall survival benefit with inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex) vs placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutant, HR-positive, HER2-negative, endocrine-resistant advanced breast cancer. These results underscore the clinical value of molecular profiling to detect actionable alterations and support the use of PI3K/AKT pathway inhibitors in appropriately selected patients, he explained.

Beyond ESR1 and PI3K pathway mutations, Kalinsky also emphasized the importance of germline and somatic testing for BRCA1/2 and PALB2 mutations, which may inform the use of PARP inhibitors. Although PARP inhibitors are approved for patients with germline BRCA1/2 mutations, there is growing interest in their role in patients with somatic mutations as well, Kalinsky concluded.