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William J. Gradishar, MD, FACP, FASCO


Potential Mechanism of Resistance in Breast Cancer Treatment: Focus on the PI3KA Pathway

By: Joshua D. Madera, MD
Posted: Monday, January 29, 2024

Efforts to identify the potential mechanism responsible for acquired resistance to PI3K-alpha (PI3KA) inhibitors have revealed that genomic alterations within the PI3KA pathway may play a critical role, according to a presentation given at the 2023 San Antonio Breast Cancer Symposium (Abstract GS03-10). These findings may assist researchers in creating novel treatment strategies to overcome these resistance mechanisms and enable treatment of patients with PIK3CA-mutated cancers, suggested Andreas Varkaris, MD, PhD, of Massachusetts General Hospital, Boston, and colleagues.

A total of 32 patients with PIK3CA-mutated advanced hormone receptor (HR)-positive, HER2-negative breast cancer were recruited for the study. All patients had previously received treatment with the PI3K inhibitors alpelisib and inavolisib. Plasma samples were serially collected from patients and subjected to targeted next-generation sequencing assays for analysis of circulating tumor DNA expression. Furthermore, 100 tissue samples were collected from patients with metastatic, PIK3CA-mutant, HR-positive, HER2-negative breast cancer who were previously treated with PI3K inhibitors. These tissue samples underwent whole-exome sequencing.

The study authors reported PI3K pathway genomic alterations in 50% of the patients. These mutations included loss of phosphatase and tensin homolog (PTEN) and activation of the RAC-alpha serine/threonine-protein kinase (AKT1). In addition, alterations to the inhibitor binding pocket were observed as secondary resistance mutations. They included the PIK3CA W780R and PIK3CA Q859K alterations. Moreover, the allosteric pan-mutant-selective PI3K inhibitor RLY-2608 was successfully able to overcome all the secondary resistance mutations.

Disclosure: Dr. Varkaris reported no conflicts of interest. For full disclosure information for the other study authors, visit

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