Abstract IA26: Exploring breast cancer vulnerabilities through apoptotic pathways

Abstract

Abstract Combined CDK4/6 inhibitor and endocrine therapy has rapidly become standard therapy for patients with early line relapsed estrogen receptor (ER)-positive, HER2-negative breast cancer. Although this combination has been shown to significantly improve progression free and overall survival, relapse is virtually inevitable. This may in part be due to the profound cytostatic effect of CDK4/6 inhibitors on tumors, which is associated with reduced apoptotic cell death. It seems likely that growth arrested and/or senescent tumor cells acquire resistance to therapy, leading to relapse. BH3 mimetics are an emerging class of drug that target pro-survival proteins such as BCL2, BCL-xL and MCL1. Venetoclax, a BH3 mimetic that has potent and specific activity against BCL2, has shown considerable promise in hematopoietic tumors such as CLL, but has yet to be fully explored in solid tumors. We have previously demonstrated safety and efficacy of combining tamoxifen with venetoclax for patients with metastatic ER-positive BCL2-positive disease using pre-clinical PDX models and a dose-finding phase 1 study [mBEP study, ISRCTN98335443], where most patients were CDK4/6 inhibitor therapy-naïve. In the post-CDK4/6 inhibitor setting, however, venetoclax did not improve clinical benefit rate or progression free survival when added to fulvestrant in the phase 2 study VERONICA [NCT03584009]. In that study a minority of tumours exhibited strong BCL2 expression and exploratory biomarker analysis revealed a trend towards improved progression free survival for patients with tumors exhibiting high BCL2 expression (IHC 3+), a BCL2:BCL-xL Histoscore ratio ≥1, or with PIK3CA wild-type status. Using pre-clinical models including patient derived xenografts of ER-positive breast cancer, we have shown that the addition of venetoclax to dual therapy comprising fulvestrant and the CDK4/6 inhibitor palbociclib elicits a superior and more durable tumor response, accompanied by increased apoptosis. These findings have formed the basis of a phase 1 clinical trial of palbociclib, letrozole and venetoclax [PALVEN, NCT03900884] in patients with early line relapsed ER and BCL2-positive metastatic breast cancer. In parallel, pre-clinical studies are underway to determine the effect of dual targeting BCL-xL and MCL1, as well as dual targeting of AKT and with a BH3 mimetic in CDK4/6 inhibitor refractory breast cancer cells. Citation Format: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman. Exploring breast cancer vulnerabilities through apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA26.