Abstract P5-02-08: Biomarker associated with response to CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer

Abstract

Abstract Background: In spite of widespread use and known mechanism of action, predictive biomarkers for the use of CDK4/6 inhibitors in conjunction with endocrine therapy have yet to emerge. Here a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS). Patients and Methods: In this cohort of 235 patients, >90% of patients were treated with Palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). The PFS mirrored that observed in randomized clinical trials. A total of 151 patient tumor tissues were used for targeted gene expression analyses with the HTG-Oncology Biomarker Panel. The association of disease state and gene expression analyses were interrogated for disease evolution and association with PFS. Results: HER2 immunohistochemistry (HER20, Her21+, Her22+) was not associated with PFS in full cohort, or AI and FUL subgroup analyses. The lack of progesterone receptor (PR+, PR-), was associated with shorter PFS in the full patient cohort (p=0.012) and selectively in patients treated with AI (p=0.005), but not FUL. Gene expression-based subtyping indicated that the majority of patients, as expected, had luminal breast cancer; however, the predominant subtypes changed with treatment and disease evolution. Primary tissue from tumor resection was dominated by luminal A subtype, which diminished in the context of metastatic disease, and was rare in post-progression specimens. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations (AI, p=0.01; FUL, p=0.03). Existing clinically developed breast cancer signatures (e.g. breast cancer index) had variable associations with PFS; however, high expression of gene signatures associated with cell cycle were broadly associated with short PFS. Concordantly, utilizing unbiased analyses, gene expression programs linked to cell cycle were associated with short PFS, while interferon response processes were associated with longer PFS. Algorithms that incorporated standard pathological and clinical variables with the gene expression data were developed that exhibited potent predictive power. Conclusions: Tumor evolution occurs on treatment with CDK4/6 inhibitors; however, analyses of pretreatment biopsies can inform the duration of PFS. These data support discrete biological processes associated with sensitivity/resistance. Predictive algorithms could be developed to inform features of treatment decision which will require prospective validation which is ongoing. Citation Format: Agnieszka Witkiewicz. Biomarker associated with response to CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-08.