Abstract 7613: Association of KAT6A expression with clinical outcomes in previously treated HR-positive and HER2-negative metastatic breast cancer

Abstract Background: KAT6A is a histone acetyltransferase that regulates gene transcription, cell cycle, senescence and cell differentiation. It is amplified and overexpressed in a subset of breast cancers and may positively regulate ER expression. Gene expression analysis in tumor samples from the PALOMA-3 study was conducted to explore potential associations of KAT6A and related biomarkers with enhanced benefit from the addition of palbociclib (PAL) to fulvestrant (FUL) in HR-positive, HER2-negative breast cancer. Methods: The PALOMA-3 trial randomly assigned 521 endocrine pretreated patients with metastatic breast cancer, including those with prior exposure to chemotherapy, to receive PAL+FUL or placebo (PBO) +FUL. Exploratory analysis was conducted on tumor gene expression levels of KAT6A and KAT6B to evaluate their association with the effect of PAL+FUL vs PBO+FUL on progression-free survival (PFS) using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. Treatment by biomarker interaction effect was also tested. Results: In the PALOMA-3 trial, the analyses were conducted in 214 patients (PAL+FUL, 137 patients; PBO+FUL, 77 patients) with baseline tissue profiled, which included 165 patients with prior chemotherapy (PAL+FUL, 101 patients; PBO+FUL, 64 patients). In patients with KAT6A data, a trend of better treatment effect (interaction p = 0.54) was observed in those with low KAT6A mRNA expression (median PFS on PAL+FUL was 11.04 months (m) and PBO+FUL was 3.65 m, HR = 0.52, 95% CI 0.32-0.85, log rank p = 0.008) versus high KAT6A expression (median PFS on PAL+FUL was 13.90 m and PBO+FUL was 11.20 m, HR = 0.66, 95% CI 0.39-1.13, p = 0.126). A treatment effect was observed in patients with prior exposure to chemotherapy who had low KAT6A expression (median PFS on PAL+FUL was 9.53 m and PBO+FUL was 3.66 m, HR = 0.55, 95% CI 0.33-0.94, p = 0.027), while this was not observed in those with high KAT6A expression (median PFS on PAL+FUL was 11.43 m and PBO+FUL was 11.33 m, HR = 1.13, 95% CI 0.61-2.09, p = 0.71), with the interaction p value of 0.12. No treatment difference was detected between treatment arms and expression levels of KAT6B (interaction p values of 0.48 and 0.36 in all patients and in those with prior chemo respectively). Potential interaction of KAT6A with other genes including ESR1 will be discussed. Conclusions: Low tumor KAT6A mRNA expression identified patients with relatively greater benefit from addition of PAL to FUL especially in those with prior exposure to both chemo- and endocrine therapies. The data support further investigation of KAT6A and its related biomarkers and their association with CDK4/6 inhibitors and/or endocrine therapy in HR+/HER2-breast cancer patients and to test if a KAT6 inhibitor can enhance CDK4/6 inhibitor and/or endocrine therapy efficacy in tumors with high KAT6A expression. Citation Format: Massimo Cristofanilli, Li Liu, Shibing Deng, Xin Huang, Fabrice André, Sibylle Loibl, Angela DeMichele, Eric Gauthier, Yuan Liu, Nicholas C. Turner. Association of KAT6A expression with clinical outcomes in previously treated HR-positive and HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7613.