Abstract A029: Biomarker analysis in HR+, HER2-, locally advanced, or metastatic breast cancer patients treated with buparlisib: results from BELLE-3
Authors: Solovieff Nadia , Wang Ying A. , Sankaran Banu , Scheuer Nicolas , El-Hashimy Mona , Weber Denis , Sellami Dalila , Di Leo Angelo 
Published: August 2018

Abstract
Background: Endocrine therapy resistance in hormone receptor-positive breast cancer often leads to activation of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin pathway. In the BELLE-3 study the progression-free survival (PFS) improvement in buparlisib (BUP) vs placebo (PBO) arm was greater in patients (pts) with PIK3CA-mutant than PIK3CA-wildtype (Wt) tumors, based on circulating tumor DNA. In the current study we report the additional exploratory biomarker results from BELLE-3. Methods: The relationship between PFS and frequently mutated genes (PIK3CA, CCND1, ESR1 and 8q11.23 region) and pathways (PI3K and CDK pathways) was explored using NGS in tumor and pts were classified as altered (Alt) vs Wt. Genes and pathways with at least 10% frequency in both arms were carried forward to correlative analyses with PFS. In addition, ESR1 mutations were detected by BEAMing technology in baseline cell free DNA (cfDNA) for 167 pts. Results: NGS data were available for 185 pts and the NGS panel covered 500+ gene mutations, short insertions/deletion, copy number alterations, and translocations. PIK3CA was altered in 41% of pts and PI3K pathway was altered in 64% of pts. Benefit of BUP treatment was observed in PIK3CA altered pts, but did not extend to other alterations in the PI3K pathway. CCND1 was altered in 19% of pts and the CDK pathway was altered in 34% of pts and improved benefit of BUP was observed in altered pts in both the groups (HR = 0.31 and 0.38 respectively). Alterations in the 8q11.23 region (ZNF703, WHSC1L1 and FGFR1) were observed in 21% of pts with the benefit of BUP observed only among wildtype. In cfDNA, a higher treatment effect was observed in the ESR1 mutant subgroup (HR = 0.76 [Wt] and 0.27 [Alt]). Subgroup analyses of ESR1 mutations revealed a greater improvement in median PFS among pts with D538G mutation (BKM vs PBO = 8.25 vs 1.51; HR = 0.18) than among pts with Y537N/S/C mutation (BKM vs PBO = 4.17 vs 2.76; HR = 0.45). The PFS of different groups analyzed by NGS is mentioned in the table. Conclusions: A trend for stronger treatment effect was observed among pts with alterations in PIK3CA, CDK pathway, CCND1 (tumor), and ESR1 (ctDNA). The possibility of correlation among identified biomarkers is currently being explored. Table: Median PFSGroupTreatmentNEventsMedian PFS, moHR (95% CI)PIK3CAWtPBO34271.480.73 (0.46 - 1.16)BUP75602.83AltPBO23191.40.44 (0.25 - 0.79)BUP53344.11PI3K pathway (excluding PIK3CA Alt pts)WtPBO19171.450.51 (0.28 - 0.93)BUP47402.83Alt*PBO15104.671.1 (0.51 - 2.39)BUP28202.86CCND1WtPBO47371.480.61 (0.41 - 0.92)BUP103733.35AltPBO1091.430.31 (0.13 - 0.76)BUP25212.1CDK pathwayWtPBO40321.480.63 (0.4 - 0.98)BUP83583.42AltPBO17141.430.38 (0.19 - 0.75)BUP45362.68q11.23 regionWtPBO48391.450.49 (0.33 - 0.73)BUP98704.11AltPBO971.410.9 (0.38 - 2.13)BUP30241.48ESR1 mutation statusWtPBO29202.70.76 (0.43 - 1.31)BUP56372.8AltPBO23202.60.27 (0.14 - 0.51)BUP59246.0
* To assess the impact of genes in the PI3K pathway other than PIK3CA, the altered group includes patients who are PIK3CA wildtype but have an alteration in a different gene in the PI3K pathway.
Citation Format: Nadia Solovieff, Ying A. Wang, Banu Sankaran, Nicolas Scheuer, Mona El-Hashimy, Denis Weber, Dalila Sellami, Angelo Di Leo. Biomarker analysis in HR+, HER2-, locally advanced, or metastatic breast cancer patients treated with buparlisib: results from BELLE-3 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A029.