Comprehensive molecular profiling from liquid and tissue for analysing the somatic mutational landscape in an Indian breast cancer cohort.

Abstract

e13080 Background: Breast cancer is a genetically and clinically heterogeneous entity, with high prevalence in the Indian population. The primary objective of this study was to characterize the somatic mutational landscape of metastatic breast cancer in Indian patients from tumor and liquid specimens. Methods: We performed molecular profiling of 341 tumor tissue specimens and 901 blood specimens from individual breast cancer patients, with paired tissue and blood processing in a sub cohort (n=101). Targeted NGS evaluating single nucleotide alterations, copy number alterations, and fusions was performed on these specimens. Results: In the cohort with tissue-based sequencing (n = 341), TP53 was the prevalently altered gene (55%). PIK3CA and ESR1 mutations were detected in 32% and 9%, respectively. BRCA1/2 alterations were detected in 10.8%, ARID1A in 7%, KEAP1 in 6%, NF1 in 6%, and ATR in 6%. ERBB2 amplification was observed in 10% of the cases. ESR1 gene fusions were detected in 3.7%. This is clinically relevant as along with other ESR1 resistance mutations, ESR1 fusions are also known as recurrent drivers of endocrine therapy resistance and are impervious to ER-targeted therapies. In a sub cohort comprising 255 specimens, TMB analysis showed a median TMB of 5 mut/Mb (range 1 - 88 mut/Mb), and 15.3% specimens with TMB-High (≥10 mut/mb). The ctDNA analysis (n = 901) revealed TP53 being the most altered (41%) gene, followed by PIK3CA (23%), ESR1(11%), EGFR (6%) and GNAS (4%). Acquired resistance mutations in ERBB2 were identified in ctDNA analysis liquid biopsy from two patients treated with HER2-targeted therapy and were absent in corresponding tissue samples. Mutations in ESR1 were more commonly seen in liquid biopsy than paired tissue, indicating this acquired resistance alteration being better captured in ctDNA than tissue due to tumor heterogeneity and tumor evolution. This indicates causative role for ESR1 mutations in endocrine resistance but not in disease pathogenesis. Conclusions: We report the largest liquid biopsy study reporting the genomic landscape from breast cancer cases of Indian origin along with tissue based molecular landscape. High concordance of liquid for PIK3CA alteration and higher sensitivity for detection of resistance conferring alterations like ESR1 and ERBB2 shows utility of liquid biopsy profiling. It reinforces the utility of liquid biopsy as effective tool that reveal clinically relevant information including mutational status and therapeutic options and seem more relevant in acquired resistance settings. [Table: see text]