421P - Comprehensive genomic profiling (CGP) unravels somatic BRCA (sBRCA) and homologous recombinant repair (HRR) gene alterations across multi-cancer spectrum

Background

Tumors deficient in DNA repair mechanism, particularly the HRR including BRCA (somatic and /or germline ) are sensitive to Platinum chemotherapy, PARP inhibitors (PARPi), and immunotherapy (IO) in cancers like breast and ovarian, however, clinical trials are ongoing in pancreatic, prostate, endometrial and other cancer types which have progressed on first-line chemotherapy. In this study, CGP identified the landscape of sBRCA and HRR as potential biomarkers across the multi-cancer cohort.

Methods

950 biopsy proven patient samples at HCG were profiled using Illumina TruSight Oncology 500 assay on NextSeq2000 in an IRB-approved study. Sequenced data was processed by StrandOmics platform.

Results

About 142 (15 %) patients in the studied cohort of multiple cancer types were found with alterations in sBRCA and HRR pathway. 208 mutations were detected across 950 cases with 66 cases reporting ≥ 1 HRR gene alterations (mean incidence of 1.4/case). 37 HRR cases were associated with elevated tumor mutation burden. sBRCA1 and sBRCA2 were found in 22 and 27 patients respectively accounting for 3% HRR pathway. Other HRR genes included ATM, RAD51, PTEN, ATRX, PALB2, MRE11A, RAD50, CDK12, ARID1A and PTEN in 12 % of HRR pathway. It is noteworthy that sBRCA and HRR gene alterations were found across diverse cancers, highest in gastrointestinal followed by breast cancer (TNBC-56%) (Table). Apart from FDA approved cancers (n=57), HRR alteration were prevalent across other diverse cancers (n=85) in the cohort. 60% patients with sBRCA and HRR mutations treated with platinum / PARPi as NACT, achieved partial to pathological complete response (pCR) while 5 cases treated with IO are on follow up. Table: 421P

Prevalence of sBRCA and HRR genes across the multi-cancer cohort of 950 cases

Conclusions

CGP identified sBRCA and HRR mutations in wide spectrum of cancers enabling the utility of PARPi as maintenance therapy, hence necessitating sBRCA and HRR testing as standard of care besides germline testing for personalized therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

B.S. Ajaikumar: Financial Interests, Institutional, Member of Board of Directors, Executive Chairman: HCG. All other authors have declared no conflicts of interest.