85MO - Pan-cancer analysis of homologous recombination (HR)-associated alterations (alts) and genome-wide loss of heterozygosity (gLOH)

Background

Alts in certain HR genes are associated with response to chemotherapy and PARP inhibitors. A comprehensive assessment of the distribution of alts in HR genes in a large pan-cancer data set could guide clinical management and trial design.

Methods

Genomic profiling on up to 465 genes, including core and peripheral HR genes BRCA1, BRCA2, PALB2, ATR, ATRX, ATM, BAP1, RAD51B, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC and MRE11 was performed in a pan-cancer cohort of ∼150,000 tumour samples (Foundation Medicine, Inc.). Zygosity predictions, gLOH and biallelic status were calculated as described (PMID: 29415044; 27908594).

Results

HR alts were identified in 18.5% of samples (Table). In BRCA-associated (BA) cancers (ovarian, breast, pancreas, prostate), most HR alts were predicted biallelic (75.0%), with a lower rate in non-BA (NBA) cancers (45.7%). Biallelic HR alts had elevated gLOH relative to HR wildtype (HR-WT) (BA: median [med] gLOH 19.2 v 9.7, p <1e-100; NBA: med gLOH 11.0 v 7.1, p <1e-100). Monoallelic alts were not associated with elevated gLOH (p = 1.0). The strength of association between biallelic HR alts and gLOH was strongest in BRCA1, RAD51D, PALB2, RAD51C and BRCA2 (med gLOH 25.5, 21.6, 19.8, 19.3, 19.0 v 7.8 in HR-WT, all p <1e-25). Other genes exhibited weak or no association with gLOH (all med gLOH <15). Additional analyses will be presented examining variant somatic/germline status. Table: 85MO

CRC, colorectal cancer; CUP, carcinoma of unknown primary origin; NSCLC, non-small cell lung cancer.

Conclusions

This study identified five genes where biallelic alterations were strongly associated with high gLOH and found no associations for heterozygous alts. These results highlight the need to incorporate both gene and biallelic status when assessing HR deficiency for personalised treatment and clinical trials.

Clinical trial identification

Editorial acknowledgement

Support for third-party editorial assistance for this abstract, furnished by Susannah Thornhill, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Funding

F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Disclosure

C. Benedikt Westphalen: Honoraria (self): Bayer, Celgene, Ipsen, Roche, Servier, Taiho; Advisory/Consultancy: Celgene, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, F. Hoffmann-La Roche; Travel/Accommodation/Expenses: Bayer, Celgene, RedHill, Roche, Servier, Taiho; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd, Basel, Switzerland. F. André: Research grant/Funding (institution): Roche, Pfizer, Lilly, Novartis, AstraZeneca, Daiichi Sankyo; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. S. Ganesan: Advisory/Consultancy: Merck, Novartis, Foundation Medicine, Roche, Foghorn Therapeutics, Inspirata; Shareholder/Stockholder/Stock options, Has equity in Inspirata: Inspirata; Spouse/Financial dependant, Spouse is an employee of Merck and has equity in Merck: Merck; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. V. Heinemann: Honoraria (self): Merck, Roche, Celgene, Amgen, Sanofi, Lilly, Sirtex, Boehringer-Ingelheim, Taiho, Servier; Advisory/Consultancy: Merck, Roche, Amgen, Sanofi, Sirtex, Servier, Celgene, Boehringer-Ingelheim, Halozyme, MSD, BMS; Research grant/Funding (institution): Merck, Roche, Amgen, Sirtex, Servier, Celgene, Boehringer-Ingelheim, Shire; Travel/Accommodation/Expenses: Merck, Roche, Amgen, Sirtex, Servier, Shire, MSD, BMS; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. E. Rouleau: Advisory/Consultancy: AstraZeneca, Roche Diagnostic, BMS; Travel/Accommodation/Expenses: AstraZeneca, BMS; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. A. Fine: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. L. Garcia Palacios: Full/Part-time employment, Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. E.S. Sokol: Full/Part-time employment: Foundation Medicine ; Shareholder/Stockholder/Stock options, Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. M. Thomas: Shareholder/Stockholder/Stock options, Full/Part-time employment, Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd. J. Mateo: Advisory/Consultancy: AstraZeneca, Amgen, MSD, Clovis Oncology, Janssen, Roche; Speaker Bureau/Expert testimony: Astellas; Research grant/Funding (institution): AstraZeneca, Pfizer Oncology; Travel/Accommodation/Expenses: AstraZeneca, Janssen, Astellas; Spouse/Financial dependant, Research grant to institution: AstraZeneca ; Non-remunerated activity/ies, Third-party editorial assistance: F. Hoffmann-La Roche Ltd; Spouse/Financial dependant, Advisory board: F. Hoffmann-La Roche Ltd.