Homologous recombination repair gene mutations for DNA Repair and Immune Oncology drug combinations
Zhongwu Lai1, Bolan Linghu1, Robert McEwen2, Darren Hodgson2, Brian Dougherty2, Carl Barrett2, Jonathan Dry1
1IMED Oncology, AstraZeneca R&D Boston, Waltham, MA, USA; 2IMED Oncology, AstraZeneca, Cambridge, United Kingdom
Exciting clinical benefit has been seen from both immune checkpoint inhibitors and PARP inhibitors in several cancer types. Initial reports have suggested the tumor mutational burden (TMB) may be a tumor agnostic marker for predicting immunotherapy (IO) response. Deficiencies in DNA damage repair (DDR) resulting from BRCA1 and BRCA2 mutations can lead to an accumulation of tumor mutations, and sensitivity to PARP inhibitors.
We hypothesized that patients with germline or somatic mutations in BRCA1/2 or other homologous recombination repair (HRR) genes, termed “HRRm”, will have higher TMB, higher immune infiltration and activity, and greater benefit from the combination of DDR and IO therapies.
We investigated the relationship between DDR deficiencies and TMB across The Cancer Genome Atlas (TCGA) disease cohorts, and data from AstraZeneca's clinical studies. We also examined the relationship between TMB and immunoscores, which quantify the in situ immune infiltrate and have been demonstrated to be prognostic.
Across many cancer types, HRRm patients have significantly higher TMB. This does not associate with immune infiltration assessed with RNA-seq, however.