The non-canonical role of homologous recombination deficiency in the development of immune-cold tumor microenvironment.

Abstract

e15032 Background: Homologous recombination deficiency (HRD) is an event triggered by impairment of the homologous recombination repair (HRR) pathway which acts on DNA double-strand breaks and interstrand cross-links (ICL). Although HRD has been shown to elevate the overall genomic instability in tumors inducing favorable responses to immune checkpoint inhibitors (ICI), its clinical utility is observed in specific cancer types like breast, ovarian, low-grade glioma, testicular germ cell tumors and kidney cancers. On the contrary, in many other cancer types, HRD is conducive to the development of immune-cold tumor microenvironment leading to unfavorable treatment responses to ICI. We present, HRD predictive scores with the corresponding IO biomarkers viz. microsatellite instability (MSI) and tumor mutation burden (TMB) pan-cancers. Methods: Retrospectively, we investigated the biomarker profile (HRD, MSI, TMB) and genomic (HRR pathway genes) profiles of 642 pan-cancer patients using a comprehensive genomic assay using OncoIndx. Results: Of the cohort of 642 pan-cancer patients, a total of 12.3% (n = 79/642) of patients were detected with high HRD scores, another 16.0% (n = 103/642) were detected with intermediate HRD scores and while 71.7% (n = 460/642) of patients showed low HRD scores. Among the cohorts of high, intermediate and low HRD scores, BRCA1/2 mutation-positive patients were 6.3% (n = 5/79), 5.8% (n = 6/103), and 5.2 (n = 24/460) respectively and HRR gene mutation-positive patients were 17.7% (n = 14/79), 25.2% (n = 26/103), 17.17% (n = 79/460) respectively. Most importantly, the immune-oncology biomarkers MSI and TMB scores were high only in 1.3% (n = 1/79) and 8.9% (n = 7/79) in HRD-high patients which were not significant compared to 1.7% (n = 8/460) and 10.4% (n = 48/460) observed in HRD-low patient cohort. Even in the cohort of patients with intermediate HRD scores, MSI and TMB did not vary significantly. Overall, no significant correlation was observed between high HRD scores vs BRCA1/2 mutations, HRR pathway gene mutations, MSI and TMB statuses. Thus, HRD scores could be predicted high, irrespective of all the associated biomarkers and pathway mutations. This indicates the utility of additional treatment options in BRCA1/2 wild-type or HRR pathway gene wild-type patients. Conclusions: Although HRD-high patients could be predictive of favorable PARPi and platinum-based therapies, their role in immune activation and ICI therapy response should be carefully considered. Even at a high score, HRD seems to be inducing non-inflammatory tumor microenvironment as opposed to triggering novel cell surface antigens and high TMB aiding in immunotherapy response. However, HRD as an individual biomarker alone adds immense therapeutic benefits even among BRCA-negative patients who could be potential for PARPi/platinum-based therapy.