Therapeutic potential of immune-cold solid tumors through homologous recombination deficiency.

e14585 Background: Genome-wide homologous recombination deficiency (HRD) score is an important parameter to select patients for HRR pathway inhibitors. HRD scores are independent therapeutic predictors unlike tumor mutation burden (TMB), and microsatellite instability (MSI) values to stratify tumors for predicting immunogenicity. Since solid tumors often choose the hallmark of immune evasion to disseminate to distant tissues, their identification and treatment through genomic signatures for immunotherapy is essential. Low TMB and MSI values are often associated with immune evasion and immune cold tumors. For such patients HRD scores can be important determinants to inform on the therapeutic potential of HRR pathway inhibitors and immune checkpoint inhibitors (ICI). In this study, we retrospectively investigated solid tumors with metastatic phenotypes exhibiting microsatellite stable (MSS), MSI-Low and TMB low phenotypes. The presence of HRR pathway deficiency in these patients may lead to chromosomal instabilities and cell surface neo-antigens thereby offering potential therapeutic benefit to PARP inhibitors and ICI. Methods: 53 metastatic cancer patients were retrospectively analysed for genome-wide HRD, TMB and MSI scores based on OncoIndx comprehensive gene panel (CGP). OncoIndx CGP targets 1080 cancer related genes along with 47 HRR genes and 1600 MSI signature sites. HRD, TMB and MSI scores were determined by sequencing the individual sample libraries in pair end mode on Illumina Nextseq platform (depth 5500X). Cutoff scores HRD high (≥50), TMB high (≥10 Mutations/MB), MSI high (≥20). Results: A cohort of 53 solid tumor patients were evaluated retrospectively of which 71.6% (n=38) patients showed metastasis (brain, Popliteal fossa, skeletal, and nodal metastasis). Of these, 9.4% (n=5) patients were detected with MSI-high, 56.6% (n=30) were MSI-Low and 1.8% (n=1) were MSS. 13.2% (n=7) patients were TMB-High, 3.7% (n=2) were TMB intermediate and 41.0% (n=22) were TMB-Low. Most importantly, 41.0% (n=22) patients were both MSI and TMB low thus transforming the tumor suggestively immune-cold. Only 22.7% (n=5) patients showed PD-L1 expression on IHC with scores ranging from TPS: 2% to 20%. In this dominantly immune-cold patient cohort, 40.9% (n=9) patients showed high/intermediate HRD (22.7% high (n=5); 18.18% Intermediate (n=4)). Conclusions: The presence of HRD in 40.9% patients in the dominant immune-cold patients was observed with increased chromosomal instability and cell surface neo-antigens. Thus, HRD could potentially transform tumors to become immune-hot to benefit from PARP inhibitors and ICI.