Homologous recombination repair gene mutations as a predictive biomarker for immunotherapy in patients with advanced melanoma

Abstract

BackgroundNowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) is one of the DNA damage response (DDR) pathways, which has been proved to correlate with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy, and immunotherapy in a variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma.MethodsData of advanced melanoma patients from an independent cohort (Samstein2018) were used to analyze the correlation with immunogenic markers and the prognostic effect of HRR on immunotherapy, and another four cohorts (pooled cohort: Miao2018, Allen 2015, Hugo2016, and Synder2014) were used for validation. Immune infiltration cell scores analyzed by TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment.ResultsCompared to patients with an HRR wild type (HRRwt), those with HRR mutations (HRRmut) in anti-CTLA-4-treated patients of the Samstein2018 cohort had higher tumor mutation burden (TMB; P = 0.0041) and longer median overall survival (mOS; P = 0.0094). In terms of results validation, it was also confirmed that the mOS (P = 0.0014) of HRRmut patients receiving anti-CTLA-4 therapy was significantly better than that of HRRwt patients in the pooled cohort, and objective response rates (ORR; P = 0.0053) were also found to be significant. However, there was no significant difference in mOS between HRRmut patients who received anti-PD-1/L1 therapy and HRRwt patients in either the discovery (Samstein2018 cohort, P = 0.94) or validation (pooled cohort, P = 0.96) set. Exploratory analysis found that although HRRmut patients showed no significant difference in mOS between anti-CTLA-4 and anti-PD-1/L1 therapy (P = 0.79), the mOS value of the anti-CTLA-4 therapy group (31.7 months) in HRRmut patients was numerically superior to the anti-PD-1/L1 therapy group (27.5 months). In contrast, the mOS of the anti-CTLA-4 therapy group was significantly lower than that of the anti-PD-1/L1 therapy group (12.4 vs. 32.0 months) in HRRwt patients. In addition, transcriptome profiling analysis revealed that the 29 (65.9%)-gene mutation of the HRR pathway associated with reshaping of the immunological microenvironment in melanoma.ConclusionsHRR mutations were associated with a higher TMB level, and better anti-CTLA-4 therapy outcomes. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.

The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response

“…Recently, an observational study enrolling 266 patients with non‐small cell lung cancer showed similar results 44 . Moreover, a previous study analyzed several public cohorts and showed that patients with HRR mutations had better outcomes after anti‐CTLA‐4 treatment in advanced melanoma 45 . However, the predictive value of HRR mutations for immunotherapeutic response in UC remains unknown.…”

“… 44 Moreover, a previous study analyzed several public cohorts and showed that patients with HRR mutations had better outcomes after anti‐CTLA‐4 treatment in advanced melanoma. 45 However, the predictive value of HRR mutations for immunotherapeutic response in UC remains unknown. Our analysis revealed that patients with HRR mutations, especially those with ATM mutations, had improved overall survival than those without HRR mutations after immunotherapy.…”

Mappingin silicogenetic networks of theKMT2Dtumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities

“…MSI is a marker for ICI treatment; however, only ∼53% of MSI cases have an objective response to ICI treatment 119 , suggesting additional biomarkers are necessary to stratify MSI cases. Several biomarkers have been proposed for ICI treatment, including HRD 120 , ARID1A LOF121 , and SETD2 LOF122 . Wang et al 123 also demonstrated that mice transplanted with KMT2D-deficient tumours were responsive to ICI treatment and that TMB was elevated in TCGA cases with KMT2D LOF .…”

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation

“…In view of the high frequency of DDR deficiency in tumorigenesis and progression, extensive efforts have been made to identify DDR-related biomarkers for predicting the response to ICI therapy. Several investigations have demonstrated that gene mutations in different DDR pathways result in a durable clinical benefit from ICI therapy in various types of cancer, including melanoma 34 , lung cancer 35 , bladder cancer 19 , and GI cancer 20 . Previous studies, however, have also shown that even though BRCA1/2 mutations may confer sensitivity to ICI therapy, this is not held in common for all patients because not all mutations induce DDR deficiency or compensate for by alternate mechanisms 36 .…”