Dataset Information

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

ABSTRACT: Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity and summarize the available translational evidence for an association between HRD and antitumor immunity across multiple tumor types. In addition, we give an overview of all available clinical data on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment strategies that combine checkpoint inhibitors with PARP inhibitors.

SUBMITTER: van Wilpe S

PROVIDER: S-EPMC8124836 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

van Wilpe Sandra S Tolmeijer Sofie H SH Koornstra Rutger H T RHT de Vries I Jolanda M IJM Gerritsen Winald R WR Ligtenberg Marjolijn M Mehra Niven N

Cancers 20210507 9

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this revi ...[more]

PMID: 34067105

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Project description:BackgroundBiliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting.Patients and methodsWe carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy.ResultsA total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35).ConclusionsPatients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors.

Project description:BackgroundTumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown.MethodsNext-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided.ResultsOf 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm.ConclusionsHRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.

Dataset Information

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

Publications

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

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