Homologous Recombination Deﬁciency in Skin Cancers - Prevalence and Clinical Implications of This Distinct Patient Cohort

Q: What was the primary objective of the study?

To determine how prevalent homologous recombination deficiency (HRD) is across skin cancer subtypes, assess its relationship with immune checkpoint inhibitor (ICI) biomarkers, and evaluate its prognostic relevance in immunotherapy-treated patients.

Q: How was HRD status defined in the analysis?

HRD status was defined by high loss of heterozygosity (LOH-high) or by mutations in homologous recombination repair (HRR) genes.

Q: Does HRD predict response or better survival with immunotherapy in skin cancer?

No. HRD was not associated with immune checkpoint inhibitor response biomarkers and did not show prognostic advantage after immunotherapy.

Sep 22, 2026

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Homologous recombination deficiency (HRD) induces DNA instability and is linked to tumor development, yet its role in skin cancers and in response to immune checkpoint inhibitor (ICI) therapy is not well established. This study quantifies HRD prevalence across skin cancer subtypes, examines associations with established ICI response biomarkers, and evaluates prognostic relevance in patients receiving immunotherapy. Results define an HRD-specific subset, showing no predictive value for ICI response or improved outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

ABSTRACT

PURPOSE

METHODS

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CONCLUSION

INTRODUCTION

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Original Reports | Precision Medicine Homologous Recombination Deﬁciency in Skin Cancers: Prevalence and Clinical Implications of This Distinct Patient Cohort George Nassief, BA1 ; Tolulope Adeyelu, PhD2; Andrew Elliott, PhD2; Jordan Phillipps, MD1; Renee Morecroft, MD1; Alice Y. Zhou, MD, PhD1 ; Peter W. Szlosarek, MD, PhD3 ; Caroline Robert, MD, PhD4 ; Farah Abdulla, MD2; Ari Vanderwalde, MD2 ; Soo J. Park, MD5; David Chen, MD, PhD6 ; and George Ansstas, MD1 DOI [https://doi.org/10.1200/PO-25-00923](https://doi.org/10.1200/PO-25-00923) | ABSTRACT | | | --- | --- | | PURPOSE | Homologous recombination deﬁciency (HRD) results in DNA instability in tumor cells and contributes to tumor pathogenesis. Although HRD-directed therapies are established in other cancers, their role in skin cancers remains unclear. Given the poor response to standard therapies in skin cancer subtypes like acral and mucosal melanoma, we aimed to characterize the prevalence of HRD across skin cancer subtypes, evaluate its correlation with immune checkpoint inhibitor (ICI) response biomarkers, and assess its prognostic relevance in patients treated with immunotherapy (IO) . | | METHODS | A total of 2,508 patients with skin cancer underwent molecular proﬁling including whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry. HRD status was deﬁned by a high loss of heterozygosity (LOH-high) or mutations in homologous recombination repair (HRR) genes. Associations between HRD and established ICI biomarkers (tumor mutational burden, PD-L1, deﬁcient mismatch repair/microsatellite instability-high, immune cell fractions, and transcriptomic signatures) were assessed. Survival outcomes on ICI therapy were assessed in cutaneous melanoma using insurance claims data. | | RESULTS | Overall, among the melanoma subtypes, mucosal and acral melanoma had a greater prevalence of LOH-high than cutaneous (30.9% v 13.1% v 8.3%, P < .001) . Generally, LOH-high in skin cancer did not correlate with mutations in HRR genes. Additionally, there was no signiﬁcant association in ICI response biomarkers and HRD among patients with skin cancers. Furthermore, HRD was not associated with a prognostic advantage following IO (hazard ratio, 0.981 [CI, 0.80 to 1.20]; P 5 . 854) . | | CONCLUSION | HRD deﬁnes a biologically distinct subset of skin cancers and is not predictive of ICI response or improved outcomes. The high prevalence of HRD in acral and mucosal melanoma highlights the need to investigate HRD-directed therapies strategies in this distinct cohort, such as poly (ADP-ribose) polymerase inhibitors or platinum-based therapies. | ACCOMPANYING CONTENT Appendix Accepted December 9, 2025 Published January 14, 2026 JCO Precis Oncol 10:e2500923 © 2026 by American Society of Clinical Oncology Licensed under the Creative Commons Attribution 4.0 License INTRODUCTION Several genomic biomarkers play a tumor-agnostic role in predicting response to immune checkpoint inhibitors (ICIs) and outcomes in melanoma.1 ,2 However, little is known about the role of homologous recombination deﬁciency (HRD) in melanoma pathogenesis and clinical outcomes. HRD is a state in which cells cannot repair DNA doublestrand breaks using the homologous recombination repair (HRR) pathway.3-5 HRD status can be quantiﬁed by different scoring systems that assess genomic scarring rather than relying on alterations in HRR pathway genes, like BRCA1/2 . One method generates a composite score derived from single or multiple genomic instability measures such as genome-wide loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LSTs) .6-9 The main therapies used for HRD are poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and platinum-based [ascopubs.org/journal/po](ascopubs.org/journal/po | 1)[ |](ascopubs.org/journal/po | 1)[ 1](ascopubs.org/journal/po | 1) Nassief et al CONTEXT Key Objective To determine t

FAQs

What was the primary objective of the study?

To determine how prevalent homologous recombination deficiency (HRD) is across skin cancer subtypes, assess its relationship with immune checkpoint inhibitor (ICI) biomarkers, and evaluate its prognostic relevance in immunotherapy-treated patients.

How was HRD status defined in the analysis?

HRD status was defined by high loss of heterozygosity (LOH-high) or by mutations in homologous recombination repair (HRR) genes.

Does HRD predict response or better survival with immunotherapy in skin cancer?

No. HRD was not associated with immune checkpoint inhibitor response biomarkers and did not show prognostic advantage after immunotherapy.

Sep 22, 2026

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