Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency–Related Loss of Heterozygosity

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Alice Zhou Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri

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Omar Butt Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri

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Michael Ansstas Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri

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Elizabeth Mauer Tempus Laboratories Inc., Chicago, Illinois

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Karam Khaddour Division of Hematology and Oncology, University of Illinois Chicago, Chicago, Illinois

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George Ansstas Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri

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There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Submitted August 10, 2022; final revision received December 5, 2022; accepted for publication December 5, 2022.

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: George Ansstas, MD, Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110. Email: gansstas@wustl.edu

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