A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer.

Autor: Boiarsky D; Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA., Tewari AK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Gulhan DC; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA., Bakouny Z; Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, NY, New York, USA., Ananda G; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Savignano H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Lakshminarayanan G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., McClure HM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Silver R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Rosalind Franklin University of Medicine and Science, Chicago, Illinois, USA., Choueiri TK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Taplin ME; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA., Berchuck JE; Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Jazyk: angličtina
Zdroj: The Prostate [Prostate] 2024 Dec; Vol. 84 (16), pp. 1479-1489. Date of Electronic Publication: 2024 Sep 09.
DOI: 10.1002/pros.24788
Abstrakt: Background: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi.
Methods: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes).
Results: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10 -7 ). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070).
Conclusions: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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