Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

Autor: Orme JJ; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA., Taza F; Division of Hematology & Medical Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., De Sarkar N; Department of Pathology and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA., Tewari AK; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Arsalan Naqvi S; Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA., Riaz IB; Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA., Childs DS; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA., Omar N; Ascension St Agnes Hospital, Baltimore, MD, USA., Adra N; Division of Hematology & Medical Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Ashkar R; Division of Hematology & Medical Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Cheng HH; University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA., Schweizer MT; University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA., Sokolova AO; Oregon Health Sciences University, Portland, OR, USA., Agarwal N; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Barata P; UH Seidman Cancer Center, Cleveland, OH, USA., Sartor O; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA., Bastos D; Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil., Smaletz O; Hospital Israelita Albert Einstein, São Paulo, Brazil., Berchuck JE; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., McClure H; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Taplin ME; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Aggarwal R; University of California San Francisco, San Francisco, CA, USA., Sternberg CN; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Vlachostergios PJ; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Alva AS; University of Michigan, Ann Arbor, MI, USA., Mehra N; Radboud University, Nijmegen, The Netherlands., Nelson PS; University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA., Hwang J; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA., Dehm SM; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Department of Urology, University of Minnesota, Minneapolis, MN, USA., Shi Q; Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Fleischmann Z; Foundation Medicine Inc, Cambridge, MA, USA., Sokol ES; Foundation Medicine Inc, Cambridge, MA, USA., Elliott A; Caris Life Sciences, Irving, TX, USA., Huang H; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA., Bryce A; Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA., Marshall CH; Johns Hopkins University School of Medicine, Baltimore, MD, USA., Antonarakis ES; Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; Masonic Cancer Center, Minneapolis, MN, USA. Electronic address: anton401@umn.edu.
Jazyk: angličtina
Zdroj: European urology oncology [Eur Urol Oncol] 2024 Aug; Vol. 7 (4), pp. 877-887. Date of Electronic Publication: 2023 Dec 09.
DOI: 10.1016/j.euo.2023.11.014
Abstrakt: Background and Objective: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC.
Methods: We conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations.
Key Findings and Limitations: Baseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1-10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15-0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18-0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15-1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05-0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1-0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05-0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40-2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed.
Conclusions and Clinical Implications: In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease.
Patient Summary: In this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation.
(Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: