[en] ("[en] BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.
OBJECTIVE: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.
DESIGN, SETTING, AND PARTICIPANTS: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.
RESULTS AND LIMITATIONS: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).
CONCLUSIONS: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.
PATIENT SUMMARY: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.","[en] ","")
Disciplines :
Oncology
Author, co-author :
Loehr, Andrea; Translational Medicine, Clovis Oncology, Inc, Boulder, CO, USA
Hussain, Arif; Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA
Patnaik, Akash; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
Bryce, Alan H; Hematology/Oncology, Mayo Clinic, Phoenix, AZ, USA
Castellano, Daniel; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
Font, Albert; Medical Oncology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
Shapiro, Jeremy; Medical Oncology, Cabrini Hospital, Malvern, VIC, Australia
Zhang, Jingsong; Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
Sautois, Brieuc ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale
Vogelzang, Nicholas J; Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
Chatta, Gurkamal; Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Courtney, Kevin; Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX, USA
Harzstark, Andrea; Hematology/Oncology, Kaiser Permanente Oncology Clinical Trials Program, San Francisco, CA, USA
Ricci, Francesco; Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France
Despain, Darrin; Biostatistics, Clovis Oncology, Inc., Boulder, CO, USA
Watkins, Simon; Clinical Development, Clovis Oncology UK Ltd, Cambridge, UK
King, Charmin; Clinical Operations, Clovis Oncology, Inc, Boulder, CO, USA
Nguyen, Minh; Translational Medicine, Clovis Oncology, Inc, Boulder, CO, USA
Simmons, Andrew D; Translational Medicine, Clovis Oncology, Inc, Boulder, CO, USA
Chowdhury, Simon; Medical Oncology, Guy's Hospital, London, UK, Sarah Cannon Research Institute, London, UK
Abida, Wassim; Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: abidam@mskcc.org
Abida, W., Patnaik, A., Campbell, D., et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol 38 (2020), 3763–3772.
Green, F., Shaprio, J.D., McDermott, R., et al. Comprehensive genomic profiling of >1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies. Cancer Res, 79(suppl 13), 2019, 727.
Abida, W., Armenia, J., Gopalan, A., et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol, 2017, 2017, PO.17.00029.
Tukachinsky, H., Madison, R.W., Chung, J.H., et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clin Cancer Res 27 (2021), 3094–3105.
Goodall, J., Mateo, J., Yuan, W., et al. Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov 7 (2017), 1006–1017.
Chung, J.H., Dewal, N., Sokol, E., et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol, 3, 2019, PO.18.00283.
Carneiro, B.A., Collier, K.A., Nagy, R.J., et al. Acquired resistance to poly (ADP-ribose) polymerase inhibitor olaparib in BRCA2-associated prostate cancer resulting from biallelic BRCA2 reversion mutations restores both germline and somatic loss-of-function mutations. JCO Precis Oncol, 2, 2018, PO.17.00176.
Cheng, H.H., Salipante, S.J., Nelson, P.S., Montgomery, B., Prichard, C.C., Polyclonal BRCA2 reversion mutations detected in circulating tumor DNA after platinum chemotherapy in a patient with metastatic prostate cancer. JCO Precis Oncol, 2, 2018, PO.17.00169.
Sorrells, S., McKinnon, K.E., McBratney, A., Sumey, C., Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse. NPJ Genom Med, 6, 2021, 17.
Simmons, A.D., Nguyen, M., Pintus, E., Polyclonal BRCA2 mutations following carboplatin treatment confer resistance to the PARP inhibitor rucaparib in a patient with mCRPC: a case report. BMC Cancer, 20, 2020, 215.
Lin, K.K., Harrell, M.I., Oza, A.M., et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov 9 (2019), 210–219.
Tobalina, L., Armenia, J., Irving, E., O'Connor, M.J., Forment, J.V., A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann Oncol 32 (2021), 103–112.
Weigelt, B., Comino-Méndez, I., de Bruijn, I., et al. Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin Cancer Res 23 (2017), 6708–6720.
Jacob, S.L., Kiedrowski, L.A., Chae, Y.K., The dynamic landscape of BRCA1 reversion mutations from indel to SNV in a patient with ovarian cancer treated with PARP-inhibitors and immunotherapy. Heliyon, 6, 2020, e03841.
Edwards, S.L., Brough, R., Lord, C.J., et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451 (2008), 1111–1115.
Wang, Y., Bernhardy, A.J., Cruz, C., et al. The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res 76 (2016), 2778–2790.
Pettitt, S.J., Krastev, D.B., Brandsma, I., et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun, 9, 2018, 1849.
Kondrashova, O., Nguyen, M., Shield-Artin, K., et al. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov 7 (2017), 984–998.
Castroviejo-Bermejo, M., Cruz, C., Llop-Guevara, A., et al. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol Med, 10, 2018, e9172.
Ter Brugge, P., Kristel, P., van der Burg, E., et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J Natl Cancer Inst, 108, 2016, djw148.
Walmsley C. Extensive convergent evolution of BRCA reversion mutations under therapeutic pressure by PARP inhibition. Abstract presented at Society of Urologic Oncology; September 11, 2021; virtual meeting.
Warner, E., Herberts, C., Fu, S., et al. BRCA2, ATM, and CDK12 defects differentially shape prostate tumor driver genomics and clinical aggression. Clin Cancer Res 27 (2021), 1650–1662.
Quigley, D., Alumkal, J.J., Wyatt, A.W., et al. Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov 7 (2017), 999–1005.
Taavitsainen, S., Annala, M., Ledet, E., et al. Evaluation of commercial circulating tumor DNA test in metastatic prostate cancer. JCO Precis Oncol, 3, 2019, PO.19.00014.
Eisenhauer, E.A., Therasse, P., Bogaerts, J., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45 (2009), 228–247.
Scher, H.I., Morris, M.J., Stadler, W.M., et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 34 (2016), 1402–1418.
Lanman, R.B., Mortimer, S.A., Zill, O.A., et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One, 10, 2015, e0140712.
Odegaard, J.I., Vincent, J.J., Mortimer, S., et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin Cancer Res 24 (2018), 3539–3549.
Crawford, B., Adams, S.B., Sittler, T., et al. Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients. Breast Cancer Res Treat 163 (2017), 383–390.
Pettitt, S.J., Frankum, J.R., Punta, M., et al. Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov 10 (2020), 1475–1488.
Waks, A.G., Cohen, O., Kochupurakkal, B., et al. Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2-mutant metastatic breast cancer (MBC). J Clin Oncol, 37(15 suppl), 2019, 1085.
Pritchard, C.C., Mateo, J., Walsh, M.F., et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 375 (2016), 443–453.
The Cancer Genome Atlas Research Network, Integrated genomic analyses of ovarian carcinoma. Nature 474 (2011), 609–615.
Pennington, K.P., Walsh, T., Harrell, M.I., et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20 (2014), 764–775.
Eoh, K.J., Park, J.S., Park, H.S., et al. BRCA1 and BRCA2 mutation predictions using the BRCAPRO and myriad models in Korean ovarian cancer patients. Gynecol Oncol 145 (2017), 137–141.
