Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
JCO Precis Oncol
2020 Jan 01;4:355-366. doi: 10.1200/po.19.00346.
Show Gene links
Show Anatomy links
Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations.
Mota JM
,
Barnett E
,
Nauseef JT
,
Nguyen B
,
Stopsack KH
,
Wibmer A
,
Flynn JR
,
Heller G
,
Danila DC
,
Rathkopf D
,
Slovin S
,
Kantoff PW
,
Scher HI
,
Morris MJ
,
Schultz N
,
Solit DB
,
Abida W
.
???displayArticle.abstract???
PURPOSE: Alterations in DNA damage repair (DDR) genes occur in up to 25% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may sensitize to platinum chemotherapy. We aimed to evaluate the efficacy of platinum-based chemotherapy in DDR-mutant (DDRmut) mCRPC.
METHODS: We assessed response to platinum chemotherapy based on DDR gene alteration status in men with mCRPC who underwent tumor and germline genomic profiling. Patients with deleterious alterations in a gene panel that included BRCA2, BRCA1, ATM, PALB2, FANCA, and CDK12 were considered DDRmut.
RESULTS: A total of 109 patients with mCRPC received platinum-based chemotherapy between October 2013 and July 2018. Sixty-four of 109 patients were taxane refractory and poly (ADP-ribose) polymerase inhibitor (PARPi) naïve. Within this subset, DDRmut was found in 16/64 patients (25%) and was associated with an increased likelihood of achieving a prostate-specific antigen (PSA) decline of 50% or more from baseline (PSA50; odds ratio, 7.0; 95% CI, 1.9 to 29.2). Time on platinum chemotherapy tended to be longer in the DDRmut group (median, 3.0 v 1.6 months; hazard ratio, 0.55, 95% CI, 0.29 to 1.24). No difference in survival was detected. Of 8 patients with DDRmut disease who received platinum-based therapy after a PARPi, 3/7 evaluable patients had radiographic partial response or stable disease, and 2/7 had a PSA50 response. None of 4 patients with ATM mutations had platinum responses regardless of prior PARPi exposure.
CONCLUSION: Patients with DDRmut disease had better response to platinum-based chemotherapy, suggesting that DDR status warrants prospective validation as a potential biomarker for patient selection. Responses to platinum chemotherapy were observed in BRCA-altered prostate cancer after PARPi progression. Additional studies are needed to determine the predictive role of individual genes on platinum sensitivity in the context of other clinical and genomic factors.
Abida,
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.
2017, Pubmed
Abida,
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.
2017,
Pubmed
Abida,
Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade.
2019,
Pubmed
Abida,
Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study.
2020,
Pubmed
Aparicio,
Platinum-based chemotherapy for variant castrate-resistant prostate cancer.
2013,
Pubmed
Armenia,
The long tail of oncogenic drivers in prostate cancer.
2018,
Pubmed
Bhattacharya,
RAD51 interconnects between DNA replication, DNA repair and immunity.
2017,
Pubmed
Chakravarty,
OncoKB: A Precision Oncology Knowledge Base.
2017,
Pubmed
Cheng,
Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer.
2016,
Pubmed
Cheng,
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology.
2015,
Pubmed
Corn,
Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial.
2019,
Pubmed
Hager,
Anti-tumour activity of platinum compounds in advanced prostate cancer-a systematic literature review.
2016,
Pubmed
Hopfner,
Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily.
2000,
Pubmed
Kang,
A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy.
2012,
Pubmed
Lin,
BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.
2019,
Pubmed
Mandelker,
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.
2017,
Pubmed
Mateo,
DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
2015,
Pubmed
Pomerantz,
The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.
2017,
Pubmed
Pritchard,
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
2016,
Pubmed
Regan,
Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials.
2010,
Pubmed
Robinson,
Integrative Clinical Genomics of Advanced Prostate Cancer.
2015,
Pubmed
Ross,
A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel.
2008,
Pubmed
Shen,
FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing.
2016,
Pubmed
Somyajit,
Distinct roles of FANCO/RAD51C protein in DNA damage signaling and repair: implications for Fanconi anemia and breast cancer susceptibility.
2012,
Pubmed
Sternberg,
Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial.
2009,
Pubmed
Telli,
Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
2016,
Pubmed
Varon,
Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.
1998,
Pubmed
Zafeiriou,
Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency.
2019,
Pubmed
Zannini,
CHK2 kinase in the DNA damage response and beyond.
2014,
Pubmed
Zehir,
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
2017,
Pubmed
