scholarly journals DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer

2018 ◽  
Vol 16 (8) ◽  
pp. 933-937 ◽  
Author(s):  
Eric Lu ◽  
George V. Thomas ◽  
Yiyi Chen ◽  
Alexander W. Wyatt ◽  
Paul Lloyd ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Parp Inhibitor ◽  
Castration Resistant Prostate Cancer ◽  
Repair Gene ◽  
Castration Resistant ◽  
Dna Repair Gene ◽  
Gene Alterations

Effect of germline DNA repair gene mutations on outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 221-221
Author(s):  
Emmanuel S. Antonarakis ◽  
Changxue Lu ◽  
Brandon Luber ◽  
Hao Wang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Repair Gene ◽  
Castration Resistant ◽  
Dna Repair Gene

221 Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.

scholarly journals Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide

2018 ◽  
Vol 74 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Changxue Lu ◽  
Brandon Luber ◽  
Chao Liang ◽  
Hao Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Repair Gene ◽  
Castration Resistant ◽  
Dna Repair Gene

scholarly journals Germline and somatic DNA repair gene alterations in prostate cancer

Cancer ◽  
2020 ◽  
Vol 126 (13) ◽  
pp. 2980-2985 ◽  
Author(s):  
Marc A. Dall’Era ◽  
John D. McPherson ◽  
Allen C. Gao ◽  
Ralph W. DeVere White ◽  
Jeffrey P. Gregg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Gene Alterations

Detection of germline deleterious mutations in prostate cancer patients with use of a validated 30-gene sequencing assay.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 223-223
Author(s):  
Panagiotis J. Vlachostergios ◽  
Ana M. Molina ◽  
Himisha Beltran ◽  
David M. Nanus ◽  
Scott T. Tagawa
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Family History ◽  
Positive Family History ◽  
High Susceptibility ◽  
Degree Relative ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
History Of ◽  
Gene Alterations

223 Background: Germline DNA repair gene alterations in men with metastatic prostate cancer (PC) unselected for family history of malignancy occur in a greater frequency compared to localized PC and the general population. We hypothesized that assessing heritable alterations in a broader panel of high-susceptibility genes, may be relevant for detecting familial associations with other cancers in PC patients. Methods: We examined a cohort of 52 PC patients (median age 60, range 45-80) with histologically confirmed PC (17 localized, 35 metastatic). Germline DNA was isolated from blood lymphocytes or buccal swabs, and targeted next-generation sequencing was conducted with use of a previously validated panel of 30 genes associated with an elevated risk for common cancers (Color Genomics). As a reference for gene aberration frequencies we used the Exome Aggregation Consortium (ExAC) database. Results: The majority of patients (48/52, 92%) had a positive family history of cancer in any relative. Nine deleterious pathogenic mutations were identified in germline DNA samples from 8/52 (15%) patients, affecting the following genes: APC (n = 2, 3.8%), BRCA2 (n = 2, 3.8%), CHEK2 (n = 3, 5.7%), ATM (n = 1, 1.9%), RAD51D (n = 1, 1.9%). APC mutations were significantly more frequent in our cohort compared to the ExAC database (0.3%, p < 0.001). The frequency of DNA repair gene alterations (7/52, 13.5%) was also significantly higher compared to the ExAC database (0.3%, p < 0.001). The median overall survival (OS) between patients with and without germline gene alterations was similar (81.5 versus 74 months, respectively). The presence of heritable gene alterations from the 30-gene panel was significantly more frequent in patients with a positive family history of any cancer (p < 0.001) or prostate, breast, ovarian cancer (p = 0.001) in a first degree relative. Conclusions: The use of a targeted panel of high-susceptibility cancer-associated genes in PC not only confirms the enrichment of germline mutations in men with PC. It can also reveal associations of PC with other cancers which may portend implications for treatment and prognosis.

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