Comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 164-164 ◽  
Author(s):  
Rebeca Lozano ◽  
Nuria Romero-Laorden ◽  
Angela del Pozo ◽  
Ana Medina ◽  
Maria Jose Mendez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Dna Repair Genes ◽  
Mutational Status ◽  
Platinum Based Chemotherapy ◽  
Brca1 Brca2 ◽  
The Impact ◽  
Repair Genes

164 Background: Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies. Such defects have been identified in 12% of mCRPC patients. Several studies are ongoing to assess the benefit of these patients from platinum-based chemotherapy and PARP inhibitors, but no conclusive data are available with regards to currently approved therapies for mCRPC, as Abiraterone or Enzalutamide. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received Abiraterone or Enzalutamide as first androgen receptor targeted therapy (ART) were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM, PALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression (bPFS) and response to the first ART received as 1st or 2nd line therapy. Results: 337 patients were eligible for this analysis. CSS from mCRPC was not significantly different between gDDR carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (23.3 Vs 34.6 months, p = 0.02). CSS from first ART, PFS and response-rates were not significantly different between both groups. However, the bPFS was significantly shorter in patients harbouring gDDR mutations (7.3 Vs 3.8 months, p = 0.04), especially in BRCA2 carriers (7.3 Vs 3.0 months, p = 0.03). Conclusions: This is the first study to prospectively follow-up DNA repair germline mutations to determine the outcome on standard treatment for mCRPC. The results suggest that different gDDR defects may have different impact on mCRPC outcomes. Clinical trial information: NCT03075735.

scholarly journals Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer

2015 ◽  
Vol 3 (5) ◽  
pp. 459-466 ◽  
Author(s):  
Yosuke Hirotsu ◽  
Hiroshi Nakagomi ◽  
Ikuko Sakamoto ◽  
Kenji Amemiya ◽  
Toshio Oyama ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Panel Analysis ◽  
Breast And Ovarian Cancer ◽  
Repair Genes ◽  
Multigene Panel

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Elisa Marie Ledet ◽  
Ellen Jaeger ◽  
Whitley Hatton ◽  
Marcus W. Moses ◽  
Alexandra Sokolova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Family History ◽  
Metastatic Prostate Cancer ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Brca Mutations ◽  
Repair Genes

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p < 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with >1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with >2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of >2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.

Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy

Lung Cancer ◽  
2012 ◽  
Vol 75 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Shengxiang Ren ◽  
Songwen Zhou ◽  
Fengyin Wu ◽  
Ling Zhang ◽  
Xuefei Li ◽  
...  
Keyword(s):  
Dna Repair ◽  
Advanced Nsclc ◽  
Dna Repair Genes ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients ◽  
Repair Genes

Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy response and applicability of circulating tumor DNA.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 140-140 ◽  
Author(s):  
Werner J. Struss ◽  
Matti Annala ◽  
Evan W Warner ◽  
Kevin Beja ◽  
Gillian Vandekerkhove ◽  
...  
Keyword(s):  
Dna Repair ◽  
Targeted Therapy ◽  
Gene Loss ◽  
Germline Mutations ◽  
Circulating Tumor Dna ◽  
Dna Repair Genes ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Repair Genes ◽  
Tumor Dna

140 Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.

Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 283-283
Author(s):  
Panagiotis J. Vlachostergios ◽  
Jyothi Manohar ◽  
Muhammad Junaid Niaz ◽  
Aileen Lee ◽  
Amy Hackett ◽  
...  
Keyword(s):  
Single Gene ◽  
Brca2 Gene ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Brca1 Brca2 ◽  
Tissue Specimens ◽  
The Impact

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.

Microsatellite Instability Induced Mutation in DNA Repair Genes, CTiP and Mre11 Confer Hypersensitivity to PARP Inhibitors in Myeloid Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 276-276
Author(s):  
Terry J Gaymes ◽  
Rajani Chelliah ◽  
Austin G Kulasekararaj ◽  
Azim M Mohamedali ◽  
Sydney Shall ◽  
...  
Keyword(s):  
Dna Repair ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Microsatellite Instability ◽  
Cell Transplantation ◽  
Parp Inhibitors ◽  
Immunocytochemical Staining ◽  
Dna Repair Genes ◽  
Repair Genes

Abstract Abstract 276 In both myelodysplatic syndrome (MDS) and acute myeloid leukaemia (AML), relapse from standard chemotherapeutic intervention is common with only 20–30% enjoying long-term disease-free survival. Allogeneic stem cell transplantation still remains the only curative treatment in MDS/AML, but only in 15–20% of patients. Older patients (>70 years) that constitute the majority of MDS/AML patients are often resistant to chemotherapy, achieve short lived remission and are not candidates for stem cell transplantation. Given the high number of patients refractory to conventional therapy and the relatively high rate of therapy relapse, efforts have been made in the search for alternative treatment strategies. Inhibition of Poly ADP ribose polymerase (PARP) activity can selectively target cancer cells through exploitation of inherent DNA repair defects. Significant single agent anti-tumour responses coupled with a wide therapeutic index have been influential in moving PARP inhibitors (PARPi) to the clinical arena. MDS/AML is characterized by chromosomal instability (CI) manifesting as deletions, translocations and chromosome losses. Single nucleotide polymorphism arrays (SNPA) karyotyping show that loss of heterozygosity (LOH) and uniparental disomy (UPD) are common in MDS/AML and thus it has been suggested that the underlying cause of this CI is a defect in double strand DNA repair. We have previously shown that 15% of AML and MDS primary patient cells and cell lines are sensitive to PARPi through exploitation of homologous recombination DNA repair defects. To explicate still further the mechanisms that support PARPi sensitivity in MDS/AML we tested for microsatellite instability (MSI) in primary high risk MDS and primary AML for the presence of frameshift mutations in specific DNA repair genes. 13 of 63 (21%) high risk MDS patients possessed MSI (9 MSI-low and 4 MSI-high). Significantly, all 13 MSI positive patients possessed chromosomal abnormalities, both gross and cryptic UPD determined by SNPA, whilst 12 patients (19%) found to be have normal cytogenetics and lacking UPD failed to demonstrate MSI. Moreover, 3 patients with MSI-high and 1 patient with MSI-low possessed a mono-allelic 1bp deletion in the CTiP exon coding microsatellite. 1bp deletion within the coding exon of CTiP would result in an abbreviated gene CTiP transcript in these patients. From a panel of 18 primary AML samples, 5 primary AML demonstrated sensitivity to the PARPi, BMN673 (100nM). Immunocytochemical staining also showed that PARPi sensitive AML cells demonstrated severely reduced rad51 and increased phospho-γH2AX foci formation compared to PARPi insensitive AML cells. This confirmed that BMN673 targeted HR deficiencies in AML PARPi sensitive cells. Strikingly, 2 of the 5 PARPi responders exhibited MSI, with 1 patient displaying a bi-allelic 1bp deletion in MRe11 and 1 patient exhibiting a mono-allelic 1bp deletion in CTiP. MSI was not observed in the 13 PARPi insensitive AML patients. Western blotting analysis identified the loss of mismatch repair proteins MLH-1 and MSH-2 respectively, in the 2 MSI positive primary AML underlying the MSI observed in the AML patients cells. Moreover, Western blotting analysis also revealed aberrant expression of Mre11 and CTiP in these patients. Finally, to confirm the relative contribution of mutant MRe11 and CTiP to PARPi sensitivity, an expression construct of MRe11 missing exons 5 to 7 (δ5–7MRe11) was transfected into the MSI negative and PARPi insensitive cell line, U937. Cytotoxicity assays and immunocytochemical staining revealed that U937 + δ5–7MRe11 demonstrated significant sensitivity to PARPi with concomitant HR DNA repair defects compared to U937 + vector control. Similarly, Si-RNA knockdown of CTiP in U937 also conferred hypersensitivity to PARPi as a result of an abrogation of functional HR DNA repair. In conclusion, we make the unique observation that MSI dependent mutations in genes that are essential for DNA repair signalling confer PARPi sensitivity in myeloid malignancy. Identification of a cohort of MDS/AML patients with MSI would signify a major development in the identification of candidates for PARPi therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma

2017 ◽  
Vol 12 (11) ◽  
pp. 1673-1678 ◽  
Author(s):  
Erin M. Parry ◽  
Dustin L. Gable ◽  
Susan E. Stanley ◽  
Sara E. Khalil ◽  
Valentin Antonescu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Lung Adenocarcinoma ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Repair Genes

scholarly journals DNA repair genes are selectively mutated in diffuse large B cell lymphomas

2013 ◽  
Vol 210 (9) ◽  
pp. 1729-1742 ◽  
Author(s):  
Noel FCC de Miranda ◽  
Roujun Peng ◽  
Konstantinos Georgiou ◽  
Chenglin Wu ◽  
Elin Falk Sörqvist ◽  
...  
Keyword(s):  
Dna Repair ◽  
B Cell ◽  
Genomic Instability ◽  
Novel Mutation ◽  
B Cell Lymphoma ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
B Cell Lymphomas ◽  
Repair Genes ◽  
Large B Cell

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.

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