Enhancing susceptibility to PARPi in homologous recombination repair dysfunction (HRD)-associated pancreatic cancer

2016 ◽  
Vol 69 ◽  
pp. S122
Author(s):  
T. Golan ◽  
E. Buzhor ◽  
S. Halparin ◽  
K. Cohen ◽  
D. Atias ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Recombination Repair

scholarly journals Arterial Administration of DNA Crosslinking Agents with Restraint of Homologous Recombination Repair by Intravenous Low-Dose Gemcitabine Is Effective for Locally Advanced Pancreatic Cancer

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 220
Author(s):  
Hiromu Mori ◽  
Shuichi Tanoue ◽  
Ryo Takaji ◽  
Shinya Ueda ◽  
Mika Okahara ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Low Dose ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Treatment Compliance ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Dna Crosslinking ◽  
Crosslinking Agents

(1) Background: Pretreatment by Rad51-inhibitory substances such as gemcitabine followed by arterial chemotherapy using antineoplastic agents causing DNA crosslink might be more beneficial for patients with locally advanced pancreatic cancers than conventional treatments. The efficacy of arterial administration of DNA crosslinking agents with pretreatment of intravenous low-dose gemcitabine for patients with unresectable locally advanced or metastatic pancreatic cancer (LAPC or MPC) is evaluated. (2) Methods: A single-arm, single-center, institutional review board-approved prospective study was conducted between 2005 and 2015. Forty-five patients (23 LAPC, 22 MPC) were included. Patients received a weekly low dose of gemcitabine intravenously for three weeks followed by arterial administration of mitomycin C and epirubicin hydrochloride at tumor-supplying arteries on the fifth or sixth week. This treatment course was repeated at 1.5-to-2-month intervals. Overall survival (OS), local progression-free survival (LPFS), and therapeutic response were evaluated. LAPC or MPC were divided according to treatment compliance, excellent or poor (1 or 2), to subgroups L1, L2, M1, and M2. (3) Results: OS of LAPC and MPC were 23 months and 13 months, respectively. The OS of LAPC with excellent treatment compliance (subgroup L1, 10 patients) was 33 months with 31 months of LPFS, and four patients (40%) had a complete response (CR). The OS of the L1 subgroup was significantly longer than those of other subgroups L2, M1, and M2, which were 17 months, 17 months, and 8 months, respectively. As Grade 3 adverse effects, severe bone marrow suppression, interstitial pneumonitis, and hemolytic uremic syndrome were observed in six (13.0%), three (6.5%), and three (6.5%) patients, respectively. (4) Conclusions: Arterial DNA crosslinking with the systemic restraint of homologous recombination repair can be a new treatment option for LAPC.

Homologous recombination repair gene mutations in Chinese pancreatic ductal adenocarcinoma patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16234-e16234
Author(s):  
Nengwen Ke ◽  
Maolin Yan ◽  
Xu Che ◽  
Yu Cheng ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Gene Mutations ◽  
Ductal Adenocarcinoma ◽  
Homologous Recombination Repair ◽  
Common Mutation ◽  
Wild Type ◽  
Recombination Repair

e16234 Background: Pancreatic cancer (PC) is a highly malignant tumor with poor prognosis. Among them, pancreatic ductal adenocarcinoma (PDAC) accounts for 80-90% of pancreatic cancer. While, the treatment of PDAC has always been a clinical challenge. PDAC with mutations in homologous recombination repair (HRR) genes such as BRCA are particularly sensitive to platinum agents. The POLO study has shown that Olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. However, investigation of prevalence of HRR gene mutations in Chinese PDAC patients need to be well defined. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from PDAC patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations and tumor mutational burden (TMB) values were assessed. The association of HRR gene mutations with TMB was assessed. The testing was carried out by OrigiMed (Shanghai, China) witch a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Using targeted capture genomic sequencing, we assessed 98 PDAC patients for germline and somatic loss-of-function mutations in 14 genes, including BRCA1, BRCA2, and 12 other genes in the HR pathway. Results: In total, 98 PDAC patients were recruited including 48 females and 50 males with a median age of 58 (range 35-84). The most frequently mutated genes were KRAS (94%), TP53 (74%), CDKN2A (36%), SMAD4 (27%), GATA6 (9%) and ATM (5%). Mutation rates varied in pancreatic cancer signaling pathway: WNT (35.71%), PI3K (11.22%), HRR (11.22%), NOTCH (3.06%), FGF (2.04%). 2.04% (2/98) patients had high TMB (defined as ≥10 muts/Mb) with a median of 2.2 muts/Mb (0-47 mus/Mb). 34.69% (34/98) of the patients had one or more actionable genetic mutations. We identified that 11.2% (11/98) patients had at least one mutation in HRR genes. The most frequently mutated HRR genes were ATM (50%), BRCA1 (16.7%), BRCA2 (25%) and PALB2 (8.3%). The most common mutation type in HRR-related gene was truncation (75%, 9/12). HRR-related germline mutations in BRCA (71.43%, 5/7), ATM (28.57%, 2/7) were detected in seven patients, six of them with cancer related family history. We confirmed that patients with HRR mutations were younger than wild type HRR (52.6 years vs. 59.3 years, p < 0. 05). We demonstrated that patients with HRR mutations had a significantly higher TMB than patients with wild type HRR (median TMB: 3.4 vs. 1.8 muts/Mb, p < 0. 05). Conclusions: HRR gene alterations occurred in 11.2% of Chinese PDAC patients HRR pathway alterations are relatively frequent in PDAC patients and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

scholarly journals Association between homologous recombination repair gene mutations and response to oxaliplatin in pancreatic cancer

Oncotarget ◽  
2018 ◽  
Vol 9 (28) ◽  
pp. 19817-19825 ◽  
Author(s):  
Tomohiro Kondo ◽  
Masashi Kanai ◽  
Tadayuki Kou ◽  
Tomohiro Sakuma ◽  
Hiroaki Mochizuki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Homologous Recombination ◽  
Gene Mutations ◽  
Homologous Recombination Repair ◽  
Repair Gene ◽  
Recombination Repair

scholarly journals Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

2021 ◽  
Vol 11 (4) ◽  
pp. 245
Author(s):  
Laura Cortesi ◽  
Claudia Piombino ◽  
Angela Toss
Keyword(s):  
Prognostic Factors ◽  
Homologous Recombination ◽  
Pancreatic Adenocarcinoma ◽  
Objective Response ◽  
Metastatic Breast ◽  
Germline Mutations ◽  
Response To Treatment ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
Recombination Repair

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

scholarly journals Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibaut S. Matis ◽  
Nadia Zayed ◽  
Bouchra Labraki ◽  
Manon de Ladurantaye ◽  
Théophane A. Matis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Large Fraction ◽  
Homologous Recombination Repair ◽  
Mutational Signatures ◽  
Recombination Repair ◽  
Multiple Case ◽  
Gene Panels ◽  
Tumor Dna

AbstractIt was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

318 Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation and/or homologous recombination repair deficiency: KEYLYNK-007

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A344-A344
Author(s):  
Timothy A Yap ◽  
Mallika Dhawan ◽  
Andrew E Hendifar ◽  
Michele Maio ◽  
Taofeek K Owonikoko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Homologous Recombination Repair ◽  
Advanced Solid Tumors ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Modified Recist ◽  
Previously Treated

BackgroundTreatment with the anti–PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other homologous recombination repair mutation (HRRm) and in those with ovarian cancer with homologous recombination repair deficiency (HRD) phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD.MethodsThis phase 2, nonrandomized, multicenter, open-label study will enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)–modified RECIST v1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs). The primary endpoint is ORR (RECIST v1.1 or PCWG–modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST v1.1 or PCWG–modified RECIST v1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. A total of 89 sites are currently enrolling in 20 countries.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov identifier, NCT04123366Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.

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