DNA helicases in homologous 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.

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

npj Breast Cancer ◽

10.1038/s41523-021-00315-8 ◽

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.

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0318 ◽

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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