Abstract
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.
Highlights
The tumor suppressor complex Breast Cancer 1 (BRCA1) and (BRCA1-associated RING domain 1 (BARD1) facilitates DNA end resection and interacts with the bridging protein partner and localizer of BRCA2 (PALB2) which in turn promotes the recruitment of breast cancer 2 (BRCA2) [9]
All trials that explore the efficacy of PARP inhibitor (PARPi) in high-penetrance risk genes (BRCA1/2, PALB2) have shown activity in those genes, definitely introducing in the metastatic breast cancer therapeutic algorithm a new standard treatment for germline mutation carriers
Patients with breast cancer who may be eligible for poly (ADP-ribose) polymerase (PARP) inhibitor therapy are often missed, even when using established diagnostic guidelines and techniques
Summary
Healthy cells defend themselves against DNA damage through different pathways. The. DNA damage can induce a single-strand break or a double-strand break. The singlestrand break can be repaired by different systems: base excision repair (BER), nucleotide excision repair (NER), or mismatch repair (MMR). The poly (ADP-ribose) polymerase (PARP) enzyme belongs to the BER system (Figure 1A), whereas ERCC excision repair 1, endonuclease non-catalytic subunit (ERCC1) enzyme repairs bulky adducts by the NER systems, and the MutL homolog 1 (MLH1), MutS homolog 6 (MSH6), and MutT homolog. 1 (MTH1) proteins repair the single nucleotide substitutions, deletions, or insertions by the MMR system. There are at least five pathways to repair DNA doublestrand breaks: non-homologous end-joining (NHEJ), alternative non-homologous endjoining, single-strand annealing, break-induced replication, and homologous recombination repair (HRR) [1,2,3].
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