Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.
- pancreatic cancer
- DNA damage
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TS and AK contributed equally.
Correction notice This article has been corrected since it published Online First. The joint author statement has been added.
Contributors All authors wrote and revised the manuscript.
Funding The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: main funding was provided by the German Cancer Aid grant to AK (111879). Additional funding came from the Deutsche Forschungsgemeinschaft (DFG, KL 2544/1–1, 1–2, 5-1, 7-1), the BIU fund (Böhringer Ingelheim), the INDIMED-Verbund PancChip and the Else-Kröner-Fresenius Memorial funding to AK. AK also received funding from the DFG within the Heisenberg programme (KL2544/6-1) and from the Baden-Württemberg Foundation via ExPo Chip. ANR-DFG collaborative research project (ANR-18-CE92-0031, DFG KL 2544/5–1) to AK. AK, LW, TS were funded by the DFG HEIST RTG GRK 2254/1. LP was funded by Bausteinprogramm of Ulm University Hospital. LW was further supported by the German Cancer Aid Priority Program Translational Oncology (70112504).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
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