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Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants

      Highlights

      • Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking.
      • BRCA1-2 alterations increase sensitivity to platinum salts and PARP inhibitors.
      • Alterations in alternative DNA damage response (DDR) genes may exert similar functional effects.
      • Better understand genetic variants is crucial for improving treatments of DDR-deficient patients.

      Abstract

      Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking. Recently germline mutations in BRCA 1 and 2 genes, leading to homologous repair deficiency, have emerged as new targets for more specific and effective therapies, exploiting the increased susceptibility to platinum salts and PARP inhibitors. In addition to BRCA, pathogenic variants in PALB2 and in other genes involved in the DNA damage response pathway (DDR) represent potential targets, as well as their respective somatic alterations. This enlarged molecularly-selected population sharing the BRCAness phenotype, is expected to show a higher sensibility to a number of DNA damaging agents and DDR inhibitors. However, the possibility of new therapeutic opportunities for DDR defective PDAC patients has to face the lack of solid evidence about the proper type and timing of targeted-treatments, the potential combination strategies and most importantly, the lack of informations on the functional impact of each specific pathogenic variant on the DDR pathway.
      This review summarizes the current and near-future options for the clinical management of PDAC patients harboring a DDR deficiency, analyzing the state of the art of the indications of platinum salts and other cytotoxic agents in the advanced and early stage PDAC, the development of PARP inhibitors and the rational for new combinations with immunotherapy and cycle checkpoint inhibitors, as well as the strategy to overcome the development of resistance over treatments.

      Keywords

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      References

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer Statistics.
        CA Cancer J Clin. 2018; 68: 7-30
        • Rahib L.
        • Smith B.D.
        • Aizenberg R.
        • Rosenzweig A.B.
        • Fleshman J.M.
        • Matrisian L.M.
        Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.
        Cancer Res. 2014; 74: 2913-2921
        • Conroy T.
        • Desseigne F.
        • Ychou M.
        • Bouché O.
        • Guimbaud R.
        • Bécouarn Y.
        • et al.
        FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
        N Engl J Med. 2011; 364: 1817-1825
        • Von Hoff D.D.
        • Ervin T.
        • Arena F.P.
        • Chiorean E.G.
        • Infante J.
        • Moore M.
        • et al.
        Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.
        N Engl J Med. 2013; 369: 1691-1703
        • Petersen G.M.
        Familial pancreatic cancer.
        Semin Oncol. 2016; 43: 548-553
        • Carnevale J.
        • Ashworth A.
        Assessing the significance of BRCA1 and BRCA2 mutations in pancreatic cancer.
        J Clin Oncol. 2015; 33: 3080-3081
        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • Futreal P.A.
        • Harshman K.
        • Tavtigian S.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA.
        Science. 1994; 5182: 66-71
      1. Perkhofer L, Cout J, Roger E, Kude de Almeida F, Baptista Simões C, Wiesmüller L, et al. DNA damage repair as target I pancreatic cancer: state-of-the-art and future perspectives. Gut 2020 Aug 27: gutjnl-2019-319984. doi: 10.1136/gutjnl-2019-319984. Epub ahead of print. PMID: 32855305.

        • Sahin I.H.
        • Lowery M.A.
        • Stadler Z.K.
        • Salo-Mullen E.
        • Iacobuzio-Donahue C.A.
        • Kelsen D.P.
        • et al.
        Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.
        Expert Rev Gastroenterol Hepatol. 2016; : 1-13https://doi.org/10.1586/17474124.2016.1153424
        • Collins N.
        • McManus R.
        • Wooster R.
        • Mangion J.
        • Seal S.
        • Lakhani S.R.
        • et al.
        Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12–13.
        Oncogene. 1995; 10: 1673-1675
        • Gudmundsson J.
        • Johannesdottir G.
        • Bergthorsson J.T.
        • Arason A.
        • Ingvarsson S.
        • Egilsson V.
        • et al.
        Different tumor types from BRCA2 carriers show wild-type chromosome deletions on 13q12-q13.
        Cancer Res. 1995; 55: 4830-4832
        • Jonsson P.
        • Bandlamudi C.
        • Cheng M.L.
        • Srinivasan P.
        • Chavan S.S.
        • Friedman N.D.
        • et al.
        Tumor lineage shapes BRCA-mediated phenotypes.
        Nature. 2019; 571: 576-579
        • Golan T.
        • O’Kane G.M.
        • Denroche R.E.
        • Raitses-Gurevich M.
        • Grant R.C.
        • Holter S.
        • et al.
        Genomic features and classification of homologous recombination deficient pancreatic ductal adenocarcinoma.
        Gastroenterology. 2021; 160: 2119-2132.e9https://doi.org/10.1053/j.gastro.2021.01.220
        • Curtin N.J.
        DNA repair dysregulation from cancer driver to therapeutic target.
        Nat Rev Cancer. 2012; 12: 801-817
        • Martin L.P.
        • Hamilton T.C.
        • Schilder R.J.
        Platinum resistance: the role of DNA repair pathways.
        Clin Cancer Res. 2008; 14: 1291-1295
        • Chartron E.
        • Theillet C.
        • Guiu S.
        • Jacot W.
        Targeting homologous repair deficiency in breast and ovarian cancers: biological pathways, pre-clinical and clinical data.
        Crit Rev Oncol Hematol. 2019; 133: 58-73
        • Golan T.
        • Kanji Z.S.
        • Epelbaum R.
        • Devaud N.
        • Dagan E.
        • Holter S.
        • et al.
        Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
        Br J Cancer. 2014; 111: 1132-1138
        • Wattenberg M.M.
        • Asch D.
        • Yu S.
        • O’Dwyer P.J.
        • Domchek S.M.
        • Nathanson K.L.
        • et al.
        Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation.
        Br J Cancer. 2020; 122: 333-339
        • Reiss K.A.
        • Yu S.
        • Judy R.
        • Symecko H.
        • Nathanson K.L.
        • Domchek S.M.
        Retrospective survival analysis of patients with advanced pancreatic ductal adenocarcinoma and germline BRCA or PALB2 mutations.
        JCO Precis Oncol. 2018; https://doi.org/10.1200/PO.18.00271
        • Rebelatto T.F.
        • Falavigna M.
        • Pozzari M.
        • Spada F.
        • Cella C.A.
        • Laffi A.
        • et al.
        Should platinum-based chemotherapy be preferred for germline Breast Cancer genes (BRCA) 1 and 2 mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis.
        Cancer Treat Rev. 2019; 80: 101895https://doi.org/10.1016/j.ctrv.2019.101895
        • Golan T.
        • Hammel P.
        • Reni M.
        • Van Cutsem E.
        • Macarulla T.
        • Hall M.J.
        • et al.
        Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
        N Engl Med. 2019; 381: 317-327
        • O’Reilly E.M.
        • Lee J.W.
        • Zalupski M.
        • Capanu M.
        • Park J.
        • Golan T.
        • et al.
        Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/ PALB2 mutation.
        J Clin Oncol. 2020; 38: 1378-1388
        • Pokataev I.
        • Fedyanin M.
        • Polyanskaya E.
        • Popova A.
        • Agafonova J.
        • Menshikova S.
        • et al.
        Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency: comparative analysis of published clinical studies.
        ESMO Open. 2020; 5: e000578https://doi.org/10.1136/esmoopen-2019-000578
        • Chaney S.G.
        • Campbell S.L.
        • Bassett E.
        • Wu Y.
        Recognition and processing of cisplatin- and oxaliplatin- DNA adducts.
        Crit Rev Oncol Hematol. 2005; 53: 3-11
        • Bruno P.M.
        • Liu Y.
        • Park G.Y.
        • Murai J.
        • Koch C.E.
        • Eisen T.J.
        • et al.
        A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress.
        Nat Med. 2017; 23: 461-471
        • Tung N.
        • Arun B.
        • Hacker M.R.
        • Hofstatter E.
        • Toppmeyer D.L.
        • Isakoff S.J.
        • et al.
        Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial).
        J Clin Oncol. 2020; 38: 1539-1548
        • Kummar S.
        • Oza A.M.
        • Fleming G.F.
        • Sullivan D.M.
        • Gandara D.R.
        • Naughton M.J.
        • et al.
        Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer.
        Clin Cancer Res. 2015; 21: 1574-1582
        • Lee C.K.
        • Scott C.
        • Lindeman G.J.
        • Hamilton A.
        • Lieschke E.
        • Gibbs E.
        • et al.
        Phase 1 trial of olaparib and oral cyclophosphamide in BRCA breast cancer, recurrent BRCA ovarian cancer, non-BRCA triple-negative breast cancer, and non-BRCA ovarian cancer.
        Br J Cancer. 2019; 120: 279-285
      2. Tacconi EMC, Badie S, De Gregoriis G, Reisländer T, Lai X, Porru M, et al. Chlorambucil targets BRCA1/2-deficient tumors and counteracts PARP inhibitor resistance. EMBO Mol Med 201911: e9982 doi: 10.15252/emmm.201809982.

        • Ding J.
        • Wu S.
        • Zhang C.
        • Garyali A.
        • Martinez-Ledesma E.
        • Gao F.
        • et al.
        BRCA1 identified as a modulator of temozolomide resistance in P53 wild-type GBM using a high-throughput shRNA-based synthetic lethality screening.
        Am J Cancer Res. 2019; 9: 2428-2441
        • Farago A.F.
        • Yeap B.Y.
        • Stanzione M.
        • Hung Y.P.
        • Heist R.S.
        • Marcoux J.P.
        • et al.
        Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.
        Cancer Discovery. 2019; 9: 1372-1387
        • Federico S.M.
        • Pappo A.S.
        • Sahr N.
        • Sykes A.
        • Campagne O.
        • Stewart C.F.
        • et al.
        A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies.
        Eur J Cancer. 2020; 137: 204-213
        • Coussy F.
        • El-Botty R.
        • Château-Joubert S.
        • Dahmani A.
        • Montaudon E.
        • Leboucher S.
        • et al.
        BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancer.
        Sci Trans Med. 2020; 12: eaax2625https://doi.org/10.1126/scitranslmed.aax2625
        • Davidson D.
        • Wang Y.
        • Aloyz R.
        • Panasci L.
        The PARP inhibitor ABT-888 synergizes with irinotecan treatment of colon cancer cell lines.
        Invest New Drug. 2013; 31: 461-468
        • Murai J.
        • Zhang Y.
        • Morris J.
        • Ji J.
        • Takeda S.
        • Doroshow J.H.
        • et al.
        Rationale for poly(ADP-ribose)polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.
        J Pharmacol Exp Ther. 2014; 349: 408-416
        • Kim J.W.
        • Min A.
        • Im S.-A.
        • Jang H.
        • Kim Y.J.
        • Kim H.-J.
        • et al.
        TDP1 and TOP1 modulation in olaparib-resistant cancer determines the efficacy of subsequent chemotherapy.
        Cancers. 2020; 12: 334https://doi.org/10.3390/cancers12020334
        • James E.
        • Waldron-Lynch M.G.
        • Saif M.W.
        Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature.
        Anticancer drugs. 2009; 20: 634-638
        • Chen X.
        • Peng F.
        • Ji Y.
        • Xiang H.
        • Wang X.
        • Liu T.
        • et al.
        Brca2 deficiency drives gastrointestinal tumor formation and is selectively inhibited by mitomycin C.
        Cel Death Disease. 2020; 11https://doi.org/10.1038/s41419-020-03013-8
        • Moiseyenko V.M.
        • Chubenko V.A.
        • Moiseyenko F.V.
        • Zhabina A.S.
        • Gorodnova T.V.
        • Komarov Y.I.
        • et al.
        Evidence for clinical efficacy of mitomycin C in heavily pretreated ovarian cancer patients carrying germ-line BRCA1 mutation.
        Med Oncol. 2014; 31https://doi.org/10.1007/s12032-014-0199-x
        • Chalasani P.
        • Kurtin S.
        • Dragovich T.
        Response to a third-line mitomycin C (MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germline BRCA2 mutation.
        JOP. 2008; 9: 305-308
        • Schöffski P.
        • Taron M.
        • Jimeno J.
        • Grosso F.
        • Sanfilipio R.
        • Casali P.G.
        • et al.
        Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study.
        Eur J cancer. 2011; 47: 1006-1012
        • Monk B.J.
        • Ghatage P.
        • Parekh T.
        • Henitz E.
        • Knoblauch R.
        • Matos-Pita A.S.
        • et al.
        Effect of BRCA1 and XPG mutations on threatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.
        Ann Oncol. 2015; 26: 914-920
        • Belli C.
        • Piemonti L.
        • D’Incalci M.
        • Zucchetti M.
        • Porcu L.
        • Cappio S.
        • et al.
        Phase II trial of savage therapy with trabectedin in metastatic pancreatic adenocarcinoma.
        Cancer Chemother Pharmacol. 2016; 77: 477-484
      3. https://clinicaltrials.gov/ct2/show/NCT04692740. Accessed April 10th 2021.

        • Zhu H.
        • Wei M.
        • Xu J.
        • Hua J.
        • Liang C.
        • Meng Q.
        • et al.
        PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications.
        Molecular cancer. 2020; 19https://doi.org/10.1186/s12943-020-01167-9
      4. Ashworth A. A synthetic lethal therapeutic approach: Poly (ADP) Ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. 2020; 26: 3785–90.

        • Golan T.
        • Hammel P.
        • Reni M.
        • Van Cutsem E.
        • Macarulla T.
        • Hall M.J.
        • et al.
        Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
        J Clin Oncol. 2021; 39 (378-378)https://doi.org/10.1200/JCO.2021.39.3
        • Hammel P.
        • Kindler H.L.
        • Reni M.
        • Van Cutsem E.
        • Macarulla T.
        • Hall M.J.
        • et al.
        Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib.
        Ann Oncol. 2019; 30: 1959-1968
        • Binder K.A.R.
        • Mick R.
        • O’Hara M.
        • Teitelbaum U.
        • Karasic T.B.
        • Schneider C.
        • et al.
        Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.
        J Clin Oncol. 2021; 39: 2497-2505https://doi.org/10.1200/JCO.21.00003
        • Tuli R.
        • Shiao S.L.
        • Nissen N.
        • Tighiouart M.
        • Kim S.
        • Osipov A.
        • et al.
        A phase 1 study of veliparib, a PARP1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer.
        EBioMedicine. 2019; 40: 375-381
        • Lowery M.A.
        • Kelsen D.P.
        • Capanu M.
        • Smith S.C.
        • Lee J.W.
        • Stadler Z.K.
        • et al.
        Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma.
        Eur J Cancer. 2018; 89: 19-26
        • Shroff R.T.
        • Hendifar A.
        • McWilliams R.R.
        • Geva R.
        • Epelbaum R.
        • Rolfe L.
        • et al.
        Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious mutation.
        JCO Precis Oncol. 2018; 2018: 1-5https://doi.org/10.1200/PO.17.00316
        • Kaufman B.
        • Shapira-Frommer R.
        • Schmutzler R.K.
        • Audeh M.W.
        • Friedlander M.
        • Balmaña J.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J Clin Oncol. 2015; 33: 244-250
        • Javle M.
        • Shacham-Shmueli E.
        • Xiao L.
        • Varadhachary G.
        • Halpern N.
        • Fogelman D.
        • et al.
        Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 phase 2 nonrandomized clinical trials.
        JAMA Oncol. 2021; https://doi.org/10.1001/jamaoncol.2021.0006
        • Murai J.
        • Huang S.-Y.
        • Renaud A.
        • Zhang Y.
        • Ji J.
        • Takeda S.
        • et al.
        Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.
        Mol Cancer Ther. 2014; 13: 433-443
        • de Bono J.
        • Ramanathan R.K.
        • Mina L.
        • Chugh R.
        • Glaspy J.
        • Rafii S.
        • et al.
        Phase I, dose-escalation, two-part trial of the PARP inhibitor Talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers.
        Cancer Discov. 2017; 7: 620-629
        • Bendell J.
        • O’Reilly E.M.
        • Middleton M.R.
        • Chau I.
        • Hochster H.
        • Fielding A.
        • et al.
        Phase I study of olaparib plus gemcitabine in patients with advanced solid tumors and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer.
        Ann Oncol. 2015; 26: 804-811
        • Yarchoan M.
        • Myzak M.C.
        • Johnson B.A.
        • De Jesus-Acosta A.
        • Le D.T.
        • Jaffee E.M.
        • et al.
        Olaparib in combination with irinotecan, cisplatin, and mitomycin c in patients with advanced pancreatic cancer.
        Oncotarget. 2017; 8: 44073-44081
        • Berlin J.
        • Ramanathan R.K.
        • Strickler J.H.
        • Subramaniam D.S.
        • Marshall J.
        • Kang Y.K.
        • et al.
        A phase 1 dose-escalation study of veliparib with bimonthly FOLFIRI in patients with advanced solid tumors.
        British J Cancer. 2018; 118: 938-946
        • Chiorean E.G.
        • Guthrie K.A.
        • Philip P.A.
        • Swisher E.M.
        • Jalikis F.
        • Pishvaian M.J.
        • et al.
        Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOGS1513.
        J Clin Oncol. 2019; 37: 4014
        • Pishvaian M.J.
        • Wang H.
        • He A.R.
        • Hwang J.J.
        • Smaglo B.G.
        • Kim S.S.
        • et al.
        A phase I/II study of veliparib (ABT-888) in combination with 5-Fluorouracil and oxaliplatin in patients with metastatic pancreatic cancer.
        Clin Cancer Res. 2020; 26: 5092-5101
        • Rothkamm K.
        • Lobrich M.
        Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.
        Proc Natl Acad Sci. 2003; 100: 5057-5062
        • Verhagen C.V.M.
        • de Haan R.
        • Hageman F.
        • Oostendorp T.P.D.
        • Carli A.L.E.
        • O’Connor M.J.
        • et al.
        Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells.
        Radiother Oncol. 2015; 116: 358-365
        • Trombetta M.G.
        • Dragun A.
        • Mayr N.A.
        • Pierce L.J.
        • et al.
        ASTRO Radiation therapy summary of the ASCO-ASTRO-SSO guideline on management of hereditary breast cancer.
        Practical Radiation Oncol. 2020; 10: 235-242
        • Kan C.
        • Zhang J.
        BRCA1 mutation: a predictive marker for radiation therapy?.
        Int J Radiat Oncol Biol Phys. 2015; 93: 281-293
        • Söderlund K.
        • Skoog L.
        • Fornander T.
        • Askmalm M.S.
        The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early brest cancer.
        Radiother Oncol. 2007; 84: 242-251
        • Kirova Y.M.
        • Savignoni A.
        • Sigal-Zafrani B.
        • de La Rochefordiere A.
        • Salmon R.J.
        • This P.
        • et al.
        is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long term results and review of the literature.
        Breast Cancer Res Treat. 2010; 120: 119-126
        • Pierce L.J.
        • Levin A.M.
        • Rebbeck T.R.
        • Ben-David M.A.
        • Friedman E.
        • Solin L.J.
        • et al.
        Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer.
        J Clin Oncol. 2006; 24: 2437-2443
        • Wolfe A.R.
        • Jain R.
        • Pawlik T.M.
        • Walker J.
        • Williams T.M.
        Radiation-induced colitis in a pancreatic cancer patient with germline BRCA2 mutation: a case report.
        Adv Radiat Oncol. 2019; 4: 10-14
        • Liu Q.
        • Tong D.
        • Liu G.
        • Yi Y.
        • Xu J.
        • Yang X.
        • et al.
        A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy.
        Cancer Biol Ther. 2018; 19: 669-675
        • Kelsey C.R.
        • Jackson I.L.
        • Langdon S.
        • Owzar K.
        • Hubbs J.
        • Vujaskovic Z.
        • et al.
        Analysis of single nucleotide polymorphisms and radiation sensitivity of the lung assessed with an objective radiologic endpoint.
        Clin Lung Cancer. 2013; 14: 267-274
        • Pokataev I.
        • Fedyanin M.
        • Polyanskaya E.
        • Popova A.
        • Agafonova J.
        • Menshikova S.
        • et al.
        Efficacy of platinum-based chemotherapy and prognosis of patients with pancreatic cancer with homologous recombination deficiency. Comparative analysis of published clinical studies.
        ESMO Open. 2020; 5: e000578https://doi.org/10.1136/esmoopen-2019-000578
        • Blair A.B.
        • Groot V.P.
        • Gemenetzis G.
        • Wei J.
        • Cameron J.L.
        • Weiss M.J.
        • et al.
        BRCA1/BRCA2 germline mutation carriers and sporadic pancreatic ductal adenocarcinoma.
        J Am Coll Surg. 2018; 226: 630-637.e1
        • Yu S.
        • Agarwal P.
        • Mamtani R.
        • Symecko H.
        • Spielman K.
        • O’Hara M.
        • et al.
        Retrospective survival analysis of patients with resected pancreatic ductal adenocarcinoma and germline BRCA or PALB2 mutation.
        JCO Precision Oncol. 2019; 3: 1-11https://doi.org/10.1200/PO.18. 00271
        • Golan T.
        • Barenboim A.
        • Lahat G.
        • Nachmany I.
        • Goykhman Y.
        • Shacham-Shmueli E.
        • et al.
        Increased rate of complete pathologic response after neoadjuvant FOLFIRINOX for BRCA mutation carriers with borderline resectable pancreatic cancer.
        Ann Surg Oncol. 2020; 27: 3963-3970
        • Golan T.
        • Sella T.
        • O’Reilly E.M.
        • Katz M.H.G.
        • Epelbaum R.
        • Kelsen D.P.
        • et al.
        Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer.
        Br J Cancer. 2017; 116: 697-702
        • Majidpoor J.
        • Mortezaee K.
        The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives.
        Clin Immunol. 2021; 226: 108707https://doi.org/10.1016/j.clim.2021.108707
        • Li A.
        • Yi M.
        • Qin A.
        • Chu Q.
        • Luo S.
        • Wu K.
        Prospects for combining immune checkpoint blockade with PARP inhibition.
        J Hematol Oncol. 2019; 12: 98https://doi.org/10.1186/s13045-019-0784-8
        • Sato H.
        • Niimi A.
        • Yasuhara T.
        • Permata T.B.M.
        • Hagiwara Y.
        • Isono M.
        • et al.
        DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells.
        Nat Commun. 2017; 8https://doi.org/10.1038/s41467-017-01883-9
        • Jiao S.
        • Xia W.
        • Yamaguchi H.
        • Wei Y.
        • Chen M.-K.
        • Hsu J.-M.
        • et al.
        PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression.
        Clin Cancer Res. 2017; 23: 3711-3720
        • Vinayak S.
        • Tolaney S.M.
        • Schwartzberg L.S.
        • Mita M.M.
        • McCann G.-L.
        • Tan A.R.
        • et al.
        TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial.
        J Clin Oncol. 2018; 36: 1011
        • Domchek S.M.
        • Postel-Vinay S.
        • Im S.-A.
        • Park Y.H.
        • Delord J.-P.
        • Italiano A.
        • et al.
        Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.
        Lancet Oncol. 2020; 21: 1155-1164
      5. Drew Y, Kaufman B, Banerjee S, Park YH, Delord J, Italiano A, et al. Phase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). Ann Oncol 2019; 30: Suppl 5: v485-v486, ISSN 0923-7534, doi.org/10.1093/annonc/mdz253.016.

        • Goel S.
        • DeCristo M.J.
        • Watt A.C.
        • BrinJones H.
        • Sceneay J.
        • Li B.B.
        • et al.
        CDK4/6 inhibition triggers antitumour immunity.
        Nature. 2017; 548: 471-475
      6. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget 2014; 5: 6512–25.

        • Dall'Acqua A.
        • Sonego M.
        • Pellizzari I.
        • Pellarin I.
        • Canzonieri V.
        • D'Andrea S.
        • et al.
        CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation.
        EMBO Mol Med. 2017; 9: 1415-1433
        • Kumarasamy V.
        • Ruiz A.
        • Nambiar R.
        • Witkiewicz A.K.
        • Knudsen E.S.
        Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer.
        Oncogene. 2020; 39: 1831-1845
        • Salvador-Barbero B.
        • Álvarez-Fernández M.
        • Zapatero-Solana E.
        • El Bakkali A.
        • Menéndez M.D.C.
        • López-Casas P.P.
        • et al.
        CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma.
        Cancer Cell. 2020; 37: 340-353.e6
        • Sakai W.
        • Swisher E.M.
        • Karlan B.Y.
        • Agarwal M.K.
        • Higgins J.
        • Friedman C.
        • et al.
        Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancer.
        Nature. 2008; 451: 1116-1120
        • Norquist B.
        • Wurz K.A.
        • Pennil C.C.
        • Garcia R.
        • Gross J.
        • Sakai W.
        • et al.
        Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas.
        JCO. 2011; 29: 3008-3015
        • Wang Y.
        • Park J.Y.P.
        • Pacis A.
        • Denroche R.E.
        • Jang G.H.
        • Zhang A.
        • et al.
        A preclinical trial and molecularly annotated patient cohort identify predictive biomarkers in homologous recombination-deficient pancreatic cancer.
        Clin Cancer Res. 2020; 26: 5462-5476
        • Chand S.
        • O'Hayer K.
        • Blanco F.F.
        • Winter J.M.
        • Brody J.R.
        The landscape of pancreatic cancer therapeutic resistance mechanisms.
        Int J Biol Sci. 2016; 12: 273-282
        • Tobalina L.
        • Armenia J.
        • Irving E.
        • O'Connor M.J.
        • Forment J.V.
        A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance.
        Ann Oncol. 2021; 32: 103-112
        • Pettitt S.J.
        • Frankum J.R.
        • Punta M.
        • Lise S.
        • Alexander J.
        • Chen Y.i.
        • et al.
        Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance.
        Cancer Discov. 2020; 10: 1475-1488
        • Lal S.
        • Burkhart R.A.
        • Beeharry N.
        • Bhattacharjee V.
        • Londin E.R.
        • Cozzitorto J.A.
        • et al.
        HuR posttranscriptionally regulates WEE1: implications for the DNA damage response in pancreatic cancer cells.
        Cancer Res. 2014; 74: 1128-1140
        • Dréan A.
        • Williamson C.T.
        • Brough R.
        • Brandsma I.
        • Menon M.
        • Konde A.
        • et al.
        Modeling therapy resistance in BRCA1/2-mutant cancers.
        Mol Cancer Ther. 2017; 16: 2022-2034
        • Yadav S.
        • Kasi P.M.
        • Bamlet W.R.
        • Ho T.P.
        • Polley E.C.
        • Hu C.
        • et al.
        Effect of germline mutations in homologous recombination repair genes on overall survivall of patients with pancreatic adenocarcinoma.
        Clin Cancer Res. 2020; 26: 6505-6512