Molecular Features and Targeted Therapy in KRAS wild-type Pancreatic Cancer
Main Article Content
Abstract
KRAS mutation is the major oncogenic event in approximately 90% of pancreatic ductal adenocarcinomas. The subset of patients with KRAS wild-type pancreatic ductal adenocarcinomas represent a distinct subgroup with a higher frequency of actionable genomic alterations. In this review article, we aim at exploring the more frequent molecular alterations found among KRAS wild-type pancreatic ductal adenocarcinomas, their prognostic implications, as well as the potential targetable therapeutic options beyond cytotoxic chemotherapy for this unique subset of patients.
Keywords:
pancreatic cancer, KRAS wild-type, targeted therapy
Article Details
How to Cite
MATHIAS-MACHADO, Maria Cecília et al.
Molecular Features and Targeted Therapy in KRAS wild-type Pancreatic Cancer.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3764>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3764.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921. doi:10.1158/0008-5472.CAN-14-0155
2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. 2023;73(1):17-48. doi:10.3322/caac.21763
3. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/NEJMoa1809775
4. di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220-1229. doi:10.1053/j.gastro.2013.01.071
5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New England Journal of Medicine. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923
6. Von Hoff DD, Ervin T, Arena FP, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369
7. Cancer Genome Atlas Research Network. Electronic address: [email protected], Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. doi:10.1016/j.ccell.2017.07.007
8. Varghese AM, Singh I, Singh R, et al. Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes. J Natl Cancer Inst. 2021;113(9):1194-1202. doi:10.1093/jnci/djab038
9. Singhi AD, George B, Greenbowe JR, et al. Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers. Gastroenterology. 2019;156(8):2242-2253.e4. doi:10.1053/j.gastro.2019.02.037
10. Philip PA, Azar I, Xiu J, et al. Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma. Clin Cancer Res. 2022;28(12):2704-2714. doi:10.1158/1078-0432.CCR-21-3581
11. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7
12. Bernards A, Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell Biol. 2004;14(7):377-385. doi:10.1016/j.tcb.2004.05.003
13. Sinicrope FA, Okamoto K, Kasi PM, Kawakami H. Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer. Clin Gastroenterol Hepatol. 2016;14(5):651-658. doi:10.1016/j.cgh.2016.02.008
14. Qian ZR, Rubinson DA, Nowak JA, et al. Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2018;4(3):e173420. doi:10.1001/jamaoncol.2017.3420
15. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17(3):153-168. doi:10.1038/s41575-019-0245-4
16. Isler JA, Vesterqvist OE, Burczynski ME. Analytical validation of genotyping assays in the biomarker laboratory. Pharmacogenomics. 2007;8(4):353-368. doi:10.2217/14622416.8.4.353
17. Lin MT, Mosier SL, Thiess M, et al. Clinical Validation of KRAS, BRAF, and EGFR Mutation Detection Using Next-Generation Sequencing. American Journal of Clinical Pathology. 2014;141(6):856-866. doi:10.1309/AJCPMWGWGO34EGOD
18. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. doi:10.1016/j.ctrv.2010.07.008
19. How Kit A, Mazaleyrat N, Daunay A, Nielsen HM, Terris B, Tost J. Sensitive detection of KRAS mutations using enhanced-ice-COLD-PCR mutation enrichment and direct sequence identification. Hum Mutat. 2013;34(11):1568-1580. doi:10.1002/humu.22427
20. Dong L, Wang S, Fu B, Wang J. Evaluation of droplet digital PCR and next generation sequencing for characterizing DNA reference material for KRAS mutation detection. Sci Rep. 2018;8(1):9650. doi:10.1038/s41598-018-27368-3
21. Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Molecular Cancer. 2021;20(1):143. doi:10.1186/s12943-021-01441-4
22. Cross J. DxS Ltd. Pharmacogenomics. 2008;9(4):463-467. doi:10.2217/14622416.9.4.463
23. Fariña Sarasqueta A, Moerland E, de Bruyne H, et al. SNaPshot and StripAssay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J Mol Diagn. 2011;13(2):199-205. doi:10.1016/j.jmoldx.2010.10.006
24. Gonzalez de Castro D, Angulo B, Gomez B, et al. A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens. Br J Cancer. 2012;107(2):345-351. doi:10.1038/bjc.2012.259
25. Harlé A, Filhine-Tresarrieu P, Husson M, et al. Rare RAS Mutations in Metastatic Colorectal Cancer Detected During Routine RAS Genotyping Using Next Generation Sequencing. Targ Oncol. 2016;11(3):363-370. doi:10.1007/s11523-015-0404-7
26. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev. 2020;39(4):1029-1038. doi:10.1007/s10555-020-09915-5
27. Khalid A, Dewitt J, Ohori NP, et al. EUS-FNA mutational analysis in differentiating autoimmune pancreatitis and pancreatic cancer. Pancreatology. 2011;11(5):482-486. doi:10.1159/000331505
28. Fuccio L, Hassan C, Laterza L, et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc. 2013;78(4):596-608. doi:10.1016/j.gie.2013.04.162
29. Pietrasz D, Pécuchet N, Garlan F, et al. Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker. Clin Cancer Res. 2017;23(1):116-123. doi:10.1158/1078-0432.CCR-16-0806
30. Kinugasa H, Nouso K, Miyahara K, et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015;121(13):2271-2280. doi:10.1002/cncr.29364
31. Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20(2):71-88. doi:10.1038/s41576-018-0071-5
32. Kim ST, Lim DH, Jang KT, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10(10):1993-1999. doi:10.1158/1535-7163.MCT-11-0269
33. Windon AL, Loaiza-Bonilla A, Jensen CE, Randall M, Morrissette JJD, Shroff SG. A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J Gastrointest Oncol. 2018;9(1):1-10. doi:10.21037/jgo.2017.10.14
34. Dai M, Jahanzaib R, Liao Y, et al. Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection. Front Oncol. 2022;12:1074538. doi:10.3389/fonc.2022.1074538
35. Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer. 2016;54:75-83. doi:10.1016/j.ejca.2015.11.012
36. Bournet B, Muscari F, Buscail C, et al. KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma. Clin Transl Gastroenterol. 2016;7(3):e157. doi:10.1038/ctg.2016.18
37. Lee B, Lipton L, Cohen J, et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. Ann Oncol. 2019;30(9):1472-1478. doi:10.1093/annonc/mdz200
38. Luchini C, Paolino G, Mattiolo P, et al. KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities. Journal of Experimental & Clinical Cancer Research. 2020;39(1):227. doi:10.1186/s13046-020-01732-6
39. Furukawa T. Impacts of activation of the mitogen-activated protein kinase pathway in pancreatic cancer. Front Oncol. 2015;5:23. doi:10.3389/fonc.2015.00023
40. Wilentz RE, Goggins M, Redston M, et al. Genetic, Immunohistochemical, and Clinical Features of Medullary Carcinoma of the Pancreas. Am J Pathol. 2000;156(5):1641-1651.
41. Luchini C, Brosens LAA, Wood LD, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut. 2021;70(1):148-156. doi:10.1136/gutjnl-2020-320726
42. Lupinacci RM, Goloudina A, Buhard O, et al. Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. Gastroenterology. 2018;154(4):1061-1065. doi:10.1053/j.gastro.2017.11.009
43. Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor receptor in pancreatic cancer. Cancers (Basel). 2011;3(2):1513-1526. doi:10.3390/cancers3021513
44. Lee J, Jang KT, Ki CS, et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007;109(8):1561-1569. doi:10.1002/cncr.22559
45. Kwak EL, Jankowski J, Thayer SP, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res. 2006;12(14 Pt 1):4283-4287. doi:10.1158/1078-0432.CCR-06-0189
46. Price KS, Kiedrowski LA, De Zarraga FI, Cusnir M, Lanman RB, Nagy RJ. The spectrum of activating EGFR mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort. JCO. 2019;37(4_suppl):237-237. doi:10.1200/JCO.2019.37.4_suppl.237
47. Boeck S, Jung A, Laubender RP, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013;108(2):469-476. doi:10.1038/bjc.2012.495
48. Renouf DJ, Tang PA, Hedley D, et al. A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. Eur J Cancer. 2014;50(11):1909-1915. doi:10.1016/j.ejca.2014.04.008
49. Park R, Al-Jumayli M, Miller K, Saeed A, Saeed A. Exceptional response to Erlotinib monotherapy in EGFR Exon 19-deleted, KRAS wild-type, Chemo-refractory advanced pancreatic adenocarcinoma. Cancer Treat Res Commun. 2021;27:100342. doi:10.1016/j.ctarc.2021.100342
50. Patel GK, Perry JB, Abdul-Rahim O, et al. Epidermal growth factor receptor-activating mutation(E746_T751>VP) in pancreatic ductal adenocarcinoma responds to erlotinib, followed by epidermal growth factor receptor resistance-mediating mutation (A647T): A case report and literature review. J Cancer Res Ther. 2020;16(4):950-954. doi:10.4103/jcrt.JCRT_729_18
51. Wang JP, Wu CY, Yeh YC, et al. Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial. Oncotarget. 2015;6(20):18162-18173. doi:10.18632/oncotarget.4216
52. Schultheis B, Reuter D, Ebert MP, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen inKRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Annals of Oncology. 2017;28(10):2429-2435. doi:10.1093/annonc/mdx343
53. Qin S, Bai Y, Wang Z, et al. Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. Journal of Clinical Oncology. 2022;40(17):LBA4011-LBA4011.
54. Han SH, Ryu KH, Kwon AY. The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma-HER2 Protein and Gene in Pancreatic Cancer. Diagnostics (Basel). 2021;11(4):653. doi:10.3390/diagnostics11040653
55. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033-1038. doi:10.1038/bjc.2012.18
56. Aumayr K, Soleiman A, Sahora K, et al. HER2 gene amplification and protein expression in pancreatic ductal adenocarcinomas. Appl Immunohistochem Mol Morphol. 2014;22(2):146-152. doi:10.1097/PAI.0b013e31828dc392
57. Li X, Zhao H, Gu J, Zheng L. Prognostic role of HER2 amplification based on fluorescence in situ hybridization (FISH) in pancreatic ductal adenocarcinoma (PDAC): a meta-analysis. World J Surg Oncol. 2016;14(1):38. doi:10.1186/s12957-016-0792-x
58. Chou A, Waddell N, Cowley MJ, et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 2013;5(8):78. doi:10.1186/gm482
59. Assenat E, Mineur L, Mollevi C, et al. Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1). Int J Cancer. 2021;148(3):682-691. doi:10.1002/ijc.33225
60. Safran H, Miner T, Bahary N, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol. 2011;34(1):50-52. doi:10.1097/coc.0b013e3181d26b01
61. McDermott RS, Calvert P, Parker M, Webb G, Moulton B, McCaffrey J. A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39). JCO. 2011;29(4_suppl):315-315. doi:10.1200/jco.2011.29.4_suppl.315
62. King DA, Smith AR, Pineda G, et al. Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling. Published online December 21, 2021:2021.12.16.21267326. doi:10.1101/2021.12.16.21267326
63. Meric-Bernstam F, Hainsworth J, Bose R, et al. MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. JCO. 2021;39(15_suppl):3004-3004. doi:10.1200/JCO.2021.39.15_suppl.3004
64. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014
65. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107(7):1039-1046. doi:10.1111/cas.12966
66. Feng K, Liu Y, Guo Y, et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell. 2018;9(10):838-847. doi:10.1007/s13238-017-0440-4
67. Ramakrishnan G, Parajuli P, Singh P, et al. NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma. Cell Rep. 2022;41(6):111623. doi:10.1016/j.celrep.2022.111623
68. Garrouche N, Ben Abdallah A, Arifa N, et al. Spectrum of gastrointestinal lesions of neurofibromatosis type 1: a pictorial review. Insights Imaging. 2018;9(5):661-671. doi:10.1007/s13244-018-0648-8
69. Dombi E, Baldwin A, Marcus LJ, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016;375(26):2550-2560. doi:10.1056/NEJMoa1605943
70. de Blank PMK, Gross AM, Akshintala S, et al. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol. 2022;24(11):1845-1856. doi:10.1093/neuonc/noac165
71. Ross JS, Wang K, Chmielecki J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer. 2016;138(4):881-890. doi:10.1002/ijc.29825
72. Hendifar A, Blais EM, Wolpin B, et al. Retrospective Case Series Analysis of RAF Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies. JCO Precis Oncol. 2021;5:PO.20.00494. doi:10.1200/PO.20.00494
73. Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183-3199. doi:10.1038/s41388-018-0171-x
74. Florou V, Nevala-Plagemann C, Mulvihill S, Garrido-Laguna I. Abstract 817: Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation. Cancer Research. 2020;80(16_Supplement):817. doi:10.1158/1538-7445.AM2020-817
75. Wang Z, He D, Chen C, Liu X, Ke N. Vemurafenib Combined With Trametinib Significantly Benefits the Survival of a Patient With Stage IV Pancreatic Ductal Adenocarcinoma With BRAF V600E Mutation: A Case Report. Front Oncol. 2021;11:801320. doi:10.3389/fonc.2021.801320
76. Li HS, Yang K, Wang Y. Remarkable response of BRAF V600E-mutated metastatic pancreatic cancer to BRAF/MEK inhibition: a case report. Gastroenterol Rep (Oxf). 2022;10:goab031. doi:10.1093/gastro/goab031
77. Sasankan S, Rebuck L, Darrah G, Harari Turquie M, Rabinowitz I. Metastatic Pancreatic Cancer with BRAF and P53 Mutations: Case Report of Therapeutic Response to Doublet Targeted Therapy. Case Rep Oncol. 2020;13(3):1239-1243. doi:10.1159/000510096
78. Seghers AK, Cuyle PJ, Van Cutsem E. Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. Target Oncol. 2020;15(3):407-410. doi:10.1007/s11523-020-00727-9
79. Ardalan B, Azqueta JI, England J, Eatz TA. Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report. Cold Spring Harb Mol Case Stud. 2021;7(5):a006108. doi:10.1101/mcs.a006108
80. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762
81. Wrzeszczynski KO, Rahman S, Frank MO, et al. Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma. Cold Spring Harb Mol Case Stud. 2019;5(6):a004424. doi:10.1101/mcs.a004424
82. Yao Z, Yaeger R, Rodrik-Outmezguine VS, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548(7666):234-238. doi:10.1038/nature23291
83. Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099
84. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study. JCO. 2020;38(4_suppl):1-1. doi:10.1200/JCO.2020.38.4_suppl.1
85. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi:10.1126/science.aan6733
86. Andre T, Berton D, Curigliano G, et al. Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study. JCO. 2022;40(16_suppl):2587-2587. doi:10.1200/JCO.2022.40.16_suppl.2587
87. Chakrabarti S, Bucheit L, Starr JS, et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer. 2022;10(6):e004485. doi:10.1136/jitc-2021-004485
88. Riazy M, Kalloger SE, Sheffield BS, et al. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Mod Pathol. 2015;28(10):1383-1389. doi:10.1038/modpathol.2015.89
89. Heining C, Horak P, Uhrig S, et al. NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. Cancer Discov. 2018;8(9):1087-1095. doi:10.1158/2159-8290.CD-18-0036
90. Jones MR, Williamson LM, Topham JT, et al. NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191
91. O’Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019;30(Suppl_8):viii36-viii40. doi:10.1093/annonc/mdz385
92. Pishvaian MJ, Garrido-Laguna I, Liu SV, Multani PS, Chow-Maneval E, Rolfo C. Entrectinib in TRK and ROS1 Fusion-Positive Metastatic Pancreatic Cancer. JCO Precision Oncology. 2018;(2):1-7. doi:10.1200/PO.18.00039
93. Philip PA, Xiu J, Hall MJ, et al. Enrichment of alterations in targetable molecular pathways in KRAS wild-type (WT) pancreatic cancer (PC). JCO. 2020;38(15_suppl):4629-4629. doi:10.1200/JCO.2020.38.15_suppl.4629
94. Fusco MJ, Saeed-Vafa D, Carballido EM, et al. Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer. JCO Precis Oncol. 2021;5:PO.20.00265. doi:10.1200/PO.20.00265
95. Uhrig S, Ellermann J, Walther T, et al. Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res. 2021;31(3):448-460. doi:10.1101/gr.257246.119
96. Berlin J, Hong DS, Deeken JF, et al. Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer. JCO. 2020;38(4_suppl):824-824. doi:10.1200/JCO.2020.38.4_suppl.824
97. Patel M, Siena S, Demetri G, et al. O-3 Efficacy and safety of entrectinib in NTRK fusion-positive gastrointestinal cancers: Updated integrated analysis of three clinical trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Annals of Oncology. 2020;31:232-233. doi:10.1016/j.annonc.2020.04.056
98. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
99. Hong DS, Shen L, van Tilburg CM, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. JCO. 2021;39(15_suppl):3108-3108. doi:10.1200/JCO.2021.39.15_suppl.3108
100. Demetri GD, De Braud F, Drilon A, et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors. Clin Cancer Res. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597
101. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. Published online September 28, 2021:jclinpath-2021-207781. doi:10.1136/jclinpath-2021-207781
102. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-2394. doi:10.1056/NEJMoa1214886
103. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795
104. Singhi AD, Ali SM, Lacy J, et al. Identification of Targetable ALK Rearrangements in Pancreatic Ductal Adenocarcinoma. Journal of the National Comprehensive Cancer Network. 2017;15(5):555-562. doi:10.6004/jnccn.2017.0058
105. Ou K, Liu X, Li W, Yang Y, Ying J, Yang L. ALK Rearrangement-Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report. Front Oncol. 2021;11:724815. doi:10.3389/fonc.2021.724815
106. Chou A, Brown IS, Kumarasinghe MP, et al. RET gene rearrangements occur in a subset of pancreatic acinar cell carcinomas. Mod Pathol. 2020;33(4):657-664. doi:10.1038/s41379-019-0373-y
107. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1
108. Subbiah V, Cassier PA, Siena S, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022;28(8):1640-1645. doi:10.1038/s41591-022-01931-y
109. Jusakul A, Cutcutache I, Yong CH, et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017;7(10):1116-1135. doi:10.1158/2159-8290.CD-17-0368
110. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1
111. Hollebecque A., M. Borad, L. Goyal, A. Schram, A. Schram. LBA12 - Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Annals of Oncology. 2022;33(suppl_7):S808-S869.
112. Subbiah V, Iannotti NO, Gutierrez M, et al. FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Ann Oncol. 2022;33(5):522-533. doi:10.1016/j.annonc.2022.02.001
113. Poon D, Tan MH, Khor D. Stage 4 pancreatic adenocarcinoma harbouring an FGFR2-TACC2 fusion mutation with complete response to erdafitinib a pan-fibroblastic growth factor receptor inhibitor. BMJ Case Rep. 2021;14(9):e244271. doi:10.1136/bcr-2021-244271
114. Ng CF, Glaspy J, Placencio-Hickok VR, et al. Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma. J Natl Compr Canc Netw. 2022;20(10):1076-1079. doi:10.6004/jnccn.2022.7039
115. Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020;31(12):1693-1703. doi:10.1016/j.annonc.2020.08.2335
116. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. JCO. 2021;39(15_suppl):3003-3003. doi:10.1200/JCO.2021.39.15_suppl.3003
117. Ghosh T, Greipp PT, Knutson D, et al. BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation. Arch Pathol Lab Med. 2022;146(7):840-845. doi:10.5858/arpa.2020-0739-OA
118. Chmielecki J, Hutchinson KE, Frampton GM, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-1405. doi:10.1158/2159-8290.CD-14-0617
119. Heydt C, Wölwer CB, Velazquez Camacho O, et al. Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation. BMC Med Genomics. 2021;14(1):62. doi:10.1186/s12920-021-00909-y
120. Gonzalez D, Stenzinger A. Homologous recombination repair deficiency (HRD): From biology to clinical exploitation. Genes Chromosomes Cancer. 2021;60(5):299-302. doi:10.1002/gcc.22939
121. Park W, Chen J, Chou JF, et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin Cancer Res. 2020;26(13):3239-3247. doi:10.1158/1078-0432.CCR-20-0418
122. O’Kane GM, Lowery MA. Moving the Needle on Precision Medicine in Pancreatic Cancer. JCO. 2022;40(24):2693-2705. doi:10.1200/JCO.21.02514
123. Zhu H, Wei M, Xu J, et al. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications. Mol Cancer. 2020;19(1):49. doi:10.1186/s12943-020-01167-9
124. Couch FJ, Johnson MR, Rabe KG, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2007;16(2):342-346. doi:10.1158/1055-9965.EPI-06-0783
125. Casolino R, Paiella S, Azzolina D, et al. Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis. JCO. 2021;39(23):2617-2631. doi:10.1200/JCO.20.03238
126. Salem ME, Marshall J, Feldman R, et al. Comparative molecular analyses of pancreatic cancer (PC): KRAS wild type vs. KRAS mutant tumors and primary tumors vs. distant metastases. JCO. 2016;34(15_suppl):4121-4121. doi:10.1200/JCO.2016.34.15_suppl.4121
127. Golan T, Sella T, O’Reilly EM, et al. Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. Br J Cancer. 2017;116(6):697-702. doi:10.1038/bjc.2017.19
128. Wattenberg MM, Asch D, Yu S, et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. 2020;122(3):333-339. doi:10.1038/s41416-019-0582-7
129. O’Reilly EM, Lee JW, Zalupski M, 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(13):1378-1388. doi:10.1200/JCO.19.02931
130. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387
131. Reiss KA, Mick R, O’Hara MH, 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(22):2497-2505. doi:10.1200/JCO.21.00003
132. Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19-26. doi:10.1016/j.ejca.2017.11.004
133. Javle M, Shacham-Shmueli E, Xiao L, et al. Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants. JAMA Oncol. 2021;7(5):693-699. doi:10.1001/jamaoncol.2021.0006
2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer Journal for Clinicians. 2023;73(1):17-48. doi:10.3322/caac.21763
3. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/NEJMoa1809775
4. di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220-1229. doi:10.1053/j.gastro.2013.01.071
5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New England Journal of Medicine. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923
6. Von Hoff DD, Ervin T, Arena FP, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369
7. Cancer Genome Atlas Research Network. Electronic address: [email protected], Cancer Genome Atlas Research Network. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. doi:10.1016/j.ccell.2017.07.007
8. Varghese AM, Singh I, Singh R, et al. Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes. J Natl Cancer Inst. 2021;113(9):1194-1202. doi:10.1093/jnci/djab038
9. Singhi AD, George B, Greenbowe JR, et al. Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers. Gastroenterology. 2019;156(8):2242-2253.e4. doi:10.1053/j.gastro.2019.02.037
10. Philip PA, Azar I, Xiu J, et al. Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma. Clin Cancer Res. 2022;28(12):2704-2714. doi:10.1158/1078-0432.CCR-21-3581
11. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7
12. Bernards A, Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell Biol. 2004;14(7):377-385. doi:10.1016/j.tcb.2004.05.003
13. Sinicrope FA, Okamoto K, Kasi PM, Kawakami H. Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer. Clin Gastroenterol Hepatol. 2016;14(5):651-658. doi:10.1016/j.cgh.2016.02.008
14. Qian ZR, Rubinson DA, Nowak JA, et al. Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2018;4(3):e173420. doi:10.1001/jamaoncol.2017.3420
15. Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17(3):153-168. doi:10.1038/s41575-019-0245-4
16. Isler JA, Vesterqvist OE, Burczynski ME. Analytical validation of genotyping assays in the biomarker laboratory. Pharmacogenomics. 2007;8(4):353-368. doi:10.2217/14622416.8.4.353
17. Lin MT, Mosier SL, Thiess M, et al. Clinical Validation of KRAS, BRAF, and EGFR Mutation Detection Using Next-Generation Sequencing. American Journal of Clinical Pathology. 2014;141(6):856-866. doi:10.1309/AJCPMWGWGO34EGOD
18. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. doi:10.1016/j.ctrv.2010.07.008
19. How Kit A, Mazaleyrat N, Daunay A, Nielsen HM, Terris B, Tost J. Sensitive detection of KRAS mutations using enhanced-ice-COLD-PCR mutation enrichment and direct sequence identification. Hum Mutat. 2013;34(11):1568-1580. doi:10.1002/humu.22427
20. Dong L, Wang S, Fu B, Wang J. Evaluation of droplet digital PCR and next generation sequencing for characterizing DNA reference material for KRAS mutation detection. Sci Rep. 2018;8(1):9650. doi:10.1038/s41598-018-27368-3
21. Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Molecular Cancer. 2021;20(1):143. doi:10.1186/s12943-021-01441-4
22. Cross J. DxS Ltd. Pharmacogenomics. 2008;9(4):463-467. doi:10.2217/14622416.9.4.463
23. Fariña Sarasqueta A, Moerland E, de Bruyne H, et al. SNaPshot and StripAssay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J Mol Diagn. 2011;13(2):199-205. doi:10.1016/j.jmoldx.2010.10.006
24. Gonzalez de Castro D, Angulo B, Gomez B, et al. A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens. Br J Cancer. 2012;107(2):345-351. doi:10.1038/bjc.2012.259
25. Harlé A, Filhine-Tresarrieu P, Husson M, et al. Rare RAS Mutations in Metastatic Colorectal Cancer Detected During Routine RAS Genotyping Using Next Generation Sequencing. Targ Oncol. 2016;11(3):363-370. doi:10.1007/s11523-015-0404-7
26. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev. 2020;39(4):1029-1038. doi:10.1007/s10555-020-09915-5
27. Khalid A, Dewitt J, Ohori NP, et al. EUS-FNA mutational analysis in differentiating autoimmune pancreatitis and pancreatic cancer. Pancreatology. 2011;11(5):482-486. doi:10.1159/000331505
28. Fuccio L, Hassan C, Laterza L, et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc. 2013;78(4):596-608. doi:10.1016/j.gie.2013.04.162
29. Pietrasz D, Pécuchet N, Garlan F, et al. Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker. Clin Cancer Res. 2017;23(1):116-123. doi:10.1158/1078-0432.CCR-16-0806
30. Kinugasa H, Nouso K, Miyahara K, et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015;121(13):2271-2280. doi:10.1002/cncr.29364
31. Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20(2):71-88. doi:10.1038/s41576-018-0071-5
32. Kim ST, Lim DH, Jang KT, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10(10):1993-1999. doi:10.1158/1535-7163.MCT-11-0269
33. Windon AL, Loaiza-Bonilla A, Jensen CE, Randall M, Morrissette JJD, Shroff SG. A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J Gastrointest Oncol. 2018;9(1):1-10. doi:10.21037/jgo.2017.10.14
34. Dai M, Jahanzaib R, Liao Y, et al. Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection. Front Oncol. 2022;12:1074538. doi:10.3389/fonc.2022.1074538
35. Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer. 2016;54:75-83. doi:10.1016/j.ejca.2015.11.012
36. Bournet B, Muscari F, Buscail C, et al. KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma. Clin Transl Gastroenterol. 2016;7(3):e157. doi:10.1038/ctg.2016.18
37. Lee B, Lipton L, Cohen J, et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. Ann Oncol. 2019;30(9):1472-1478. doi:10.1093/annonc/mdz200
38. Luchini C, Paolino G, Mattiolo P, et al. KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities. Journal of Experimental & Clinical Cancer Research. 2020;39(1):227. doi:10.1186/s13046-020-01732-6
39. Furukawa T. Impacts of activation of the mitogen-activated protein kinase pathway in pancreatic cancer. Front Oncol. 2015;5:23. doi:10.3389/fonc.2015.00023
40. Wilentz RE, Goggins M, Redston M, et al. Genetic, Immunohistochemical, and Clinical Features of Medullary Carcinoma of the Pancreas. Am J Pathol. 2000;156(5):1641-1651.
41. Luchini C, Brosens LAA, Wood LD, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut. 2021;70(1):148-156. doi:10.1136/gutjnl-2020-320726
42. Lupinacci RM, Goloudina A, Buhard O, et al. Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. Gastroenterology. 2018;154(4):1061-1065. doi:10.1053/j.gastro.2017.11.009
43. Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor receptor in pancreatic cancer. Cancers (Basel). 2011;3(2):1513-1526. doi:10.3390/cancers3021513
44. Lee J, Jang KT, Ki CS, et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007;109(8):1561-1569. doi:10.1002/cncr.22559
45. Kwak EL, Jankowski J, Thayer SP, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res. 2006;12(14 Pt 1):4283-4287. doi:10.1158/1078-0432.CCR-06-0189
46. Price KS, Kiedrowski LA, De Zarraga FI, Cusnir M, Lanman RB, Nagy RJ. The spectrum of activating EGFR mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort. JCO. 2019;37(4_suppl):237-237. doi:10.1200/JCO.2019.37.4_suppl.237
47. Boeck S, Jung A, Laubender RP, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013;108(2):469-476. doi:10.1038/bjc.2012.495
48. Renouf DJ, Tang PA, Hedley D, et al. A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. Eur J Cancer. 2014;50(11):1909-1915. doi:10.1016/j.ejca.2014.04.008
49. Park R, Al-Jumayli M, Miller K, Saeed A, Saeed A. Exceptional response to Erlotinib monotherapy in EGFR Exon 19-deleted, KRAS wild-type, Chemo-refractory advanced pancreatic adenocarcinoma. Cancer Treat Res Commun. 2021;27:100342. doi:10.1016/j.ctarc.2021.100342
50. Patel GK, Perry JB, Abdul-Rahim O, et al. Epidermal growth factor receptor-activating mutation(E746_T751>VP) in pancreatic ductal adenocarcinoma responds to erlotinib, followed by epidermal growth factor receptor resistance-mediating mutation (A647T): A case report and literature review. J Cancer Res Ther. 2020;16(4):950-954. doi:10.4103/jcrt.JCRT_729_18
51. Wang JP, Wu CY, Yeh YC, et al. Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial. Oncotarget. 2015;6(20):18162-18173. doi:10.18632/oncotarget.4216
52. Schultheis B, Reuter D, Ebert MP, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen inKRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Annals of Oncology. 2017;28(10):2429-2435. doi:10.1093/annonc/mdx343
53. Qin S, Bai Y, Wang Z, et al. Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. Journal of Clinical Oncology. 2022;40(17):LBA4011-LBA4011.
54. Han SH, Ryu KH, Kwon AY. The Prognostic Impact of HER2 Genetic and Protein Expression in Pancreatic Carcinoma-HER2 Protein and Gene in Pancreatic Cancer. Diagnostics (Basel). 2021;11(4):653. doi:10.3390/diagnostics11040653
55. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033-1038. doi:10.1038/bjc.2012.18
56. Aumayr K, Soleiman A, Sahora K, et al. HER2 gene amplification and protein expression in pancreatic ductal adenocarcinomas. Appl Immunohistochem Mol Morphol. 2014;22(2):146-152. doi:10.1097/PAI.0b013e31828dc392
57. Li X, Zhao H, Gu J, Zheng L. Prognostic role of HER2 amplification based on fluorescence in situ hybridization (FISH) in pancreatic ductal adenocarcinoma (PDAC): a meta-analysis. World J Surg Oncol. 2016;14(1):38. doi:10.1186/s12957-016-0792-x
58. Chou A, Waddell N, Cowley MJ, et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 2013;5(8):78. doi:10.1186/gm482
59. Assenat E, Mineur L, Mollevi C, et al. Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1). Int J Cancer. 2021;148(3):682-691. doi:10.1002/ijc.33225
60. Safran H, Miner T, Bahary N, et al. Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol. 2011;34(1):50-52. doi:10.1097/coc.0b013e3181d26b01
61. McDermott RS, Calvert P, Parker M, Webb G, Moulton B, McCaffrey J. A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39). JCO. 2011;29(4_suppl):315-315. doi:10.1200/jco.2011.29.4_suppl.315
62. King DA, Smith AR, Pineda G, et al. Complete remission in a patient with widely metastatic HER2-amplified pancreatic adenocarcinoma following multimodal therapy informed by tumor sequencing and organoid profiling. Published online December 21, 2021:2021.12.16.21267326. doi:10.1101/2021.12.16.21267326
63. Meric-Bernstam F, Hainsworth J, Bose R, et al. MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. JCO. 2021;39(15_suppl):3004-3004. doi:10.1200/JCO.2021.39.15_suppl.3004
64. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014
65. Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107(7):1039-1046. doi:10.1111/cas.12966
66. Feng K, Liu Y, Guo Y, et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell. 2018;9(10):838-847. doi:10.1007/s13238-017-0440-4
67. Ramakrishnan G, Parajuli P, Singh P, et al. NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma. Cell Rep. 2022;41(6):111623. doi:10.1016/j.celrep.2022.111623
68. Garrouche N, Ben Abdallah A, Arifa N, et al. Spectrum of gastrointestinal lesions of neurofibromatosis type 1: a pictorial review. Insights Imaging. 2018;9(5):661-671. doi:10.1007/s13244-018-0648-8
69. Dombi E, Baldwin A, Marcus LJ, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016;375(26):2550-2560. doi:10.1056/NEJMoa1605943
70. de Blank PMK, Gross AM, Akshintala S, et al. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol. 2022;24(11):1845-1856. doi:10.1093/neuonc/noac165
71. Ross JS, Wang K, Chmielecki J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer. 2016;138(4):881-890. doi:10.1002/ijc.29825
72. Hendifar A, Blais EM, Wolpin B, et al. Retrospective Case Series Analysis of RAF Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies. JCO Precis Oncol. 2021;5:PO.20.00494. doi:10.1200/PO.20.00494
73. Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183-3199. doi:10.1038/s41388-018-0171-x
74. Florou V, Nevala-Plagemann C, Mulvihill S, Garrido-Laguna I. Abstract 817: Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation. Cancer Research. 2020;80(16_Supplement):817. doi:10.1158/1538-7445.AM2020-817
75. Wang Z, He D, Chen C, Liu X, Ke N. Vemurafenib Combined With Trametinib Significantly Benefits the Survival of a Patient With Stage IV Pancreatic Ductal Adenocarcinoma With BRAF V600E Mutation: A Case Report. Front Oncol. 2021;11:801320. doi:10.3389/fonc.2021.801320
76. Li HS, Yang K, Wang Y. Remarkable response of BRAF V600E-mutated metastatic pancreatic cancer to BRAF/MEK inhibition: a case report. Gastroenterol Rep (Oxf). 2022;10:goab031. doi:10.1093/gastro/goab031
77. Sasankan S, Rebuck L, Darrah G, Harari Turquie M, Rabinowitz I. Metastatic Pancreatic Cancer with BRAF and P53 Mutations: Case Report of Therapeutic Response to Doublet Targeted Therapy. Case Rep Oncol. 2020;13(3):1239-1243. doi:10.1159/000510096
78. Seghers AK, Cuyle PJ, Van Cutsem E. Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. Target Oncol. 2020;15(3):407-410. doi:10.1007/s11523-020-00727-9
79. Ardalan B, Azqueta JI, England J, Eatz TA. Potential benefit of treatment with MEK inhibitors and chemotherapy in BRAF-mutated KRAS wild-type pancreatic ductal adenocarcinoma patients: a case report. Cold Spring Harb Mol Case Stud. 2021;7(5):a006108. doi:10.1101/mcs.a006108
80. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762
81. Wrzeszczynski KO, Rahman S, Frank MO, et al. Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma. Cold Spring Harb Mol Case Stud. 2019;5(6):a004424. doi:10.1101/mcs.a004424
82. Yao Z, Yaeger R, Rodrik-Outmezguine VS, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548(7666):234-238. doi:10.1038/nature23291
83. Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res. 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099
84. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study. JCO. 2020;38(4_suppl):1-1. doi:10.1200/JCO.2020.38.4_suppl.1
85. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi:10.1126/science.aan6733
86. Andre T, Berton D, Curigliano G, et al. Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study. JCO. 2022;40(16_suppl):2587-2587. doi:10.1200/JCO.2022.40.16_suppl.2587
87. Chakrabarti S, Bucheit L, Starr JS, et al. Detection of microsatellite instability-high (MSI-H) by liquid biopsy predicts robust and durable response to immunotherapy in patients with pancreatic cancer. J Immunother Cancer. 2022;10(6):e004485. doi:10.1136/jitc-2021-004485
88. Riazy M, Kalloger SE, Sheffield BS, et al. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Mod Pathol. 2015;28(10):1383-1389. doi:10.1038/modpathol.2015.89
89. Heining C, Horak P, Uhrig S, et al. NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. Cancer Discov. 2018;8(9):1087-1095. doi:10.1158/2159-8290.CD-18-0036
90. Jones MR, Williamson LM, Topham JT, et al. NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191
91. O’Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019;30(Suppl_8):viii36-viii40. doi:10.1093/annonc/mdz385
92. Pishvaian MJ, Garrido-Laguna I, Liu SV, Multani PS, Chow-Maneval E, Rolfo C. Entrectinib in TRK and ROS1 Fusion-Positive Metastatic Pancreatic Cancer. JCO Precision Oncology. 2018;(2):1-7. doi:10.1200/PO.18.00039
93. Philip PA, Xiu J, Hall MJ, et al. Enrichment of alterations in targetable molecular pathways in KRAS wild-type (WT) pancreatic cancer (PC). JCO. 2020;38(15_suppl):4629-4629. doi:10.1200/JCO.2020.38.15_suppl.4629
94. Fusco MJ, Saeed-Vafa D, Carballido EM, et al. Identification of Targetable Gene Fusions and Structural Rearrangements to Foster Precision Medicine in KRAS Wild-Type Pancreatic Cancer. JCO Precis Oncol. 2021;5:PO.20.00265. doi:10.1200/PO.20.00265
95. Uhrig S, Ellermann J, Walther T, et al. Accurate and efficient detection of gene fusions from RNA sequencing data. Genome Res. 2021;31(3):448-460. doi:10.1101/gr.257246.119
96. Berlin J, Hong DS, Deeken JF, et al. Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer. JCO. 2020;38(4_suppl):824-824. doi:10.1200/JCO.2020.38.4_suppl.824
97. Patel M, Siena S, Demetri G, et al. O-3 Efficacy and safety of entrectinib in NTRK fusion-positive gastrointestinal cancers: Updated integrated analysis of three clinical trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Annals of Oncology. 2020;31:232-233. doi:10.1016/j.annonc.2020.04.056
98. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
99. Hong DS, Shen L, van Tilburg CM, et al. Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer. JCO. 2021;39(15_suppl):3108-3108. doi:10.1200/JCO.2021.39.15_suppl.3108
100. Demetri GD, De Braud F, Drilon A, et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors. Clin Cancer Res. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597
101. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. Published online September 28, 2021:jclinpath-2021-207781. doi:10.1136/jclinpath-2021-207781
102. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-2394. doi:10.1056/NEJMoa1214886
103. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2017;377(9):829-838. doi:10.1056/NEJMoa1704795
104. Singhi AD, Ali SM, Lacy J, et al. Identification of Targetable ALK Rearrangements in Pancreatic Ductal Adenocarcinoma. Journal of the National Comprehensive Cancer Network. 2017;15(5):555-562. doi:10.6004/jnccn.2017.0058
105. Ou K, Liu X, Li W, Yang Y, Ying J, Yang L. ALK Rearrangement-Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report. Front Oncol. 2021;11:724815. doi:10.3389/fonc.2021.724815
106. Chou A, Brown IS, Kumarasinghe MP, et al. RET gene rearrangements occur in a subset of pancreatic acinar cell carcinomas. Mod Pathol. 2020;33(4):657-664. doi:10.1038/s41379-019-0373-y
107. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1
108. Subbiah V, Cassier PA, Siena S, et al. Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial. Nat Med. 2022;28(8):1640-1645. doi:10.1038/s41591-022-01931-y
109. Jusakul A, Cutcutache I, Yong CH, et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017;7(10):1116-1135. doi:10.1158/2159-8290.CD-17-0368
110. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1
111. Hollebecque A., M. Borad, L. Goyal, A. Schram, A. Schram. LBA12 - Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Annals of Oncology. 2022;33(suppl_7):S808-S869.
112. Subbiah V, Iannotti NO, Gutierrez M, et al. FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Ann Oncol. 2022;33(5):522-533. doi:10.1016/j.annonc.2022.02.001
113. Poon D, Tan MH, Khor D. Stage 4 pancreatic adenocarcinoma harbouring an FGFR2-TACC2 fusion mutation with complete response to erdafitinib a pan-fibroblastic growth factor receptor inhibitor. BMJ Case Rep. 2021;14(9):e244271. doi:10.1136/bcr-2021-244271
114. Ng CF, Glaspy J, Placencio-Hickok VR, et al. Exceptional Response to Erdafitinib in FGFR2-Mutated Metastatic Pancreatic Ductal Adenocarcinoma. J Natl Compr Canc Netw. 2022;20(10):1076-1079. doi:10.6004/jnccn.2022.7039
115. Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020;31(12):1693-1703. doi:10.1016/j.annonc.2020.08.2335
116. Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. JCO. 2021;39(15_suppl):3003-3003. doi:10.1200/JCO.2021.39.15_suppl.3003
117. Ghosh T, Greipp PT, Knutson D, et al. BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation. Arch Pathol Lab Med. 2022;146(7):840-845. doi:10.5858/arpa.2020-0739-OA
118. Chmielecki J, Hutchinson KE, Frampton GM, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-1405. doi:10.1158/2159-8290.CD-14-0617
119. Heydt C, Wölwer CB, Velazquez Camacho O, et al. Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation. BMC Med Genomics. 2021;14(1):62. doi:10.1186/s12920-021-00909-y
120. Gonzalez D, Stenzinger A. Homologous recombination repair deficiency (HRD): From biology to clinical exploitation. Genes Chromosomes Cancer. 2021;60(5):299-302. doi:10.1002/gcc.22939
121. Park W, Chen J, Chou JF, et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clin Cancer Res. 2020;26(13):3239-3247. doi:10.1158/1078-0432.CCR-20-0418
122. O’Kane GM, Lowery MA. Moving the Needle on Precision Medicine in Pancreatic Cancer. JCO. 2022;40(24):2693-2705. doi:10.1200/JCO.21.02514
123. Zhu H, Wei M, Xu J, et al. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications. Mol Cancer. 2020;19(1):49. doi:10.1186/s12943-020-01167-9
124. Couch FJ, Johnson MR, Rabe KG, et al. The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2007;16(2):342-346. doi:10.1158/1055-9965.EPI-06-0783
125. Casolino R, Paiella S, Azzolina D, et al. Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis. JCO. 2021;39(23):2617-2631. doi:10.1200/JCO.20.03238
126. Salem ME, Marshall J, Feldman R, et al. Comparative molecular analyses of pancreatic cancer (PC): KRAS wild type vs. KRAS mutant tumors and primary tumors vs. distant metastases. JCO. 2016;34(15_suppl):4121-4121. doi:10.1200/JCO.2016.34.15_suppl.4121
127. Golan T, Sella T, O’Reilly EM, et al. Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. Br J Cancer. 2017;116(6):697-702. doi:10.1038/bjc.2017.19
128. Wattenberg MM, Asch D, Yu S, et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. 2020;122(3):333-339. doi:10.1038/s41416-019-0582-7
129. O’Reilly EM, Lee JW, Zalupski M, 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(13):1378-1388. doi:10.1200/JCO.19.02931
130. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387
131. Reiss KA, Mick R, O’Hara MH, 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(22):2497-2505. doi:10.1200/JCO.21.00003
132. Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19-26. doi:10.1016/j.ejca.2017.11.004
133. Javle M, Shacham-Shmueli E, Xiao L, et al. Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline BRCA Variants. JAMA Oncol. 2021;7(5):693-699. doi:10.1001/jamaoncol.2021.0006