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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

Open Access 01-12-2020 | Pathology | Review

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Authors: Claudio Luchini, Gaetano Paolino, Paola Mattiolo, Maria L. Piredda, Alessandro Cavaliere, Marina Gaule, Davide Melisi, Roberto Salvia, Giuseppe Malleo, Jae Il Shin, Sarah Cargnin, Salvatore Terrazzino, Rita T. Lawlor, Michele Milella, Aldo Scarpa

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.
The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.
This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
2.
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;74:2913–21.CrossRef
3.
Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet. 2016;388:73–85.CrossRef
4.
Luchini C, Capelli P, Scarpa A. Pancreatic ductal adenocarcinoma and its variants. Surg Pathol Clin. 2016;9:547–60.CrossRef
5.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.CrossRef
6.
7.
Herbst B, Zheng L. Precision medicine in pancreatic cancer: treating every patient as an exception. Lancet Gastroenterol Hepatol. 2019;4:805–10.CrossRef
8.
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.CrossRef
9.
Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.CrossRef
10.
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.CrossRef
11.
Singhi AD, George B, Greenbowe JR, Chung J, Suh J, Maitra A, 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;156:2242–53 e4.CrossRef
12.
Luchini C, Veronese N, Nottegar A, Cappelletti V, Daidone MG, Smith L, Parris C, Brosens LAA, Caruso MG, Cheng L, Wolfgang CL, Wood LD, MilellaM, Salvia R, Scarpa A. Liquid biopsy as surrogate for tissue for molecular profiling in pancreatic cancer: A meta-analysis towards precision medicine. Cancers (Basel). 2019;11:1152.
13.
Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50:2072–81.CrossRef
14.
Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018;143:2053–64.CrossRef
15.
Van Laethem JL, Riess H, Jassem J, Haas M, Martens UM, Weekes C, et al. Phase I/II study of refametinib (BAY 86–9766) in combination with gemcitabine in advanced pancreatic cancer. Target Oncol. 2017;12:97–109.CrossRef
16.
Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Investig New Drugs. 2012;30:1216–23.CrossRef
17.
Dueland S, Valle JW, Bell K, Faluyi O, Staiger H, Gjertsen TJ, et al. TG01/GM-CSF and adjuvant gemcitabine in patients with resected RAS-mutant adenocarcinoma of the pancreas. Ann Oncol. 2017;28:v227–8.CrossRef
18.
Eriksen JA, Gladhaug IP, Rosseland A, Risberg Handeland K, Buanes T. An observational clinical study with RAS peptide vaccine TG01 evaluating immune response, safety and overall survival in patients with non-resectable pancreatic cancer. Ann Oncol. 2017;28:v409–10.CrossRef
19.
Richards D, Muscarella P, Bekaii-Saab T, Wilfong L, Rosemurgy A, Ross S, et al. A phase 2 adjuvant trial of GI-4000 plus gemcitabine vs. gemcitabine alone in ras+ patients with resected pancreas cancer: R1 subgroup analysis. Ann Oncol. 2012;23:iv5.CrossRef
20.
Weden S, Klemp M, Gladhaug IP, Moller M, Eriksen JA, Gaudernack G, et al. Long term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011;128:1120–8.CrossRef
21.
Singh RR, Goldberg J, Varghese AM, Yu KH, Park W, O'Reilly EM. Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: a scoping review. Cancer Treat Rev. 2019;75:27–38.CrossRef
22.
Laheru D, Shah P, Rajeshkumar NV, McAllister F, Taylor G, Goldsweig H, et al. Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer. Investig New Drugs. 2012;30:2391–9.CrossRef
23.
Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22:1430–8.CrossRef
24.
Yan Z, Ohuchida K, Fei S, Zheng B, Guan W, Feng H, et al. Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis. J Exp Clin Cancer Res. 2019;38:221.CrossRef
25.
Sun Y, Peng W, He W, Luo M, Chang G, Shen J, et al. Transgelin-2 is a novel target of KRAS-ERK signaling involved in the development of pancreatic cancer. J Exp Clin Cancer Res. 2018;37:166.CrossRef
26.
Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8:a031435.
27.
Kim ST, Lim DH, Jang KT, Lim T, Lee J, Choi YL, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10:1993–9.CrossRef
28.
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;9:1–10.CrossRef
29.
Mottini C, Tomihara H, Carrella D, Lamolinara A, Iezzi M, Huang JK, et al. Predictive signatures inform the effective repurposing of Decitabine to treat KRAS-dependent pancreatic ductal adenocarcinoma. Cancer Res. 2019;79:5612–25.CrossRef
30.
Furukawa T. Impacts of activation of the mitogen-activated protein kinase pathway in pancreatic cancer. Front Oncol. 2015;5:23.CrossRef
31.
Thatcher JD. The Ras-MAPK signal transduction pathway. Sci Signal. 2010;3:tr1.
32.
Gibbs JB, Sigal IS, Poe M, Scolnick EM. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci U S A. 1984;81:5704–8.CrossRef
33.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRef
34.
Milella M, Falcone I, Conciatori F, Matteoni S, Sacconi A, De Luca T, et al. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Sci Rep. 2017;7:43013.CrossRef
35.
Ciuffreda L, Del Curatolo A, Falcone I, Conciatori F, Bazzichetto C, Cognetti F, et al. Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer. Ann Oncol. 2017;28:2896–8.CrossRef
36.
Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, et al. Effect of Selumetinib and MK-2206 vs Oxaliplatin and fluorouracil in patients with metastatic pancreatic Cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3:516–22.CrossRef
37.
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911–2.CrossRef
38.
Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. Nuclear translocation of p42/p44 mitogen activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J. 1999;18:664–74.CrossRef
39.
Pishvaian MJ, Bender RJ, Halverson D, Rahib L, Hendifar AE, Mikhail S, et al. Molecular profiling of patients with pancreatic cancer: initial results from the know your tumor initiative. Clin Cancer Res. 2018;24:5018–27.CrossRef
40.
Wrzeszczynski KO, Rahman S, Frank MO, Arora K, Shah M, Geiger H, Felice V, Manaa D, Dikoglu E, Khaira D, Chimpiri AR, Michelini VV, JobanputraV, Darnell RB, Powers S, Choi M. 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:a004424.
41.
Del Curatolo A, Conciatori F, Cesta Incani U, Bazzichetto C, Falcone I, Corbo V, et al. Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. J Exp Clin Cancer Res. 2018;37:140.CrossRef
42.
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol. 2000;156:1641–51.CrossRef
43.
Lupinacci RM, Bachet JB, André T, Duval A, Svrcek M. Pancreatic ductal adenocarcinoma harboring microsatellite instability / DNA mismatch repair deficiency. Towards personalized medicine. Surg Oncol. 2019;28:121–7.CrossRef
44.
45.
Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019;30:1232–43.CrossRef
46.
Middha S, Zhang L, Nafa K, Jayakumaran G, Wong D, Kim HR, Sadowska J, Berger MF, Delair DF, Shia J, Stadler Z, Klimstra DS, Ladanyi M, Zehir A, Hechtman JF. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data. JCO Precis Oncol. 2017;2017:PO.17.00084.
47.
Salipante SJ, Scroggins SM, Hampel HL, Turner EH, Pritchard CC. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60:1192–9.CrossRef
48.
Humphris JL, Patch AM, Nones K, Bailey PJ, Johns AL, McKay S, et al. Hypermutation in pancreatic Cancer. Gastroenterology. 2017;152:68–74 e2.CrossRef
49.
Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J, et al. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16:805–12.CrossRef
50.
Hu ZI, Shia J, Stadler ZK, Varghese AM, Capanu M, Salo-Mullen E, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res. 2018;24:1326–36.CrossRef
51.
Lupinacci RM, Goloudina A, Buhard O, Bachet JB, Maréchal R, Demetter P, et al. Prevalence of microsatellite instability in Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2018;154:1061–5.CrossRef
52.
Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nyström-Lahti M, Pylkkänen L, et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res. 1993;53:5849–52.PubMed
53.
Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51.CrossRef
54.
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRef
55.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.CrossRef
56.
Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.CrossRef
57.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.CrossRef
58.
Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient Cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1–10.CrossRef
59.
Singhi AD, Ali SM, Lacy J, Hendifar A, Nguyen K, Koo J, et al. Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma. J Natl Compr Cancer Netw. 2017;15:555–62.CrossRef
60.
Pishvaian MJ, Rolfo CD, Liu SV, Multani PS, Maneval EC, Garrido-Laguna I. Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions. J Clin Oncol. 2018;36(4_suppl):521.
61.
Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4:1398–405.CrossRef
62.
Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M, et al. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov. 2018;8:1096–111.CrossRef
63.
Jonna S, Feldman RA, Swensen J, Gatalica Z, Korn WM, Borghaei H, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25:4966–72.CrossRef
64.
Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012;12:553–63.CrossRef
65.
Jones MR, Williamson LM, Topham JT, Lee MK, Goytain A, Ho J, et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin Cancer Res. 2019;25:4674–81.PubMed
66.
Heining C, Horak P, Uhrig S, Codo PL, Klink B, Hutter B, et al. NRG1 fusions in KRAS wild-type pancreatic Cancer. Cancer Discov. 2018;8:1087–95.CrossRef
67.
Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A, et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov. 2018;8:686–95.CrossRef
68.
Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, et al. Next-generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. J Clin Oncol. 2014;32:e63–6.CrossRef
69.
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance Olaparib for Germline BRCA-mutated metastatic pancreatic Cancer. N Engl J Med. 2019;381:317–27.CrossRef
70.
Tang M, Chen J, Goldstein D, Links M, Lord S, Marschner I, et al. Evaluation of phase II trial Design in Advanced Pancreatic Cancer. Pancreas. 2019;48:1274–84.CrossRef
71.
Di Martino MT, Meschini S, Scotlandi K, Riganti C, De Smaele E, Zazzeroni F, et al. From single gene analysis to single cell profiling: a new era for precision medicine. J Exp Clin Cancer Res. 2020;39:48.CrossRef
72.
Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, 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;21:508–18.CrossRef
Metadata
Title
KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities
Authors
Claudio Luchini
Gaetano Paolino
Paola Mattiolo
Maria L. Piredda
Alessandro Cavaliere
Marina Gaule
Davide Melisi
Roberto Salvia
Giuseppe Malleo
Jae Il Shin
Sarah Cargnin
Salvatore Terrazzino
Rita T. Lawlor
Michele Milella
Aldo Scarpa
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01732-6

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