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Unusual dMMR Phenotype Locally Advanced Pancreatic Ductal Adenocarcinoma with Germline and Somatic BRCA2 Mutation in a Jehovah Witness Patient

Published:October 23, 2022DOI:https://doi.org/10.1016/j.clcc.2022.10.002

      Clinical Practice Points

      • PDAC is a genetically heterogenous disease with various molecular subtypes which may explain variations in treatment response. Genetic mutations and altered molecular pathways serve as targets in therapy and may improve outcomes.
      • Neoadjuvant systemic therapy with or without radiation followed by evaluation for surgery is an accepted treatment approach for locally advanced disease with the goal of enabling an R0 resection to achieve improved disease-free and overall survival.
      • In many cancers, including pancreatic cancer, MSI is a predictive biomarker for response to immunotherapy, and a prognostic factor for survival. Treatment with neoadjuvant chemoimmunotherapy in this group of patients usually leads to pathologic complete responses.
      • Although rare (15%), an unusual dMMR phenotype, evidenced by discordance between IHC staining of MMR proteins and next gen sequencing, do exist. In this group of patients available data show varying responses to immunotherapy ranging from complete, to partial responses to stable disease.
      • We present successful treatment outcome in a locally advanced PDAC case with dMMR and germline plus somatic BRCA2 mutation treated with available chemotherapy immunotherapy and targeted therapy options.

      Keywords

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      References

      1. Available at: https://www.cancer.org/cancer/pancreatic-cancer/about/key-statistics.html accessed date: 11.12.2022.

        • Iodice S
        • Gandini S
        • Maisonneuve P
        • Lowenfels AB.
        Tobacco and the risk of pancreatic cancer: a review and meta-analysis.
        Langenbecks Arch Surg. 2008; 393: 535-545https://doi.org/10.1007/s00423-007-0266-2
        • Lucenteforte E
        • La Vecchia C
        • Silverman D
        • et al.
        Alcohol consumption and pancreatic cancer; a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).
        Ann Oncol. 2012; 23: 374-382https://doi.org/10.1093/annonc/mdr120
        • Andersen DK
        • Andren-Sandberg Å
        • Duell EJ
        • et al.
        Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop.
        Pancreas. 2013; 42: 1227-1237https://doi.org/10.1097/MPA.0b013e3182a9ad9d
        • Bosetti C
        • Rosato V
        • Li D.
        Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.
        Ann Oncol. 2014; 25: 2065-2072https://doi.org/10.1093/annonc/mdu276
        • Hemminki K
        • Li X.
        Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden.
        Int J Cancer. 2003; 103: 525-530https://doi.org/10.1002/ijc.10863
        • Klein AP
        • Brune KA
        • Petersen GM
        • et al.
        Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
        Cancer Res. 2004; 64: 2634-2638https://doi.org/10.1158/0008-5472.can-03-3823
        • Permuth-Wey J
        • Egan KM.
        Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis.
        Fam Cancer. 2009; 8: 109-117https://doi.org/10.1007/s10689-008-9214-8
        • Giardiello FM
        • Brensinger JD
        • Tersmette AC
        • et al.
        Very high risk of cancer in familial Peutz-Jeghers syndrome.
        Gastroenterology. 2000; 119: 1447-1453https://doi.org/10.1053/gast.2000.20228
        • Rebours V
        • Boutron-Ruault M-C
        • Schnee M
        • et al.
        Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series.
        Am J Gastroenterol. 2008; 103: 111-119https://doi.org/10.1111/j.1572-0241.2007.01597.x
        • Lynch HT
        • Fusaro RM
        • Lynch JF
        • Brand R.
        Pancreatic cancer and the FAMMM syndrome.
        Fam Cancer. 2008; 7: 103-112https://doi.org/10.1007/s10689-007-9166-4
        • Breast Cancer Linkage Consortium
        Cancer risks in BRCA2 mutation carriers.
        J Natl Cancer Inst. 1999; 91: 1310-1316https://doi.org/10.1093/jnci/91.15.1310
        • Murphy KM
        • Brune KA
        • Griffin C
        • et al.
        Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.
        Cancer Res. 2002; 62: 3789-3793
        • Kastrinos F
        • Mukherjee B
        • Tayob N
        • et al.
        Risk of pancreatic cancer in families with Lynch syndrome.
        JAMA. 2009; 302: 1790-1795
        • Aarnio M
        • Sankila R
        • Pukkala E
        • et al.
        Cancer risk in mutation carriers of DNA-mismatch-repair genes.
        Int J Cancer. 1999; 81: 214-218
        • Chen CC
        • Feng W
        • Lim PX
        • Kass EM
        • Jasin M.
        Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and cancer.
        Annu Rev Cancer Biol. 2018; 2: 313-336
        • Mocci E
        • Milne RL
        • Mendez-Villamil EY
        • et al.
        Risk of pancreatic cancer in breast cancer families from the breast cancer family registry cancer.
        Epidemiol Biomarkers Prev. 2013; 22: 803-811
        • Lowery MA
        • Wong W
        • Jordan EJ
        • et al.
        Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms.
        J Natl Cancer Inst. 2018; 110: 1067-1074
        • Lowery MA
        • Jordan EJ
        • Basturk O
        • et al.
        Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype.
        Clin Cancer Res. 2017; 23: 6094-6100
        • Ligtenberg M.J.
        • Kuiper R.P.
        • Chan T.L.
        • et al.
        Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1.
        Nat. Genet. 2009; 41: 112-117
        • Veigl M.L.
        • Kasturi L.
        • Olechnowicz J.
        • et al.
        Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.
        Proc.Natl. Acad. Sci. U.S.A. 1998; 95: 8698-8702
        • Haraldsdottir S.
        • Hampel H.
        • Tomsic J.
        • et al.
        Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.
        Gastroenterology. 2014; 147: 1308-1316
        • Jiricny J.
        Postreplicative mismatch repair.
        Cold Spring Harb Perspect Biol. 2013; 5a012633
        • Humphris J.L.
        • Patch A.M.
        • Nones K.
        • et al.
        Hypermutation in pancreatic cancer.
        Gastroenterology. 2017; 152: 68-74
        • Lupinacci R.M.
        • Goloudina A.
        • Buhard O.
        • et al.
        Prevalence of microsatellite instability in intraductal papillary mucinous neoplasms of the pancreas.
        Gastroenterology. 2018; 154: 1061-1065
        • Hu Z.I.
        • Shia J.
        • Stadler Z.K.
        • et al.
        Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations.
        Clin. Canc. Res. 2018; 24: 1326-1336
        • Janssen QP
        • Buettner S
        • Suker M
        • et al.
        Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis.
        J Natl Cancer Inst. 2019; 111: 782-794https://doi.org/10.1093/jnci/djz073
        • Suker M
        • Beumer BR
        • Sadot E
        • et al.
        FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.
        Lancet Oncol. 2016; 17: 801-810https://doi.org/10.1016/S1470-2045(16)00172-8
        • Cristescu R
        • Lee J
        • Nebozhyn M
        • et al.
        Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.
        Nat Med. 2015; 21: 449-456
        • Engel KB
        • Moore HM.
        Effects of preanalytical variables on the detection of proteins by immunohistochemistry in formalin-fixed, paraffin embedded tissue.
        Arch Pathol Lab Med. 2011; 135: 537-543
        • Shia J.
        Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry.
        J Mol Diagn. 2008; 10: 293-300
        • Alpert L
        • Pai RK
        • Srivastava A
        • et al.
        Colorectal carcinomas with isolated loss of PMS2 staining by immunohistochemistry.
        Arch Pathol Lab Med. 2018; 142: 523-528
        • Stelloo E
        • Jansen AML
        • Osse EM
        • et al.
        Practical guidance for mismatch repair-deficiency testing in endometrial cancer.
        Ann Oncol. 2017; 28: 96-102
        • Jaffrelot M.
        • Farés N.
        • Brunac A.C.
        • et al.
        An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes.
        Mod Pathol. 2022; 35: 427-437
        • Rainone M
        • Singh I
        • Salo-Mullen EE
        • et al.
        An emerging paradigm for germline testing in pancreatic ductal adenocarcinoma and immediate implications for clinical practice.
        JAMA Oncol. 2020; 6: 764-771
        • Rosen MN
        • Goodwin RA
        • Vickers MM.
        BRCA mutated pancreatic cancer: a change is coming.
        World J Gastroenterol. 2021; 27: 1943-1958
        • Golan T
        • Hammel P
        • Reni M
        • et al.
        Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
        N Engl J Med. 2019; 381: 317-327
        • Le DT
        • Durham JN
        • Smith KN
        • et al.
        Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
        Science. 2017; 357 (28): 409-413
        • Domchek SM
        • Postel-Vinay S
        • Im SA
        • et al.
        Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicenter, phase 1/2, basket study.
        Lancet Oncol. 2020; 21: 1155-1164
        • Vinayak S
        • Tolaney SM
        • Schwartzberg L
        • et al.
        Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer.
        JAMA Oncol. 2019; 5: 1132-1140
        • Zhou Z
        • Li M.
        Evaluation of BRCA1 and BRCA2 as indicators of response to immune checkpoint inhibitors.
        JAMA Netw Open. 2021; 4e217728