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Current Treatment Options in Oncology

Erschienen in:

01.08.2016 | Lower Gastrointestinal Cancers (AB Benson, Section Editor)

Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer

verfasst von: Dionisia Quiroga, DO, PhD, H. Kim Lyerly, MD, Michael A. Morse, MD

Erschienen in: Current Treatment Options in Oncology | Ausgabe 8/2016

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Opinion statement

Division of colorectal cancers (CRCs) into molecular subsets yields important consequences for prognosis and therapeutic response. The microsatellite instability (MSI) immune subgroup, accounting for 15 % of early-stage and 3 % of metastatic CRCs, are a result of deficient cellular DNA mismatch repair (dMMR) mechanisms. dMMR CRCs are notable for greater survivability, yet lack of benefit from fluoropyrimidine-based therapy in early-stage disease as compared to proficient DNA mismatch repair (pMMR) CRCs but are substantially lethal when metastatic. The surging interest in cancer immunotherapy, particularly checkpoint blockade, has further led to a focus on MSI tumors, which are notable for their substantial T cell infiltrate. In this review, we will discuss the biologic underpinnings for the immunogenicity of dMMR CRC and the preclinical development of therapies intended to modulate this immune response. Next, we will discuss the previous and ongoing clinical trials specifically designed to evaluate immunotherapeutic treatment of dMMR CRCs. Building on the success of the early immune checkpoint inhibitor clinical trials for dMMR CRC, combinations with other anti-tumor immunotherapies may provide an even more robust response, thereby, creating an alternative treatment regimen for those who have failed standard therapies or possibly resulting in prophylactic therapies for patients with highly oncogenic hereditary mismatch repair deficiencies.

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.PubMedCrossRef

Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–73.PubMedPubMedCentralCrossRef

3.•

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6. Description of the CRC consensus molecular subtypes, including the MSI immune group.PubMedPubMedCentralCrossRef

Raut CP, Pawlik TM, Rodriguez-Bigas MA. Clinicopathologic features in colorectal cancer patients with microsatellite instability. Mutat Res. 2004;568:275–82.PubMedCrossRef

Veigl ML, 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;95:8698–702.PubMedPubMedCentralCrossRef

Mensenkamp AR, Vogelaar IP, van Zelst-Stams WAG, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014;146:643–6.e8.PubMedCrossRef

Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110:1020–7.PubMedCrossRef

Wu Y, Berends MJ, Mensink RG, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65:1291–8.PubMedPubMedCentralCrossRef

Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419–28.PubMedPubMedCentralCrossRef

10.

Wu Y, Berends MJ, Post JG, et al. Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Gastroenterology. 2001;120:1580–7.PubMedCrossRef

11.

Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21:1174–9.PubMedCrossRef

12.

Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–8.PubMedCrossRef

13.

Akiyama Y, Iwanaga R, Ishikawa T, et al. Mutations of the transforming growth factor-beta type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability. Cancer. 1996;78:2478–84.PubMedCrossRef

14.

Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275:967–9.PubMedCrossRef

15.

Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.PubMedCrossRef

16.

Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.PubMedCrossRef

17.

Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821–9.PubMedPubMedCentralCrossRef

18.

Park JH, Powell AG, Roxburgh CSD, Horgan PG, McMillan DC, Edwards J. Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment. Br J Cancer. 2016. doi:10.1038/bjc.2016.17.PubMedCentral

19.

Greenson JK, Bonner JD, Ben-Yzhak O, et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am J Surg Pathol. 2003;27:563–70.PubMedCrossRef

20.

Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91:2417–22.PubMedCrossRef

21.

Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831–9.PubMedCrossRef

22.

Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol. 2014;25:1032–8.PubMedPubMedCentralCrossRef

23.

Venderbosch S, Nagtegaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20:5322–30.PubMedPubMedCentralCrossRef

24.•

Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51. First article to reveal MSD CRCs as having increased expression of immune checkpoint molecules.PubMedCrossRef

25.

Bodmer W, Bishop T, Karran P. Genetic steps in colorectal cancer. Nat Genet. 1994;6:217–9.PubMedCrossRef

26.

Saeterdal I, Gjertsen MK, Straten P, Eriksen JA, Gaudernack G. A TGF betaRII frameshift-mutation-derived CTL epitope recognised by HLA-A2-restricted CD8+ T cells. Cancer Immunol Immunother. 2001;50:469–76.PubMedCrossRef

27.

Schwitalle Y, Linnebacher M, Ripberger E, Gebert J, von Knebel Doeberitz M. Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun. 2004;4:14.PubMed

28.

Ripberger E, Linnebacher M, Schwitalle Y, Gebert J, von Knebel Doeberitz M. Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol. 2003;23:415–23.PubMedCrossRef

29.

Linnebacher M, Wienck A, Boeck I, Klar E. Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (−1) frame of U79260(FTO). J Biomed Biotechnol. 2010;2010:841451.PubMedPubMedCentralCrossRef

30.

Garbe Y, Maletzki C, Linnebacher M. An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+ cytotoxic T cell epitopes. PLoS One. 2011;6:e26517.PubMedPubMedCentralCrossRef

31.

Linnebacher M, Gebert J, Rudy W, et al. Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens. Int J Cancer. 2001;93:6–11.PubMedCrossRef

32.

Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008;134:988–97.PubMedCrossRef

33.

Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel DM, Kloor M. Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Fam Cancer. 2011;10:557–65.PubMedCrossRef

34.

Sandel MH, Dadabayev AR, Menon AG, et al. Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization. Clin Cancer Res. 2005;11:2576–82.PubMedCrossRef

35.

De Smedt L, Lemahieu J, Palmans S, et al. Microsatellite instable vs stable colon carcinomas: analysis of tumour heterogeneity, inflammation and angiogenesis. Br J Cancer. 2015;113:500–9.PubMedCrossRef

36.

Reuschenbach M, Kloor M, Morak M, et al. Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam Cancer. 2010;9:173–9.PubMedPubMedCentralCrossRef

37.

Genuardi M, Viel A, Bonora D, et al. Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. Hum Genet. 1998;102:15–20.PubMedCrossRef

38.

Goel A, Li M-S, Nagasaka T, et al. Association of JC virus T-antigen expression with the methylator phenotype in sporadic colorectal cancers. Gastroenterology. 2006;130:1950–61.PubMedCrossRef

39.

Iwata T, Fujita T, Hirao N, et al. Frequent immune responses to a cancer/testis antigen, CAGE, in patients with microsatellite instability-positive endometrial cancer. Clin Cancer Res. 2005;11:3949–57.PubMedCrossRef

40.

Guidoboni M, Gafà R, Viel A, et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol. 2001;159:297–304.PubMedPubMedCentralCrossRef

41.

Dolcetti R, Viel A, Doglioni C, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154:1805–13.PubMedPubMedCentralCrossRef

42.

Michael-Robinson JM, Pandeya N, Cummings MC, et al. Fas ligand and tumour counter-attack in colorectal cancer stratified according to microsatellite instability status. J Pathol. 2003;201:46–54.PubMedCrossRef

43.

Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.PubMed

44.

Pagès F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.PubMedCrossRef

45.

Prall F, Dührkop T, Weirich V, et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol. 2004;35:808–16.PubMedCrossRef

46.

Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.PubMedCrossRef

47.

Michel S, Benner A, Tariverdian M, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008;99:1867–73.PubMedPubMedCentralCrossRef

48.

Quinn E, Hawkins N, Yip YL, Suter C, Ward R. CD103+ intraepithelial lymphocytes—a unique population in microsatellite unstable sporadic colorectal cancer. Eur J Cancer. 2003;39:469–75.PubMedCrossRef

49.

Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500.PubMedCrossRef

50.

Hanke T, Melling N, Simon R, et al. High intratumoral FOXP3⁺ T regulatory cell (Tregs) density is an independent good prognosticator in nodal negative colorectal cancer. Int J Clin Exp Pathol. 2015;8:8227–35.PubMedPubMedCentral

51.

Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18.PubMedCrossRef

52.

Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101:2620–7.PubMedCrossRef

53.

Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–103.PubMedCrossRef

54.

Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92:4150–66.PubMed

55.

Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–71.PubMedCrossRef

56.

Pogue-Geile K, Yothers G, Taniyama Y, et al. Defective mismatch repair and benefit from bevacizumab for colon cancer: findings from NSABP C-08. J Natl Cancer Inst. 2013;105:989–92.PubMedPubMedCentralCrossRef

57.

Dierssen JWF, de Miranda NFCC, Ferrone S, et al. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer. 2007;7:33.PubMedPubMedCentralCrossRef

58.

Kloor M, Michel S, Buckowitz B, et al. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int J Cancer. 2007;121:454–8.PubMedCrossRef

59.••

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20. Phase II clinical trial showing efficacy of anti-PD-1 inhibitor treatment in advanced dMMR CRC patients.PubMedPubMedCentralCrossRef

60.

Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74.PubMedPubMedCentralCrossRef

61.

Schulze T, Kemmner W, Weitz J, Wernecke K-D, Schirrmacher V, Schlag PM. Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother. 2009;58:61–9.PubMedCrossRef

62.

Nair SK, Morse M, Boczkowski D, et al. Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells. Ann Surg. 2002;235:540–9.PubMedPubMedCentralCrossRef

63.

Liu K-J, Wang C-C, Chen L-T, et al. Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A*0201 and HLA-A*2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides. Clin Cancer Res. 2004;10:2645–51.PubMedCrossRef

64.

Morse MA, Chapman R, Powderly J, et al. Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients. Clin Cancer Res. 2011;17:4844–53.PubMedPubMedCentralCrossRef

65.

Morse MA, Chaudhry A, Gabitzsch ES, et al. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol Immunother. 2013;62:1293–301.PubMedPubMedCentralCrossRef

66.

Kaufman HL, Lenz H-J, Marshall J, et al. Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin Cancer Res. 2008;14:4843–9.PubMedCrossRef

67.••

de Weger VA, Turksma AW, Voorham QJM, et al. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res. 2012;18:882–9. Retrospective analysis of pMMR and dMMR CRC patients who were administered a tumor cell vaccine.PubMedCrossRef

68.

Vermorken JB, Claessen AM, van Tinteren H, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet. 1999;353:345–50.PubMedCrossRef

69.

Reuschenbach M, Dörre J, Waterboer T, et al. A multiplex method for the detection of serum antibodies against in silico-predicted tumor antigens. Cancer Immunol Immunother. 2014;63:1251–9.PubMedCrossRef

70.

Saul A, Lawrence G, Smillie A, et al. Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant. Vaccine. 1999;17:3145–59.PubMedCrossRef

71.

Kloor M, Reuschenbach M, Karbach J, Rafiyan M, Al-Batran S-E, Pauligk C, et al. Vaccination of MSI-H colorectal cancer patients with frameshift peptide antigens: a phase I/IIa clinical trial. J. Clin. Oncol. 33, (suppl; abstr 3020) (2015).

72.

He L, Deng T, Luo H-S. Association between cytotoxic T-lymphocyte antigen-4 + 49A/G polymorphism and colorectal cancer risk: a meta-analysis. Int J Clin Exp Med. 2015;8:3752–60.PubMedPubMedCentral

73.

Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28:3485–90.PubMedCrossRef

74.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.PubMedPubMedCentralCrossRef

75.

Shi S-J, Wang L-J, Wang G-D, et al. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One. 2013;8:e76012.PubMedPubMedCentralCrossRef

76.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedPubMedCentralCrossRef

77.

Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.PubMedPubMedCentralCrossRef

78.

Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedPubMedCentralCrossRef

79.

Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013;19:462–8.PubMedCrossRef

80.

Campesato LF, Barroso-Sousa R, Jimenez L, et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget. 2015;6:34221–7.PubMedPubMedCentral

81.

Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207–11.PubMedCrossRef

82.

Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.PubMedPubMedCentralCrossRef

83.

Tougeron D, Fauquembergue E, Rouquette A, et al. Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod Pathol. 2009;22:1186–95.PubMedCrossRef

84.

Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18.PubMedCrossRef

85.

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.PubMedCrossRef

86.

Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.PubMedCrossRef

87.

Le DT, Yoshino T, Jäger D, Andre T, Bendell JC, Wang R, et al. KEYNOTE-164: Phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma. J. Clin. Oncol. 34, (suppl 4S; abstr TPS787) (2016).

88.

Diaz LA, Le DT, Yoshino T, Andre T, Bendell JC, Zhang Y, et al. KEYNOTE-177: First-line, open-label, randomized, phase III study of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma. J. Clin. Oncol. 34, (suppl 4S; abstr TPS789) (2016).

89.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.PubMedCrossRef

90.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.PubMedCrossRef

91.

Yamamoto H, Adachi Y, Taniguchi H, et al. Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol. 2012;18:2745–55.PubMedPubMedCentralCrossRef

92.

Vilar E, Bartnik CM, Stenzel SL, et al. MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. Cancer Res. 2011;71:2632–42.PubMedPubMedCentralCrossRef

93.

Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.PubMedCrossRef

94.

Tahara M, Inoue T, Sato F, et al. The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks. Mol Cancer Ther. 2014;13:1170–80.PubMedCrossRef

95.

Leichman L, Groshen S, O’Neil BH, et al. Phase II study of olaparib (AZD-2281) after standard systemic therapies for disseminated colorectal cancer. Oncologist. 2016;21:172–7.PubMedCrossRef

96.

Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–26.PubMedPubMedCentralCrossRef

97.

Sinicrope FA, Mahoney MR, Smyrk TC, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol. 2013;31:3664–72.PubMedPubMedCentralCrossRef

98.

Tougeron D, Mouillet G, Trouilloud I, et al. Efficacy of adjuvant chemotherapy in colon cancer with microsatellite instability: a large multicenter AGEO study. J Natl Cancer Inst. 2016;108:djv438.PubMedCrossRef

99.

Aebi S, Kurdi-Haidar B, Gordon R, et al. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res. 1996;56:3087–90.PubMed

100.

Tesniere A, Schlemmer F, Boige V, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–91.PubMedCrossRef

101.

Velho S, Fernandes MS, Leite M, Figueiredo C, Seruca R. Causes and consequences of microsatellite instability in gastric carcinogenesis. World J Gastroenterol. 2014;20:16433–42.PubMedPubMedCentralCrossRef

102.

V S, Bhagat R, C S P, V R P, Krishnamoorthy L. Microsatellite instability, promoter methylation and protein expression of the DNA mismatch repair genes in epithelial ovarian cancer. Genomics. 2014;104:257–63.

103.

Baldinu P, Cossu A, Manca A, et al. Microsatellite instability and mutation analysis of candidate genes in unselected sardinian patients with endometrial carcinoma. Cancer. 2002;94:3157–68.PubMedCrossRef

104.

Grindedal EM, Møller P, Eeles R, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009;18:2460–7.PubMedCrossRef

105.

Dong X, Li Y, Chang P, Hess KR, Abbruzzese JL, Li D. DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer. Mol Carcinog. 2012;51:491–9.PubMedCrossRef

Titel: Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer
verfasst von: Dionisia Quiroga, DO, PhD
H. Kim Lyerly, MD
Michael A. Morse, MD
Publikationsdatum: 01.08.2016
Verlag: Springer US
Erschienen in: Current Treatment Options in Oncology / Ausgabe 8/2016
Print ISSN: 1527-2729
Elektronische ISSN: 1534-6277
DOI: https://doi.org/10.1007/s11864-016-0414-4

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Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer

Opinion statement

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