High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus

Abstract

Colorectal cancer is one of the leading malignancies and still accounts for almost 25 000 deaths in Germany each year. Although there is accumulating data on the molecular basis, treatment and clinical outcome of patients within clinical trials evidence from the real-world setting is mostly lacking. We started the molecular registry trial Colopredict Plus in 2013 to collect clinical and molecular data from a real-world cohort of patients with early colon cancer stage II and III in 70 German colon cancer centers focusing on the prognostic impact of high microsatellite instability. In this interim report, we characterize a clinical cohort of 2615 patients, of whom 1787 tissue probes were analyzed. Microsatellite status was assessed using immunhistochemistry and fragment length analysis, with a concordance of 91.4 %. These established histopathological methods are sensitive and cost-effective. The median age was 72 years, significantly higher compared to clinical trial populations, with a median Charlson Comorbidity Index of 3. The stage-dependent incidence of microsatellite instability was 23.7 % and was associated with female gender, BRAF-mutation, UICC stage II and localization in the right colon. Survival calculated in disease free, relapse free and overall survival significantly differed between MSI-H and MSS, in favor of MSI-H patients. Multivariate age-adjusted analyses of relapse-free survival, disease-free survival, and overall survival highlighted microsatellite instability as a robust and positive prognostic marker for early colon cancer independent of age.

Zusammenfassung

Das kolorektale Karzinom ist weiterhin eine der häufigsten Tumorerkrankungen mit einer Mortalität von fast 25 000 pro Jahr in Deutschland. Obwohl wir mehr und mehr Daten zur molekularen Basis, zu neuen Behandlungsmethoden und Verläufen von Patienten im Rahmen klinischer Studien generieren, gibt es nur wenige Informationen aus der klinischen Versorgungsrealität. Wir starteten die molekulare Registerstudie Colopredict Plus im Jahre 2013, um klinische sowie molekulare Daten von einer „Real-World“-Kohorte von Patienten mit Kolonkarzinomen im UICC-Stadium II und III aus 70 deutschen Darmkrebszentren zu dokumentieren. Der Fokus liegt hier auf dem prognostischen Wert einer hochgradigen Mikrosatelliteninstabilität. In dieser Interimsanalyse charakterisieren wir das klinische Kollektiv von 2615 Patienten, von denen 1787 Tumorproben analysiert wurden. Der Mikrosatellitenstatus wurde via Immunhistochemie und Fragmentlängenanalyse mit einer Konkordanz von 91,4 % durchgeführt, was eine kosteneffektive histopathologische Nachweismethodik darstellt. Das mediane Alter lag bei 72 Jahren und damit deutlich höher als üblicherweise in klinischen Studien, der mediane Charlson Comorbidity Index lag bei 3. Die stadienabhängige Mikrosatelliteninstabilität-Inzidenz lag bei 23,7 % und war assoziiert mit dem weiblichen Geschlecht, BRAF-Mutationen, UICC-Stadium II und der Primärtumorlokalisation im rechten Kolon. Das Überleben berechnet in krankheitsfreiem, rezidivfreiem sowie Gesamtüberleben unterschied sich signifikant zugunsten der MSI-H-Patienten. Multivariate altersadjustierte Analysen des rezidivfreien und krankheitsfreien Überlebens sowie des Gesamtüberlebens bestätigten eine hochgradige Mikrosatelliteninstabilität als robusten und positiven prognostischer Marker für frühe Kolonkarzinome unabhängig vom Alter.

Key words

microsatellite instability - colon cancer - real world data - BRAF - registry

Schlüsselwörter

MSI-H - Kolonkarzinom - Überleben - Prognosemarker

Publication History

Received: 24 November 2019

Accepted: 05 April 2020

Article published online:
16 June 2020

• References

• 1 Barnes B, Kraywinkel K, Kurth BM. et al. Bericht zum Krebsgeschehen in Deutschland 2016 (ed Institut RK). 28-29
• 2 Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014; 383: 1490-1502
• 3 Brenner H, Chen C. The colorectal cancer epidemic: challenges and opportunities for primary, secondary and tertiary prevention. Br J Cancer 2018; 119: 785-792
• 4 Lackman M, Vickers MM, Hsu T. Physician-reported reasons for non-enrollment of older adults in cancer clinical trials. J Geriatr Oncol 2019; 11: 31-36
• 5 Ludmir EB, Mainwaring W, Lin TA. et al. Factors associated with age disparities among cancer clinical trial participants. JAMA Oncol 2019; DOI: 10.1001/jamaoncol.2019.2055.
• 6 Wildiers H, Heeren P, Puts M. et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014; 32: 2595-2603
• 7 Mohile SG, Velarde C, Hurria A. et al. Geriatric assessment-guided care processes for older adults: a Delphi consensus of geriatric oncology experts. J Natl Compr Canc Netw 2015; 13: 1120-1130
• 8 Hurria A, Levit LA, Dale W. et al. Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol 2015; 33: 3826-3833
• 9 Colinet B, Jacot W, Bertrand D. et al. A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: description and comparison with the Charlson's index. Br J Cancer 2005; 93: 1098-1105
• 10 Dienstmann R, Mason MJ, Sinicrope FA. et al. Prediction of overall survival in stage II and III CC beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol 2017; 28: 1023-1031
• 11 Koopman M, Kortman GA, Mekenkamp L. et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009; 100: 266-273
• 12 Klingbiel D, Saridaki Z, Roth AD. et al. Prognosis of stage II and III CC treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol 2015; 26: 126-132
• 13 Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011; 42: 1-10
• 14 De Palma FDE, D'Argenio V, Pol J. et al The molecular hallmarks of the serrated pathway in colorectal cancer. Cancers (Basel) 2019; 11: pii: E1017 . doi: 10.3390/cancers11071017
• 15 Deng G, Bell I, Crawley S. et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004; 10: 191-195
• 16 Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol 2015; 89: 899-921
• 17 Schmiegel W, Buchberger B, Follmann M. et al. S3-Leitlinie Kolorektales Karzinom. Z Gastroenterol 2017; 55: 1344-1498
• 18 Franke AJ, Skelton WP, Gaffar M. et al. Differences in the characteristics of younger and older MSI-H colorectal cancer (CRC) as determined by universal reflex testing. J Clin Oncol 2018; 36: 3593-3593
• 19 Taieb J, Kourie HR, Emile JF. et al. Association of prognostic value of primary tumor location in stage III CC with RAS and BRAF mutational status. JAMA Oncol 2018; 4: e173695
• 20 Zaanan A, Shi Q, Taieb J. et al. Role of deficient dna mismatch repair status in patients with stage III CC treated with FOLFOX adjuvant chemotherapy: a pooled analysis from 2 randomized clinical trials. JAMA Oncol 2018; 4: 379-383
• 21 Taieb J, Le Malicot K, Shi Q. et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III CC. J Natl Cancer Inst 2016; 109: djw272
• 22 André T, de Gramont A, Vernerey D. et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III CC: updated 10-Year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol 2015; 33: 4176-4187
• 23 Sinicrope FA, Mahoney MR, Smyrk TC. et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III CC from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013; 31: 3664-3372
• 24 Zaanan A, Fléjou JF, Emile JF. et al. Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III CC patients treated with adjuvant FOLFOX chemotherapy. Clin Cancer Res 2011; 17: 7470-7478
• 25 de Jong A, van Puijenbroek M, Hendriks Y. et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004; 10: 972-980
• 26 Boland CR, Thibodeau SN, Hamilton SR. et al. A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58: 5248-5257
• 27 Rodriguez-Bigas MA, Boland CR, Hamilton SR. et al. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997; 89: 1758-1762
• 28 Völkel V, Draeger T, Gerken M. et al. long-term survival of patients with colon and rectum carcinomas: is there a difference between cancer centers and non-certified hospitals?. Gesundheitswesen 2019; 81: 801-807
• 29 Papamichael D, Audisio RA, Glimelius B. et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol 2015; 26: 463-476
• 30 Canouï-Poitrine F, Lièvre A, Dayde F. et al. Inclusion of older patients with cancer in clinical trials: The SAGE prospective multicenter cohort survey. Oncologist 2019; 24: e1351-e1359
• 31 Report from German CC centers. https://www.onkozert.de/2019/03/21/jahresberichte-der-zertifizierungssysteme-2019/
• 32 Mejri N, Dridi M, El Benna H. et al. Tumor location impact in stage II and III CC: epidemiological and outcome evaluation. J Gastrointest Oncol 2018; 9: 263-268
• 33 Newton K, Jorgensen NM, Wallace AJ. et al. Tumour MLH1 promoter region methylation testing is an effective pre-screen for Lynch Syndrome (HNPCC). J Med Genet 2014; 51: 789-796
• 34 Klutstein M, Nejman D, Greenfield R. et al. DNA methylation in cancer and aging. Cancer Res 2016; 76: 3446-3450
• 35 Nakagawa H, Nouvo GJ, Zervos EE. et al. Age-related hypermethylation of the 5 region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res 2001; 61: 6991-6995
• 36 Benz S, Gerken M, Klinkhammer-Schalke M. Versorgungssituation des Kolorektalen Karzinoms, Deutscher Krebskongress 2018, Nationale Qualitätskonferenz.
• 37 Lindor NM, Burgart LJ, Leontovich O. et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002; 20: 1043-1048
• 38 Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol 2015; 16: 30