Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer.
adjuvant chemotherapy
colon cancer
dMMR
high risk
stage III
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
02
04
2020
revised:
11
05
2020
accepted:
31
05
2020
pubmed:
23
7
2020
medline:
16
6
2021
entrez:
23
7
2020
Statut:
ppublish
Résumé
The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC. Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0-18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS). A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI-high (MSI-H) and met the inclusion criteria of the final analysis. MSI-low (MSI-L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non-Hispanic white. The median age was 65 years (range, 19-90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High-risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High-risk stage III was associated with worse OS compared with low-risk stage III on univariate (P < .001) analysis and displayed a similar trend on multivariable analysis, without a statistically significant difference. Multiagent AC was associated with improved OS compared with no treatment on univariate (P < .001) and multivariable (P < .001) analysis. When stratified by risk status, multiagent AC was associated with improved OS compared with no treatment for high-risk (P < .001) and low-risk (P < .001) stage III disease. Adjuvant chemotherapy is associated with better OS in stage III dMMR/MSI-H CC. An enhanced benefit was shown for high-risk stage III disease.
Sections du résumé
BACKGROUND
The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC.
METHODS
Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0-18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS).
RESULTS
A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI-high (MSI-H) and met the inclusion criteria of the final analysis. MSI-low (MSI-L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non-Hispanic white. The median age was 65 years (range, 19-90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High-risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High-risk stage III was associated with worse OS compared with low-risk stage III on univariate (P < .001) analysis and displayed a similar trend on multivariable analysis, without a statistically significant difference. Multiagent AC was associated with improved OS compared with no treatment on univariate (P < .001) and multivariable (P < .001) analysis. When stratified by risk status, multiagent AC was associated with improved OS compared with no treatment for high-risk (P < .001) and low-risk (P < .001) stage III disease.
CONCLUSION
Adjuvant chemotherapy is associated with better OS in stage III dMMR/MSI-H CC. An enhanced benefit was shown for high-risk stage III disease.
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4136-4147Informations de copyright
© 2020 American Cancer Society.
Références
Cronin KA, Lake AJ, Scott S, et al. Annual Report to the nation on the status of cancer, part I: national cancer statistics. Cancer. 2018;124:2785-2800. doi:10.1002/cncr.31551
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34. doi:10.3322/caac.21551
American Cancer Society. Colorectal cancer facts & figures 2017-2019. American Cancer Society; 2017.
Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol. 1999;17:3553-3559. doi:10.1200/jco.1999.17.11.3553
Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993;11:1879-1887. doi:10.1200/jco.1993.11.10.1879
Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. doi:10.1056/NEJMoa032709
Andre T, de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: 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. doi:10.1200/jco.2015.63.4238
Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05. A baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010;17:959-966. doi:10.1245/s10434-009-0881-y
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. doi:10.1007/s11864-015-0348-2
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816-819.
Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247-257. doi:10.1056/NEJMoa022289
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609-618. doi:10.1200/jco.2005.01.086
Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. 2000;119:921-928. doi:10.1053/gast.2000.18161
Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831-3839. doi:10.1158/1078-0432.CCR-07-0366
Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917-923.
Hoadley KA, Yau C, Wolf DM, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell. 2014;158:929-944. doi:10.1016/j.cell.2014.06.049
Kheirelseid EAH, Miller N, Chang KH, et al. Mismatch repair protein expression in colorectal cancer. J Gastrointest Oncol. 2013;4:397-408. doi:10.3978/j.issn.2078-6891.2013.021
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;28:3219-3226. doi:10.1200/jco.2009.27.1825
Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi64-vi72. doi:10.1093/annonc/mdt354
Benson AB 3rd, Venook AP, Cederquist L, et al. Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15:370-398. doi:10.6004/jnccn.2017.0036
Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307:1383-1393. doi:10.1001/jama.2012.385
Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:862-873. doi:10.1016/s1470-2045(14)70227-x
Zaanan A, Shi Q, Taieb J, et al. Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: a pooled analysis from 2 randomized clinical trials. JAMA Oncol. 2018;4:379-383. doi:10.1001/jamaoncol.2017.2899
Kazama Y, Watanabe T, Knazawa T, Tanaka J, Tanaka T, Nagawa H. Microsatellite instability in poorly differentiated adenocarcinomas of the colon and rectum: relationship to clinicopathological features. J Clin Pathol. 2007;60:701-704. doi:10.1136/jcp.2006.039081
Xiao H, Soon YS, Hong S-M, et al. Poorly differentiated colorectal cancers: correlation of microsatellite instability with clinicopathologic features and survival. Am J Clin Pathol. 2013;140:341-347. doi:10.1309/ajcp8p2dynkgrbvi
Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 2015;5:16-18. doi:10.1158/2159-8290.Cd-14-1397
Kwon Y, Park M, Jang M, et al. Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype. Oncotarget. 2017;8:39367-39381. doi:10.18632/oncotarget.17023
NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-1450.
Weiss JM, Schumacher J, Allen GO, et al. Adjuvant chemotherapy for stage II right-sided and left-sided colon cancer: analysis of SEER-medicare data. Ann Surg Oncol. 2014;21:1781-1791. doi:10.1245/s10434-014-3631-8
Morris EJ, Maughan NJ, Forman D, Quirke P. Who to treat with adjuvant therapy in Dukes B/stage II colorectal cancer? The need for high quality pathology. Gut. 2007;56:1419-1425. doi:10.1136/gut.2006.116830
Klingbiel D, Saridaki Z, Roth AD, Bosman FT, Delorenzi M, Tejpar S. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol. 2015;26:126-132. doi:10.1093/annonc/mdu499
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. doi:10.1056/nejm200001133420201
Bertagnolli MM, Redston M, Compton CC, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer-a study of CALGB 9581 and 89803. J Clin Oncol. 2011;29:3153-3162. doi:10.1200/jco.2010.33.0092
Sinicrope FA, Foster NR, Thibodeau SN, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863-875. doi:10.1093/jnci/djr153
Tejpar S, Bosman F, Delorenzi M, et al. Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). J Clin Oncol. 2009;27:4001. doi:10.1200/jco.2009.27.15_suppl.4001
Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261-1270. doi:10.1200/jco.2010.30.1366
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;31:3664-3672. doi:10.1200/jco.2013.48.9591
Westra JL, Schaapveld M, Hollema H, et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol. 2005;23:5635-5643. doi:10.1200/jco.2005.04.096
Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566-576. doi:10.1038/s41591-020-0805-8
Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466-474. doi:10.1200/jco.2009.23.3452
Bosman FT, Yan P, Tejpar S, et al. Tissue biomarker development in a multicentre trial context: a feasibility study on the PETACC3 stage II and III colon cancer adjuvant treatment trial. Clin Cancer Res. 2009;15:5528-5533. doi:10.1158/1078-0432.Ccr-09-0741
Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012;104:1635-1646. doi:10.1093/jnci/djs427
Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. doi:10.1634/theoncologist.2009-0233
Wang B, Li F, Zhou X, Ma Y, Fu W. Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis. World J Surg Oncol. 2019;17:169. doi:10.1186/s12957-019-1706-5
Lee DY, Teng A, Pedersen RC, et al. Racial and socioeconomic treatment disparities in adolescents and young adults with stage II-III rectal cancer. Ann Surg Oncol. 2017;24:311-318. doi:10.1245/s10434-016-5626-0
Sinicrope FA, Ou F-S, Zemla T, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502). J Clin Oncol. 2019;37:e15169. doi:10.1200/JCO.2019.37.15_suppl.e15169
Lau D, Kalaitzaki E, Church DN, et al. Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. ESMO Open. 2020;5:e000638. doi:10.1136/esmoopen-2019-000638
Ogino S, Giannakis M. Immunoscore for (colorectal) cancer precision medicine. Lancet. 2018;391:2084-2086. doi:10.1016/s0140-6736(18)30953-x