Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803

Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

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Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10003 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10003-10003 ◽

Cited By ~ 8

Author(s):

M. M. Bertagnolli ◽

C. C. Compton ◽

D. Niedzwiecki ◽

R. S. Warren ◽

S. Jewell ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Statistical Significance ◽

Disease Free Survival ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Colon Cancers ◽

Early Results ◽

The Impact

10003 Background: Colon cancers exhibiting a high level of microsatellite instability (MSI-H) show distinct clinicopathological features, including both better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the impact of adjuvant chemotherapy containing irinotecan in patients with MSI-H colon cancers. Methods: CALGB protocol 89803 randomized 1264 patients with resected stage III colon cancer to receive post-operative 5-FU and leucovorin (LV) with or without irinotecan. Paraffin blocks containing primary tumor and normal tissue were collected. Microsatellite instablility was assessed using a panel of mono- and di-nucleotide markers. Disease free survival (DFS) was measured from trial entry until documented disease progression or death from any cause. A statistical significance level of 0.2 was used in screening to generate hypotheses regarding MSI status and outcome. Median follow-up at analysis was 3.8 years. Overall C89803 showed no advantage for addition of irinotecan to 5-FU/LV. Results: Patients with and without tumor samples analyzed did not differ by treatment, age, gender, primary site, T-stage, differentiation, # positive nodes, or mucinous type. Of 482 tumors analyzed, 75 (16%) demonstrated MSI-H. MSI-H cancers were more likely to be located in the proximal colon (p<0.0001), of high histologic grade (p<0.0001) and mucinous histology (p<0.0001), and also had increased numbers of tumor-containing lymph nodes (mean # positive nodes/case = 3.5 for MSI Low/Stable vs. 4.7 for MSI-H; p = 0.04). At the time of analysis 143 of 482 patients (36%) analyzed experienced tumor recurrence and/or death due to any cause. For patients with MSI-H tumors, DFS was better in those treated with irinotecan in addition to 5-FU/LV (logrank p=0.18). Among patients with MSI Low/Stable tumors there was no difference in DFS between those treated with and without irinotecan (logrank p =0.39). Conclusions: Early results from CALGB protocol 89803 indicate that addition of postoperative irinotecan to 5-FU/LV may improve DFS in patients with stage III colon cancers that exhibit MSI-H. Longer follow-up is required to confirm this finding. [Table: see text]

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p27Kip1 in Stage III Colon Cancer: Implications for Outcome following Adjuvant Chemotherapy in Cancer and Leukemia Group B Protocol 89803

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-08-2674 ◽

2009 ◽

Vol 15 (6) ◽

pp. 2116-2122 ◽

Cited By ~ 12

Author(s):

Monica M. Bertagnolli ◽

Robert S. Warren ◽

Donna Niedzwiecki ◽

Elke Mueller ◽

Carolyn C. Compton ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Group B ◽

Leukemia Group

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Prognostic value of microsatellite instability (MSI)/deficient mismatch repair (MMR) and BRAFV600E mutation in recurring stage III colon cancer: insights from an ACCENT pooled analysis of seven adjuvant chemotherapy trials

Digestive Medicine Research ◽

10.21037/dmr.2020.04.01 ◽

2020 ◽

Vol 3 ◽

pp. 113-113

Author(s):

Anuratha Sakthianandeswaren ◽

Dmitri Mouradov ◽

Oliver M. Sieber

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Prognostic Value ◽

Pooled Analysis ◽

Stage Iii ◽

Brafv600e Mutation ◽

Stage Iii Colon Cancer ◽

Deficient Mismatch Repair

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Prognostic significance of BRAF mutation alone and in combination with microsatellite instability in stage III colon cancer

Asia-Pacific Journal of Clinical Oncology ◽

10.1111/ajco.13096 ◽

2018 ◽

Vol 15 (1) ◽

pp. 69-74 ◽

Cited By ~ 3

Author(s):

Hanumant Chouhan ◽

Tarik Sammour ◽

Michelle L. Thomas ◽

James W. Moore

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Braf Mutation ◽

Prognostic Significance ◽

Stage Iii ◽

Stage Iii Colon Cancer

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Microsatellite instability status does not predict total lymph node or negative lymph node retrieval in stage III colon cancer

Human Pathology ◽

10.1016/j.humpath.2011.10.002 ◽

2012 ◽

Vol 43 (8) ◽

pp. 1258-1264 ◽

Cited By ~ 12

Author(s):

Erin MacQuarrie ◽

Thomas Arnason ◽

Jennette Gruchy ◽

Sen Yan ◽

Arik Drucker ◽

...

Keyword(s):

Colon Cancer ◽

Lymph Node ◽

Microsatellite Instability ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Negative Lymph Node ◽

Lymph Node Retrieval ◽

Total Lymph Node

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Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence: Results of an accent meta-analysis of seven studies.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3525 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3525-3525 ◽

Cited By ~ 1

Author(s):

Julien Taieb ◽

Levi Pederson ◽

Qian Shi ◽

Steven R Alberts ◽

Norman Wolmark ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Mismatch Repair ◽

Statistical Significance ◽

Multivariable Analysis ◽

Disease Recurrence ◽

Stage Iii ◽

Wild Type ◽

Poor Prognostic Factor ◽

Stage Iii Colon Cancer

3525 Background: Microsatellite instable/deficient mismatch repair (MSI) metastatic colorectal cancers have been reported to be of poor prognosis. The interaction between MSI and BRAFV600E mutation complicates the picture. Methods: Patients with resected stage III CC from 7 studies with disease recurrence and data available for MSI and BRAFV600E status were analyzed. The primary endpoint was survival after recurrence (SAR) to assess the prognostic roles of MSI and BRAFV600E, respectively. Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features (data collected 12/1998 to 11/2009). Results: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI tumors (n = 220) had significantly better SAR (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.69-0.98; P = .029) than patients with microsatellite stable /proficient MMR (MSS) tumors (n = 1766). This was also observed when looking at patients treated by the standard FOLFOX adjuvant regimen only (aHR, 0.76; 0.58-1.00; P = .048). Same trends were observed when looking at MSI/dMMR patients outcome in BRAFV600E wild-type (aHR, 0.84; P = .10) and mutant (aHR, 0.88; P = .43) subgroups separately, without reaching statistical significance. As previously described poor SAR was observed in BRAFV600E mutants vs wild type patients (n = 244; aHR, 2.06; 95% CI, 1.73-2.46; P < .0001) and this was also true in BRAFV600E mutants MSI/dMMR patients (n = 77, aHR, 2.65 ; 95% CI, 1.67-4.21; p < .0001). Other factors associated with a poor SAR were : olderage, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence (by 1y increase). Conclusions: In stage III colon cancer patients recurring after adjuvant chemotherapy and before the era of immuno-oncologic agents, MSI/dMMR was associated with a better survival compared to MSS. BRAFV600E mutation seems to be a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.

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