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

Abstract

A B S T R A C T PurposeColon 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 MethodsCancer 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 ConclusionLoss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

“…13,14 Our study is unique in that we specifically excluded potential Lynch syndrome patients from our survival analysis and demonstrate no significant overall or recurrence-free survival differences between patients with early-onset colorectal carcinoma and those patients with colorectal carcinoma 440 years of age. However, we did detect a trend to increased recurrence incidence in patients with colorectal carcinoma r40 years of age.…”

“…3,12 Most of the published data are confounded by inclusion of hereditary colorectal carcinoma, particularly Lynch syndrome-associated colorectal carcinomas, which have differing genetic events leading to tumorigenesis and often have improved survival compared with non-syndromic colorectal carcinoma. 13,14 We performed a histologic, molecular, and immunophenotypic analysis of patients with sporadic early-onset (r40 years of age) colorectal carcinoma seen at our institution from the years 2000-2010 and compared the tumors to a cohort of consecutively resected colorectal carcinomas with available pathologic material seen in patients 440 years of age. Our results demonstrate that colorectal carcinoma is not infrequently diagnosed in patients r40 years of age and is not often the result of underlying Lynch syndrome or associated with other cancer-predisposing genetic conditions or chronic inflammatory conditions.…”

A Prognostic Model To Predict Survival In Stage III Colon Cancer Patients Based on Histological Grade, Preoperative Carcinoembryonic Antigen Level and the Neutrophil Lymphocyte Ratio

“…Many genes and proteins had been uncovered as participated in the development and metastasis of colon cancer, and those genes and proteins also showed correlation with OS of stage III colon cancer patients (Bertagnolli et al, 2009;Ogino et al, 2009;Ogino et al, 2012;Belt et al, 2012). Indeed, the knowledge about those biomacromolecule provide us in-depth understanding about cancers.…”

“…In recent years, neutrophil lymphocyte ratio (NLR), which is thought as an indicator of systemic inflammation (Chiang et al, 2012), also has been reported as a prognostic factor for poor overall survival (OS) in colon cancer patients (Chiang et al, 2012). What's more, correlations between survival and several of genes or proteins, including KRAS (Ogino et al, 2009), BRAF (Ogino et al, 2012, microsatellite instability (Bertagnolli et al, 2009), cell cycle proteins (Belt et al, 2012) and MMP (Wong et al, 2011), were also observed. However, the available published papers still leave some to be desired.…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Initially, in the Cancer and Leukemia Group B (CALGB) 89803 trial, the use of irinotecan-based adjuvant chemotherapy in advanced (Stage-III and stage-IV) MSI CRC was suggestive of a positive effect compared to MSS tumours (Bertagnolli et al, 2009;Fallik et al, 2003;Klingbiel et al, 2015;Ogino et al, 2012;Saltz et al, 2007). However, it later proved ineffectual in this and several other randomized phase III studies (Dahan et al, 2009;Hagan et al, 2013;Klingbiel et al, 2015;Saltz et al, 2007;Taieb et al, 2014).…”