Microsatellite Stable Patients Research Articles

Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX.

e14005 Background: Microsatellite instability (MSI) results from defective mismatch repair and is observed in 15–20% of colorectal cancers (CRCs). Patients with MSI do not benefit from 5-fluorouracil (5-FU)-based chemotherapy. The standard treatment in adjuvant setting for stage III and for high-risk stage II is FOLFOX according to MOSAIC study. This study aimed to determine the benefit of FOLFOX treatment for MSI compared with Microsatellite stable (MSS) patients in adjuvant setting. Methods: We prospectively analyzed 105 patients who had been treated by adjuvant FOLFOX 4 chemotherapy after curative resection (R0) of CRC between May 2004 and December 2008. MSI phenotype was assessed by measuring the length of five quasi-monomorphic mononuleotidic microsatellite markers (NR21, NR24, NR27, BAT25, BAT26) on an 3100 genetic analyzer (Applied Biosystems). MSI was defined as a reduction in size of three markers or more. Disease Free Survival (DFS) was compared among MSI and MSS patients (Kaplan-Meier). The numbers of 5-year relapses were compared using a chi-square test. Results: Among the 105 tumor specimens, there were 28 (27 %) patients stage II (with high risk of relapse) and 66 (63 %) with stage III. Median age was 66 years. There were 58 men, and 84 colon and 21 rectum cancers; 12 stage II MSI and 8 stage III MSI. MSI patients had significantly less relapses than MSS patients : 2/20 (10 %) compared with 29/82 (36 %) (chi-square = 4.89; p = 0.02). Survival curves for MSI and MSS patients were not statistically different (log-rank = 2.74; p = 0.10). Univariate analysis showed that stage (p = 0.0006) and MSI status (p = 0.01) were statistically significant predictors of DFS, whereas age was not. Multivariate analysis showed that only stage predicted DFS (p = 0.01), with a nonsignificant trend for MSI status (p = 0.08). Conclusions: In this cohort of CRC patients treated with FOLFOX 4, MSI status was associated with a better prognosis in univariate analysis, with a non significant trend in multivariate analysis. Contrasting with previous results obtained with 5-FU alone, the FOLFOX combination used had no detrimental effect. No significant financial relationships to disclose.

Does microsatellite instability predict the effect of adjuvant chemotherapy in stage III colorectal cancer? A meta-analysis

4121 Background: Microsatellite instability (MSI) is a prognostic factor in colorectal cancer. Whether it predicts the effect of adjuvant chemotherapy (CT) on overall survival (OS) and relapse-free survival (RFS) is controversial. Methods: Studies were identified by an electronic search using online PubMed, with simultaneous keywords (colorectal neoplasm, microsatellite instability, chemotherapy, prognosis). Abstracts from ASCO and AACR proceedings were reviewed. Articles were obtained from cross-checking of references and from a previous prognostic meta-analysis (MA) (Popat, 2005). We used EasyMA software, available online. A Hazard Ratio (HR) < 1 for MSI-high (MSI-H) status compared with microsatellite stable (MSS) meant a better survival. Results: Our MA found 21 studies (4 abstracts). Statistical calculations were performed in 11 studies (5087 patients including 2879 receiving 5FU-based CT; mean age: 63 years; 1489 stage II, 2648 stage III (64%)). MSI-H was found in 644 patients (15% of total), MSS in 3624. Seven studies (2 randomized) assessed 2 cohorts receiving or not adjuvant CT, 4 studies only included patients receiving CT. Global HR OS (9 studies) was 0.79 (95% confidence interval or CI: 0.64–0.98; p = 0.03). Global HR RFS (8 studies) was 0.67 (95% CI: 0.54–0.83; p < 0.001). A MA on stage III patients (4 studies, 719 patients, 137 MSI-H) found a higher survival among MSI-H than MSS patients receiving CT (HR OS: 0.71, 95% CI 0.49–1.03; HR RFS 0.56, 95% CI 0.42–0.75). Interaction between MSI status and CT status was statistically significant on OS and RFS (4 studies). A MA among MSI-H patients (7 studies) found no survival difference between patients under CT or not: HR OS: 0.70 (95% CI 0.44–1.09), HR RFS: 0.96 (95% CI: 0.62–1.49). Conclusions: Adjuvant CT significantly improved survival in MSI-H compared with MSS patients. MSI-H stage III patients receiving CT survived more than MSS. MSI-H status did not predict response to CT compared with no treatment. No significant financial relationships to disclose.

Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis

Background Microsatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial. Materials and methods Studies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI). Results A MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not. For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62–1.49); HR OS (6 studies): 0.70 (95% CI: 0.44–1.09; p = 0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67–0.87)). Conclusion We found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.

Tumor microsatellite-instability status to predict benefit of adjuvant chemotherapy for stage III colon cancer

4046 Background: Microsatellite instability (MSI) is an alternative pathway to colon cancer pathogenesis and may be categorized by the degree of MSI exhibited as MSI-high (MSI-H), MSI-low (MSI-L) or microsatellite stable (MSS). The aim of this study was to determine the prognostic impact MSI status on survival in stage III colon cancer. Methods: A total of 197 patients who received curative resection of stage III colon cancer from 1991 through 2002 were identified. Records of these patients were retrospectively evaluated to determine chemotherapy (CTx) use and vital status. DNA extracted from paraffin embedded tumor specimens was amplified by polymerase chain reaction using a panel of 7 markers. MSI-H was defined as instability in >40% of markers and low as instability in >0% but <40% of markers. Overall survival based on MSI and CTx status was compared using Kaplan-Meier analysis and the log-rank test and Cox multiple regression to adjust for covariates. Results: Median follow-up was 5.4 years. There were 25 (13%) MSI-H, 38 (19%) MSI-L and 134 (68%) MSS patients. Median age was 56 years (MSI-H), 65 years (MSI-L) and 62 years (MSS). 5-fluorouracil adjuvant CTx was completed in 135 (69%), not completed in 36 (18%) and unknown in 26 (13%) patients. Tumors were left sided in 56% of the cohort, 72% among MSI-H, 60% among MSI-L, 51% among MSS. 5-year overall survival after adjuvant CTx ranged 71–82% and was not significantly different among the groups. Completion of CTx improved survival among MSS, HR 0.18 (95% confidence [CI] 0.07–0.42, p<0.0001), but not among MSI- H, HR 0.83 (95% CI 0.19–3.60, p=0.79), with an intermediate effect among MSI-L, HR 0.36 (95% CI 0.09–1.47, p=0.0562). The effect of completing adjuvant CTx persisted after adjustment for age, sex, stage (IIIA, B, C), and histology, RR 0.19 (95% CI 0.089–0.41, p<0.0001), RR 0.059 (95% CI 0.009–0.39, p=0.003), RR 0.26 (95% CI 0.01–13.3, p=0.31) for MSS, MSI-L, and MSI-H, respectively. Conclusions: 5-fluorouracil based adjuvant chemotherapy did not affect overall survival in patients with stage III colon cancer who are MSI-H due to a high baseline survival rate without adjuvant therapy. Adjuvant chemotherapy did improve survival in patients who are MSS and an intermediate effect was seen in paitents who are MSI-L. No significant financial relationships to disclose.

Adjuvant Chemotherapy in Colorectal Cancer Patients with Microsatellite Instability

To the Editor: In a recent issue of Clinical Cancer Research ([1][1]), we read Benatti et al.'s article with interest, therein they showed significantly better survival in microsatellite instability high (MSI-H) patients than microsatellite stable patients, and concluded that the type of genomic

Low Microsatellite Instability Is Associated With Poor Prognosis in Stage C Colon Cancer

The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O(6)-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.

Asociación entre la inestabilidad de microsatélites y las características clínicas y anatomopatológicas en pacientes con cáncer de colon esporádico

Currently, colon cancer is a leading cause of cancer death world-wide. It progresses according to three molecular pathways, named suppressor, mutador and methylator. Microsatellite instability is a hallmark of the lack of reparation, of DNA mismatches and it characterizes a subset of colon tumors (unstable tumors, MSI). MSI-H patients (high degree of microsatellite instability) seem to share clinico-pathological differences with MSS (microsatellite stable) and MSI-L (low degree of microsatellite instability) patients. In this study, associations between high degree of microsatellite instability and pathological (location, mucinous content, differentiation grade, stages T3N0, stages II and III) and clinical features (response to chemotherapy, disease-free survival and overall survival) were evaluated. 117 patients with sporadic colon cancer were classified into two populations (MSS/MSI-L and MSI-H) by using PCR and electrophoresis of seven microsatellites, according to the National Cancer Institute recommendations. MSI-H tumors tended to be located in the right colon (p = 0.022) and were of mucinous histologic type (p = 0.04). No differences in disease-free survival and overall survival between group of stage II and III patients with MSS/ MSI-L and corresponding ones with MSI-H colon cancer were found (p = 0.54, p = 0.37, respectively). Conversely, MSI-H patients with stage II colon cancer had a favourable prognosis (p = 0.027). Nevertheless, response to 5-fluorouracil (5-FU) and leucovorin was similar in MSS/ MSI-L and MSI-H groups (p = 0.38). MSI-H patients are characterized by certain pathological features; those MSI-H patients with a stage II seem to have a better prognosis than MSS/ MSI-L patients.

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival

Colorectal cancer with microsatellite instability has a characteristic clinicopathologic profile, featuring right-sided, lymphocyte-rich tumors with a better prognosis than microsatellite stable (MSS) carcinoma. Mucinous and signet ring cell carcinomas are both over-represented among microsatellite instability-high cancers. The clinicopathologic features of mucinous microsatellite instability-high cancer parallel those of the overall microsatellite instability-high set, but it is not known whether the same is true for signet ring cell carcinoma, particularly given the fact that signet ring histology is a well-documented adverse prognostic factor. We recorded age, sex, tumor size, site, grade, stage, histologic pattern, growth pattern, Crohn-like reaction, vascular invasion and tumor-infiltrating lymphocytes in 72 resected signet ring cell carcinomas of the colorectum. Microsatellite instability was determined by a combination of polymerase chain reaction and immunohistochemical stains for hMLH1, hMSH2 and hMSH6. Tumors with instability at >30% of informative markers and/or loss of hMLH1 or hMSH2 expression were designated microsatellite instability-high; all others were classified as MSS. A total of 22 (31%) signet ring cell carcinomas were microsatellite instability-high. Compared to MSS signet ring cell carcinoma, they were more likely to be right-sided (81 vs 45%, P=0.005) and to affect older patients (68 vs 26%, P=0.0007) of female sex (59 vs 28%, P=0.03). Crohn-like reaction (45 vs 16%, P=0.02) and high tumor infiltrating lymphocyte counts (32 vs 8%, P=0.03) were more common in the microsatellite instability-high setting. There was no significant difference in 5-year survival in microsatellite instability-high vs MSS patients (41 vs 34%, P=0.3). In conclusion, approximately one-third of signet ring carcinomas of the colorectum are microsatellite instability-high. Microsatellite instability-high signet ring carcinomas share clinicopathologic features with other microsatellite instability-high cancers: older age group, female preponderance, right-sided location, Crohn-like reaction and numerous tumor-infiltrating lymphocytes. Microsatellite instability status does not appear to be a significant predictor of survival in signet ring cell carcinoma of the colorectum.

The role of microsatellite instability in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix

Objectives This study was conducted to define the role of microsatellite instability (MSI) in cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC) of the cervix. We also tested the validity of using markers recommended for MSI study in colonic carcinoma by the National Cancer Institute (NCI) for cervical neoplasm. Methods Twenty normal cervical, 24 low-grade CIN (CIN-L), 59 high-grade CIN (CIN-H), and 93 SCC tissues were examined for MSI after microdissection. A polymerase chain reaction based MSI detection was performed using five markers recommended by the NCI for colonic cancer (panel one) as well as five other markers (panel two) found to be informative in earlier studies. High-frequency MSI (MSI-H) was defined as instability in ≥2 of 5 loci if one panel was used and ≥30% of loci when more than five loci were used. Low-frequency MSI (MSI-L) was diagnosed if instability was noted but did not meet the criteria of MSI-H. Findings were correlated with clinicopathologic information. Results The combined use of panel one and two markers showed no MSI in normal cervical or CIN-L tissue, MSI-L in 1 CIN-H (1.7%), MSI-L in 16 (17.2%), and MSI-H in 11 (11.8%) SCC, respectively. The NCI-recommended panel alone detected 19 of 27 MSI-positive SCC. MSI-positive was not related to patient age, disease stage, and tumor grade. The overall survival of MSI-positive patients was significantly worse than that of microsatellite stable patients ( P = 0.02). An increasing trend of MSI-H rate with higher disease stages was noted ( P = 0.035) but MSI-H was not associated with poor prognosis. Conclusions The NCI recommended panel of markers might not be useful in MSI study for SCC and using more than five markers improves the MSI detection. MSI is rare in cervical dysplasia but is present in a subset of SCC. The association between MSI-positivity and prognosis awaits future confirmation.

Microsatellite instability is an independent indicator of recurrence in sporadic stage I-II endometrial adenocarcinoma.

The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients. Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS). Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P =.003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P =.0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles. The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.