Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan BDoes microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer 45: 1890-1896

Department of Oncology, APHP, Hôpital Avicenne, Bobigny, France.
European journal of cancer (Oxford, England: 1990) (Impact Factor: 5.42). 06/2009; 45(10):1890-6. DOI: 10.1016/j.ejca.2009.04.018
Source: PubMed


Microsatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial.
Studies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI).
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)).
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.

Download full-text


Available from: Gerard Yves Perret,
  • Source
    • "Morphologic characteristics of MMR deficient tumors include an expanding tumor growth pattern, poor and mucinous differentiation, a solid/medullary growth pattern, lack of “dirty necrosis” and lymphocytic reactions such as peritumoral lymphocyte infiltration, Crohn-like reactions and presence of tumor-infiltrating lymphocytes (TIL) [6,8-10]. Increasing evidence suggests that the identification of MMR deficient tumors provides clinically relevant information, but universal MMR screening has not yet gained widespread application in clinical practice [11-13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification of mismatch-repair (MMR) defective colon cancer is clinically relevant for diagnostic, prognostic and potentially also for treatment predictive purposes. Preselection of tumors for MMR analysis can be obtained with predictive models, which need to demonstrate ease of application and favorable reproducibility. We validated the MMR index for the identification of prognostically favorable MMR deficient colon cancers and compared performance to 5 other prediction models. In total, 474 colon cancers diagnosed >= age 50 were evaluated with correlation between clinicopathologic variables and immunohistochemical MMR protein expression. Female sex, age >=60 years, proximal tumor location, expanding growth pattern, lack of dirty necrosis, mucinous differentiation and presence of tumor-infiltrating lymphocytes significantly correlated with MMR deficiency. Presence of at least 4 of the MMR index factors identified MMR deficient tumors with 93% sensitivity and 76% specificity and showed favorable reproducibility with a kappa value of 0.88. The MMR index also performed favorably when compared to 5 other predictive models. The MMR index is easy to apply and efficiently identifies MMR defective colon cancers with high sensitivity and specificity. The model shows stable performance with low inter-observer variability and favorable performance when compared to other MMR predictive models.
    BMC Clinical Pathology 12/2013; 13(1):33. DOI:10.1186/1472-6890-13-33
  • Source
    • "Cost-effectiveness data suggest IHC is a better first step because targeted DNA testing can be peformed based on IHC findings. However, there is also the argument that MSI-high (MSI-H) tumors may be less reponsive to 5FU, thus providing additional treatment information (Des Guetz et al. 2009; Sinicrope and Sargent 2009). The high concordance between absent protein staining by IHC and a MSI-H pattern in colorectal tumors allows for either method to be a reasonable approach (Palomaki et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: An electronic survey of the National Society of Genetic Counselors Cancer Special Interest Group was conducted in July 2011 to assess Lynch syndrome tumor screening programs and identify barriers to implementation. Over half of respondents (52.8 %) reported having a routine Lynch syndrome tumor screening protocol for newly diagnosed colon and/or endometrial cancers, and approximately half of these used a universal approach. There was an increase in the number of those screening over time, especially in the past 3 years. Tumor screening methods varied; 34/53 (64.2 %) started with immunohistochemistry, 11/53 (20.8 %) started with microsatellite instability testing and 8/53 (15.1 %) performed both on newly diagnosed colorectal tumors. Just 21.7 % (23/106) of respondents indicated they have a tumor screening program in place for newly diagnosed endometrial cancers. Written consent is rarely obtained (7.1 %) and the method of how results were returned to the patient was variable among respondents. Prevalent barriers to implementation were concern about cost, bringing key players together and convincing medical staff of the necessity. Use of Lynch syndrome tumor screening is in clinical practice, but protocols vary widely. This survey provides a glimpse of current practices and common barriers, and identifies the need for tumor screening algorithms with outcomes data.
    Journal of Genetic Counseling 05/2013; 23(1). DOI:10.1007/s10897-013-9603-5 · 2.24 Impact Factor
  • Source
    • "CIMP-high tumours form part of the serrated pathway and develop from precursor lesions, which have a different histological appearance to standard colonic adenomas [16,17]. In addition to the known difference in prognosis for these tumours, there has also been the suggestion that they may also be associated with a lack of clinical benefit from standard 5-fluorouracil (5-FU)-based chemotherapy [18,19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.
    01/2013; 4(1):3. DOI:10.1186/1878-5085-4-3
Show more