Can the CIMP status be used to stratify the colorectal cancer patients who respond to adjuvant chemotherapy?

Recently, Jover et al. [1] reported the relationship between the CpG island methylator phenotype (CIMP) and the likelihood of responding to 5-fluorouracil (FU)-based adjuvant chemotherapy for patients with stage II and III colorectal cancer [1]. Those authors suggested that adjuvant 5-FU chemotherapy improved the disease-free survival only in the patients with CIMP-negative colorectal cancer, although the CIMP status did not independently affect the disease-free survival in their patient cohort. There are several interesting aspects of this study that deserve attention. First, the DNA methylation/CIMP status in colorectal cancer has been reported to have variable prognostic significance in different studies [2–4]. Shen et al. [2] suggested that concurrent methylation of two or more genes of the CIMP-associated subset (MINT1, MINT3, p14, and p16) defined a group of cases with markedly reduced overall survival and the hazard ratio was 3.22 (P< 0.0001 on the multivariate analysis) and they reached conclusions similar to those of Jover et al. [1] However, Van Rijnsoever et al. [4] used a definition of two or more CpG sites methylated out of three (p16, MDR1, and MINT-2) and they reported that the CIMPþ status is a predictive factor for a survival benefit from 5-FU chemotherapy in colorectal cancer patients and this is independent of the MSIþ status and the p53 status. As pointed by Jover et al. [1], some of the contradictory results may be due to the discrepancies of the methodology that were used in different studies (the techniques and markers), and at present, there is no consensus definition for the CIMP marker panel. In their current study, Jover et al. [1] used a new panel (CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1) described by Weisenberger et al. [3]. However, the evaluation of Ogino et al. [5] and Shen et al. [2] did not support the notion that this new panel outperformed the classic panel consisting of five traditional CIMP markers (CDKN2A, MINT1, MINT2, MINT31, and MLH1). In addition, the problem of the cutoff to stratify CIMP has not been sufficiently discussed, leading to different thresholds in various reports. Jover et al. [1] used the cutoffs of 5% and 10% for the markers and these figures were chosen after determining the average methylation level of each marker in normal colonic mucosa samples. However, these cutoffs would be expected to vary from gene to gene and they may be affected by many experimental parameters, such as types/batches of the primers and probes, as well as the different patient populations. Second, it is unclear whether there is a relationship between the CIMP status and the response to adjuvant 5-FU chemotherapy only in patients with stage II colorectal cancer. This study by Jover et al. [1] did not address the impact of adjuvant 5-FU chemotherapy relative to the CIMP status in each subgroup (stage II vs. stage III). Currently, patients with resected stage III colon cancer should be considered for adjuvant chemotherapy because of the significant survival benefit of adjuvant therapy. However, the decision-making regarding the use of adjuvant therapy for patients with stage II disease is not simple, although high-risk stage II patients (T4, poor histologic grade, lymphovascular invasion, perineural invasion, obstruction, and less than harvested 12 lymph nodes) have been recommended to receive adjuvant therapy. Therefore, I believe the CIMP status needs to be evaluated through a subgroup analysis of patients with stage II disease. More accurate identification of patients who are at a high risk of recurrence and appropriate selection of adjuvant therapy for stage II colon cancer may improve the patient’s oncologic outcomes. Finally, as Jover et al. [1] stated in their report, their patient population came from an observational study, and the decisions about adjuvant therapy were not properly randomized. Of the 196 patients with stage II and III cancer, only 101 (51.5%) received adjuvant 5-FUbased chemotherapy. Moreover, adjuvant therapy was more frequently administered to the CIMP-negative patients. Therefore, I believe that the study by Jover et al. should raise a few appropriate questions about these issues. Further randomized trials are needed to reevaluate and confirm these observations, and to allow better identifying the patients with a high risk of recurrence and who may benefit from adjuvant therapy.