Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype

Abstract

AIMTo identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer.METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed.RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence.CONCLUSIONWe report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.

DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer

“…Although a significant relationship was demonstrated between CIMP-intermediate status and EMVI positivity, this was not translated in to a disease-free or overall survival disadvantage for CIMP-intermediate patients based on Kaplan-Meier analysis, despite EMVI-positivity being an independent risk-factor for disease recurrence (Cox Proportional Hazard r D 5.98 (1.10-32.50), p D 0.038). These findings are in keeping with prior results in a similar cohort from our own unit, 37 which indicate a positive correlation between CIMP-high status and EMVI in a series of 160 rectal cancers undergoing neoadjuvant treatment; although this did not translate into a significant relationship to survival. There was also no significant relationship between KRAS or BRAF and CIMP.…”

“…42,43 Although patients receiving neoadjuvant therapy were excluded in our study, the relationship between methylation and response to CRT (neoadjuvant and adjuvant) is likely to be significant, as has been identified in previous studies. 37,44 The benefits of neoadjuvant therapy in rectal cancer are clear, but it is acknowledged that a tumour's response to neoadjuvant therapy is currently not predictable, 45 and identifying significant factors that affect response may be beneficial in managing patients. Currently, cNC status, mucinous tumours, and poorly differentiated tumours have all been associated with poor response to neoadjuvant therapy, 46 but the prognostic values of these measures is limited and has no clinical utility in restricting access to pre-surgical therapies.…”

Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis

“…The pooled OR for stage III/IV disease (compared to I/II disease) in the CIMP-H subgroup compared with the CIMP-0 subgroup was 1.01 (95% CI = 0.87-1.17, I 2 = 48.1%). In pooled analysis, no association was observed for CIMP with N staging [OR for N1/2 vs N0 = 1.14 (95% CI = 0.87-1.49, I 2 = 38.9%)] [16] , [20] , [21] , [25] , [36] , [39] , [50] , [51] , [61] , [65] , [69] , [71] , [72] , [75] , [77] , [83] , [94] and M staging [OR for M1/M2 vs M0 = 0.92 (95% CI = 0.56-1.57, I 2 = 38.5%)] [20] , [39] , [45] , [53] , [65] , [95] . Similarly, no association of CIMP was observed with synchronous CRC [58] , [96] , [97] or presence of liver metastases [61] , [98] , [99] .…”

“…In contrast, the likelihood of CIMP in Hispanic patients was indistinguishable from non-Hispanic white patients (OR = 1.04, 95% CI = 0.70-1.55). The association of CIMP-H with gender was studied across 56 studies, representing a total of 22,950 CRC patients [9] , [16] , [17] , [19] , [20] , [21] , [22] , [24] , [25] , [27] , [28] , [30] , [31] , [33] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] . The pooled prevalence of CIMP-H in males and females was 18% (95% CI = 15%-20%) and 26% (95% CI = 22%-29%), respectively, indicating a predisposition for CIMP-H tumors towards female gender (pooled OR = 1.59, 95% CI = 1.40-1.81) .…”

“…The pooled OR for right-sided location (as opposed to left-sided or rectal location) in the CIMP-H subgroup compared with the CIMP-0 subgroup was 4.84 (95% CI = 3.60-5.61, I 2 = 80%). The association of CIMP with T staging was investigated across 11 studies, representing 3255 cases [20] , [21] , [36] , [50] , [51] , [62] , [65] , [69] , [71] , [77] , [89] . The pooled OR for T-stage (T3/T4) (as compared to T1/T2) in the CIMP-H subgroup compared with CIMP-0 subgroup was 2.03 (95% CI = 1.16-3.55, I 2 = 61%).…”