Clinical utility of colon cancer molecular subtypes: Validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort.

Abstract

3509 Background: The molecular subtyping of colon cancers (CC) has been the subject of several recent publications, leading to an international consensus. The clinical relevance of these molecular classifications remains to be evaluated on large prospective patient cohorts using a tool that can be widely used on formalin-fixed paraffin-embedded (FFPE) samples. Methods: We aimed to evaluate the clinical relevance of two molecular subtyping systems, CMS (Guinney et al. 2015) and CCMST (Marisa et al. 2013), on the PETACC-8 cohort, a randomized phase III trial comparing adjuvant FOLFOX with or without cetuximab in patients with stage III CC. For each of these two classification systems, a predictor tool was developed and adapted to FFPE samples. The NanoString nCounter platform was used to screen 196 genes. Predictors were built from 249 frozen tumor samples previously used to build our classification system and 61 new paired FFPE/frozen samples. Both predictors were then applied to 1781 PETACC-8 FFPE samples. Subtypes associations to clinical and molecular features were analyzed. Results: The CMS predictor assigned 297 samples to CMS1 (17%), 585 to CMS2 (34%), 68 to CMS3 (4%) and 770 to CMS4 (45%). CMS were significantly associated with several molecular and clinical features, including MSI status (49% in CMS1, p < 0.001), CIMP status (47% in CMS1, p < 0.001), KRAS mutation (75% in CMS3, p < 0.001), BRAF mutation (34% in CMS1, p < 0.001), tumor location (less proximal tumors in CMS2, p < 0.001), validating the predictor tool developed. The classification was significantly associated to prognosis in multivariate analysis, CMS4 subtype having a shorter overall survival (hazard ratio = 1.7, p= 0.021). A deleterious effect of cetuximab was observed in CMS1 (p < 0.05). Similar results were obtained with the CCMST classification. Conclusions: We validated molecular CC subtyping predictors for both CMS and CCMST classifications on PETACC-8 FFPE samples. The prognostic value of CMS and CCMST classifications was confirmed, stem-like tumors being associated with a poor prognosis. These results pave the avenue for widely use of the CC molecular classification in clinical routine.

Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial

“…For both, RASwt (P < 0.001) and RASmt (P ¼ 0.025) tumors, CMS was able to significantly predict survival with CMS1 being the subgroup with worst survival and CMS2 for RASwt and CMS4 for RASmt tumors defining the respective cohorts with the longest survival. This is in line not only with the prognostic relevance of CMS reported before [5] but also with data from the adjuvant PETACC8 study as well as the palliative CALGB80405 study, both presented at ASCO annual meeting in 2017 [11,13]. While FIRE-3 is the only study with FOLFIRI as the predefined chemotherapeutic backbone, there seems to be no significant [14] difference in the prognostic effect of CMS with regard to FOLFOX or FOLFIRI treatment [14].…”

“…In CALGB80405, treatment results obtained in CMS1 were significantly in favor of the bevacizumab arm, while cetuximab-treated patients had a markedly worse outcome [13]. This association of CMS1 and poor efficacy of cetuximab has also been observed in the adjuvant PETACC8 trial, where CMS1 patients treated with FOLFOX plus cetuximab had a shorter disease-free survival compared with FOLFOX alone [11]. This observation supports the hypothesis that in CMS1-patients a detrimental effect is induced when oxaliplatin-based therapy is combined with cetuximab.…”

“…This observation may suggest that all CMS cohorts have a similar ability to progress from UICC stage II/III to the metastatic stage IV. However, analyses of the National Surgical Adjuvant Breast and Bowel Project-C07, Pan-European Trials in Alimentary traCt Cancer (PETACC)-3, and PETACC-8 trials demonstrate that not all tumors have the same risk of disease recurrence [10][11][12]. For patients in the adjuvant setting, CMS4 had a higher risk of disease recurrence [11].…”

“…However, analyses of the National Surgical Adjuvant Breast and Bowel Project-C07, Pan-European Trials in Alimentary traCt Cancer (PETACC)-3, and PETACC-8 trials demonstrate that not all tumors have the same risk of disease recurrence [10][11][12]. For patients in the adjuvant setting, CMS4 had a higher risk of disease recurrence [11]. Those differences may be attributed to the relatively small number of patients in FIRE-3 when compared with the number of adjuvant trials.…”

Current Update of Laboratory Molecular Diagnostics Advancement in Management of Colorectal Cancer (CRC)

“…Notably, positive drug response to bevacizumab and cetuximab was demonstrated specifically in CMS1 and CMS4, respectively. [100][101][102][103]. Significant correlations with known CRC biomarkers such as MSI-H, KRAS, and BRAF mutations were also reported [100].…”