Molecular Markers Identify Subtypes of Stage III Colon Cancer Associated With Patient Outcomes

Abstract

Background & Aims Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. Methods We used a PCR-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n=783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. Results Tumors were categorized into 5 subtypes based on MMR status and detection of BRAFV600E or mutations in KRAS, which were mutually exclusive. Three subtypes were MMR proficient: those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAFV600E were proximal (76%), high grade (44%), N2 stage (59%), and detected in women (59%), compared to MMR-proficient tumors without BRAFV600E or mutations in KRAS (33%, 19%, 41%, and 42%, respectively; all P<.0001). A significantly lower proportion of patients with MMR-proficient tumors with BRAFV600E (hazard ratio, 1.43; 95% confidence interval, 1.11–1.85, Padjusted=.0065) or mutant KRAS (hazard ratio, 1.48; 95% confidence interval, 1.27–1.74, Padjusted<.0001) survived disease free for 5 years compared to patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival of patients with MMR-deficient sporadic or familial subtypes was similar to that of patients with MMR-proficient tumors without BRAFV600E or mutations in KRAS. The observed differences in survival of patients with different tumor subtypes was validated in an independent cohort. Conclusions We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAFV600E or mutations in KRAS had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAFV600E or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…In prospectively col- (Andre et al, 2015;Gavin et al, 2013;Guastadisegni et al, 2010;Klingbiel et al, 2015;Popat et al, 2005;Roth et al, 2012;Sinicrope et al, 2015). lected tumor tissue MSI was detected in 314 of 2580 stage-III CRCs and was prognostic overall for time to relapse (TTR), but not for DFS or OS (Sinicrope et al, 2013a).…”

“…2. Prognosis -Several studies have shown dMMR CRC has a better prognosis than MMR proficient (pMMR) CRC Guastadisegni et al, 2010;Klingbiel et al, 2015;Popat et al, 2005;Roth et al, 2010;Sinicrope et al, 2015). MSI tumours are less prone to lymph node (Mohan et al, 2016) and synchronous liver metastasis (Nordholm-Carstensen et al, 2015).…”

The pathomorphologist’s role in the era of personalised therapy regarding the case of colorectal tumours

“…In such cases, the patients are mostly women above 70 years of age with tumours located in the proximal part of the colon. Here mucinous and poorly differentiated cancers are dominating with metastases mostly to the lymph nodes and more rarely to the lungs [36,37]. The BRAF mutation indicates an adverse course of the disease [38], yet its prediction significance still remains an issue that requires some further research [34].…”

Serrated polyps as precursor lesions of colorectal cancer: current status and future directions. Mini-review.

“…The difference between the proximal and distal localization is also confi rmed with genomic profi les: the majority of proximal serrated polyps developed after BRAF mutations, they are CIN-negative with high levels of MSI and CIMP. The majority of distal tumours develop after a KRAS mutation, they are CIN-positive with low levels of MSI and CIMP [23].…”