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Katherine Van Loon and Alan P. Venook

No definitive evidence shows benefit from adjuvant therapy for stage II colon cancer, and its role remains controversial. Although a trend toward improved disease-free survival (DFS) has been reported in subgroup analyses from clinical trials that included patients with stage II disease, time trends for recurrences of stage II disease indicate that DFS is not a reliable surrogate for overall survival (OS). Several clinical trials have been conducted to answer the question of whether adjuvant therapy benefits patients with stage II disease, but none have been adequately powered to detect what would be a small OS benefit. Features that are currently used to assign high risk for recurrence (tumor perforation, lymphovascular invasion, <12 lymph nodes analyzed, and poorly differentiated histology) may or may not be associated with clinical outcome, and they are not predictive of treatment benefit. Risks of adjuvant therapy are nonnegligible and must be weighed against a large number of patients needed to be treated to realize benefit. Future research should aim to answer the questions of whether microsatellite instability, nodal sampling, molecular markers, and genetic signatures are useful tools to guide decision-making. Given what is now known, the viewpoint is that the aggregate data do not support adjuvant therapy for patients with normal-risk stage II colon cancer.

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Chloe E. Atreya, Claire Greene, Ryan M. McWhirter, Nabia S. Ikram, I. Elaine Allen, Katherine Van Loon, Alan P. Venook, Benjamin M. Yeh and Spencer C. Behr

Background: BRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan-Meier and Cox regression methods. Results: The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02). Conclusions: Greater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location.