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Why a One Size Fits All Approach to RAS Might Not Fit Colorectal Cancer

Jonathan M. Loree and Scott Kopetz

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Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes

Michael S. Lee, David G. Menter, and Scott Kopetz

Although clinical management of colon cancer generally has not accounted for the primary tumor site, left-sided and right-sided colon cancers harbor different clinical and biologic characteristics. Right-sided colon cancers are more likely to have genome-wide hypermethylation via the CpG island methylator phenotype (CIMP), hypermutated state via microsatellite instability, and BRAF mutation. There are also differential exposures to potential carcinogenic toxins and microbiota in the right and left colon. Gene expression analyses further shed light on distinct biologic subtypes of colorectal cancers (CRCs), with 4 consensus molecular subtypes (CMSs) identified. Importantly, these subtypes are differentially distributed between right- and left-sided CRCs, with greater proportions of the “microsatellite unstable/immune” CMS1 and the “metabolic” CMS3 subtypes found in right-sided colon cancers. This review summarizes important biologic distinctions between right- and left-sided CRCs that likely impact prognosis and may predict for differential responses to biologic therapy. Given the inferior prognosis of stage III–IV right-sided CRCs and emerging data suggesting that anti–epidermal growth factor receptor antibody therapy is associated with worse survival in right-sided stage IV CRCs compared with left-sided cancers, these biologic differences between right- and left-sided CRCs provide critical context and may provide opportunities to personalize therapy.

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A New Surveillance Algorithm After Resection of Colorectal Liver Metastases Based on Changes in Recurrence Risk and RAS Mutation Status

Yoshikuni Kawaguchi, Scott Kopetz, Heather A. Lillemoe, Hyunsoo Hwang, Xuemei Wang, Ching-Wei D. Tzeng, Yun Shin Chun, Thomas A. Aloia, and Jean-Nicolas Vauthey

Background: The optimal surveillance strategy after resection of colorectal liver metastases (CLM) is unknown. We evaluated changes in recurrence risk after CLM resection and developed a surveillance algorithm. Methods: Patients undergoing CLM resection during 1998 to 2015 were identified from a prospectively compiled database and analyzed if they had the potential for follow-up longer than the longest observed time to recurrence in this cohort. Changes in recurrence risk and risk factors for recurrence were evaluated. All statistical tests were 2-sided. Results: Among 2,105 patients who were initially identified and underwent CLM resection, the latest recurrence was observed at 87 months; 1,221 consecutive patients from 1998 through 2011 with the potential for at least 87 months of follow-up were included. The risk of recurrence was highest at 0 to 2 years after CLM resection, lower at 2 to 4 years after CLM resection, and steadily lower after 4 years after CLM resection. Factors associated with increased recurrence risk at the time of surgery were primary lymph node metastasis (hazard ratio [HR], 1.54; 95% CI, 1.21–1.97; P<.001), multiple CLM (HR, 1.31; 95% CI, 1.06–1.63; P=.015), largest liver metastasis diameter >5 cm (HR, 1.64; 95% CI, 1.23–2.19; P<.001), and RAS mutation (HR, 1.29; 95% CI, 1.04–1.59; P=.020). In patients without recurrence at 2 years, the only factor still associated with increased recurrence risk was RAS mutation. In those patients, the recurrence rate at 4 years was 59.3% in patients with RAS mutation versus 27.8% in patients with RAS wild-type (P=.019). Conclusions: For patients who have undergone CLM resection, we propose surveillance every 3 to 4 months during years 0 to 2, every 3 to 4 months (if mutant RAS) versus every 4 to 6 months (if RAS wild-type) during years 2 to 4, and every 6 to 12 months if recurrence-free at 4 years.