Concomitant dysregulation of the estrogen receptor and BRAF/MEK signaling pathways is common in colorectal cancer and predicts a worse prognosis.

PURPOSE: Recurrence is a major cause of colorectal cancer (CRC)-related death. As yet, the accurate identification of CRC patients at high risk of recurrence is still a major clinical challenge. Previously, we found that an estrogen receptor (ER) pathway gene signature may predict disease recurrence in CRC patients. The aim of this study is to evaluate the potential application of additional pathway-specific gene signatures in the prediction of CRC recurrence.

METHODS: The activities of 26 cancer-related pathways in CRC were semi-quantified using gene signature-based Bayesian binary regression analysis, and putative associations of the pathways with cancer recurrence risk were assessed using survival analysis.

RESULTS: Among the 26 pathways tested, inactivation of the estrogen receptor (ER) pathway was found to be one of the most common events in CRC. Inactivation of this pathway was found to be frequently accompanied by over-activation of the BRAF/MEK pathway, and these two pathways were found to be associated with opposite effects on several clinicopathological CRC features, including microsatellite instability, subsite location, advanced stage and recurrence. Survival analysis of four independent CRC patient cohorts revealed that while the BRAF/MEK pathway was more strongly associated with recurrence than the ER pathway in mixed-stage CRCs, the ER pathway was a better predictor of recurrence than the BRAF/MEK pathway in stage II CRC. A combined use of these two pathways improved the prediction of CRC recurrence in both mixed stage CRC (n = 1122; overall HR: 2.518, 95% CI: 1.570-4.038, p < 0.001) and stage II CRC (n = 535; overall HR: 1.976, 95% CI: 1.306-2.989, p = 0.001).

CONCLUSIONS: Combined activity of the ER and BRAF/MEK pathways may represent a novel biomarker for CRC prognosis and clinical management.