Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

Abstract

Background Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left‐sided tumors may exhibit superior survival compared with right‐sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2‐negative stage II CRC tumors are associated with a lower rate of disease‐free survival than CDX2‐positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Materials and Methods We retrospectively analyzed patients with T3 mismatch repair‐proficient (MMR‐P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location. Results The analysis included 1,147 patients with MMR‐P stage II CRC (median age 69 years [range 29–93]). Tumor distribution across the colon was as follows: 46% (n = 551) were right‐sided and 54% (n = 596) were left‐sided. RS was higher in right‐sided tumors (p = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = .04). Right‐sided tumors exhibited more CDX2‐negative tumors (p = .07). Conclusion Our study indicates that right‐sided colorectal tumors may display worse prognosis compared with left‐sided tumors in MMR‐P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment. Implications for Practice Sidedness matters, even in stage II colorectal cancer (CRC). Using two previously established prognostic tools, the Oncotype DX assay and CDX2 expression, this study found that right‐sided tumors may display worse prognosis compared with left‐sided tumors in mismatch repair‐proficient stage II CRC. Therefore, primary tumor location should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

Is primary sidedness a prognostic factor in patients with resected colon cancer liver metastases (CLM)?

“…However, these studies have consistently demonstrated the negative impact of rightsided colon tumors in patients with CS III. [11][12][13][14] Few studies to date have evaluated patients with resected metastatic disease. Retrospective analyses presented at the ASCO 2017 Gastrointestinal Cancers Symposium (including two American populations and one Japanese population) considered patients who underwent resection of liver metastases, and the results suggest that patients with right-sided colon tumors had an inferior overall survival (OS) but no significant difference in disease-free survival (DFS).…”

Poorer Survival in Patients with Cecum Cancer Compared with Sigmoid Colon Cancer

“…Right-sided and left-sided colons deriving from different embryologic origin are clinically and molecularly distinct. However, the influence of primary tumor locations on the prognosis remains controversial [ 20 , 22 , 23 , 24 , 25 ]. In the present study, we found that patients with RCC had worse CSS and OS than LCC, and the two tumor locations with the greatest survival difference were cecum and sigmoid colon.…”

“…By analyzing the data of patients with non-metastatic, invasive right-sided adenocarcinoma of the colon from 1988 to 2014 who underwent partial colectomy in SEER, Nasseri at al found that cecum cancers were prone to poorer disease-specific survival (median 86.0, 93.0, and 89.0 months, respectively, p < 0.001) and OS (median not reached, p < 0.001) compared with cancers in other sites of the right colon [ 19 ]. In addition, Ben-Aharon et al also found that the Oncotype Recurrence Score, a clinically validated predictor of recurrence risk in patients with stage II CRC, gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = 0.04) [ 20 ]. In the present study, patients with cecum cancer had more poorly differentiated tumor, advanced LNM, and late TNM stage compared with sigmoid colon cancer, which is in line with results of previous studies [ 1 , 2 , 9 , 28 ].…”

“…Ward et al hypothesized three pathways through which tumor site impacts survival differences, including TNM stage, microsatellite instability (MSI), and other genetic drivers [ 14 ]. Many previous studies have suggested that the potential molecular mechanism contributing to the different prognosis between RCC and LCC might be associated with differences in gene expression and signaling pathways [ 14 , 20 , 28 , 32 , 33 , 34 , 35 , 36 ]. Some chemotherapy regimens were also found to have different efficacy between LCC and RCC due to different microsatellite status [ 34 ].…”

“…Therefore, the conflicting results may be partly due to the inconsistency of location grouping criteria, and the dichotomy model (right-sided vs. left-sided colon) may be inappropriate for the study of colon cancer [ 16 , 17 , 18 , 19 ]. Moreover, the prognostic differences between specific subsites (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon) have also been reported in a few studies [ 19 , 20 , 21 ]. In order to further explore the effects of tumor locations on prognosis, it is essential to find two parts with the greatest survival differences by comparing different primary tumor locations.…”