Primary tumor sidedness is an independent prognostic marker for survival in metastatic colorectal cancer: Results from a large retrospective cohort with mutational analysis

Abstract

Recent reports demonstrate inferior outcomes associated with primary right‐sided vs left‐sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow‐up 30.4 months). Mutational profiling for >150 mutations across commonly mutated cancer genes including RAS, PIK3CA, BRAF, and PTEN as well as treatment data, including receipt of a biologic agent, were collected. Univariable/multivariable models were used to analyze relationships between collected data and OS. Among 367 patients, sidedness breakdown was as follows: 234 left (64%), 133 right (36%). 56% were male, with a median age at diagnosis of 57 (range 24‐89). A total of 143 patients had RAS mutations. Five‐year OS was 41%, median OS was 54 months (range 1‐149). Five‐year OS for left‐ vs right‐sided tumors was 46% vs 24% (P < .0001). On univariable analysis, among both RAS wildtype and mutant tumors, left‐sided tumors continued to have improved OS vs right‐sided tumors (HR: 0.49, 95% CI: 0.34‐0.69 RAS wildtype; HR: 0.61, 95% CI: 0.40‐0.95 RAS mutant). Left‐sidedness was an important prognostic factor for OS among RAS wildtype patients despite treatment with or without a biologic agent (P < .05). Left‐sidedness remained significant for improved OS on multivariable analysis (P < .0001). Left‐sided primary tumor remained most important prognostic factor for OS, even when adjusting for mutational status and receipt of biologic agent.

Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study

“…Among RAS wt patients treated with anti-EGFR agents, we observed a significantly superior OS for those with primary tumor located on the lift side, with a trend toward superiority for PFS. Similarly, in the retrospective analyses of the CRYSTAL and FIRE-3 [29], AIO KRK-0104 trial [31], and CALGB/SWOG 80405 trial [28] higher OS and PFS were found among patients with LCC treated with anti-EGFR agents. A superior OS for patients with LCC treated with Panitumumab or Cetuximab has also been reported by Arnold et al in their pooled analysis of randomized trials [30].…”

“…Evidences have been provided suggesting that primary tumor location is not only prognostic, but also predictive of the efficacy of anti-EGFR agents. In fact, several retrospective studies and meta-analyses have suggested a relevant prognostic role of primary tumor location, with RCC being associated with an inferior outcome [20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Some studies have also suggested that the site of the primary tumor predicts for the efficacy of anti-EGFR monoclonal antibodies, with this being restricted to RAS wt LCC [28][29][30][31][32][33][34].…”

“…However, very few of the available studies have specifically addressed these issues in the population of patients with RAS wt metastatic tumors, which may be characterized by a more favorable prognosis as compared to the RAS-mutated ones [35]. Moreover, in some cases the effect of sidedness was excluded for RAS mutated tumors [31].…”

Radiomics analysis of pre-treatment [18F]FDG PET/CT for patients with metastatic colorectal cancer undergoing palliative systemic treatment

“…Sidedness of the primary tumour is a surrogate prognostic biomarker, and lesions originating from right-sided primary tumours harbour genetic alterations associated with resistance to anti-EGFR therapy [ 31 , 32 ]. Indeed, using the [ 18 F]FDG PET data, we found poorer metabolic features for patients with right-sided disease, such as a higher tumour bulk in patients in the first-line group and less spherical disease in patients in the third-line group.…”

Left-sided location is a risk factor for lymph node metastasis of T1 colorectal cancer: a single-center retrospective study

“…Compared with right-sided CRC, left-sided advanced (T2–T4) CRC has the following features: longer overall survival; younger patients; higher number of male patients; less mucinous or poorly differentiated histology; less associated with BRAF and APC mutations, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP); and better response to anti-epidermal growth factor receptor (EGFR) therapies. In addition, apart from having a different embryological origin, the proximal colon from the midgut and the distal colon and the rectum from the hindgut, the left-sided colon displays peculiar differences in its mucosal immunology, probably because of differences in the gut microbiota [ 8 – 13 ].…”