KRAS Status is Associated with Metabolic Parameters in Metastatic Colorectal Cancer According to Primary Tumour Location

Abstract

Colorectal cancer (CRC) is characterized by complex interplay between macroenvironmental factors and tumour microenvironment, leading to variable outcomes in CRC patients. To date, there is still a need to identify macroenvironment/microenvironment factors that could define subgroup of patients that would benefit from specific anti-cancer treatment in order to improve patient selection for individualized targeted-based therapy. Aim of this study was to evaluate associations between metabolic parameters and KRAS status in metastatic CRC (mCRC) according to a new tumour site classification. Retrospective data were extracted from a total of 201 patients diagnosed with mCRC between 2012 and 2017 extracted from an established CRC database at our tertiary institute. Clinical-pathological data, including age, gender, BMI, hypertension, diabetes, pre-CRC diagnosis serum lipid levels and KRAS status were recorded. Categorical characteristics were compared using chi-squared test. Continuous characteristics were compared using Mann-Whitney U test. Log rank test was used to compare hazards for survival. In all comparisons, a two-sided P value <0.05 was considered statistically significant. Out of 201 patients, 170 patients with complete serum lipid profile were included in the analysis. In recto-sigmoid cancers there was a statistically significant association between high cholesterol:high-density lipoprotein (chol:HDL) ratio and KRAS mutation (OR 2.69, 95% CI 1.1-6.4, p = 0,02). In non recto-sigmoid cancers, high cholesterol was associated with KRAS WT (OR 0.39, CI 0.15-0.97, p = 0.04). In 22 patients with KRAS mutated recto-sigmoid cancer stage IV at diagnosis normal chol:HDL ratio was associated with a trend to better survival (p = 0.06). High chol:HDL ratio was significantly associated with KRAS mutated metastatic recto-sigmoid cancers. A subgroup of mCRC patients with KRAS mutated recto-sigmoid cancer may benefit from optimal lipid lowering treatment.

Keywords: Colorectal cancer; KRAS; Lipids; Metabolic syndrome; Tumour location.

Fig. 1

Survival analysis. Kaplan Meier survival curves of 22 patients with KRAS mutated recto-sigmoid cancer stage IV at diagnosis stratified by chol:HDL ratio (a); survival curves of 19 patients with KRAS mutated non recto-sigmoid cancers stage IV at diagnosis stratified by chol:HDL ratio (b). Patients with KRAS mutated recto-sigmoid cancer with normal chol:HDL ratio exhibited a better survival compared to patients with high chol:HDL ratio, not observed in non recto-sigmoid cancer

Fig. 2

Survival analysis. Kaplan Meier survival curves of 26 patients with KRAS WT recto-sigmoid cancer stage IV at diagnosis stratified according to chol:HDL (a); Kaplan Meier survival curves of 26 patients with KRAS WT non recto-sigmoid cancer stage IV at diagnosis stratified according to chol:HDL (b). Results revealed no difference in survival in patients with KRAS WT cancer stratified by chol:HDL ratio for both tumour locations

Fig. 3

Survival analysis. Kaplan Meier survival curves in 13 patients with KRAS mutated recto-sigmoid cancer stage III at diagnosis stratified by chol:HDL ratio (a); Kaplan Meier survival curves in 16 patients with KRAS mutated non recto-sigmoid cancer stage III at diagnosis (b). Results show better survival in KRAS mutated recto-sigmoid cancer patients with high chol:HDL ratio compared to normal chol:HDL ratio

Fig. 4

Representation of KRAS nanoclusters in plasma membrane and signaling pathways. GTP: guanosin 5′-triphosphate; MAPK: Mitogen-activated protein kinase; RAF: Rapidly Accelerated Fibrosarcoma; MEK: mitogen-activated protein kinase kinase; ERK: Extracellular signal-Regulated Kinase; PI3K: Phosphoinositide 3-kinase; AKT: serine/threonine protein kinase; mTOR: mammalian target of rapamycin