Body mass index and impaired fasting blood glucose as predictive factor of time to progression (TTP) in cetuximab-based colorectal cancer treatment.

Cetuximab is an anti-EGFR monoclonal antibody with antitumor efficacy in metastatic colorectal cancer harboring wild-type K-Ras gene. However, not all patients K-Ras wild-type benefit from Cetuximab, underscoring the need for additional markers to help in patient selection. Preclinical evidence suggests that the EGFR and insulin-like growth factor-1 receptor (IGF-1R) pathways interact to drive tumor growth and survival. Scartozzi et al. demonstrated that the hyperinsulinemic state and higher insulin levels upregulate IGF-I production, leading this state a potential biomarker for Cetuximab efficacy in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan. The aim of our study was to evaluate the feasibility to stratify patients more likely to benefit from Cetuximab treatment using two well-known signs of hyperinsulinemic state such as the high Body Mass Index (BMI) and impaired Fasting Blood Glucose (FBG). We retrospectively collected 250 metastatic colorectal cancer patients K-Ras wild type treated with Cetuximab containing regimens. From this cohort we selected 99 patients who received Cetuximab + chemotherapic regimens as first line and 77 patients who previously progressed under CPT11 based combination regimens and were subsequently treated with Cetuximab + CPT11 regimen. We dichotomized each subset into two groups according the presence of both elevated BMI (cut-off v 24.99 sec. WHO Criteria) and high fasting blood glucose (cut-off 100 mg/dL sec American Diabetes Association), and we evaluated the Time to progression (TTP) of these two groups. In the 77 CPT11- refractory patients (mean age 63.8; female: male 22: 54) during Cetuximab + CPT11 treatment, we observed a statistically significant lower TTP in the group with both elevated BMI and FBG compared with group with presence of none or only one of the two parameters (52: 25 pts; Median TTP 6.8 mo vs. 4.5 mo; p = 0.034). Copresence of both BMI and FBG was confirmed as predictive factor independent from age, sex and treatment line (2th, 3th, 4th or 5th) by multivariate Cox proportional hazards analysis (p = 0,018 ; HR 1,899). TTP was not significantly shorter in patients with only elevated fasting blood glucose (35: 42 pts.; p = 0,178; Median TTP 7.1 mo vs 5.5 mo) or BMI (38: 39 pts.; p = 0,305; Median TTP 6.8 mo vs. 5.6 mo). On the other hand, in the 99 patients (mean age 64; female: male 49: 50) treated with Cetuximab + chemotherapy (Folfox/Folfiri) as first line, we did not found any statistically difference between population with both elevated BMI and FBG compared with patients with presence of none or only one of the two parameters (75: 24 pts. ; Median TTP 8.3 mo vs. 7.7 mo; p = 0.624). TTP was also not significantly different evaluating only FBG (54: 45 pts.; Median TTP 7.2 mo vs. 7.9 mo; p = 0.941) and only BMI alone (48: 29 pts. Median TTP 7.0 mo vs. 6.5 mo; p = 0.135). The statistically significant poorer outcome in patients with both BMI and FBG treated with Cetuximab + CPT11 after CPT11 failure could be explained by the reduction in Cetuximab efficacy due to the probable presence of upregulation of vicar pathways such as IGF I R linked to hyperinsulinemic state. The absence of the predictive value of these two markers combination in chemonaive patients could be related to the strong masking effect related to concurrent chemotherapy. These preliminary observations need to be confirmed in larger and perspective populations.