Identifying potential predictive biomarkers differentiating sensitivity/resistance to VEGF signaling inhibitors (VEGFi) will enhance use of these therapies. We used >580 pre and on-treatment serum samples and 259 tumours diagnostic biopsies from mCRC patients enrolled in a Phase III trial (HORIZON II) treated with chemotherapy ± cediranib(a VEGFi), to screen the potential predictive value of multiple serum proteins and tumour genes.
At baseline leptin was the most significant marker associated with OS of patients treated with chemo-ced (Pinteraction<0.001). Leptin concentration correlated with the body mass index (BMI) and obese patients (BMI>30) showed improved OS when treated with chemo-ced compared to non-obese patients (HR=0.55, 0.36-0.85, p=0.008). In the same patients, we identified two gene expression signatures associated with benefit on chemo-ced. Patients characterized by a high expression of GAHGL (Glucose metabolism, Angiogenesis, Hypoxia, Glutamine metabolism, Leptin signaling) (Pinteraction=0.028) and low expression of LOPS (Lipid metabolism, Oxidative activity, Proliferation and Serine synthesis) gene signature (Pinteraction=0.002) had improved OS in chemo-ced treated patients. Serum leptin concentration was found positively correlated with expression of genes involved in GAHGL in patients.
In addition a baseline signature (BS) of 47 biomarkers including VEGFA, VEGFD, VEGFR2, VEGFR3 and TIE-2, defined two distinct subgroups of patients. Patients treated with chemotherapy plus cediranib who had ‘high’ BS had shorter PFS (HR=1.82, p=0.003) than patients with ‘low’ BS. This BS had no effect on PFS of the patients treated with chemotherapy plus placebo.
Finally, we identified a profile of 16 pharmacodynamic (PD) proteins on treatment associated with PFS (HR=0.58, p<0.001) and OS (HR=0.52, p<0.001) in patients treated with chemotherapy plus cediranib. This PD profile had no effect on PFS and OS in patients treated with chemotherapy plus placebo.
This work provides original candidate biomarkers to select patients most likely to benefit from VEGFi therapies.
Citation Format: Aurelien J.C. Pommier, Stuart Spencer, Shethah Morgan, Chris Womack, Juliane M. Jurgensmeier, Susan Critchlow, Simon T. Barry. Soluble biomarkers identify mCRC patients subgroups showing increased benefit from the VEGF signaling inhibitor cediranib in combination with chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4811. doi:10.1158/1538-7445.AM2014-4811