Aims: Inhibition of angiogenesis is an effective treatment option for metastatic colorectal cancer. Predictive biomarkers to select patients who are most likely to benefit from this therapeutic strategy are lacking. We conducted a pilot, retrospective biomarker study in a cohort of metastatic colorectal cancer patients treated with bevacizumab. The objectives of this study were to evaluate the prognostic value of biomarker expression in metastases and to compare their expression in paired tumor specimens.
Materials and methods: Eligible patients were treated with a bevacizumab-containing therapy; from these patients, tumor tissue from metastases was available. PTEN, PI3K p110a, c-MET, and CAIX were analyzed by immunohistochemistry.
Results: Forty-two patients received bevacizumab, 13 (31%) with first-line and 29 (69%) with second-line chemotherapy. Expression of CAIX, PI3K p110a, and c-MET in metastases did not predict objective response. PTEN loss was associated with response to treatment (p=0.02) and this association remained significant after adjusting for prognostic variables (p=0.006). However, no association with survival outcomes was found. In 32 patients (76%) with available paired specimens, we observed an equal expression between primary tumors and corresponding metastases in 75% of cases for CAIX in epithelial tumor cells, 56% for CAIX in stromal cells, 63% for PTEN, and 87% for c-MET.
Conclusion: PTEN loss in metastases appears to be associated with response to bevacizumab-based therapy. However, larger studies are necessary to confirm the potential role of the PI3K/AKT/mTOR pathway in modulating the therapeutic effect of bevacizumab. Tumor heterogeneity should be taken into consideration when analyzing tumor tissues for biomarker studies.