BACKGROUND: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. METHODS: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high. CONCLUSIONS: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.

• Keywords
• Anti-VEGF, Antitumor immune response, Metastatic colorectal cancer, Primary colorectal carcinoma sidedness, Regulatory T cells, T cell subsets,
• MeSH
• Adenocarcinoma blood   drug therapy   mortality   pathology   MeSH
• Bevacizumab administration & dosage   therapeutic use   MeSH
• T-Lymphocytes, Cytotoxic metabolism   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Angiogenesis Inhibitors administration & dosage   therapeutic use   MeSH
• Colorectal Neoplasms blood   drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis drug therapy   MeSH
• Survival Rate MeSH
• Biomarkers, Tumor metabolism   MeSH
• Follow-Up Studies MeSH
• Lymphocyte Count MeSH
• Prospective Studies MeSH
• Proto-Oncogene Proteins p21(ras) analysis   MeSH
• T-Lymphocytes, Regulatory metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Vascular Endothelial Growth Factor A antagonists & inhibitors   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Bevacizumab MeSH
• Angiogenesis Inhibitors MeSH
• KRAS protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Proto-Oncogene Proteins p21(ras) MeSH
• Vascular Endothelial Growth Factor A MeSH
• VEGFA protein, human MeSH Browser

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35-45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

• Keywords
• Bevacizumab, Chemotherapy, Colorectal cancer, KRAS, Mutation,
• MeSH
• Alleles * MeSH
• Bevacizumab therapeutic use   MeSH
• Adult MeSH
• Kaplan-Meier Estimate MeSH
• Codon MeSH
• Colorectal Neoplasms drug therapy   genetics   mortality   pathology   MeSH
• Combined Modality Therapy MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Mutation * MeSH
• Retreatment MeSH
• Prognosis MeSH
• Proportional Hazards Models MeSH
• ras Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Bevacizumab MeSH
• Codon MeSH
• ras Proteins MeSH