Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer.

PURPOSE: Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab. PATIENTS AND METHODS: In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizumab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. MVD was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses. RESULTS: In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22. VEGF or THBS-2 expression and MVD were not significant prognostic factors. CONCLUSION: These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.

Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab.

BACKGROUND: A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab. METHODS: Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis. RESULTS: In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras/b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% CI = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.18) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was overexpressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival. CONCLUSIONS: We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer.

Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate.

We conducted an expression analysis of prostate stem cell antigen (PSCA)in normal urogenital tissues, benign prostatic hyperplasia (n = 21), prostatic intraepithelial neoplasia (n = 33), and primary (n = 137) and metastatic (n = 42) prostate adenocarcinoma, using isotopic in situ hybridization on tissue microarrays. In normal prostate, we observe PSCA expression in the terminally differentiated, secretory epithelium; strong expression was also seen in normal urothelium. Forty-eight percent of primary and 64% of metastatic prostatic adenocarcinomas expressed PSCA RNA. Our studies did not confirm a positive correlation between level of PSCA RNA expression and high Gleason grade. We characterized monoclonal anti-PSCA antibodies that recognize PSCA expressed on the surface of live cells, are efficiently internalized after antigen recognition, and kill tumor cells in vitro in an antigen-specific fashion upon conjugation with maytansinoid. Unconjugated anti-PSCA antibodies demonstrated efficacy against PSCA-positive tumors by delaying progressive tumor growth in vivo. Maytansinoid-conjugated antibodies caused complete regression of established tumors in a large proportion of animals. Our results strongly suggest that maytansinoid-conjugated anti-PSCA monoclonal antibodies should be evaluated as a therapeutic modality for patients with advanced prostate cancer.