P5-13-04: Changes in Phosphorylation Status at VEGFR2 and Basal Tumor Hypoxic Volume Assessed by Misonidazol (MISO) Positron Emission Tomography (PET/CT) as Potential Biomarkers for Predicting Response to Bevacizumab in Breast Cancer.
Authors: J Garcia-Foncilla, MJ Garcia-Velloso, I Dominguez, S Morales, B Hernando, R Sanchez, I Alvarez, A Anton, JJ Illarramendi, Juan A De, P Martinez, A Lahuerta, A Llombart, M Garcia-Gonzalez, Romera J Lao, T Purtolas, S Scherer, Luis Sabariz, JM Lopez-Vega, E Galve, A Plazaola, V Boni
Journal: Cancer Research (2011)

Abstract Background: To evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in stage II-III, previously untreated breast cancers (BC) patients (pts) in the context of a phase II, single-arm, multicenter and prospective clinical trial. To address this aim, we examined baseline and induced changes after a single bevacizumab administration as potential early predictors of response. Methods: Pts received a single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/kg) every 21 days (C2-C5) following by surgery. Early assessment of tumor changes was performed by paired tumor-biopsies and MISO PET/CT before and 14–21 days after bevacizumab administration (C1). Biomarker expression was assessed by immunohistochemistry (IHC) (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) on formalin-fixed, paraffin-embedded tissue before and after bevacizumab infusion (C1). MISO SUV and tumor volume depicted by PET were calculated. Pathological response on surgical specimens was assessed according to Miller/Payne classification. Pts with tumor reduction &amp;gt;90% were considered as best responders (G4-G5) whether tumor reduction &amp;lt;90% were considered as no responders. Association between pathological response, IHC and MISO biomarkers was analyzed using Mann-Whitney test. ROC curve was performed to test sensibility and specificity of the biomarker found significantly associated with response and its value as independent predictor was tested in the multivariate analysis using logistic regression. Results: This analysis was performed on the training set including 73 patients (49 yr, range 29–70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration and basaline MISO tumor volume was found significantly associated with response (p=0.03 and 0.057). Decrease in the phosphorilation status of VEGFR2 (Y951) &amp;gt;70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 — 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96−0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusion: These findings underline the potential value of early decrease in phosphorilation status of VEGFR2 after bevacizumab infusion as predictive biomarker of response to anti-angiogenic therapy in breast cancer. Moreover, tumor hypoxic volume obtained by MISO might be associated with response. A validation set is warranted to confirm these findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-04.