P2-09-02: Predicting Response to Bevacizumab in Primary Breast Cancer Using 18F-Fluorothymidina (FLT) and 18F-Misonidazole (MISO) Positron Emission/Computed Tomography (PET/CT) as Imaging Biomarkers.
Authors: Dominguez I , Boni V , Garcia-Velloso MJ , Lopez-Vega JM , Martinez P , Plazaola A , Llombart A , Anton A , Galve E , Alvarez IM , Hernando B , Sanchez-Gomez R , Illarramendi JJ , Morales S , De Juan A , Richter JA , Lahuerta A , Garcia-Gonzalez M , Lao Romera J , Puertolas T , Scherer S , Sabariz Luis , Garcia-Foncillas J 
Published: June 2012

Background: To investigate the hypothesis that early changes in tumor proliferation and hypoxic status induced by bevacizumab and assessed by imaging biomarkers might predict response to bevacizumab therapy.

Methods: 73 chemotherapy naïve, stage II-III breast cancer (BC) patients (pts) were enrolled in the training set of this phase II, single-arm, multicenter and prospective clinical trial from October 2009 until November 2010. Pts received single infusion of bevacizumab (15 mg/kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) 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. Tumor proliferation and hypoxic status were evaluated using FLT and MISO PET/CT at baseline and 14–21 days after bevacizumab (C1). Standardized uptake values (SUV) for FLT and MISO and ratios to reference tissues, mediastinum (T/Me) or muscle (T/Mu), for MISO were calculated. Pathological response on surgical specimens was assessed according to Miller/Payne grading system. Pts with reduction in tumor cells &gt;30% (G3-G4-G5) or &lt;30% (G1-G2) were respectively considered as responders and no-responders. Association between pathological response, baseline and changes induced by bevacizumab (C1) in imaging biomarkers was analyzed using Mann-Whitney test. Receiver operating characteristic (ROC) curve was performed to test sensitivity and specificity of the biomarker found associated to response. Its value as independent predictor was tested in multivariate analysis using logistic regression. Results: Median baseline MISO and FLT SUV values in tumors were 1.2 (range 0.69−2.39) and 2.89 (range 0.97−7.18). Significant change after C1 was observed in FLT (2.7 vs 1.8, p&lt;0.001) but no in MISO uptake. Fifty-two (74%) pts achieved response (G3-G4-G5) whether 18 (24%) were considered as no responder (G1-G2); for 3 (4%) patients Miller/Payne tumor evaluation was not available. Response showed a trend toward an association with negative estrogen receptors (ER) expression (p=0.08) and triple negative tumors (11/73) (p=0.05). FLT SUV baseline and changes after C1 in MISO SUV, T/Mu and T/Me were all significantly associated with pathological response (p=0.057, 0.03, 0.016, 0.010). ER expression and T/Mu change remained significantly associated with response in multivariate analysis (OR=24.8, IC95% 1.8-334, p=0.01 and OR=0.95, IC 95% 0.92−0.99, p value=0.02). Decrease in MISO T/Mu uptake &gt;20% yielded a ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with 94% sensitivity and 87% specificity. Conclusion: Bevacizumab determined a marked decrease in tumor proliferation. Interestingly, a decrease greater than 20% in tumor hypoxic status after C1 and assessed by MISO was found significantly associated with pathological response suggesting a potential value of early decrease in hypoxic tumor status as predictive biomarker of response. Bevacizumab, causing normalization of the tumor microvasculature, seems to potentiate the effect of cytotoxic agents on primary BC. A validation set is warranted to confirm these findings.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-02.