Abstract P4-01-11: Limits of [18F]-FLT PET as a clinical biomarker of proliferation in breast cancer
Authors: EV Schmidt, S Blackman, R Iannone, ET Senderak, RA Railkar, JL Evelhoch, PD Mozley, EA Perez, M McDonough, M Rimawi, S Tolaney, S-B Kim, H-C Chung
Journal: Cancer Research (2013)

Abstract Background: Imaging biomarkers of cellular division offer promise as non-invasive measures of tumor response. 3’-deoxy-3’[18F]-fluorothymidine ([18F]-FLT) positron emission tomography (PET) imaging generally correlates with pathology-based measurements of cancer proliferation, especially the Ki67 score. Though clinical studies have associated changes in [18F]-FLT uptake with therapeutic response, clinical studies validating its ability to assess cell proliferation are comparatively lacking. The goal of this study was to determine quantitative relationships between [18F]-FLT compared with molecular and cellular metrics of proliferation during treatment for locally advanced breast cancer (LABC). Methods: Baseline [18F]−FLT-PET scans were obtained prior to the initiation of chemotherapy for LABC from patients enrolled at several academic oncology study sites. MRI scans, and transmission CT scans were obtained. Core needle biopsies were obtained to determine Ki-67 indices using immuno-histochemistry and to assess an mRNA signature based measurement of proliferation. Prospectively specified quantitative relationships between PET, Ki67 immunohistochemistry and the mRNA signature were evaluated using image-matched tumor specimens. Correlations between volumetric MRI changes and pathologic responses were evaluated in a post-hoc exploratory analysis. Results: Motivated by the hypothesis that effective chemotherapies should decrease tumor cell proliferation, FLT-PET was compared with biomarkers of proliferation including Ki67 and the mRNA signature during neoadjuvant treatment for LABC. [18F]-FLT correlated both with the Ki67 labeling index (SUVmean r = 0.53) and with the proliferation signature (SUVmean r = 0.7), validating the principle of thymidine analogue imaging. However, variability in the [18F]-FLT PET and tumor cell proliferation measures likely contributed to correlations less than pre-specified target values considered appropriate for clinical use (r &amp;gt; 0.78). Moreover, none of the proliferation biomarkers predicted pathologic complete responses at the end of neoadjuvant therapy ∼16 weeks after the 3 week response scan. In contrast, an evaluation of change in tumor volume measured by MRI after 3 weeks of therapy confirmed its superior ability to predict pCR and tumor re-staging. Conclusion: With large numbers of cancer drugs entering therapeutic pipelines, early efficacy measures remain critical for drug development. The 3-4 month neoadjuvant treatment paradigm for LABC offers unique opportunities for drug evaluation. Functional imaging using [18F]-FLT has been advanced as an assessor of cellular proliferation, potentially offering a non-invasive approach to response evaluation. While [18F]-FLT generally correlated with proliferation, its lack of association with patient responses likely limit its clinical utility. On the other hand, the predictive value of MRI offers unique opportunities for future trial designs and confirms previous reports (1). 1. N. M. Hylton et al., Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy. Radiology 263, 663 (2012). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-11.