High-level clonal amplification of FGFR2 predicts for sensitivity to FGFR inhibitor. High-level clonal amplification of FGFR2 predicts for sensitivity.

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High-level clonal amplification of FGFR2 predicts for sensitivity to FGFR inhibitor. High-level clonal amplification of FGFR2 predicts for sensitivity to FGFR inhibitor. A, FGFR1 copy number and FGFR2 copy number in breast and gastric cancers, respectively, assessed by digital PCR, from 17 patients treated with AZD4547. Red indicates patients who had a confirmed partial response to AZD4547, gray indicates patients with a partial metabolic change on day 15 18F-FDG-PET but without a clinical response, and black indicates patients without response. Response to AZD4547 is seen only in cancers with high-level copy-number amplification (P = 0.0026, Mann–Whitney U test), and partial metabolic change in FGFR2-amplified cancers is seen only in cancers with high-level copy-number amplification (P = 0.0022, Mann–Whitney U test). B, FGFR2 mRNA expression assessed in baseline tumor biopsies by reverse transcription digital PCR (left), with FGFR2 immunohistochemistry (right), color coding as in A. FGFR2 mRNA expression was normalized to reference the genes β-Actin and GAPDH. Data are presented as the mean of the FGFR2:β-Actin and FGFR2:GAPDH ratios. C, assessment of clonality of FGFR2 amplification by FGFR2 FISH on tumor sections, assessed with automated MIRAX analysis, divided by cancers that demonstrated clinical response (269 and 316) and no clinical response. Percentage of tumor cells with amplification is displayed, along with representative image from MIRAX analysis color coded by the presence of amplified tumor cells (red) and nonamplified tumor cells (blue). The presence of nonamplified tumor cells in patient 99 was confirmed visually. D, comparison of FGFR2 mRNA expression assessed by NanoString in tumor biopsies from baseline and day 15. A substantial fall in FGFR2 expression is seen in the highly FGFR2-amplified but heterogeneous tumor from patient 135, potentially reflecting subclonal loss of FGFR2 overexpression tumor clone. E, analysis of FGFR2 copy number in plasma DNA, from plasma samples taken at baseline. #, baseline plasma was not collected for patient 99, cfDNA was isolated from cycle 1 day 8 predose. Alex Pearson et al. Cancer Discov 2016;6:838-851 ©2016 by American Association for Cancer Research