Spotlight on Clinical Response Discordant Cellular Response to Presurgical Letrozole in Bilateral Synchronous ERþ Breast Cancers with a KRAS Mutation or FGFR1 Gene Amplification

We describe herein a patient presenting with bilateral estrogen-receptor–positive (ERþ) breast tumors who was enrolled in a clinical trial exploring molecular aberrations associated with hormone-refractory tumor cell proliferation. Short-term (two week) hormonal therapy with the aromatase inhibitor letrozole substantially reduced proliferation as measured by Ki67 immunohistochemistry in one tumor, whereas the second was essentially unchanged. Extensive molecular and genetic work-up of the two tumors yielded divergent lesions in the two tumors: an activating KRASmutation in the responsive tumor and an amplification of the fibroblast growth factor receptor-1 (FGFR1) locus in the treatment-refractory tumor. These findings provide an insight to possible mechanisms of resistance to antiestrogen therapy in ERþ breast cancers. First, they illustrate the necessity of clinically approved assays to identify FGFR1 gene amplification, which occur in approximately 5% of breast tumors and have been linked to antiestrogen resistance. It is quite possible that the addition of FGFR inhibitors to ER-targeted therapywill yield a superior antitumor effect and improvedpatient outcome. Second, they suggest that the role of activating mutations in RAS, although rare in breast cancer, may need to be explored in the context of ERþ breast tumors. Mol Cancer Ther; 11(10); 2301–5. 2012 AACR.