Pilot Study Of Potential Activation Of C-Myc By Aurora Kinase A In Everolimus-Resistant Localized Esophageal Cancer Treated With Xelox Followed By Carboplatin/Radiation

The mammalian target of rapamycin (mTOR) signaling has been implicated in esophageal cancer progression. Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. Preclinical data suggested that Aurora Kinase A (AURKA) plays an important role in the development of everolimus resistance and that this is mediated through upregulation of c-MYC. We postulated that patients with persistent disease at time of surgery after neoadjuvant therapy would have higher levels of both AURKA and c-MYC. We conducted a multi-institutional phase IB trial to determine the recommended phase II dose of concurrent everolimus with carboplatin and radiation in patients with localized esophageal cancer. Patients with Stage II/III esophageal cancer and ECOG performance status 0-1 were enrolled. Following two cycles of induction Capecitabine/Oxaliplatin (XELOX), patients were restaged and those without evidence of disease progression, received radiation to a total dose of 50.4 Gy in 28 fractions with concurrent weekly carboplatin (AUC=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation was determined to be 2.5 mg QOD. Paraffin-embedded tissue blocks from the surgical specimen were used for immunohistochemical analysis for AURKA and c-MYC and levels of these markers were correlated with pathologic response. Nineteen patients were enrolled. There were two screen failures (thrombocytopenia, metastases) and four patients were removed from study due to poor tolerance of XELOX (n = 2) or disease progression (n = 2). Thirteen patients completed concurrent chemoradiation therapy and were deemed resectable. All patients had adenocarcinoma, median age was 58 and 85% were males. All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response rate of 23%. The 2-year PFS and OS were 50% and 49.6%, respectively. Only 6 of the 13 patients had tissue available for biomarker analysis. All 6 patients had viable disease on final pathologic assessment suggesting resistance to everolimus. Five patients with high levels of AURKA also had high levels of c-MYC expression (83%). The one patient with low level of AURKA also had low levels of c-MYC expression (16%). Biomarker studies from this Phase IB trial suggest that AURKA is associated with c-MYC dependent resistance to mTOR inhibition. Targeting AURKA may be a novel therapeutic strategy that can be used in everolimus-resistant tumors that show overexpression of AURKA.