NY-ESO-1 as a predictive marker for neoadjuvant chemotherapy in stage IIIa non-small cell lung cancer (NSCLC).

Abstract

10576 Background: The use of neoadjuvant chemotherapy in stage IIIa NSCLC is controversial with trials consistently failing to demonstrate a significant benefit. The ability to identify chemoresponsive tumors should aid clinical trial design and outcome. Cancer-Testis antigens (CTAg), such as MAGE A3, are currently being investigated as immunotherapeutic targets in the adjuvant setting. CTAgs are expressed in over 50% of both squamous cell and adenocarcinomas but restricted to testis in normal tissues. Since CTAgs have been proposed as markers of drug-resistant stem-like cells, we investigated their expression and association with chemosensitivity. Methods: Stage IIIa patients treated with neoadjuvant chemotherapy at the Austin Hospital (AH) Melbourne and Weill Cornell Medical College (WCMC) New York were investigated. Preoperative mediastinal lymphadenectomy tissues were stained for a panel of CTAgs including NY-ESO-1, MAGE-A, MAGE-C1/CT7, GAGE and CT45 by immunohistochemistry. DNA was isolated from paraffin sections from the WCMC dataset and mutationally profiled using Sequenom’s MassArray platform. Molecular results were correlated to clinical characteristics, chemoresponsiveness (defined as pathological down-staging of TNM status), progression free and overall survival (OS). Results: 95 patients (WCMC: 70, AH: 25) were studied. Staining for one or more CTAgs was positive in 50% of samples regardless of histology. NY-ESO-1 was expressed in 33% of samples. DNA was isolated from 63/70 WCMC samples. Mutations were seen predominantly in the EGFR (5/63) and KRAS (8/63) genes. CTAg expression occurred independent to KRAS mutant tumors. NY-ESO-1 expression occurred independent to EGFR and KRAS mutations and was significantly associated with chemosensitivity in both datasets (Chi square p=0.010). Improved OS was only seen in the AH dataset (HR 0.36; 95% CI 0.14-0.96, p=0.04). Conclusions: Expression of NY-ESO-1 predicts response to neoadjuvant chemotherapy in stage IIIa NSCLC. Expression occurred independent of common mutations but in both adenocarcinoma and squamous cell carcinoma. Given their immunogenicity, immunological mechanisms for these responses are being investigated.