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Rationale:High expression of the excision repair cross-complementation group 1 protein (ERCC1) has been associated with diminished benefit to cisplatin in advanced non-small cell lung cancer (NSCLC); and high expression of Thymidylate Synthase (TS) has predicted lack of response to pemetrexed. In contrast to NSCLC, relatively little work has yet been published in malignant pleural mesothelioma (MPM) on these molecular markers and their capacity to predict response to treatment. The purpose of this study was to evaluate the ability of intratumoral ERCC1 and TS expression levels to predict responses to cisplatinum and pemetrexed chemotherapy respectively in patients with MPM. Materials and Methods:We evaluated a cohort of 69 patients with MPM with complete clinical follow-up for semi-quantitative expression of TS and ERCC1 by immunohistochemistry (IHC) using a modified Remmele's score (range 0-12). Our primary outcome was the association between TS and ERCC1 expression and radiographic response to pemetrexed and cisplatin respectively. Results:The mean age at diagnosis was 67 years. Forty eight subjects were males. The mean overall survival was 14 months. Heterogeneity in the expression of both markers was noted, but overall expression was low. The mean immuonoreactive scores for TS and ERCC1 were 1.7 and 2.2 respectively. We found no significant association between TS or ERCC1 expression and response to chemotherapy. Conclusions:In contrast to one published report, TS and ERRC1 expression levels failed to predict responsiveness to pemetrexed or cisplatin. We are currently expanding the size of this cohort, and based on preclinical data, plan to evaluate pS6, p48 and pSTAT1 to determine if these markers are associated with response to chemotherapy.

7092 Background: Currently there are no validated biomarkers for assessment or prediction of disease burden or activity in SCLC. Enumeration of CTCs by CellSearch is FDA approved, highly reproducible and validated in other malignancies. Application as a prognostic and predictive marker in SCLC is limited due to a lack of studies documenting serial monitoring in pts on therapy. Methods: We are conducting a prospective study serially enumerating CTCs in pts with newly diagnosed SCLC. CTC number (per 7.5 ml peripheral blood) and percentage of CTCs demonstrating DNA damage and apoptosis based on γH2AX and M30 staining respectively, are being assessed prior to initiation of chemotherapy, during each cycle and at relapse. We are correlating CTC number with disease stage, number of metastatic sites, response to therapy, and time to progression (TTP). Results: 21 SCLC pts are evaluable. 9 pts with limited disease (LD) had median baseline CTC value of 1 (0-8); only 2 of 9 pts had >5 CTCs. 12 pts with extensive disease (ED) had median baseline CTC value of 80.5 (0-37780); 8 of 12 pts had >5 detectable CTCs (p value 0.02). Amongst the 12 pts with ED, median baseline CTC count was higher in pts with ≥3 (n=3) compared to 1-2 sites of metastatic disease (n=9) (2668 vs 71; p value 0.52). Median percentage of CTCs positive for γH2AX and M30 was also higher for pts with ≥3 compared to 1-2 metastatic sites (83, 164.5 vs. 2, 7.5) (p-value 0.40, 0.69). Serial CTC data are available on 3 pts with ED; all had responsive disease and reduction in CTC number to 0-1 after 2 cycles of chemotherapy. As this protocol is ongoing, correlation of CTCs with updated response status and TTP will be presented at the ASCO meeting. Conclusions: CTCs can be isolated and serially enumerated in pts with SCLC. Baseline CTCs correlate directly with disease stage. In pts with ≥ 3 metastatic sites, baseline CTCs tend to be greater and show higher levels of DNA damage and apoptosis compared to those with 1-2 metastatic sites. Reduction in CTCs is associated with radiographic response to therapy. Correlation between absolute number at baseline and TTP is not yet known.