Personalizing treatment with pemetrexed (PEM) in patients with malignant mesothelioma (MPM) and non-small cell lung cancer (NSCLC): The role of thimidylate synthase.

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e21001 Background: PEM was first approved for the treatment of MPM in combination with cisplatin, more recently as first line and maintenance therapy for advanced nonsquamous NSCLC. TS levels may predict response to PEM; high levels of expression are speculated to predict resistance to PEM. To evaluate whether TS protein levels, rather than histologic type, could be used to select patients with NSCLC and MPM for treatment with PEM, we assessed the variability of expression of TS in NSCLC and MPM tissue samples. Methods: We pursued semi-quantification of TS protein levels by immunohistochemistry (IHC) on tissue microarrays from 83 adenocarcinoma, 92 squamous, large cell, not-other-specified (NOS) NSCLC and 40 MPM samples. An IHC scoring system (IRS) was implemented based on stains: IRS scores of 0-2, 3-7 and 8-12 signified low, moderate and high TS protein expression respectively. Results: Of 49 squamous-cell samples, 22% had low expression of TS, indicating that PEM could potentially be effective in a subset of patients with squamous lung cancer. 24% expressed high levels of TS, 55% had an IRS greater than 6, in contrast to 23% of the adenocarcinoma samples. Of 83 adenocarcinoma samples, 56.5% and 9.6% had moderate and high expression of TS respectively. Similarly, 47% and 35% of the MPM samples showed moderate and high levels of TS expression respectively (Table). Correlation of clinical response to PEM with levels of TS expression is ongoing. Conclusions: Based on these preliminary data, TS levels are highly variable across both NSCLC and MPM tissue samples, and a substantial minority of patients with squamous histology may have a molecular profile that correlates with sensitivity to PEM. The role of TS as a biomarker for personalized therapy with PEM in patients with NSCLC and MPM requires prospective validation. TS expression Tumor type Negative (IRS = 0-2) Low (IRS = 3-7) High (IRS = 8-12) Mesothelioma (n = 40) 17.5% 47.5% 35% Adeno (n = 83) 33.6% 56.5% 9.6% Squamous, large cell, and NOS (n=92) 23.8% 50.8% 25% Squamous (n = 49) 22.2% 50.8% 24.4% Large cell (n = 11) 18% 54% 27.2% NOS/BAC (n = 12) 16.6% 41.5% 41.6% No significant financial relationships to disclose.