In recent years, major strides in cancer research have made it possible to select personalized chemotherapy recommendations based on an individual patient’s tumor biology. The prognostic and/or predictive ability of biomarkers seeks to tailor the use of targeted chemotherapy and can result in improved clinical outcomes with reduced toxicity. A proliferation of new technology and pharmacotherapeutics in the setting of current FDA Clinical Laboratory Improvement Amendment (CLIA) standards has resulted in a recent surge in direct-to-physician biomarker tests. However, in the absence of clinical validation, there is the concern that the biomarkers may be utilized prematurely, resulting in improper chemotherapy selection and patient harm. Thymidylate synthase (TS) has been marketed as a predictive biomarker for the use of pemetrexed in NSCLC. We will examine the evidence behind the use of TS as a predictive biomarker to predict response to pemetrexed in NSCLC. At this time, the evidence does not currently support using TS assays to guide chemotherapy selection outside of a clinical research protocol. 1. Introduction This paper reviews the literature regarding thymidylate synthase as a predictive biomarker for pemetrexed response in NSCLC. It aims to identify the lack of clinical validation and the harms of direct-to-physician biomarkers assays and their use outside of a research protocol. It also covers the different modalities available for biomarker assays and the lack of standardization in TS quantification. 2. Background Lung cancer remains one of the most frequently diagnosed cancers in the United States; in 2013, over 225,000 Americans will be diagnosed with lung cancer, including over 125,000 who will present with metastatic disease [1, 2]. Unfortunately, the 5-year survival of non-small-cell lung cancer (NSCLC) remains only 16%, with little improvement over the last 30 years. The ECOG 1594 trial demonstrated equal efficacy of several platinum-based doublets (PBDs), but the trial was published before the advent of pemetrexed chemotherapy [3]. Medical oncologists must select from several chemotherapy regimens for the initial treatment of EGFR wild-type, ALK rearrangement-negative advanced NSCLC, including pemetrexed. In this paper, we will examine the evidence behind the use of thymidylate synthase as a biomarker to predict response to pemetrexed in NSCLC. Pemetrexed has shown efficacy in advanced non-small cell lung cancer (NSCLC) not only in combination with cisplatin as first-line therapy [4] but also as a single agent for second-line treatment [5]
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