Introduction The current treatment of locally advanced non-small cell lung cancer (NSCLC) is debated. Induction strategies with dose-dense chemotherapy may provide additional benefit. My research focuses on improving treatment and understanding mechanisms of chemotherapy resistance in this patient population. A phase II protocol with genomic correlates is proposed.
Methods Patients with stage III NSCLC will be enrolled in a trial examining the efficacy of dose-dense neoadjuvant/induction chemotherapy with cisplatin and docetaxel. The primary outcome is overall response. The understanding mechanism of chemotherapy resistance is a secondary outcome and involves complementary in vivo and in vitro approaches. In vivo, pretreatment tumor samples are collected and processed for microarray analysis based on radiographic response. In vitro, chemotherapy sensitivity assays on lung cancer cell lines are performed with subsequent microarray analysis based on a spectrum of sensitivity. Genes and pathways associated with resistance will be identified. The ability of in vitro results to predict response in vivo will be assessed. Combining in vivo and in vitro analyses will prioritize candidate genes and/or pathways associated with resistance for future evaluation.
Results Dose-dense chemotherapy appears safe and well tolerated in 4 of 42 planned patients. Toxicity and response assessments are ongoing. In vitro, EC50 determinations (drug-specific concentration resulting in cell growth halfway between the baseline and maximum response) in 40 lung cancer cell lines revealed greater than a 21-fold and 17-fold difference between the most and least sensitive cell lines for cisplatin (221-4,662 nM) and docetaxel (0.28-4.8 nM), respectively. Expression analysis of tumor tissue collected as part of the trial and from cell lines is ongoing and will be reported at the meeting.
Conclusions Validation of identified signatures, genes, and pathways will be crucial in understanding the underlying biology associated with resistance mechanisms and will allow for the identification of patients for whom standard cytotoxic agents, as well as pathway-specific targeted therapeutics, will most benefit.
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