Prospective evaluation of RRM1 as a predictor of response to gemcitabine/carboplatin (GC) in non-small cell lung cancer (NSCLC)

Abstract

7054 Background: RRM1 is the regulatory subunit of ribonucleotide reductase. It is a molecular target of G. RRM1 increases upon continuous exposure of cell lines to G. Preliminary data suggest improved survival for patients with low as opposed to high tumoral expression of RRM1 when treated with G-based chemotherapy. Methods: We determined the efficacy of G and C as induction therapy in patients with locally advanced NSCLC. Trial eligibility included measurable disease, no prior chemotherapy or RT, PS 0–1, and no weight loss. Patients were staged with CT, PET, and brain MRI. GC consisted of two 28-day cycles of G, 1,000 mg/m2 d1&8 and C, AUC 5 d 1. Unidimensional tumor measurements were obtained before and after GC. The study required tumor collection prior to therapy by core needle biopsy. Specimens were frozen in LN. Tumor cells were collected by LCM. Real-time quantitative RT-PCR gene analysis was performed in triplicate per sample for RRM1 and 18SrRNA. Results: Between 11/03 and 7/05, 30 eligible patients were enrolled, and the required tumor biopsies were obtained in all. In one patient, a pneumothorax developed that required chest tube placement. Disease response ranged from a 9% increase to a 100% decrease. 14/26 had SD, 11/26 PR, and 1/26 CR. The patients’ age was 47- 87 years; 12 were women; 13 had IIIA and 13 IIIB; 10 had sq, 7 ad, and 9 LC or NOS NSCLC. RRM1 expression ranged from 0.18 to 129.3. There was a significant (p = 0.014) inverse correlation (r = −0.474) between RRM1 expression and disease response. When grouping patients into those with response (CR/PR) and without response (SD), RRM1 expression was significantly (p = 0.027) associated with response. No significant association was found between RRM1 expression and other parameters. Conclusions: In a prospective clinical trial intratumoral RRM1 expression was significantly and inversely correlated with disease response to gemcitabine and carboplatin. These results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine-based chemotherapy. No significant financial relationships to disclose.