Abstract PD07-10: Breast Cancer Patients Carrying the CYP2C8*3 Variant Are More Likely To Achieve Clinical Complete Response from Neoadjuvant Paclitaxel Treatment
Authors: Hertz DL , Dees EC , Motsinger-Reif AA , Drobish A , Winham SJ , McLeod HL , Carey LA. 
Published: April 2011

Background: Complete response to neoadjuvant chemotherapy is a good prognostic indicator in breast cancer patients. Neoadjuvant treatment has shown comparable efficacy to adjuvant treatment while providing an opportunity to evaluate tumor response to therapy. Paclitaxel is one of the most frequently used chemotherapeutic agents in the neoadjuvant setting. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity.

Materials and Methods: Subjects included in this study were treated with paclitaxel-containing regimens in the neoadjuvant setting. Most received sequential anthracycline-and taxane-based therapy in which clinical response to each phase was collected separately. Clinical data, including patient and tumor characteristics and treatment outcomes, was collected prospectively in an observational registry. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria while toxicity data was collected from physician notes. The primary endpoint of this study was achievement of clinical complete response (cCR) during taxane treatment. Secondary endpoints included clinical response rate (cRR, complete response + partial response, cPR), any grade 3 or higher toxicity, and grade 3 or higher neuropathy from paclitaxel treatment. Blood was collected at diagnosis and genotyped using pyrosequencing. The genotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1b, CYP3A5*3C, ABCB1 1236, ABCB1 2677, and ABCB1 3435.

Results: 112 breast cancer patients treated with neoadjuvant paclitaxel were included in this analysis. The median age was 50, 28 were African-American, tumor stage included II (42 patients), III (60 patients), and presenting stage IV (10 patients), 60 were grade 3, 57 were ER+, and 32 were HER2+, of whom 21 received trastuzumab as part of the paclitaxel regimen. Response rate was 27.7% cCR, 31.3% cPR to the paclitaxel component. CYP2C8*3 carriers (23/112, 20.5%) had higher rates of clinical complete response to neoadjuvant paclitaxel treatment (55% versus 22%; p=.006). This association remained significant after adjustment for race, tumor grade, ER status, and whether paclitaxel treatment was preceded by another phase of chemotherapy. There were trends for increased clinical response rate (cRR; p=.052) and greater risk of grade 3 or higher peripheral neuropathy (p=.072) in subjects carrying the CYP2C8*3 variant. On multivariate analysis, other paclitaxel drug-metabolizing enzyme polymorphisms did not appear related to either response or toxicity.

Discussion: CYP2C8 is the primary enzyme responsible for paclitaxel metabolism, and the *3 variant has demonstrated decreased catalytic activity toward paclitaxel in vivo, leading to increased exposure of the patient to the active parent compound. Our results demonstrate that patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-10.