106P Pharmacogenetic profiling in osteosarcoma to predict response and toxicity to neoadjuvant MAP: A study from the GEIS 33 protocol

MAP (methotrexate, Adriamycin and cisplatin) neoadjuvant chemotherapy is the osteosarcoma standard of care. To date, there are no biomarkers to predict pathological response to treatment which is a major prognostic factor. Additionally, no biomarkers exist to predict toxicity derived from the treatment that may lead to treatment delays or serious complications. The aim of this study, embedded in the GEIS33 protocol, was to evaluate the role of germline single nucleotide polymorphisms (SNPs) as predictive biomarkers for toxicity and response in localised osteosarcoma patients treated with MAP. Peripheral blood DNA was extracted from 69 patients enrolled in the GEIS33 protocol that evaluated the value of P-glycoprotein as a stratification factor for localised osteosarcoma. A total of 13 polymorphisms in 8 genes involved in DNA repair and drug metabolism pathways were selected using HapMap and literature review. Genotyping was performed by real-time PCR using TagMan probes. Of the 69 patients treated with 2 cycles of neoadjuvant MAP, 26 (37.7%) patients achieved a good pathological response (>90%). P-glycoprotein expression was positive in 35 patients but did not correlate with pathological response.In the multivariate analysis including 66 evaluable patients, two SNPs (ERCC2/XPD rs1799793 and ABCC2 rs2273697) correlated with the probability of achieving good pathological response. Toxicity was evaluated in 43-56 patients depending on the tested parameter. In the multivariate analysis, ABCC1 rs1128503 and ABCC3 rs4793665 were associated with methotrexate hepatotoxicity grade 3-4. ABCC1 rs1045642 was associated with the risk of grade 3-4 thrombopenia and ABCC2 rs3740066 with the risk of neutropenia grade 3-4. SNPs in the DNA single nucleotide repair and drug metabolisms pathways may serve as predictive biomarkers of response. Additionally, these polymorphisms may help tailor MAP neoadjuvant treatment to prevent toxicity and treatment delays.