Abstract 106P
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Grupo Español de Investigación en Sarcomas GEIS.
Funding
Grupo Español de Investigación en Sarcomas GEIS.
Disclosure
A. Sebio Garcia: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Expert Testimony: PharmaMar, Deciphera, GSK; Financial Interests, Personal, Training: Boston Scientific; Non-Financial Interests, Personal, Other, Board of Directors member: GEIS. J. Martin-Broto: Financial Interests, Personal, Expert Testimony, Honoraria: Lilly, PharmaMar, Eisai, Bayer, Roche, Boehringer Ingelheim, Amgen; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Advisory Board, Speaker: Tecnofarma, Asofarma; Financial Interests, Institutional, Invited Speaker: PharmaMar, Eisai, Novartis, IMMIX Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint, Deciphera, NEKTAR, FORMA, Amgen, Daiichi Sankyo, Lilly, AROG, Adaptimmune, GSK, Ran Therapeutics, INHIBRX, Ayala Pharmaceuticals, Philogen, Cebiotex, PTC Therapeutics, Inc. and SpringWorks therapeutics. F.J. Bautista Sirvent: Non-Financial Interests, Personal, Principal Investigator: Sanofi; Financial Interests, Personal, Advisory Board: Bayer, Roche, Amgen, Eisai, EusaPharma; Financial Interests, Personal, Invited Speaker: Roche. J. Martinez-Garcia: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis, GSK-Thesaro, PharmaMar; Financial Interests, Institutional, Research Grant: Roche, GSK; Other, Personal, Other, Travel/accommodation/expenses for oncology meeting: PharmaMar, GSK-Thesaro, Pfizer. J. Martinez Trufero: Financial Interests, Personal, Advisory Board, Advisory Board meeting: PharmaMar, Eisai; Financial Interests, Personal, Invited Speaker: Roche, Eisai, Merck, Medicamenta, MSD, Ipsen; Financial Interests, Personal, Advisory Board, Advisory Board Meeting: GSK, Deciphera, Boehringer Ingelheim, Eisai; Financial Interests, Personal, Other, Meeting travel expenses: Roche, PharmaMar; Financial Interests, Institutional, Invited Speaker, Clinical trial: RAIN Therapeutics, Blueprint, Lilly, Kariopharm Therapeutics, Syneos Health, Boehringer Ingelheim, Ayala Pharmaceuticals, SynOx Therapeutics; Non-Financial Interests, Personal, Member of Board of Directors, Spanish group of Sarcoma Research: GEIS Group; Non-Financial Interests, Personal, Member of Board of Directors, Spanish Group of Head and Neck cancer Research: TTCC Group. C.M. Valverde Morales: Financial Interests, Personal, Advisory Board: PharmaMar, Bayer, GSK, Mundipharma, Lilly, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker, Clinical Trial: Adaptimmune, Karyopharm, Lilly, Foghorn Therapeutics, Ayala therapeutics, Inhibrx; Financial Interests, Institutional, Invited Speaker, Clinical Proyect: Bayer; Non-Financial Interests, Personal, Member of Board of Directors, President 2018-ongoing: GEIS- Spanish Sarcoma Group for Research. M.A. Vaz Salgado: Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer. R.M. Alvarez: Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Roche; Financial Interests, Personal, Other, conference registration: MSD Oncology; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Invited Speaker: Janssen Oncology, Rain Therapeutics, Boehringer Ingelheim, Cebiotex, Novartis. All other authors have declared no conflicts of interest.