1697P - VEGFR2 and ITGA polymorphisms as novel pan-sarcoma biomarkers for sensitivity prediction as well as toxicity prevention anti-angiogenesis therapy in pediatric and young adult patients

Abstract

BackgroundThe impact of germline mutations of the angiogenesis pathways on the therapeutic response has been extensively studied for the carcinoma population. However, such information is almost unknown for pediatric and young adult sarcoma, for which the field has seen the rapid growth the use of the anti-angiogenic therapy. MethodsIn this study, we retrospectively analyzed 79 tissue sarcoma patients less than 45 yrs old receiving anti-angiogenic therapy (apatinib). In 67 (84%) of these patients, twenty previously reported single nuclear polymorphism (SNPs) in the angiogenesis pathway were genotyped to screen for potential toxicity and predictive biomarkers. ResultsThe mean 6mo PFS rate was 64%, with the duration of response varying from no response to more than 26 months. Multivariate analysis indicated that hand-foot reactions, hair depigmentation and spontaneously pneumothorax (SP) remain independent toxicity biomarkers for greater PFS. Interestingly, we observed a strong correlation of ITGA2 rs1126643 polymorphism vs surgical wound complications (C/C 4% vs C/T 24% vs T/T 33% , p=0.008) as well as SP (C/C 13.8% vs C/T 36.4% vs T/T 66%), suggesting that integrin mechanisms might underle both toxicities. Moreover, VEGFR2 rs2071559 polymorphism remains the only sensitivity biomarker for mPFS (mutation vs WT, 12mo vs 5mo), regardless of the sarcoma subtypes. Suprisingly, such mutations were associated with the incidence of hair depigmentation (R=0.398, p=0.026), further supporting that hair discoloration is a mechanism-based toxicity biomarker. Moreover, significantly higher frequencies such mutations (0.53 for ITGA polymorphism, 0.59 for VEGFR2 polymorphism) were seen in our cohort than the general Han Chinese (1000G project database) suggesting a theoretical impact on the sarcomagenesis. ConclusionsOur study is the first one examining the angiogenesis germline polymorphism for the younger population in bone and soft tissue cancer. VEGFR2 (rs2071559) as well as ITGA (rs1126643) might serve as pan-sarcoma biomarkers for VEGFR2-targeted therapy and warrant further validation for its biological and clinical implications. Legal entity responsible for the studyRuijin Hospital, Orthopaedic Oncology Group. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.