406OVEGFR2 and ITGA polymorphisms as novel predictors of therapeutic response and toxicities for pediatric and young adult sarcoma undergoing anti-angiogenic therapy

Background The 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’s sarcoma, for which the field has seen the rapid growing popularity of the use of the anti-angiogenic therapy. Methods In this study, we retrospectively analyzed 79 tissue sarcoma patients less than 45 yrs receiving anti-angiogenic therapy (apatinib). In 67 (84%) of these patients, twenty previously reported single nuclear polymorphism (SNPs) in angiogenesis pathway were genotyped to screen for potential toxicity and predictive biomarkers. Results The mean 6 mo 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 biomarker 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 mechanism might underline both toxicities. Moreover, VEGFR2 rs2071559 polymorphism remains the only sensitivity biomarker for mPFS (mutation vs WT, 12 mo vs 5 mo), regardless of the sarcoma subtypes. Surprisingly, such mutations were to be 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, a significant higher frequecies of such two mutations (0.53 for ITGA polymorphism, 0.59 for VEGFR2 polymorphism) in our cohort than general Han Chinese (1000G project database) suggest a theoretical impact on the sarcomagenesis. Conclusions Our 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 study Ruijin Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.