Induction chemotherapy (IC) followed by concomitant radiotherapy and weekly cisplatin (CCRT) versus CCRT alone in patients with locally advanced (LA) nasopharyngeal carcinoma (NPC): Twenty-year follow-up of a randomized phase II study conducted by th

6088 Background: Non-endemic NPC is associated with inferior outcomes compared to the endemic form. HeCOG conducted a randomized phase II study to compare IC followed by CCRT with CCRT alone in patients with LA NPC. Here, we report the 20-year follow-up data with biomarker analysis. Methods: Patients were randomly allocated 1:1 to CCRT alone or 3 cycles of IC with Epirubicin, Paclitaxel, and Cisplatin followed by CCRT. Random assignment was stratified by histology (type I versus type II+III) and stage (IIB+III versus IV). The primary objective of this analysis was to identify clinical and molecular features associated with PFS and OS. Clinical (141 cases /72 Group A, 69 Group B) and biomarker data (IHC / CISH: 109 Cases, NGS: 61 Cases / 29 Group A; 32 Group B) were analyzed using descriptive statistics, traditional survival Analysis techniques (Kaplan-Meier, Cox) and machine learning approaches (random survival forest). Results: Regarding the clinicopathological characteristics, only age at the beginning of the study (HR=1.05, 95%CI=(1.03, 1.06), p<0.001) and the CCRT response was associated with OS ( PD: HR=20.03, 95%CI=(9.02, 44.48), p<0.001; SD: HR=5.17, 95%CI=(2.01, 13.32), p=0.001, respectively). For NGS mutational status, irrespective of effect, only MSH2 (HR=3.37, 95%CI=(1.27, 8.92), p=0.015) and PIK3CA (HR=2.71, 95%CI=(1.03, 7.12), p=0.043) displayed significant association with OS, while random survival forest additionally yielded significant associations for BRCA1 , CD274 , TSC1 , KRAS and KIT . Considering pathogenic mutations only, CD8B , KDM4A, MLH1 , MSH6 , and RANBP2 displayed significant association with OS. Concerning IHC, ECADH (HR=1.16, 95%CI=(1.03, 1.32), p=0.018), GSK3B (HR=1.21, 95%CI=(1.01, 1.44), p=0.036) and AE1AE3 (HR=0.13, 95%CI=(0.02, 0.96), p=0.018), displayed significant association with OS, with higher values of ECADH and GSK3B indicating worse outcome, whereas AE1AE3 expression indicates better outcome. Conclusions: Age at diagnosis and response to CCRT emerge as the most important clinical factors forlong-term survival in LA non-endemic NPC.We identified potential molecular correlates for long-term outcomes to be validated in prospective studies. Clinical trial information: ACTRN 12609000730202 .