Sonic Hedgehog (SHH) Status Determines the Chemotherapeutic Outcomes in High Risk Stage II and III Head and Neck Cancer Patients

Abstract

Importance: Head and neck squamous cell carcinoma (HNSCC) still poses therapeutic challenges due to local recurrence and metastasis. Objective: Explore a reliable biomarker to stratify patients who benefit from adjuvant chemotherapy in HNSCC patients. Design: We analyzed a cohort of HNSCC patients to identify potential candidate biomarker and analyzed overall survival (OS) and disease-free survival (DFS) of these patients who benefit from adjuvant chemotherapy. Results: : Sonic hedgehog (Shh), a secreted signaling molecule identified as a potential candidate biomarker in our analysis. A group of HNSCC patients (106/183) were negative to Shh. In the discovery dataset, the OS (HR 3·231, CI 1·23-8·53, p<0·017) and DFS (HR 3·774, CI 1·6178·007, p<0·0021) remained lower among Shh-neg patients tumors. In the TCGA validation dataset (n=312), the OS (35% vs 50%, p<0·046) and DFS (24% vs 85%, p<0·002) remained lower in the Shh-neg patients, corroborating our discovery cohort. Among the patients with stage II and III tumors, the 5-year OS (80% vs 37% and 70% vs 20%) and DFS (55% vs 26% and 27% vs 8%) remained lower. When patients stratified with or without adjuvant chemotherapy in the stage II and stage III tumors for disease progression, the 5-year DFS were longer in the Shh-neg tumors who were treated with adjuvant chemotherapy (stage II; 80% vs 50%, p<0.019, stage III; 70% vs 55%, p< 0.11). Conclusions: This study identified that lack of Shh expression in a group of HNSCC patients with stage II and stage III tumors likely to benefit from adjuvant chemotherapy. Funding Statement: Grant-in-Aid from Bangladesh Medical Research Council (BMRC), and University Grant Commission (UGC), Ministry of Education of Bangladesh with the assistance of the World Bank under Higher Education Quality Enhancement Project (HEQEP)– Window -4 (Grant Id. CP4023). Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: This retrospective study included 183 patients (CMCH cohort, discovery cohort) with stage I to IV HNSCC, who received treatment at Chittagong Medical College and Hospital (CMCH) affiliated with The University of Chittagong, Bangladesh between September 2014 and October 2016. The institutional review board of the participating institute approved the study. All patients recruited in this study were given a written consent.