Abstract 608: Identification of genomic alteration which affects resistance to induction chemotherapy in patients with locally-advanced head and neck squamous cell carcinoma
Authors: Ock Chan-Young , Son Bongjun , Lee Seungyoun , Moon Jaewoo , Kim Sehui , Keam Bhumsuk , Kim Tae Min , Jeon Yoon Kyung , Lee Se-Hoon , Kim Dong-Wan , Heo Dae Seog 
Published: August 2015

Background: As induction chemotherapy (IC) has been introduced for purpose of organ preservation in head and neck squamous cell carcinoma (HNSCC), survival benefit of IC was not definite in unselected patients. Although previous studies showed that patients with bulky nodal stage had more benefit from IC, distinct genomic profile of patients with good or poor responder to IC has not been evaluated. Purpose of this study is to find out candidates of genomic alterations which affect response to IC as well as clinical outcomes.

Methods: Targeted gene sequencing (TGS) for 486 COSMIC alterations of 37 genes including TP53, EGFR, KRAS, NRAS, and TP63 was designed for identification of genomic alterations to predict outcomes of IC. Pretreated tissues of 45 patients who treated with IC underwent to TGS. Alterations with total coverage less than 500 were excluded, and the cutoff of significant altered frequency was &gt; 0.01. Patients were divided into 2 groups. Poor responders were defined as best response to IC was progressive disease or stable disease by RECIST 1.1 with progression-free survival &lt; 18 months. Otherwise, patients were classified as good responder. Cox regression for survival analysis and chi-square for comparing alteration frequencies were used. Two-sided P value was considered significant if &lt; 0.05.

Results: Patients with good response (N = 23) had significantly favorable survival outcome than poor responders (N = 22, 3-year overall survival (OS) rate: 95.0% vs. 42.3%, P = 0.002). Mean total coverage was 1941 per locus. Genomic alteration profiles showed that TP53 mutation (good: 69.6% vs poor: 81.8%, P = 0.339) and EGFR mutation (good: 78.3% vs poor: 68.2%, P = 0.445) were highly altered in both groups without statistical significance. Frequency of alteration of SMAD4 was higher in good responders (26.1% vs 4.5%, P = 0.046), and alteration of JAK3 was lower in good responders (0% vs 22.7%, P = 0.015). We also compared altered frequency of each alteration in good and poor responders. Significant alterations which were only found in poor responder with frequency &gt; 5% and significantly affected to survival outcomes were selected. Thirteen alterations including EGFR R831H, A840T, E866K were associated with poor survival outcomes. Patients who had any of 13 significant alterations (N = 10, 22.2%) had poorer survival outcomes (3-year OS rate 84.5% vs 20.0%, P &lt; 0.001). Among them, patients who had any of EGFR R831H, EGFR A840T, EGFR E866K (N = 5, 11.1%) had poorer survival after IC. EGFR alterations, which might be underestimated in previous low-depth sequencing data, were found in deep sequencing analysis, and these alterations significantly affect response to IC and survival outcomes.

Conclusion: Targeted deep sequencing of HNSCC treated with IC was useful to predict response to IC. Validation of significant alteration in separate cohort should be warranted.

Citation Format: Chan-Young Ock, Bongjun Son, Seungyoun Lee, Jaewoo Moon, Sehui Kim, Bhumsuk Keam, Tae Min Kim, Yoon Kyung Jeon, Se-Hoon Lee, Dong-Wan Kim, Dae Seog Heo. Identification of genomic alteration which affects resistance to induction chemotherapy in patients with locally-advanced head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 608. doi:10.1158/1538-7445.AM2015-608