Abstract
Simple SummaryOrgan preservation protocols have become first line therapy for the majority of advanced laryngeal cancers. Unfortunately, up to one third of patients will develop recurrent disease requiring salvage surgery. These tumors tend to display aggressive features when compared to primary disease. The aim of this study is to identify genomic alterations associated with poor prognosis in the recurrent setting to guide precision therapy and identify potential targetable pathways. Here we show that mutations in the oxidation pathway, specifically the KEAP1-NFR2 pathway, predict survival in a cohort of patients undergoing salvage laryngectomy.Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. Sixty-two patients were sequenced using a targeted panel, of which twenty-two also underwent transcriptome sequencing. Alterations were grouped based on biologic pathways and survival outcomes were assessed using Kaplan-Meier analysis and multivariate cox regression. Select pathways were evaluated against The Cancer Genome Atlas (TCGA) data. Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, p = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, p = 0.02). Multivariate analysis showed mutations in the Oxidation pathway remained an independent predictor of disease specific survival (HR 3.2, 95% CI 1.1–9.2, p = 0.03). Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity. Further, TCGA analyses demonstrated the prognostic value of oxidation pathway alterations in previously untreated disease. Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer. These prognostic genetic biomarkers may inform precision medicine protocols and identify putatively targetable pathways to improve survival in this cohort.
Highlights
In the era after the VA larynx and RTOG 91-11 trials, organ preservation protocols with radiation (RT) or chemoradiation (CRT) have become first line therapy for many patients with locoregionally advanced laryngeal squamous cell carcinoma (LSCC) [1,2]
We subsequently evaluated whether hypoxia scores were predictive of survival in our cohort and found that there is a trend towards worse five-year disease specific survival in patients with high Ragnum Scores compared to patients with low Ragnum scores, (67% vs. 100%, p = 0.2, Figure 4C) and likely limited byCancers the low number
Using the The Cancer Genome Atlas (TCGA) Head and Neck Squamous Cell (HNSC) data set, we found that the presence of alterations in the oxidation pathway predicted worse five-year disease specific survival (DSS)
Summary
In the era after the VA larynx and RTOG 91-11 trials, organ preservation protocols with radiation (RT) or chemoradiation (CRT) have become first line therapy for many patients with locoregionally advanced laryngeal squamous cell carcinoma (LSCC) [1,2]. Despite the benefit of laryngeal preservation, disease free survival rates range between 27–70%, and up to one third of patients will require subsequent salvage laryngectomy [1,3,4]. Even when recurrence is operable, survival rates among patients undergoing salvage surgery is approximately 50% and around 30% patients will develop a second recurrence [5,6,7,8]. Work by our group aiming to illuminate the genomic landscape of recurrent LSCC led to targeted sequencing of a small subset of patients with recurrent laryngeal carcinoma after primary surgery or CRT [13]. A study by Lee et al further identified alterations in p53 expression between previously untreated LSCC and matched recurrent tumors after radiation [14]
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