Clonal repopulation dynamics in recurrent human papillomavirus-associated head and neck cancer.

Abstract

e17517 Background: Despite the better prognosis for human papillomavirus (HPV)-associated head and neck cancer (HNC) relative to HPV-negative HNC, 10 to 25% of HPV-associated cases recur within 3 years of completing therapy. We sought to investigate clonal repopulation dynamics in recurrent HPV-related oropharyngeal squamous cell carcinoma (OPSCC). Methods: Deep sequencing ( > 500X) using a CLIA-certified, targeted 262-gene multiplexed assay was performed on DNA extracted from 11 pairs of matched FFPE-preserved primary and subsequent recurrent p16-positive OPSCC samples including two pairs from the University of Washington and nine from the University of Pittsburgh. Results: 82% of patients were male with a median (IQR) age of 62 (15) years. Nine of eleven patients presented with advanced stage disease. Five were initially treated with surgery and concurrent chemoradiation, two with surgery, and four with concurrent chemoradiation. Median (IQR) time to recurrence was 10 (10.5) months. Four patients reported a history of tobacco use. The mean (SD) number of somatic nucleotide variants (SNVs) per tumor was 16.4 (12.2). 42% of SNVs occurred in the primary alone while 28% were unique to recurrences. 28% of SNVs were shared between primary-recurrent pairs. Three patients with distant or regional recurrences had different mutational profiles between the primary and recurrence suggesting repopulation by an early-appearing clone vs sampling error. One patient developed two local recurrences with conserved mutations in addition to de novo mutations in each subsequent recurrence suggesting repopulation by early and late evolving clones. Genes with a substantial functional impact that were frequently mutated in primary tumors include IDH2 and FBXW7. Recurrently mutated genes found in recurrent tumors include TET3, PIK3CA, STK11, and HDAC4. Conclusions: In thistargeted exome sequencing study of matched primary-recurrent OPSCC tumor pairs, we observed clonal repopulation with both transmitted and de novo mutations. Intriguingly, we noted a predilection for mutations involving genes regulating metabolism including IDH2 among primary tumors which has potential implications for precision medicine approaches.