Abstract
Simple SummaryThe DNA damage repair (DDR) gene profile is largely unexplored in head and neck squamous cell cancer (HNSCC), leaving little known about the treatment of HNSCC with PARP inhibitors. In this retrospective study, the prevalence of mutated DDR genes was studied in the tissue and/or blood samples (tDNA and ctDNA samples, respectively) of 170 patients with HNSCC. These findings were correlated with demographic and outcome data. DDR gene mutations were significantly increased in older patients, patients with primary tumors located in the larynx, patients with more advanced cancers at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with primary tumors in the oropharynx were less likely to have DDR gene mutations. Patients with DDR gene mutations identified in blood samples were found to have worse survival. The combined mutational analysis in blood and tumor demonstrated a high prevalence and an important prognostic role of DDR gene mutations in HNSCC, supporting further clinical research of PARP inhibitors in the genomic guided treatment of HNSCC.PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments.
Highlights
Over the past decade, generation sequencing (NGS) of genetic material contained in blood and tissue samples has revolutionized the field of oncology [1,2,3]
Presence of mutated DNA damage repair (DDR) genes was reported per patient, stipulating the specific DDR gene mutated and sample source
Detailed information about the prevalence of specific mutated DDR genes can be located in Table 3 and in Figure 1, and the allocation of the DDR gene mutations among patients can be viewed in Pathogenic or Presumed Pathogenic Mutations)
Summary
Generation sequencing (NGS) of genetic material contained in blood and tissue samples (tDNA and ctDNA, respectively) has revolutionized the field of oncology [1,2,3] Such discoveries have allowed for the treatment of non-small cell lung cancer with EGFR, ALK and MET inhibitors and basal cell cancer with hedgehog pathway inhibitors with improved outcomes. Despite the benefits of NGS in the management of many malignancies, the mutational landscape of squamous cell cancers of the head and neck (HNSCC) remains largely undescribed This has left the field without targeted management strategies and reliable prognostication based on an individual cancer’s genetic profile [4]. Therapies targeted to this pathway (such as adenoviral p53 gene therapy and use of small molecules to restore TP53 function/disrupt inactivation of wild-type p53)
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