Introduction: Head and neck cancers are among the most common human malignancies in the world, with high rates of morbidity and mortality. These tumors are mostly caused by heavy tobacco smoking; however, high-risk human papillomavirus (HR-HPV) infection has been increasingly associated with tumors in the oropharynx. Oropharynx squamous cell carcinomas (OPSCC) associated with HR-HPV infection represent a distinct clinical and epidemiologic entity, with differences in clinical presentation and treatment outcome reflecting distinct genetic and biologic profiles. Initial treatment decisions are critical to improve patient survival; therefore, considering that multimodality therapy is often toxic, treatment choice should balance tolerability, function preservation, and global response to therapy. Molecular markers may be beneficial in a better classification of patients, thus aiding in a more consistent tailoring of patient treatment and follow-up.
Objective: The aim of this study was to identify specific clinical and molecular profiles that classify subgroups of OPSCC patients according to their outcome.
Materials and Methods: Thirty OPSCC samples from patients treated with a chemoradiation-based organ-preservation protocol were included in this study. P16 protein expression was used as a surrogate marker for HR-HPV. The methylation status of 5 genes was evaluated by quantitative methylation-specific PCR (qMSP), and next-generation sequencing of a 15-gene panel was performed using the Ion Torrent PGM platform.
Results: The majority of patients (93.3%) were male, tobacco users (85.2%), presented with advanced disease (90%), and 36.7% were HR-HPV positive. Specific gene-promoter hypermethylation was observed in 32.1-50% of the OPSCC evaluated and, as expected, CCNA1 methylation was associated with HPV(+ve) cases (p=0.035). Eighteen patients (58.1%) had at least 1 gene mutated: 87.5% of HPV(-ve) and 57.1% of HPV(+ve) cases. Interestingly, 60% of smokers HPV(+ve) cases were wild-type for TP53 variants (p=0.003). The absence of deleterious variants in several genes (EZH2, FAT1, FBWX7, HRAS, IRF6, PIK3CA, and PTEN) was significantly associated with a complete response of the primary tumor site to the organ-preservation treatment protocol (p<0.004).
Conclusions: Even though all samples analyzed were of the oropharynx, several differences regarding molecular and clinical characteristics were identified. An association between molecular markers and the profile of therapy response can be useful in decision-making of the initial treatment and improve patient survival. More cases are being evaluated in order to assess whether the differences identified are able to significantly classify these patients into molecular subgroups associated with different outcomes and help in more thorough patient management.
Citation Format: Ana Carolina de Carvalho, Matias Eliseo Melendez, Cristovam Scapulatempo Neto, Gabriela Carvalho Fernandes, Lidia Maria Rebolho Batista Arantes, Bruna Pereira Sorroche, Gisele Caravina de Almeida, Rui Manuel Reis, Sandra Perdomo, André Lopes Carvalho. Depicting clinically relevant molecular alterations in oropharynx squamous cell carcinoma samples treated with an organ preservation protocol [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A30.