Targeted Therapy in Oropharyngeal Squamous Cell Carcinoma: The Implications of HPV for Therapy

Abstract

Oropharyngeal cancers caused by human papillomaviruses (HPV) have a different epidemiology, prognosis, genetic mutational landscape, response to treatment, and outcome when compared to HPV-negative cancers. In this review, a summary of our current understanding of HPV in head and neck cancer and the important advances that have shown HPV to be an etiological agent are discussed. HPV-positive and HPV-negative tumors are compared discussing clinicopathological factors, prognosis, outcome following treatment, and the molecular and genetic differences. Currently, the standard of care for oropharyngeal cancer is both surgery and post-operative radiotherapy with or without cisplatin or concurrent chemo-radiotherapy. The latter is used more often, especially in cancers of tonsil and base of tongue. However, there is increased interest in trying to de-intensify treatment and in the development of new treatments to target the underlying different molecular pathways of HPV-positive cancers. The current clinical trials involving surgery, chemotherapy, and radiation therapy are discussed. The new targeted treatments are also summarized. Although there is currently is no evidence from prospective studies to support a change in the treatment algorithm, the treatment options for patients with HPV-positive disease are likely to change in the future.

Keywords: Human papillomavirus; Oropharyngeal; Radiotherapy; Robotic surgery; Squamous cell carcinoma; Targeted therapy.

Fig. 1

The net drift percentage (net drift represents the net sum of the linear trend in period and cohort effects from age-cohort-period models) in oropharyngeal and oral cavity cancers among men stratified by age (1983–2002) for selected countries [4]. Black square oropharynx, white square oral cavity. Adapted with permission from Chaturvedi et al. [4]

Fig. 2

Kaplan–Meier curves for overall stratified by tumor HPV status for the entire study population [49]. HPV human papillomavirus. Reproduced with permission from Fakhry et al. [49]

Fig. 3

Risk classification for oropharynx cancer according to HPV status for OS [53]. Low-risk patients include HPV positive patients with either less than 10 smoking pack-years or more than 10 smoking pack-years, but N0–N2a nodal disease. The intermediate group consists of patients with HPV-positive patients with more than 10 smoking pack-years and N2b–N3 nodal disease and patients with HPV negative tumors with less than 10 smoking pack-years and T2–3 primary tumors. The high-risk group includes patients with HPV-negative tumors with less than 10 smoking pack-years, but T4 primary tumors or had more than 10 smoking pack-years. HPV human papillomavirus, OS overall survival. Reproduced with permission from Chau et al. [53]

Fig. 4

Kaplan–Meier plots showing impact of prognostic factors on DSS in p16-positive and p16-negative patients. a pT classification, b pN classification, c margin status, d ECS. 5-year DSS and P values based on log rank test [56]. DSS disease-specific survival, ECS extra-capsular spread. Reproduced with permission from Iyer et al. [56]

Fig. 5

A graphical description of the results of The Cancer Genome Atlas (TCGA) Network study comparing somatic alterations and altered protein expression that represent plausible therapeutic targets in HPV-positive and negative tumors [59]. Important genes are shown with their associated alteration (key below graph depicts gene aberration). HPV-positive tumors showed loss of TRAF3, activating mutations of PIK3CA, and amplification of E2F1. HPV-negative tumors contained amplicons on 11q with CCND1, FADD, BIRC2, and YAP1, or concurrent mutations of CASP8 with HRAS, targets for cell cycle death, and NF-kB. Reproduced with permission from [59]

Fig. 6

The protocol for the Eastern Cooperative Oncology Group (ECOG) 3311 study (NCT01898494). Patients are stratified with low-risk patients receiving observation post operatively and high-risk patients receive chemo-radiotherapy. Intermediate risk patients are randomized to low-dose or normal-dose radiotherapy. Reproduced with permission from: http://ecog-acrin.org/clinical-trials/e3311-educational-materials