Keynote Address V: Towards Personalized Treatment for Head and Neck Cancer

Abstract

The yield of the cancer genome project is providing extraordinary potential for the identification of new drug targets, for selecting individuals for specific therapies, and for predicting the outcome of an individual with cancer. For a number of malignancies affecting the head and neck region, e.g. melanoma, lymphoma and sarcoma, we are already using genetic knowledge to select patients for specific targeted therapies. One example is the use of vemurafenib for patients with melanoma that harbors a BRAF mutation. For the majority of squamous cells carcinomas of the head and neck (HNSCC), genetic knowledge has not yet resulted in stratified approaches to therapy. Apart from site classification, SCCHN can also be grouped into those with p53 mutations (the vast majority of smoking and alcohol-induced tumors) and those harboring human papillomavirus (mainly HPV-16). HPV+ HNSCC is an emerging disease representing a distinct clinical and epidemiological entity. Understanding the genetic basis of both HPV+ and HPV- HNSCC could allow therapeutic targeting of affected pathways for a stratified medicine approach. Recent gene sequencing studies indicate that various mutations within the PI3 kinase (PI3K) signaling pathway are found in both subgroups. E.g. PIK3CA mutation or amplification, and PTEN inactivation by gene copy loss or mutation are present in over 50% of oropharyngeal SCC, suggesting that targeting the PI3K/AKT/mTOR pathway might be an attractive approach in these patients. Other receptor tyrosine kinase mutations occurring at low frequency e.gs FGFR1, FGFR3 and EGFR could be use to select patients for targeted therapies against these proteins, should they be established as driver mutations in these tumors. One significant challenge of targeted therapies based on gene sequencing information is the observation of intra-tumor genetic heterogeneity. Because HNSCC are often readily accessible to multiple biopsies, this is an area where knowledge gained from HNSCC could be exploited to other solid tumors. Another area of significant interest is the use of immune therapy, e.g. anti-PD1 or anti-CTLA4 antibodies to treat solid tumors. Biomarkers predicting which patients will respond to these approaches are in development. Although surgery, chemotherapy or chemo-radiotherapy will remain the mainstay of treatment for most HNSCC in the foreseeable future, the introduction of molecular targeted therapies and immune therapies will play an ever more important role in the future management of HNSCC.