PATH Trial: Personalized Approaches in the Treatment of Head and Neck Cancer

Head and neck cancer is the 12th most common cancer in Canada, with 6450 patients diagnosed per year.1 The majority of head and neck cancers are squamous cell carcinoma (H&N SCC). The majority of H&N SCC patients present with locally advanced disease, however despite advances in intensive combined multi-modality treatment, approximately 35% of patients diagnosed with head and neck cancer will die of their disease.2 The primary curative intent treatment modalities for head and neck cancer are surgery and radiotherapy (with or without concurrent chemotherapy). Radiotherapy is used as the primary curative intent modality for H&N SCC for organ preservation of the oral cavity, pharynx and larynx to maintain speech and swallowing function. It is also used for unresectable cancers and in the adjuvant setting after surgery for patients with locally advanced disease.

Despite modern radiotherapy technologies allowing the delivery of high doses of radiotherapy (60-70 Gy) with curative intent, many patients have radioresistant SCC, with local, regional or distant progression during or shortly after radiotherapy. There are very few, if any, radiologic and pathologic predictors to determine which patients with H&N SCC will respond well to radiotherapy. Varying clinical responses are seen, with some patients having complete clinical resolution of their tumours within the first few weeks of radiotherapy, whereas others have minimal response, or even progressive disease during treatment. The only molecular marker used for patient stratification for definitive management is the presence of Human Papilloma Virus-16 (HPV) in oropharyngeal cancer, although its impact is tempered by smoking history (Ang DOI: 10.1056/NEJMoa0912217).

This study aims to assess genomic predictors of radioresistant and chemoresistant H&N SCC, defined as diagnosis of local, regional or distant recurrence within twelve months of completing curative intent radiotherapy with or without chemotherapy. Diagnosis of recurrent disease after radiotherapy is associated with poor survival outcomes, with a median survival of 8 months.3

Additionally, , this study aims to elucidate the genomic characteristics of virally-mediated H&N cancers and their impact on chemoradiation response. Currently, 40-45% of H&N cancers seen at BC Cancer are linked to viral infections, namely Epstein Barr virus (EBV) and human papilloma virus (HPV). Through prior research at the Genome Sciences Centre, BC Cancer experts are showing that the HPV genome can integrate into the human genome, resulting in profound genomic disruptions. Because these disruptions are exceedingly complicated, methods to study them did not exist until recently. The availability of Nanopore technology, a cutting-edge new strategy that sequences longer strands of DNA to detect novel genomic features will enable investigators to look at: how viral genomes integrate into human genomes and how they change; how these genomic changes reveal new insights into H&N cancers and how to treat them; and whether or not virally-mediated genomic changes lead to radio-resistance or radio-sensitivity. Through the study of H&N cancers, we aim to gain valuable knowledge that may be relevant to other virally-mediated cancers.

HPV positive oropharyngeal SCC has a distinct clinical phenotype, staging and biology compared to HPV negative H&N SCC, however deeper understanding of underlying genomic differences are lacking. The Cancer Genome Atlas (TCGA) has conducted the largest comprehensive genomic study of 528 H&N SCC tumours to date, however only 36 HPV positive tumors were included, resulting in limited comparison of genomic analysis between HPV positive and HPV negative tumours (PMID 31703248). In addition, TCGA-HNSCC cohort is largely derived from patients who underwent oral cavity surgery, rather than chemoradiation and lacks clinical correlatives of response to treatment including chemoradiation. PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal squamous cell carcinoma, however the clinical significance of PIK3CA mutations and other genomic alterations in response to chemoradiation is unclear.