Combining HPV Status and Intratumour Heterogeneity for Predicting Outcome in Head and Neck Squamous Cell Carcinoma Patients

Evaluation of Mutant-Allele Tumour Heterogeneity as a prognostic biomarker with patients HPV status

Evaluation of next-generation sequencing (NGS) data and associated clinical records of head and neck squamous cell carcinoma (HNSCC) patients from several institutions, made available through The Cancer Genome Atlas (TCGA), showed that combining Mutant-Allele Tumour Heterogeneity (MATH) as a biomarker with the patient's HPV status provides an effective indicator of improved patient outcome, according to research presented at the 2014 Multidisciplinary Head and Neck Cancer Symposium (20-22 February, 2014, Stottsdale, USA).

Study rationale

Based on 74 cases from a single institution, the researchers had previously shown that a measure of intratumour genetic heterogeneity derived from NGS data, MATH is related to outcome in HNSCC. However, only a limited number of HPV- positive cases were available for that initial study. Therefore, they sought to determine in the larger TCGA dataset, whether the MATH biomarker of intratumour genetic heterogeneity improves HNSCC outcome prediction based on HPV status.

The results

The TCGA data available for HNSCC included 302 patients, with 35 patients with HPV-positive tumours. The researchers' examination confirmed that high tumour MATH at time of surgery is an indicator of poor outcome (high-MATH hazard ratio (HR) = 2.1; p = 0.0002) and that HPV-positive HNSCC patients have lower average MATH values than HPV-negative HNSCC patients (p = 0.007).

In bivariate analysis, both MATH and HPV were significantly associated with survival. When stratified by HPV status, MATH was similarly related to outcome in clinically defined subsets of patients regardless of clinical characteristics (tumour margins, nodal classification or tumour staging). Median follow-up with the 173 surviving patients was 22 months.

A tumour can contain many different types of cancer cells. Standard DNA sequencing discovers both the DNA mutations that differ among cancer cells and gives a measure of diversity. Genetic heterogeneity of each tumour was assessed by MATH, the percentage ratio of the width to the center of the distribution of tumour-specific mutant-allele fractions. In order to compare to previous studies, analysis was limited to mutant-allele fractions no less than 0.075, and the high-MATH cut-off value of 32, previously found to distinguish outcome classes, was used. Cox proportional hazards analysis was used to evaluate the relations of MATH and HPV to overall survival.

"Calculating patients' MATH marker as well as their HPV status is a more reliable predictor of patient survival, and the methodology that we used to measure MATH is simple enough that it could be adopted readily in the clinic," said lead author Dr James Rocco, PhD, a head and neck surgical oncologist at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary, and the Daniel Miller Chair in Otology and Laryngology at Harvard Medical School in Boston, USA.

According to Dr Rocco, "now that we know that both HPV status and intra-tumor heterogeneity matter for patient outcome, we are in a better position to personalise therapy for our patients. We can try less toxic therapies in patients likely to be cured, and try new or alternate therapies in patients likely to fail. In addition, it may help identify the patients most likely to benefit from clinical trials."

The authors concluded that their results support the evaluation of MATH as a prognostic biomarker to be added to HPV status in the design of clinical trials and in treatment choices.

The study authors reported no potential conflicts of interest.

The abstract entitled "Mutant-Allele Tumor Heterogeneity (MATH) Adds to Human Papillomavirus (HPV) Status in Predicting Outcome in Head and Neck Squamous Cell Carcinoma (HNSCC)" was presented during a scientific session on 21 February at the 2014 Multidisciplinary Head and Neck Cancer Symposium. The 2014 Multidisciplinary Head and Neck Cancer Symposium was sponsored by the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO) and the American Head & Neck Society (AHNS).