Combining Mutant-Allele Tumor 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 being held at the JW Marriott Camelback Inn Resort & Spa in Scottsdale, Arizona, February 20 – 22, 2014. This interpretation is based on an 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) [1][2].
The MATH measurement was originally created by researchers at the Center for Cancer Research and Department of Surgery, Massachusetts General Hospital in Boston, MA, to quantify the degree of heterogeneity of a distinct tumor. The concept is based on the assumption that multiple genetic mutations are responsible for the transformation of normal cells into cancerous cells. When cancerous cells evolve the malignant cells becomes increasingly different, both from their ancestor cells and from each other. Hence, when treating cancer patients, researchers agree that the more heterogeneous a tumor is, the harder it is to treat. The hypothesis is supported by the fact that tumor genetic heterogeneity is significantly associated with tumor progression and adverse treatment outcomes in patients with HNSCC. [3]
Researchers have found that the prognostic value of some known biomarkers may be the result of their association with high genetic heterogeneity. MATH provides a useful measure of that heterogeneity to be prospectively validated as next-generation sequencing (NGS) data from homogeneously treated patient cohorts become available.[3]
Calculating patients? MATH marker as well as their HPV status is a more reliable predictor of patient survival… the methodology … is simple enough that it could be adopted readily in the clinic…
The TCGA data available for HNSCC patients included 302 patients, with 35 HPV-positive patients. The researchers? examination confirmed that high tumor MATH at time of surgery is an indicator of poor outcome (high-MATH hazard ratio (HR) = 2.1; 95% confidence interval (CI), 1.4 to 3.2; p = 0.0002, logrank test) and that HPV-positive HNSCC patients have lower average MATH values than HPV-negative HNSCC patients. 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 (tumor margins, nodal classification or tumor staging). Median follow-up with the 173 surviving patients was 22 months.
Different cancer cells
A tumor 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 tumor was assessed by MATH, the percentage ratio of the width to the center of the distribution of tumor-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 cutoff 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.
A reliable predictor
?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 author James Rocco, MD, 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. ?Now that we know that both HPV status and intra-tumor heterogeneity matter for patient outcome, we are in a better position to personalize 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.?
For more information:
[1] Mutant-Allele Tumor Heterogeneity (MATH) Adds to Human Papillomavirus (HPV) Status in Predicting Outcome in Head and Neck Squamous Cell Carcinoma (HNSCC), presented at the 2014 Multidisciplinary Head and Neck Cancer Symposium by James Rocco,MD, PhD.
[2] Mroz EA1, Rocco JW. MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol. 2013 Mar;49(3):211-5. doi: 10.1016/j.oraloncology.2012.09.007. Epub 2012 Oct 15. [Article][PubMed]
[3] Mroz EA, Tward AD, Pickering CR, Myers JN, Ferris RL, Rocco JW. High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer. 2013 Aug 15;119(16):3034-42. doi: 10.1002/cncr.28150. Epub 2013 May 20. [Article][PubMed]
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