—Edmund Mroz, PhD
This method of measuring heterogeneity can be applied to most types of cancer, so our work should help researchers determine whether a similar relationship between heterogeneity and outcome occurs in other tumors.
A new measure of cell heterogeneity within a tumor may predict treatment outcomes of patients with squamous cell carcinoma of the head and neck.
In a recent report,1 investigators at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary reported how the mutant allele tumor heterogeneity measure, referred to as “MATH” was a better predictor of survival than most traditional risk factors in a small group of patients with squamous cell carcinoma of the head and neck.
“Our findings will eventually allow better matching of treatments to individual patients, based on this characteristic of their tumors,” said lead author Edmund Mroz, PhD, of the MGH Center for Cancer Research. “This method of measuring heterogeneity can be applied to most types of cancer, so our work should help researchers determine whether a similar relationship between heterogeneity and outcome occurs in other tumors,” Dr. Mroz reported.
Measuring Tumor Heterogeneity
For decades investigators have hypothesized that tumors with a high degree of genetic heterogeneity would be more difficult to treat because particular subgroups might be more likely to survive a particular drug or radiation or to have spread before diagnosis. Although recent studies have identified specific genes and proteins that can confer treatment resistance in tumors, there previously has been no way of conveniently measuring tumor heterogeneity.
Gene Sequencing Data
Working in the laboratory of senior author James Rocco, MD, PhD, Director of the Massachusetts Eye and Ear Infirmary/Massachusetts General Hospital Head and Neck Molecular Oncology Research Laboratory, Dr. Mroz and his colleagues developed their new measure by analyzing advanced gene sequencing data to produce a value reflecting the genetic diversity within a tumor—not only the number of genetic mutations but how broadly particular mutations are shared within different subgroups of tumor cells. They first described this measure, called mutant-allele tumor heterogeneity, or MATH in an earlier report.2
In the current study, the investigators used mutant-allele tumor heterogeneity to analyze genetic data from the tumors of 74 patients with squamous cell head and neck carcinoma for whom they had complete treatment and outcome information. Not only did they find that higher mutant-allele tumor heterogeneity values were strongly associated with shorter overall survival—with each unit of increase reflecting a 5% increase in the risk of death—but that relationship was also seen within groups of patients already at risk for poor outcome.
For example, among patients with human papillomavirus–negative tumors, those with higher mutant-allele tumor heterogeneity values were less likely to survive than those with lower values.
Mutant-allele Tumor Heterogeneity Values Strongly Related to Outcomes
Overall, mutant-allele tumor heterogeneity values were more strongly related to outcomes than most previously identified risk factors and improved outcome predictions based on all other risk factors the researchers examined.
The impact of mutant-allele tumor heterogeneity value on outcome appeared strongest among patients treated with chemotherapy, which may reflect a greater likelihood that highly heterogeneous tumors contain treatment-resistant cells, Dr. Mroz said. He also noted that what reduces the chance of survival appears to be the subgroups of cells with different mutations within a tumor, not the process of mutation itself. “If all the tumor cells have gone through the same series of mutations, a single treatment might still be able to kill all of them. But if there are subgroups with different sets of mutations, one subgroup might be resistant to one type of treatment, while another subgroup might resist a different therapy,” he said.
In addition to combining mutant-allele tumor heterogeneity values with clinical characteristics to better predict a patient’s chance of successful treatment, Dr. Mroz noted that mutant-allele tumor heterogeneity could someday help determine treatment choice—directing the use of more aggressive therapies against tumors with higher values, while allowing patients with lower values to receive less intense standard treatment. Mutant-allele tumor heterogeneity could be just as useful at predicting outcomes for other solid tumors, the investigators noted, but added that would need to be shown in future studies.
“Our results have important implications for the future of oncology care,” said Dr. Rocco, the Daniel Miller Associate Professor of Otology and Laryngology at Harvard Medical School. “Mutant-allele tumor heterogeneity offers a simple, quantitative way to test hypotheses about intratumor genetic heterogeneity, including the likelihood that targeted therapy will succeed. They also raise important questions about how genetic heterogeneity develops within a tumor and whether heterogeneity can be exploited therapeutically.” ■
Disclosure: The authors reported that the study was supported by National Institute of Dental and Craniofacial Research grants R01DE022087 and RC2DE020958, National Cancer Institute grant R21CA119591, Cancer Prevention Research Institute of Texas grant RP100233, and the Bacardi MEEI Biobank Fund. Massachusetts General Hospital has filed a patent application for the mutant-allele tumor heterogeneity measure.
1. Mroz EA, Tward AD, Pickering CR, et al: High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma. Cancer. May 20, 2013 (early release online).
2. Mroz EA, Rocco JW: MATH, a novel measure of intrtumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol 49(3): 211-215, 2013.