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Influence of Unrecognized Molecular Heterogeneity on Randomized Clinical Trials

From the Department of Biostatistics, Harvard School of Public Health and Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, and the Department of Oncology, University of Western Ontario and the London Regional Cancer Centre, London, Ontario, Canada.

Address reprint requests to Rebecca A. Betensky, PhD, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115; email: betensky{at}hsph.harvard.edu

PURPOSE: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients’ outcomes.

PATIENTS AND METHODS: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase II studies.

RESULTS: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase II trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders.

CONCLUSION: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancer.

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