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Denominator Problem Precision Medicine — SCE Medical Oncology MCQ

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ModerateClinical Trials & StatisticsDenominator Problem Precision MedicineSCE Medical Oncology

A phase III trial tests a new targeted therapy in a molecularly-selected population (only patients with a specific mutation). The trial enrolls 250 patients per arm and uses PFS as the primary endpoint. The median PFS is 12 months (experimental) vs 6 months (control), HR 0.50. However, only 3% of screened patients have the target mutation. What is the main limitation of this precision medicine approach?

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Correct answer: A — The 'denominator problem' — while the treatment benefit is large for the 3% of molecularly-selected patients, the vast majority screened do not benefit; the overall population-level impact is small despite the impressive HR in the selected subgroup

The 'denominator problem' is a fundamental challenge in precision oncology: highly effective targeted therapies may benefit only a small proportion of the total patient population. For example, NTRK inhibitors achieve >75% ORR but NTRK fusions occur in <1% of common solid tumours. This creates tension between: individual patient benefit (dramatic responses in selected patients) and population-level impact (most patients don't benefit). The solution involves: comprehensive molecular testing at scale, basket trials across tumour types, and equitable access to both testing and treatment.

Reference: JRCPTB Curriculum; ESMO 2024 Precision Medicine; Hyman et al NEJM 2015