Tumour heterogeneity in the clinic

Abstract

Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Subpopulations of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity. Sequencing technologies can be used to characterize intratumour heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression. Genetic interpatient and intratumour heterogeneity can pose challenges for the design of clinical trials that use these data.

Figure 1. Clinical-trial design frameworks

In a population of molecularly profiled patients who have tumours of different histologies (shown by position of tumour) and molecular aberrations (shown as different colours), the framework for a clinical trial can take a number of forms. a, Histology-based clinical trials evaluate different molecular aberrations by enrolling patients with the same tumour histology but who harbour different aberrations, and match groups of patients to different drugs. b, Histology-independent, aberration-specific clinical trials, or ‘basket’ trials, enrol patients with different tumour histologies but who harbour the same or related molecular aberrations, and match drugs to the aberration specific or related groups. c, Standard N-of-1 trials randomly assign patients to different drugs in different sequential orders, with washout periods between drugs to minimize crossover effects. At completion, the individual effect of each drug and the average effects of each drug across individuals can be analysed. d, Modified N-of-1 trials use each patient as his or her own control and compare the treatment effect of the current matched drug with that of the most recent earlier drug.