A state-of the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer
Authors listG Middleton H Robbins F Andre Charles Swanton
BACKGROUND: Building on the success of targeted therapy in certain well-defined cancer genotypes, three platform studies - NCI-MATCH, LUNG-MAP and The National Lung Matrix Trial (NLMT) have attempted to discover new genotype-matched therapies for people with cancer. PATIENTS AND METHODS: We review the outputs from these platform studies. This review led us to propose a series of recommendations and considerations that we hope will inform future precision medicine programmes in cancer RESULTS: The three studies collectively screened over 13,000 patients. Across 37 genotype matched cohorts there have been 66/875 responders, an overall response rate of 7.5%. Targeting copy number gain yielded 5/199 responses across 9 biomarker:drug matched cohorts, a response rate of 2.5%. CONCLUSIONS: The majority of these studies used single-agent targeted therapies. Whilst pre-clinical data can suggest rational combination treatment to reverse adaptive resistance or block parallel activated pathways there is an essential need for accurate modelling of the toxicity:activity trade-off of combinations. Agent selection is often sub-optimal; dose expansion should only be performed with agents with clear clinical proof of mechanism and the high target selectivity. Targeting copy number change has been disappointing; it is crucial to define the drivers on shared amplicons that include the targeted aberration. Maximising outcomes with currently available targeted therapies requires moving towards a more contextualised stratified medicine acknowledging the criticality of the genomic, transcriptional and immunological context on which the targeted aberration is inscribed. Genomic complexity and instability is likely to be a leading cause of targeted therapy failure in genomically complex cancers. Pre-clinical models must be developed that more accurately capture the genomic complexity of human disease. The degree of attrition of studies performed after standard of care therapy suggest that serious efforts be made to develop a suite of precision medicine studies in the minimal residual disease setting.
Journal Annals of Oncology
Issue number 2