Complete and durable responses to molecular targeted therapies are rare in patients with advanced solid cancers, resulting in residual disease and tumour progression that limits patient survival. In an article published in the Nature Medicine, the investigators from the University of California, San Francisco, US discuss the emerging need to more fully understand the molecular basis of residual disease and therapeutic strategies to minimise or eliminate residual disease in order to move from temporary to chronic control of disease, or a cure.
In particular, they propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit the residual cells.
Residual disease is a population of tumour cells within a mostly therapy-sensitive tumour that survives initial treatment, resulting in accumulation of a drug-resistant population that, in turn, enables eventual therapy failure and tumour progression in the presence of ongoing treatment.
Consistent with the concept that residual disease cells can ultimately drive therapy failure and tumour progression, there is a correlation in clinical trials between tumour-therapy-response rates and progression-free survival for certain cancers. The residual disease may either be detected early during therapy by conventional radiographic imaging showing an incomplete tumour response or be occult, in which case an initial complete response to the therapy is followed by eventual therapy failure and tumour progression in the presence of ongoing treatment.
The biological mechanisms underlying the occurrence of residual disease in patients at the time of maximal initial-therapy response remain poorly understood, mostly owing to the lack of direct analysis of samples from patients with residual disease and the lack of cancer models that faithfully recapitulate human tumour responses, with a few notable exceptions.
Understanding the biological links between an incomplete response to therapy, residual disease, and therapy-resistant tumour progression, and identifying and therapeutically targeting the residual disease cells, are essential in enhancing therapeutic responses and preventing, or minimising, therapy failure. More-potent, next-generation, oncoprotein-targeted inhibitors will not be sufficient to overcome the problem of residual disease.
In their article, the authors create a framework for understanding and targeting residual disease in oncogene-driven solid tumours. They highlight the current knowledge of the etiology of clinical residual disease, which is poorly understood as compared to those of innate or acquired resistance. They propose strategies to fill in the knowledge gaps of residual disease and to accelerate clinical progress through rational therapeutic strategies that directly combat the residual-disease state in oncogene-driven solid tumours.
In the part on presence and etiology of residual disease, they discuss about principles of residual disease, intrinsic resistance, tumour cell adaptation and pharmacokinetic therapy failure. In the part on targeting residual disease, the authors discuss about rational polytherapy and the clinical context. In the part on redefining the target and therapeutic landscape, they discuss about new strategies, the relevance of immune strategies, indefinite versus discontinuation therapy, clinical endpoints and clinical trials. Finally, they call on the research community to harness the available resources to refocus efforts to better diagnosis, monitoring, and therapeutical elimination of residual disease.