Next-generation clinical trials: Novel strategies to address the challenge of tumor molecular heterogeneity.
Bottom Line: The promise of 'personalized cancer care' with therapies toward specific molecular aberrations has potential to improve outcomes.These issues have become hurdles to advancing cancer treatment outcomes with novel molecularly targeted agents.Finally intra-patient heterogeneity through time may be addressed by serial biomarker assessment at the time of tumor progression.
Affiliation: University of Chicago Medical Center, Department of Medicine, Section of Hematology & Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. Electronic address: email@example.com.Show MeSH
Related in: MedlinePlus
Mentions: Continuing with the EGFR example, a ‘driver vs wheel’ metaphor of a ‘run-away 18-wheeler truck’ can help to conceptualize the current appreciation of inter-patient heterogeneity of molecular ‘oncogenic drivers’ (the gas pedal) and loss of tumor suppressors (the brakes) (Figure 1A). When EGFR is the genomic ‘driver’ of a tumor (ie. EGFR mutation or EGFR amplification; in appropriately ‘pushing the gas pedal’), using targeted inhibition towards that driver generally has resulted in significantly improved clinical outcomes in that patient subset, (Petty et al., 2014; Zhang et al., 2013; Zhou et al., 2011) albeit until development of resistance with consequent progression (Figure 1C). On the other hand, in settings when EGFR is ‘over-expressed’ without genomic activation, or even less impressively merely ‘expressed’, similar to any of hundreds to thousands of other proteins in a tumor, EGFR may only be one of many wheels (downstream effectors) on the truck (cancer cell) (Figure 1A). Therefore, it is not critical and is easily expendable if neutralized, with other wheels (parallel escape signaling) taking up the slack. (Waddell et al., 2013; Lordick et al., 2013a).
Affiliation: University of Chicago Medical Center, Department of Medicine, Section of Hematology & Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. Electronic address: firstname.lastname@example.org.