Challenging Standard-of-Care Paradigms in the Precision Oncology Era

Abstract

The pace of genomic and immunological breakthroughs in oncology is accelerating, making it likely that large randomized trials will increasingly become outdated before their completion. Traditional clinical research/practice paradigms must adapt to the reality unveiled by genomics, especially the need for customized drug combinations, rather than one-size-fits-all monotherapy. The raison-d'être of precision oncology is to offer 'the right drug for the right patient at the right time', a process enabled by transformative tissue and blood-based genomic technologies. Genomically targeted therapies are most suitable in early disease, when molecular heterogeneity is less pronounced, while immunotherapy is most effective against tumors with unstable genomes. Next-generation cancer research/practice models will need to overcome the tyranny of tradition and emphasize an innovative, precise and personalized patient-centric approach.

Keywords: genomics; immunotherapy; personalized medicine; precision oncology; targeted therapy.

Key Figure 1. The snowflake theory and changing drug development paradigms

Top panel: Cancers are akin to malignant snowflakes: No two snowflakes are identical, and it seems that it is also extremely unusual for two metastatic tumors to have the same genomic fingerprint. As it turns out, if metastatic tumors are akin to malignant snowflakes in their distinctiveness, individual tumors become the ultimate extrapolation of rare and ultra-rare tumors--N-of-one malignancies. Bottom panel: Moving from drug-centric (top panel) to patient-centric trials and care (middle and bottom panels). If each cancer is unique and complex, precisely targeting it requires personalized combination therapy regimens. Bottom panel shows that personalized therapy is already routine in patient care outside the oncology setting. Abbreviations: CHF = congestive heart failure; RA = rheumatoid arthritis

Figure 2. Six blind men and elephants

Beyond genomics—transcriptomics, proteomics and more: The comprehensive molecular profile of the not-too-distant future may include genomics, transcriptomics, proteomics, metabolomics, microbiomics epigenomics, mutanomics, lipidomics, and immunogenotyping, and may hence predict response to multiple modalities including immunotherapy and chemotherapy [–56]. Each of these modalities gives us a piece of the puzzle, akin to the parable of the six blind men who each touch a different part of the elephant, such as the tusk versus the trunk, and therefore have vastly different views of the elephant. “Panomics” testing is a requisite of comprehensive analysis and may require complex computer algorithms for data integration and computation.