The next steps in next-gen sequencing of cancer genomes

Abstract

The necessary infrastructure to carry out genomics-driven oncology is now widely available and has resulted in the exponential increase in characterized cancer genomes. While a subset of genomic alterations is clinically actionable, the majority of somatic events remain classified as variants of unknown significance and will require functional characterization. A careful cataloging of the genomic alterations and their response to therapeutic intervention should allow the compilation of an "actionability atlas" and the creation of a genomic taxonomy stratified by tumor type and oncogenic pathway activation. The next phase of genomic medicine will therefore require talented bioinformaticians, genomic navigators, and multidisciplinary approaches to decode complex cancer genomes and guide potential therapy. Equally important will be the ethical and interpretable return of results to practicing oncologists. Finally, the integration of genomics into clinical trials is likely to speed the development of predictive biomarkers of response to targeted therapy as well as define pathways to acquired resistance.

Figure 3. Next-gen sequencing and the complexity of human tumors.

Next-gen sequencing of tumors delivers a high-resolution snapshot of the genomics of tumor cells. With the exception of whole-exome sequencing, which may help identify tumor neoantigens, it does not generally inform us about the tumor microenvironment. Other “omic” platforms, such as RNA sequencing, proteomics and IHC, and polychromatic flow cytometry, would complement the current next-gen sequencing platforms, allowing further characterization of tumor cell–autonomous information and also facilitating the generation of immune, vascular, and stromal portraits that may have prognostic and predictive value. IF, immunofluorescence.

Figure 2. Integration of pathway and organ site clinical trials.

(A) Current oncology clinical trials are generally structured based on organ site, in which novel compounds (A, B, and C) are tested in specific cancers. (B) There are, however, commonalities in oncogenic pathways among cancers such as activation of the EGFR, FGFR3, and BRAF pathways. These pathways can be targeted with relatively specific inhibitors (X, Y, and Z). Some clinical trials are beginning to enroll patients on the basis of pathway activation (i.e., FGFR or BRAF mutations). (C) This approach, while reasonable, will likely require attention to both pathway activation and organ site. For example, BRAF mutations are found in a number of cancers including melanoma, thyroid, colon, and bladder. While BRAF inhibition has shown efficacy in BRAF-mutant melanoma and thyroid cancer, it does not appear to benefit patients with BRAF-mutant CRC. Whether BRAF inhibition in bladder cancer is of use remains unknown.

Figure 1. Genomics-based oncology workflow and integration of an actionability atlas.

The sequencing of cancer genomes requires coordinated efforts and constant modification. Patients are consented to access archival tumor tissue or fresh tumor tissue obtained from a new biopsy. Genomic profiles are generated by next-gen sequencing of tumor and normal (germline) tissues and are discussed at MTBs. The decision to report variants back to the patient and physician is made by consensus at the MTB in part based on a categorization of genes predetermined by an independent panel of clinical experts (the Clinical Committee for Genomic Research [CCGR]). Potential outcomes of the reporting of an actionable variant include: enrollment in a clinical trial, off-label use of a current FDA-approved agent, or continued SOC treatment. Systematic cataloging of outcomes into a proposed actionability atlas should aid future decision making.