Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Abstract

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

Keywords: HRD; MSI-H; TMB; colorectal cancer; genetic testing; lung cancer; melanoma; mutations; targeted therapy.

Figure 1

Spectrum of actionable mutations in lung carcinomas, colorectal cancers and skin melanomas.

Figure 2

Common predictive mutations in major cancer types. Some mutation tests are more or less organ-specific, while other DNA assays are helpful in several categories of cancer patients.

Figure 3

Examples of tissue-specific and agnostic drug targets. Most known druggable mutations occur in tyrosine kinase membrane receptors, however, some of these molecules can relocate to other cellular compartments due to mutational events. Some targets and drugs are generally relevant only to a single tumor category (e.g., EGFR mutations in NSCLC), other indications include several cancer types (e.g., use of BRAF inhibitors for BRAF V600E mutated tumors), and a few targeted therapies are considered agnostic. The T-shaped lines illustrate the blockade of particular targets by various drugs.