The Promise and the Reality of Genomics to Guide Precision Medicine in Pediatric Oncology: The Decade Ahead

Abstract

Much has been written about the promise of "precision medicine," especially in oncology, where somatic mutations can influence the response of cancer cells to "targeted therapy." There have been successful examples of targeted therapy improving the outcome of some childhood cancers, such as the addition of an ABL class tyrosine kinase inhibitor to conventional chemotherapy substantially improving the cure rate for patients with BCR-ABL1 positive acute lymphoblastic leukemia. Although there are other mutations serving as putative targets in various childhood leukemias and solid tumors, effective targeted therapy has yet to be established for them in prospective clinical trials. There are also uncertainties about which "targeted therapy" to use when patients have multiple targetable genomic lesions in their cancer cells, given the paucity of data upon which to develop evidence-based guidelines for selecting and integrating targeted agents for individual patients. There are also multiple examples of inherited germline variants for which evidence-based guidelines have been developed by the Clinical Pharmacogenetics Implementation Consortium to guide the selection and dosing of medications in children with cancer. Clinical pharmacology is poised to play a critical role in both the discovery and development of new targeted anticancer agents and their evidence-based translation into better treatment for children with cancer. To embrace these challenges and opportunities of "precision medicine," clinical and basic pharmacologists must expand the depth of our science and the bandwidth of our translational capacity if we are to optimize precision medicine and advance the treatment of cancer in children and adults.

Figure 1.. Complexity in selecting optimal medications based on combinations of germline and somatic genome variation in cancer.

Somatic (tumor) and germline (normal) genome variation is reflected for three hypothetical patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), based on actual genome variants documented from sequencing patients with this disease (17). For each hypothetical patient, genes indicated have already been shown to have functional alterations in ALL (mutations or structural alterations in leukemia cells, inherited variants altering function in germline DNA), and those with mutations in each patient are indicated in red font with an asterisk. Somatic variants are often activating, whereas germline genes are typically loss-of-function (TPMT, NUDT15, CYP2D6) or more rarely gain-of-function (CYP2C19 and CYP2D6 duplication alleles). Potential selection of medications targeting somatic mutations is based on in vitro or in vivo activity of each medication against target proteins. Multiple variants often occur in the same leukemia cell, as documented in prior sequencing studies (17), and often only a subset are treated, as depicted for each patient. All inherited germline variants are essentially always present in the tumor (not depicted). Selection of optimal therapy using inherited germline variants follows evidence-based CPIC guidelines (for medications below the dotted red line). A substantial number of additional somatic and inherited genome variants are known to exist in this disease, adding further complexity to evidenced-based selection of optimal treatment.