Abstract PL04-02: Pharmacogenomics of chemotherapeutic-induced toxicities: Challenges and opportunities
Authors: M. Eileen Dolan
Journal: Cancer Research (2018)

Abstract The field of pharmacogenomics, which seeks to relate human genetic variants to variability in drug response, has evolved considerably over the past several decades. The initial successes in the field generally focused on single genetic variants within drug metabolizing genes that had large effects on patient sensitivity to a given drug. However, advances in DNA technology have driven the field from an a priori hypothesis-dependent candidate gene approach to a discovery-oriented, genome-wide approach that requires few assumptions regarding which variants are most relevant for the outcome of interest. Genome-wide association studies (GWAS) have significantly broadened the scope of studies to provide an evaluation of single nucleotide polymorphisms (SNPs) throughout the genome that may contribute to drug response or toxicity. Aside from genotype-phenotype association mapping and the identification of key genetic variants, these studies can provide insight into the mechanism of action of drug therapy when coupled with experimental approaches revealing the biological basis of the SNP-to-pharmacological phenotype association. As the field of genomics evolves and the regulatory “grammar” of DNA is further understood, the process of generating substantive evidence explaining genotype-phenotype correlations should gain momentum. By revealing the protein targets of regulatory SNPs associated with drug efficacy and toxicity, the possibility of identifying synergistic compounds to amplify efficacy and/or protective compounds to attenuate toxicities grows, enabling rational drug development. Nevertheless, GWAS has limitations, many of which are not unique to pharmacogenomics. GWAS generally do preclude the investigation of structural and rare variants. Additionally, there may be a high number of false positive findings in GWAS or a large number of SNPs each contributing modestly to the downstream phenotype. This could result in a lack of SNPs meeting genome-wide significance. Functional validation of signals can be challenging due to genomic variants that may have cell type-dependent roles, thereby requiring appropriate experimental models. Furthermore, the phenotype could be the consequence of the interaction among various cell types. While animal models may address these problems, significant divergence, particularly in the non-coding region where the majority of significant GWAS signals lie, becomes problematic. This contributes to the difficulty in understanding functional consequences of some signals throughout the genome. Replication is another particularly challenging obstacle in GWAS because both the demographics and the phenotypes must closely resemble the discovery set, and large clinical sample sizes are required to generate sufficient statistical power to overcome the multiple hypothesis burden that plagues GWAS. In oncology, pharmacogenomics is uniquely challenging due to considerations in somatic and germline variation, difficulty in performing and replicating large well-powered clinical GWAS, and difficulty in assigning genetic effects to a single pharmacological agent when most cancers are treated with multi-drug regimens. However, identifying genetic predictors associated with long-term debilitating toxicities resulting from anticancer agents can be impactful since there are over 28 million cancer survivors worldwide. To date, there have been GWAS of many chemotherapy-induced adverse sequelae including peripheral neuropathy, myelosuppression, hepatotoxicity, ototoxicity, pancreatitis, cardiotoxicity, and osteonecrosis, as well as others. Severe toxicities often present as comorbidities, and can drastically alter a patient's quality of life, or even prevent effective administration of the treatment regimen. Toxicities can occur at various times during or after treatment and are sometimes subject to a physician's best judgment rather than objectively quantifiable measures. In fact, most toxicities associated with chemotherapeutic agents are semi-quantitative with the exception of myelosuppression and ototoxicity. However, ototoxicity requires audiometry measures by a hearing specialist. There is also a lack of population diversity in GWAS of anticancer agent toxicity. There are a number of reasons for this, including fewer underrepresented minority populations on clinical trials, lower participation by underrepresented populations in genomic studies, and the requirement of large sample sizes to cover the broad range of genetic diversity in humans. Most array designs only capture a fraction of variation in African populations and complex statistical methods are required for admixed populations. Although there has been a recent increase in East Asian participation in pharmacogenomic trials, individuals of African descent are still woefully underrepresented. Importantly, given that allele frequencies vary in different populations and that some alleles are ancestry specific, findings in one population do not always translate to others. Therefore, the lack of studies of pharmacogenomics in underrepresented populations will only widen the known health disparity gap. The identification of causal associations of adverse sequelae is a hallmark paradigm of precision medicine, and may eventually enable treatment regimens and doses to be tailored specifically to the individual patient to maximize treatment efficacy while limiting off-target toxicities. However, despite a number of pharmacogenomic discoveries and compelling evidence, very few germline pharmacogenomic tests in oncology are used today in routine clinical practice. This is due, in part, to limited avenues for testing, delays in the receipt of pharmacogenomic results even when testing is pursued, lack of understanding of cost effectiveness. This is being tackled by several large academic centers focused on the implementation of pharmacogenomics discoveries into routine clinical care to help guide clinical decisions. However, the true challenge will be in the mainstream adoption of these tests by physicians in the community. Citation Format: M. Eileen Dolan. Pharmacogenomics of chemotherapeutic-induced toxicities: Challenges and opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr PL04-02.