What is the association between germline polymorphisms and chemotherapy-induced toxicities in cancer patients?Background
Chemotherapeutic drugs for cancer often have narrow therapeutic indices, are applied where the need for a favourable response is acute, and have toxic effects that are commonly life threatening or debilitating.1 Toxicity is commonly described as an adverse event that is attributable to the agent of interest. Chemotherapy-induced toxicities (or adverse events) can be grouped by their pathophysiological or anatomical features, some examples of which include skin and subcutaneous tissue disorders, gastrointestinal disorders, blood and lymphatic system disorders, and renal and urinary disorders.2 Toxicities are typically classified from grade 1 (mild symptoms or asymptomatic) to grade 4 (life-threatening), with grade 5 indicating death.2Background
Due to chemotherapy-induced toxicities contributing to lowered quality of life, morbidity, treatment cancellation and in some cases death,3 as well as a significant portion of cancer supportive care medical costs (34% to 86% in one study),4 chemotherapy and oncology have become key areas of pharmacogenetic research. Pharmacogenetic studies aim to identify genetic markers that are predictive of outcomes from pharmacological interventions.1,5 The ability to use genetic information to predict which patients are at the greatest risk of suffering chemotherapy-induced toxicities could greatly improve the overall care of cancer patients by enabling physicians to optimize drug selection, treatment schedule, cumulative dose delivered, prophylactic measures, and patient monitoring. For these reasons, in addition to the potential of personalized medicine to contribute to the selection of therapeutic strategies most likely to be effective, personalized medicine has been identified as an important goal in cancer therapy.Background
Individual genetic germline variation (as distinct from mutations in cancerous cells) are potentially valuable sources of information to inform personalized medicine. These include single nucleotide polymorphisms (SNPs) which are the simplest form of genetic variance, variable tandem repeats or minisatelites and microsatellites.5 Polymorphisms are most often associated with reduced activity or translation of the encoded product; however some polymorphisms can result in increases in activity or translation.5 Numerous studies and systematic reviews have investigated the association of polymorphisms with toxicity from different chemotherapies and different cancers.6–8 These have varied from candidate gene studies of specific polymorphisms informed by biological plausibility, to genome-wide association studies (GWAS). Although the clinical impact of this field of research has so far been limited, there are instances where research findings have been sufficiently convincing as to result in Food and Drug Administration (FDA)-mandated label changes to make physicians aware of pertinent germline pharmacogenetic information during prescription.1Background
In order for biomarkers to be considered clinically useful, there needs to be extensive validation and replication.9 Given that studies that investigate the association of polymorphisms with chemotherapy-induced toxicity are often carried out on relatively small populations, use retrospective data, are by definition observational rather than experimental, and (particularly for GWAS studies) have a high probability of false discovery; this is especially important in this context. Consequently, the field of research concerning the association between polymorphisms and cancer toxicity is an area for which the systematic review of literature - and where possible the meta-analysis of available data - is crucial to enable the translation of primary findings to clinical practice.Background
As such, this umbrella review is being conducted to synthesize the findings of all up-to-date systematic reviews on associations between germline variation and chemotherapy-induced toxicity. This will allow the identification of polymorphisms shown by primary investigation, validation and the systematic synthesis of findings to be proven markers of chemotherapy-induced toxicity - and therefore potentially ready for clinical application as risk factors to inform personalized medicine.Background
Additionally, this review will identify those areas of research that have not been subjected to systematic review. This is important as for personalized medicine informed by genetic variance to become a clinical reality, there must be a concerted effort to synthesize all relevant evidence so that it is available in a form that can effectively inform clinical practice and policy. No previous umbrella reviews have been performed on this topic.