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Great strides in precision medicine: Personalized oncology and molecular diagnostics
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
Clinical trials between standard chemotherapeutic agents and targeted therapies such as small-molecule inhibitors vastly differ, according to Badalian-Very (2014, 73): There are several fundamental differences between cytotoxic chemotherapies and small molecular inhibitors. Dose-related toxicities have traditionally been considered [central] end points of Phase I trials and the maximum tolerated dose (MTD) was regarded as the optimal dose providing the best efficacy with manageable toxicity. Recently, development of targeted inhibitors has challenged the paradigms used in cytotoxic chemotherapy trial design. In precision medicine pharmacokinetic (PK) and pharmacodynamic (PD) end points tend to take a backseat to toxicity. Molecularly targeted agents do not always maintain the same dose–toxicity relationship as cytotoxic agents and tend to produce minimal organ toxicity. Furthermore, molecular therapeutic agents usually result in prolonged disease stabilization and provide clinical benefit without tumor shrinkage, a characteristic seen with cytotoxic agents, therefore necessitating alternative measures of antitumor efficacy. These end points include biologically relevant drug exposures, PD biomarker measures of target inhibition, and intermediate end-point biomarkers, such as … biomarkers. In the field of cancer, pharmacogenomics is complicated by the fact that two genomes are involved: the germline genome of the patient and the somatic genome of tumor, the latter of which is of primary interest. This genome predicts whether specific targeting agents will have a desired effect in the individual. On the other hand, germline pharmacogenetics can identify patients likely to demonstrate severe toxicities when given cytotoxic treatments (Badalian-Very, 2014, 73).
Pharmacogenomics of chronic obstructive pulmonary disease
Published in Expert Review of Respiratory Medicine, 2019
Several considerations are important when attempting a COPD pharmacogenomics study, some of which are specific to COPD and some more generally applicable to pharmacogenomics studies. An example of the latter is the availability of a sufficient sample size of well-characterized subjects treated with the relevant drug. In the past, these samples have most commonly been collected as part of clinical trials, though some pharmacogenomics questions can be addressed in observational studies. Therefore, to reach the necessary numbers many pharmacogenomics studies require commitment from industry sponsors or collaborations with academic investigators. While DNA variants are easily assessed in blood samples, other potentially relevant biomarkers, such as gene expression, may require samples from the appropriate target tissue. For cancer pharmacogenomics studies, this has been less of a limitation, since tissue sampling is a standard part of clinical care. However, invasive procedures such as bronchoscopy and lung biopsy are not routinely performed in the evaluation of COPD patients, limiting the availability of these samples for research and clinical translation.