Kelly Kristin Filipski

Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting

Purpose: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. Experimental Design: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR. Results: In wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(−/−) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(−/−) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(−/−) mice. Conclusion: Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes. Clin Cancer Res; 16(19); 4789–99. ©2010 AACR.

Pharmacogenomics in oncology care

Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized control trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed.

Multi-marker Solid Tumor Panels Using Next-generation Sequencing to Direct Molecularly Targeted Therapies

In contemporary oncology practices there is an increasing emphasis on concurrent evaluation of multiple genomic alterations within the biological pathways driving tumorigenesis. At the foundation of this paradigm shift are several commercially available tumor panels using next-generation sequencing to develop a more complete molecular blueprint of the tumor. Ideally, these would be used to identify clinically actionable variants that can be matched with available molecularly targeted therapy, regardless of the tumor site or histology. Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions. The uniqueness of these tests from other genomic applications used to guide clinical treatment decisions lie in the sequencing platforms used to generate large amounts of genomic data, which have their own related issues regarding analytic and clinical validity, necessary precursors to the evaluation of clinical utility. The generation and interpretation of these data will require new evidentiary standards for establishing not only clinical utility, but also analytical and clinical validity for this emerging paradigm in oncology practice.

Implementation of the 21-gene recurrence score test in the United States in 2011

Purpose:We examined hospital use of the 21-gene breast cancer test in the United States. We report state-level differences in utilization and propose a model for predicting implementation of guideline-recommended genomic testing.Methods:Genomic Health provided test orders for calendar year 2011.We summarized utilization at the hospital and state levels. Using logistic regression, we analyzed the association between the likelihood to order the test and the hospital’s institutional and regional characteristics.Results:In 2011, 45% of 4,712 acute-care hospitals ordered the test, which suggests that 25% of newly diagnosed invasive female breast cancer cases were tested. Significant predictors of testing included participation in National Cancer Institute (NCI) clinical research cooperative groups (odds ratio (OR) 3.73; 95% confidence interval, 2.96–4.70), advanced imaging (OR, 2.19; CI, 1.78–2.68), high-complexity laboratory (OR, 2.15; CI, 1.24–3.70), affiliation with a medical school (OR, 1.57; CI, 1.31–1.88), and reconstructive surgery (OR, 1.23; CI, 1.01–1.50). Significant regional predictors included metropolitan county (OR, 3.77; CI, 2.83–5.03), above-mean income (OR, 1.37; CI, 1.11–1.69), and education (OR, 1.26; CI, 1.03–1.54). Negative predictors included designation as a critical-access hospital (OR, 0.10; CI, 0.07–0.14) and distance from an NCI cancer center (OR, 0.998; CI, 0.997–0.999), with a 15% decrease in likelihood for every 100 miles.Conclusion:Despite considerable market penetration of the test, there are significant regional and site-of-care differences in implementation, particularly in rural states.Genet Med 18 10, 982–990.

Epidermal Growth Factor Receptor Mutational Testing and Erlotinib Treatment Among Veterans Diagnosed With Lung Cancer in the United States Department of Veterans Affairs

Introduction We examined mutational testing of the epidermal growth factor gene (EGFR) and erlotinib treatment among veterans diagnosed with non–small‐cell lung cancer in the United States Department of Veterans Affairs (VA). Our objectives were to identify the prevalence of clinically actionable EGFR mutations, to determine whether testing and treatment were guideline concordant, to evaluate the impact of testing and treatment on survival, and to estimate the rate of testing. Patients and Methods Test results were linked to electronic health records from VA Corporate Data Warehouse and the VA Central Cancer Registry. We analyzed patient demographic and clinical characteristics, prevalence of EGFR mutations, and timing of EGFR mutational testing and erlotinib treatment based on pharmacy records. Overall survival was assessed by Kaplan‐Meier analysis. Results Among 973 patients tested at 70 VA medical centers between 2011 and 2013, 64 (7%) had sensitizing EGFR mutations, 694 (71%) were EGFR wild type, and 168 (17%) had clinically insignificant polymorphisms or variants of unknown significance. Results were not documented in 47 tests (5%). Erlotinib administration was in agreement with test results in 843 cases (87%). Conclusion Veterans have a much lower rate of sensitizing EGFR mutations than the reported average of 10% to 15%, which correlates with a high rate of smoking among veterans. This may partially explain clinicians’ reluctance to prescribe EGFR testing, which results in underutilization. Although test results appear to have influenced erlotinib treatment decisions, we documented a substantial number of cases where treatment was not applied in accordance with clinical guidelines, potentially resulting in worse outcomes and unnecessary cost. Micro‐Abstract We examined epidermal growth factor receptor gene (EGFR) testing and erlotinib treatment among veterans with non–small‐cell lung cancer. Veterans had a low (7%) prevalence of EGFR mutations. There were several patients where EGFR testing and erlotinib treatment departed from clinical practice guidelines. Integration of decision support tools into the electronic health record could improve the quality of cancer care.

Dosing recommendations for pharmacogenetic interactions related to drug metabolism.

Objective Pharmacogenomic studies have established the important contribution of drug-metabolizing enzyme genotype toward drug toxicity and treatment failure; however, clinical implementation of pharmacogenomics has been slow. The aim of this study was to systematically review the information on drug-metabolizing enzyme pharmacogenomics available in the US drug labeling, practice guidelines, and recommendations. Methods Drug-metabolizing enzyme genotype and phenotype information was assessed in US FDA drug labeling, clinical practice guidelines, and independent technology assessors to evaluate the consistency in information sources for healthcare providers. Results Eighty four gene–drug pairs were identified as having drug-metabolizing enzyme genotype or phenotype information within the label. The manner in which pharmacogenomic information was presented was heterogeneous both within the label and between clinical practice recommendations. Conclusion For proper implementation of pharmacogenomics in clinical practice, information sources for healthcare providers should relay consistent and clear information for the appropriate use of biomarkers.

Clinical decisions surrounding genomic and proteomic testing among United States veterans treated for lung cancer within the Veterans Health Administration

BackgroundCurrent clinical guidelines recommend epidermal growth factor receptor (EGFR) mutational testing in patients with metastatic non-small cell lung cancer (NSCLC) to predict the benefit of the tyrosine kinase inhibitor erlotinib as first-line treatment. Proteomic (VeriStrat) testing is recommended for patients with EGFR negative or unknown status when erlotinib is being considered. Departure from this clinical algorithm can increase costs and may result in worse outcomes. We examined EGFR and proteomic testing among patients with NSCLC within the Department of Veterans Affairs (VA). We explored adherence to guidelines and the impact of test results on treatment decisions and cost of care.MethodsProteomic and EGFR test results from 2013 to 2015 were merged with VA electronic health records and pharmacy data. Chart reviews were conducted. Cases were categorized based on the appropriateness of testing and treatment.ResultsOf the 69 patients with NSCLC who underwent proteomic testing, 33 (48%) were EGFR-negative and 36 (52%) did not have documented EGFR status. We analyzed 138 clinical decisions surrounding EGFR/proteomic testing and erlotinib treatment. Most decisions (105, or 76%) were concordant with clinical practice guidelines. However, for 24 (17%) decisions documentation of testing or justification of treatment was inadequate, and 9 (7%) decisions represented clear departures from guidelines.ConclusionEGFR testing, the least expensive clinical intervention analyzed in this study, was significantly underutilized or undocumented. The records of more than half of the patients lacked information on EGFR status. Our analysis illustrated several clinical scenarios where the timing of proteomic testing and erlotinib diverged from the recommended algorithm, resulting in excessive costs of care with no documented improvements in health outcomes.

The Clinical Sequencing Evidence-Generating Research Consortium: Integrating Genomic Sequencing in Diverse and Medically Underserved Populations

The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.