Interpreting the clinical utility of a pharmacogenomic marker based on observational association studies

Sorich, Michael J.; Coory, Michael

doi:10.1038/tpj.2013.35

Cited by 13 publications

(10 citation statements)

References 34 publications

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“…Future directions of research include evaluation of LIPI as a marker of heterogeneity in ICI treatment effect (both relative and absolute) for randomized clinical trials across other ICIs used for advanced NSCLC (durvalumab, nivolumab, and pembrolizumab), first-line use of ICIs, and combination use of ICIs. 15,16,21 In conclusion, LIPI is a convenient and significant prognostic biomarker of OS, PFS, and ORR for patients with advanced NSCLC treated with atezolizumab. However, pretreatment LIPI also predicts survival and response outcomes for patients treated with docetaxel; thus, it is not specifically predictive for treatment with ICIs.…”

Section: Discussionmentioning

confidence: 90%

Evaluation of the Lung Immune Prognostic Index for Prediction of Survival and Response in Patients Treated With Atezolizumab for NSCLC: Pooled Analysis of Clinical Trials

Sorich

Rowland

Karapetis

et al. 2019

Journal of Thoracic Oncology

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Introduction: There is substantial variability in survival and response outcomes for patients using immune checkpoint inhibitors (ICIs), and predictive markers are required to guide treatment decisions. A lung immune prognostic index (LIPI) was recently developed to predict ICI treatment outcomes and we aim to evaluate whether LIPI is predictive of survival and response for patients treated with atezolizumab for advanced NSCLC. Methods: Pooled analysis was performed of patient-level data of four clinical trials of atezolizumab for NSCLC. Based on pre-treatment derived neutrophil-to-lymphocyte ratio greater than 3 and lactate dehydrogenase greater than the upper limit of normal, patients were assigned to one of three groups: good LIPI, 0 risk factors; intermediate LIPI, 1 risk factor; or poor LIPI, 2 risk factors. The primary outcome was overall survival (OS). Results: In a pooled cohort of 1,489 patients treated with atezolizumab, the LIPI group was significantly associated with OS (p < 0.001), progression-free survival (p < 0.001), and response (p < 0.001). Median OS for good (n ¼ 678), intermediate (n ¼ 631), and poor (n ¼ 180) LIPI groups was 18.4 months, 11.3 months, and 4.5 months, respectively. Association between LIPI and OS was consistently identified across a range of atezolizumab-treated subgroups. For docetaxel-treated patients (n ¼ 687), LIPI was similarly associated with survival (p < 0.001) and response (p ¼ 0.005). Conclusions: Pre-treatment LIPI is a convenient prognostic marker able to identify atezolizumab-treated patient groups with significantly different survival and response outcomes. However, LIPI is also a prognostic marker of survival and response for patients treated with chemotherapy; thus, it is not specifically predictive for ICI treatment.

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Section: Discussionmentioning

confidence: 90%

Evaluation of the Lung Immune Prognostic Index for Prediction of Survival and Response in Patients Treated With Atezolizumab for NSCLC: Pooled Analysis of Clinical Trials

Sorich

Rowland

Karapetis

et al. 2019

Journal of Thoracic Oncology

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“…It encodes an adenosine triphosphate (ATP)-binding cassette transporter protein, which is responsible for intracellular glucuronidation and the conjugation of GSH with clinically important drugs. The protein encoded by ABCC2 is a member of the multidrug resistance like protein subfamily, which is involved in resistance to various drugs [17, 18]. ABCC2 protein is involved in biliary transport and is expressed in the canalicular (apical) part of hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

ABCC2-24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients

Xing

Shan

et al. 2016

Oncotarget

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Several studies have evaluated the efficacy of neoadjuvant treatment using oxaliplatin and fluoropyrimidines in advanced gastric cancer (GC). However, preoperative biomarkers predictive of clinical outcome remain lacking. We examined polymorphisms in the MTHFR, DPYD, UMPS, ABCB1, ABCC2, GSTP1, ERCC1, and XRCC1 genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 103 GC patients treated with preoperative chemotherapy. DNA was extracted from peripheral blood cells, and the genotypes were analyzed using a SNaPShotTM assay, polymerase chain reaction amplification, and sequencing. The ABCC2-24C > T (rs717620) genotype was associated with pathologic response to neoadjuvant chemotherapy. Patients with the TT and TC genotypes responded to neoadjuvant chemotherapy 3.80 times more often than those with the CC genotype (95% CI: 1.27–11.32). Patients with the CC genotype also had poorer outcomes than those with other genotypes. Thus, ABCC2-24C > T polymorphism may help to predict the response to preoperative chemotherapy in GC patients.

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“…Challenges faced while determining the clinical utility of a companion diagnostic 44 are underpinned by the need to show evidence that patient outcomes are improved by testing. This relies heavily on the pharmacogenetics-guided treatment options that are available once information from a pharmacogenetic test is available to inform prescribing decisions.…”

Section: Clinical Utilitymentioning

confidence: 99%

“… 50 – 52 While there may be sufficient evidence to indicate that a pharmacogenetic marker is predictive of adverse events, pharmacogenetics-based evidence guiding the new dosage of a drug and the subsequent impact of altered doses of medicines on patients’ outcome is scarce and demonstrating clinical utility requires evidence linking the alternative dosing strategy with patient outcomes. 43 , 44 …”

Section: Clinical Utilitymentioning

confidence: 99%

Economic evaluations of personalized medicine: existing challenges and current developments

Shabaruddin¹,

Fleeman²,

Payne³

2015

PGPM

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Personalized medicine, with the aim of safely, effectively, and cost-effectively targeting treatment to a prespecified patient population, has always been a long-time goal within health care. It is often argued that personalizing treatment will inevitably improve clinical outcomes for patients and help achieve more effective use of health care resources. Demand is increasing for demonstrable evidence of clinical and cost-effectiveness to support the use of personalized medicine in health care. This paper begins with an overview of the existing challenges in conducting economic evaluations of genetics- and genomics-targeted technologies, as an example of personalized medicine. Our paper illustrates the complexity of the challenges faced by these technologies by highlighting the variations in the issues faced by diagnostic tests for somatic variations, generally referring to genetic variation in a tumor, and germline variations, generally referring to inherited genetic variation in enzymes involved in drug metabolic pathways. These tests are typically aimed at stratifying patient populations into subgroups on the basis of clinical effectiveness (response) or safety (avoidance of adverse events). The paper summarizes the data requirements for economic evaluations of genetics and genomics-based technologies while outlining that the main challenges relating to data requirements revolve around the availability and quality of existing data. We conclude by discussing current developments aimed to address the challenges of assessing the cost-effectiveness of genetics and genomics-based technologies, which revolve around two central issues that are interlinked: the need to adapt available evaluation methods and identifying who is responsible for generating evidence for these technologies.

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Interpreting the clinical utility of a pharmacogenomic marker based on observational association studies

Cited by 13 publications

References 34 publications

Evaluation of the Lung Immune Prognostic Index for Prediction of Survival and Response in Patients Treated With Atezolizumab for NSCLC: Pooled Analysis of Clinical Trials

Evaluation of the Lung Immune Prognostic Index for Prediction of Survival and Response in Patients Treated With Atezolizumab for NSCLC: Pooled Analysis of Clinical Trials

ABCC2-24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients

Economic evaluations of personalized medicine: existing challenges and current developments

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