Genetic Testing in Cancer Therapeutics

Ezzeldin, Hany; Diasio, Robert B.

doi:10.1158/1078-0432.ccr-06-0707

Cited by 12 publications

(9 citation statements)

References 36 publications

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“…This can result in severe and life-threatening hematopoietic toxicity. The TMPT gene has been shown to exhibit at least 9 variable alleles in white populations (68,69 ). Most cases of decreased TMPT activity have been found in patients with 3 of these alleles, TPMT*2, TPMT*3A, and TMPT*3C.…”

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

“…Subjects heterozygous for these alleles have intermediate activity, whereas those homozygous are TMPT deficient. Subjects that are compound heterozygotes (e.g., TPMT*2/TPMT*3A and TPMT*3A/ TMPT*3C) also lack the transferase (68,69 ).…”

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

“…In the populations studied to date, approximately 90% of subjects have high activity of TMPT, 10% have intermediate activity, and 0.3% have little or no detectable activity (69 ). Multiple studies have shown that subjects with TMPT deficiency are at high risk of developing hematopoietic toxicity if given standard doses of thiopurines.…”

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

“…Multiple studies have shown that subjects with TMPT deficiency are at high risk of developing hematopoietic toxicity if given standard doses of thiopurines. In addition, subjects who are heterozygotes have an intermediate risk of dose-limiting toxicity, whereas those with 2 copies of the wild-type gene can receive the standard dose (69 ).…”

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

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A Personalized Approach to Cancer Treatment: How Biomarkers Can Help

2008

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Background: The present approach to cancer treatment is often referred to as “trial and error” or “one size fits all.” This practice is inefficient and frequently results in inappropriate therapy and treatment-related toxicity. In contrast, personalized treatment has the potential to increase efficacy and decrease toxicity. Content: We reviewed the literature relevant to prognostic, predictive, and toxicity-related markers in cancer, with particular attention to systematic reviews, prospective randomized trials, and guidelines issued by expert panels. To achieve personalized treatment for cancer, we need markers for determining prognosis, predicting response to therapy, and predicting severe toxicity related to treatment. Among the best-validated prognostic markers currently available are serum concentrations of α-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH) for patients with nonseminoma germ cell tumors and tissue concentrations of both urokinase plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) for breast cancer patients. Clinically useful therapy predictive markers are estrogen and progesterone receptors to select patients with breast cancer for treatment with endocrine therapy and human epidermal growth factor receptor 2 (HER-2) to select breast cancer patients for treatment with trastuzumab (Herceptin). Markers available for identifying drug-induced adverse reactions include thiopurine methyltransferase (TPMT) to predict toxicity from thiopurines in the treatment of acute lymphoblastic leukemia and uridine diphosphate glucuronyltransferase to predict toxicity from irinotecan in the treatment of colorectal cancer. Conclusions: Validated prognostic, predictive, and toxicity markers should help cancer treatment move from the current trial-and-error approach to more personalized treatment.

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Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

Section: Tpmt For Predicting Toxicity From Thiopurinesmentioning

confidence: 99%

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A Personalized Approach to Cancer Treatment: How Biomarkers Can Help

2008

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“…To move or "translate" a genetic test from the research lab setting to the clinical setting requires that a number of objectives can be met 4 . Sensitivity, reliability, reproducibility are all required as part of the validation that FDA and other regulatory bodies require.…”

Section: Clin Cancer Res 4139 2006;12(14) July 15 2006mentioning

confidence: 99%

Overview of Cancer Pharmacogenomics

Diasio¹

2008

AACR Education book

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It has become increasingly clear that much of the variability in drug response (both efficacy and toxicity) observed in the population is due to genetic causes. Th e overall eff ect is most obvious for drugs such as cancer chemotherapy agents which have a relatively narrow therapeutic window such that the diff erence between the mean eff ective dose and mean toxic dose is not large and any small change can lead to a diff erence in effi cacy or toxicity. As we began to understand the specifi c genes coding for important metabolic steps 20-30 yrs. ago, it became possible to associate specifi c genetic defects with certain drug responses; the clinical fi ndings actually stimulating a search for the biochemical and in turn genetic defects. Th is led to an appreciation of specifi c pharmacogenetic syndromes. Th e advent of the modern genomic era with sequencing of the entire human genome has opened up the possibility that with high throughput, multigene screening methodologies, one can actually use an opposite approach probing the genome to look for sequence variations which could then be associated with clinical fi ndings. In the past several years, we have had regulatory agencies such as FDA begin to establish guidelines in the development of pharmacogenomics tests. FDA has approved pharmacogenomic tests so far for at least 3 chemotherapy agents and more are likely to follow.

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Genetic testing: predictive value of genotyping for diagnosis and management of disease

Özgüç

2011

EPMA Journal

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This article describes predictive, preventive value of genetic tests and the implication of the use of testing for personalized treatment. This year marks the 10th anniversity of publishing of the sequence of the human genome. One important area of application of this mega project is a development of genetic tests for mutation detection in single gene disorders that has impact for pediatric age group patients and analyzing susceptibility genes as risk factors in common disorders. Types of genetic tests, new emerging technologies will enable developments of high-throughput approaches by microarrays of great application capacity as described here. As it is usual for all technologies used in health care, bioethical concerns has to be delt with. The ethical, social and governance issues associated with genetic testing are discussed.

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Genetic Testing in Cancer Therapeutics

Cited by 12 publications

References 36 publications

A Personalized Approach to Cancer Treatment: How Biomarkers Can Help

A Personalized Approach to Cancer Treatment: How Biomarkers Can Help

Overview of Cancer Pharmacogenomics

Genetic testing: predictive value of genotyping for diagnosis and management of disease

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