Dataset Information

Pharmacogenomic potential in advanced cancer patients.

ABSTRACT:

Purpose

The prevalence of pharmacogenetically actionable medications in advanced cancer patients whose therapy may be optimized with genotype data was determined.

Methods

Patients enrolled in our institutional molecular tumor board observational cohort were included in this study. Collected data included demographics, type(s) of cancer, and outpatient medications. Medications were classified as "pharmacogenetically actionable" if there are Clinical Pharmacogenetics Implementation Consortium (CPIC) therapeutic recommendations for that medication based on the presence of germline variations. The prevalence of pharmacogenetically actionable medications in the study population was determined, and the frequency of opportunities for pharmacogenetic prescribing and adverse event (AE) mitigation were estimated.

Results

In a cohort of 193 patients with advanced cancer, 65% of patients were taking a pharmacogenetically actionable medication. Approximately 10% of the outpatient medications taken by the study population had a pharmacogenetic association. The most common pharmacogenetically actionable medications being used were ondansetron (47%), capecitabine (10%), and sertraline (7%). Using published genetic variation frequencies and AE risk, we conservatively estimated that 7.1% of cancer patients would be eligible for genetic-based medication adjustment, and 101 AEs would be prevented in 10,000 patients genotyped.

Conclusion

Medications with pharmacogenetic associations are used commonly in the advanced cancer patient population. This widespread exposure supports the implementation of prospective genotyping in the treatment of these high-risk patients.

SUBMITTER: Nichols D

PROVIDER: S-EPMC7936720 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Pharmacogenomic potential in advanced cancer patients.

Nichols Dan D Arnold Susanne S Weiss Heidi L HL Wu Jianrong J Durbin Eric B EB Miller Rachel R Kolesar Jill J

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 20190301 7

<h4>Purpose</h4>The prevalence of pharmacogenetically actionable medications in advanced cancer patients whose therapy may be optimized with genotype data was determined.<h4>Methods</h4>Patients enrolled in our institutional molecular tumor board observational cohort were included in this study. Collected data included demographics, type(s) of cancer, and outpatient medications. Medications were classified as "pharmacogenetically actionable" if there are Clinical Pharmacogenetics Implementation ...[more]

PMID: 31361818

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Project description:Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

Dataset Information

Pharmacogenomic potential in advanced cancer patients.

Purpose

Methods

Results

Conclusion

Publications

Pharmacogenomic potential in advanced cancer patients.

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