Capecitabine Pharmacogenetics: Historical Milestones and Progress Toward Clinical Implementation

Syn, Nicholas; Lee, Soo‐Chin; Goh, Boon-Cher; Yong, Wei-Peng

doi:10.2217/pgs-2016-0133

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…The utility of molecular screening protocols to support early phase clinical trial enrollment in Asian cancer patients remains unclear since most precision oncology initiatives have been performed in the United States and Europe in predominantly Caucasian populations. [4][5][6][7][8][9][10][11][12][13] However, there is increasing appreciation for ethnogeographical variability in the epidemiology of genomic mutations across diverse populations [14][15][16][17][18][19][20] which may impact the feasibility of accruing patients into biomarker-enriched clinical trials. For instance, "druggable" EGFR kinase domain mutations are established to occur at a much higher incidence in East Asian patients with non-small cell lung cancers compared to patients of European ancestry.…”

Section: Introductionmentioning

confidence: 99%

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Heong

Syn

Lee

et al. 2017

Intl Journal of Cancer

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The value of precision oncology initiatives in Asian contexts remains unresolved. Here, we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays, such as immunohistochemistry, copy number analysis and in situ hybridization tests, were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5-4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1-68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks.

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Section: Introductionmentioning

confidence: 99%

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Heong

Syn

Lee

et al. 2017

Intl Journal of Cancer

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“…Capecitabine is a third-generation fluoropyrimidine that is approved for pretreated metastatic breast cancer (Syn et al, 2016). Capecitabine is commonly used after anthracycline/ taxane-based therapies failure during palliative therapy.…”

Section: Capecitabinementioning

confidence: 99%

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

2020

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Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determinants in chemotherapy response and the development of side effects. Some pharmacogenomic studies were designed to explore germline variants that can be used as biomarkers for predicting developing toxicity or adverse events during chemotherapy in BC. In this review, we reassess and summarize the major findings of pharmacogenomic studies of chemotherapy toxicity during BC management. In addition, deficiencies hampering utilizing these findings and the potential targets of future research are emphasized. Main insufficiencies in toxicity pharmacogenomics studies originate from study design, sample limitations, heterogeneity of selected genes, variants, and toxicity definitions. With the advent of high throughput genotyping techniques, researchers are expected to explore the identified as well as the potential genetic biomarkers of toxicity and efficacy to improve BC management. However, to achieve this, the limitations of previous work should be evaluated and avoided to reach more conclusive and translatable evidence for personalizing BC chemotherapy.

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“…Inter-individual and inter-regional heterogeneity subsists with regard to toxicity and efficacy profiles and may be partially elucidated by genetic variation [21]. Gene polymorphisms can describe a vicinity of patient pharmacodynamic variability of anticancer drugs, especially fluoropyrimidines.…”

Section: Hfs and Pharmacogenomicsmentioning

confidence: 99%

“…TYMS is an enzyme which catalyzes the conversion of dUMP to dTMP and is the main intracellular target of the active 5-FU metabolite, 5-FdUMP, which compose a ternary complex with TYMS and 5-10 MTHF. However, mechanism of resistance to 5-FU is due to mainly raised TYMS expression [21]. Ooyama et al observed that the copy number of TYMS (18p11.32) exhibited a strong association with drug resistance, which may lead to the use of TYMS copy number as a predictive marker for fluoropyrimidines drug sensitivity [26].…”

Section: Hfs and Pharmacogenomicsmentioning

confidence: 99%

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Hand and Foot Syndrome Associated with Capecitabine

Alsaloumi¹,

Shawagfeh²,

Başgut³

2020

ACO

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Having cancer impacts the patient both psychologically and physically. However, if cancer is accompanied with HFS, the patient’s condition gets even worse. Capecitabine is a prodrug approved to treat several types of cancer such as breast and colorectal cancer. It is associated with several adverse effects such as hand and foot syndrome (HFS) which mostly affects the palms and legs. The provoked mechanisms of HFS are not clear yet. They require further validation of HFS pathogenesis. Up to now, prevention and treatment of HFS are not clearly solidified. Evidence supports the use of celecoxib, urea-based creams, and vitamin E to reduce the severity and the incidence of HFS. This review aims to provide the gaps and ways to further clinical evaluations.

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Capecitabine Pharmacogenetics: Historical Milestones and Progress Toward Clinical Implementation

Cited by 7 publications

References 21 publications

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

Hand and Foot Syndrome Associated with Capecitabine

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