5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

Improvements in adjuvant therapy have led to a sustained fall in recurrences after early breast cancer. The differential reduction in local and systemic recurrences is poorly understood. This study aimed to explore changes in the distribution of loco-regional and distant recurrences in clinical trials reported over the last 20 years. We also aimed to determine the relative impact of adjuvant chemotherapy and endocrine therapy. MEDLINE search for adjuvant, phase III randomized breast cancer clinical studies between January 1990 and March 2011 was performed. Neoadjuvant, single agent biologics and studies that did not report the proportion of loco-regional and distant recurrences were excluded. The change in the frequency of recurrences was assessed as the nonparametric correlation between the number of loco-regional recurrences as a proportion of all recurrences and time. Studies were weighted by sample size. The differential effect of chemotherapy and endocrine therapy was also assessed. Fifty-three randomized clinical trials with a total of 86,598 patients were included in the analysis. Between 1990 and 2011, the proportion of loco-regional recurrences has decreased from approximately 30 to 15 % (Spearman's ρ = -0.40, p < 0.001). There was no interaction between type of surgery (mastectomy vs. lumpectomy), administration of adjuvant radiation therapy and menopausal status and the correlation of loco-regional recurrences and time. Chemotherapy regimen showed a larger negative correlation compared with endocrine therapy ( ρ = 0.49 vs. ρ = 0.24). Advances in treatment of early breast cancer have differentially reduced the proportion of loco-regional recurrences compared with distant recurrences. In recent trials, loco-regional recurrences account for less than 10-15 % of all recurrences. These falling event rates may affect patient care, especially when deciding on treatments influencing loco-regional control. This change may also impact on the design of clinical trials assessing loco-regional therapy such as surgery and/or local radiation therapy.

Non-small-cell lung cancer (nsclc) constitutes about 85% of all lung cancers. Approximately 50% of patients diagnosed with nsclc present with advanced disease (stage iii or iv) that is not amenable to curative treatment. The number of patients with stage iiib or iv disease who are alive at 1 year after diagnosis has increased from 10% in the untreated population in the early 1980s to 50% in patients with a good performance status receiving treatment today. However, those statistics remain dismal, and the two dominant reasons are the large number of patients diagnosed with advanced-stage disease and the observed primary or secondary resistance to current therapies. The present article addresses the question of drug resistance in lung cancer, focusing on subjects that are currently topical and under intense scrutiny.