Pharmacological Basis of Breast Cancer Resistance to Therapies - An Overview.

Breast Cancer (BC) is a molecular heterogeneous disease and patients with similar clinico-pathological characteristics often display different response to treatment. Cellular processes, including uncontrolled cell-cycle, constitutive activation of signalling pathways and alterations in DNA-repair mechanisms are the main altered features in breast cancer. These cellular processes play significant roles in the emergence of resistance to therapies. The introduction of target therapies and immunotherapy significantly improved the survival of breast cancer patients. The incorporation of novel biomarkers together with the introduction of new therapeutic options may help to overcome treatment resistance. Molecular profiling promises to help in refine personalized treatment decisions and catalyse the development of further strategies when resistances inevitably occurs. This review provides a summary of genetic and molecular aspects of resistance mechanisms to available treatments for BC patients, and its clinical implications.

Dihydropyrimidine dehydrogenase deficiency in patients with severe toxicity after 5-fluorouracil: a retrospective single-center study.

BACKGROUND: 5-Fluorouracil (5-FU) is an agent frequently used in the treatment of solid cancers. A deficiency in the enzyme that catabolizes 5-FU leads to severe toxicity. The gene responsible for this enzyme is DPYD, located on chromosome 1q22. The most prevalent alteration described is DPYD*2A, which leads to a splicing defect and thus skipping of the translation of an entire exon. The objectives of this retrospective study were to describe the frequencies of DPYD gene mutations in a Belgian population and to correlate them with the grade of toxicity. METHODS: This was a retrospective, single-center study conducted at the University Hospitals Leuven, by reviewing a database of patients screened for DPYD gene mutations between May 2009 and June 2015 after prolonged grade 3-4 toxicity. Polymerase chain reaction sequencing of exons 2, 6, 10, 11, 13, 18, 19 and 22, and pyrosequencing of exon 14 were performed by an in-house laboratory. RESULTS: Of the 80 patients screened, 65 were heterozygous or compound heterozygous for DPYD and 3 had a homozygous mutation. The most prevalent mutation in our population was DPYD*9A. CONCLUSIONS: Despite previous reports, in our small retrospective study the most prevalent variation in patients with severe adverse events was DPYD*9A. As this variant has previously been reported to be benign, we suggest that screening for dihydropyrimidine dehydrogenase deficiency should be extended across multiple exons of the DPYD gene.

4th ESPT Conference: pharmacogenomics and personalized medicine - research progress and clinical implementation.

The Fourth European Society of Pharmacogenomics and Personalized Therapy biennial conference was organized in collaboration with the Italian Society of Personalized Medicine (SIMeP) and was held at Benedictine Monastery of San Nicolò l'Arena in Catania, Sicily (Italy) on 4-7 October 2017. The congress addressed the research progress and clinical implementation in pharmacogenomics and personalized medicine. The Fourth European Society of Pharmacogenomics and Personalized Therapy congress brought together leading international scientists and healthcare professionals actively working in the fields of pharmacogenomics and personalized therapy. Altogether, 25 speakers in 15 session comprehensively covered broad spectrum of pharmacogenetics and pharmacogenomics research, clinical applications in different clinical disciplines attended by 270 delegates.

Incidence and relative risk of adverse events of special interest in patients with castration resistant prostate cancer treated with CYP-17 inhibitors: A meta-analysis of published trials.

Abiraterone acetate and orteronel are two CYP-17 inhibitors that have been studied in prostate cancer. They have shown relevant toxicities, including fluid retention/oedema, hypokalaemia, hypertension, liver function test abnormalities and cardiac events. The goal of this study was to determine the risk of special adverse events related to CYP- 17 inhibitor in patients with metastatic castration-resistant prostate cancer (CRCP). Summary data from four randomized phase III trials comparing CYP-17 inhibitors and prednisone versus placebo and prednisone in metastatic CRCP patients were meta-analysed. Pooled risk ratios (RRs) for the risk of all-grade and grade 3-4 adverse events of special interest were calculated. Data from 4916 patients (2849 in the AA experimental arm; 2067 in the control arm) were analysed. The incidence of grade 3-4 adverse events was never more than 10% of the patients. However, compared with placebo, the CYP-17 inhibitor significantly increased the all-grade events of hypertension (RR=1.53; 95% CI=1.3-1.8; p<0.00001), hypokalaemia (RR=1.56; 95% CI=1.29-1.89; p<0.00001), cardiac disorders (RR=1.47; 95% CI=1.27-1.7; p<0.00001) liver function test abnormalities (RR=1.93; 95% CI=1.15-3.24; p=0.01) grade≥3 adverse events, hypokalaemia (RR=4.23; 95% CI=1.28-13.99; p=0.02) and cardiac disorders (RR=1.55; 95% CI=1.18-2.05; p=0.002). A lot of adverse events such as hypertension, hypokalaemia, cardiac disorders and liver function test abnormalities are increased during CYP-17 inhibitor based therapy. Strict monitoring of these side effects should be considered during CYP- 17 inhibitor therapy in prostate cancer patients.