Potential Utility of Pre-Emptive Germline Pharmacogenetics in Breast Cancer.

Patients with breast cancer often receive many drugs to manage the cancer, side effects associated with cancer treatment, and co-morbidities (i.e., polypharmacy). Drug-drug and drug-gene interactions contribute to the risk of adverse events (AEs), which could lead to non-adherence and reduced efficacy. Here we investigated several well-characterized inherited (germline) pharmacogenetic (PGx) targets in 225 patients with breast cancer. All relevant clinical, pharmaceutical, and PGx diplotype data were aggregated into a single unifying informatics platform to enable an exploratory analysis of the cohort and to evaluate pharmacy ordering patterns. Of the drugs recorded, there were 38 for which high levels of evidence for clinical actionability with PGx was available from the US FDA and/or the Clinical Pharmacogenetics Implementation Consortium (CPIC). These data were associated with 10 pharmacogenes: DPYD, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, G6PD, MT-RNR1, SLCO1B1, and VKORC1. All patients were taking at least one of the 38 drugs and had inherited at least one actionable PGx variant that would have informed prescribing decisions if this information had been available pre-emptively. The non-cancer drugs with PGx implications that were common (prescribed to at least one-third of patients) included anti-depressants, anti-infectives, non-steroidal anti-inflammatory drugs, opioids, and proton pump inhibitors. Based on these results, we conclude that pre-emptive PGx testing may benefit patients with breast cancer by informing drug and dose selection to maximize efficacy and minimize AEs.

Interactions between hepatic lipase and apolipoprotein E gene polymorphisms affect serum lipid profiles of healthy Canadian adults.

The purpose of this study was to assess the individual and interactive effects between hepatic lipase (LIPC; C-514T, G-250A) and apolipoprotein E (APOE) (E2, E3, E4) gene polymorphisms on levels of plasma lipoprotein cholesterol and triglyceride among healthy, young, Canadian adults (n = 440). All subjects with at least one APOE2 allele had significantly lower low-density lipoprotein cholesterol, total cholesterol, and total cholesterol - high-density lipoprotein cholesterol ratio when compared with those with the APOE3 or APOE4 allele. There were significant differences in the LIPC allele and genotype frequencies between Caucasian (n = 207) and Asian (n = 211) individuals, but ethnicity did not contribute to the variations in circulating lipids. In addition, the lowest triglyceride levels (0.87 +/- 0.27 mmol.mL(-1)) were found in all APOE2 individuals carrying LIPC-514-CC and LIPC-250-GG genotypes, whereas the highest triglyceride levels (1.29 +/- 0.34 -1.32 +/- 0.32 mmol.mL(-1)) were found in APOE2 individuals carrying the opposite genotypes, LIPC-514TT and LIPC-250AA. These observations, distinct from the anti-atherogenic effects of APOE2 through the lowering of low-density lipoprotein cholesterol and LIPC on high-density lipoprotein cholesterol, suggest that there is an interactive effect between APOE and LIPC genotypes on plasma triglyceride levels. These results provide the basis for further studies on establishing which genotype combinations would be the most protective against hypertriglyceridemia.