Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial.

The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.

Role of traditional and new biomarkers in breast carcinogenesis.

In recent decades, several biomarkers have been investigated as predictors of breast cancer risk, development, prognosis and treatment efficacy.The detection of biomarkers strongly associated with breast carcinogenesis has an enormous potential, especially for selecting subjects at high risk of developing breast cancer who could benefit from chemopreventive treatments.Although the number of potential biomarkers continues to increase, a unique biomarker for breast cancer risk prediction has not been identified and it is probable that a panel of biomarkers will prove optimal. Further studies are needed to validate breast cancer biomarkers evaluation for individual risk assessment.This review summarizes the main biomarkers, which are important at different stages of breast carcinogenesis with updates from the recent literature.

The effect of transdermal estradiol or oral conjugated oestrogen and fenretinide versus placebo on haemostasis and cardiovascular risk biomarkers in a randomized breast cancer chemoprevention trial.

BACKGROUND: We have previously reported the favourable effect of transdermal estradiol (E2), relative to oral conjugated equine oestrogen (CEE), on ultrasensitive C-reactive protein after 12 months of treatment in a retinoid-placebo controlled two-by-two randomized breast cancer prevention trial (Decensi A et al (2002) Circulation106 10 1224-8). Here, we investigate the changes in lipids and clotting profile in patients of the same trial. METHODS AND RESULTS: Recent post-menopausal women were randomised to either oral CEE 0.625 mg/day and placebo (n = 55), CEE and fenretinide 200 mg/day (n = 56), transdermal E2 50 mg/day and placebo (n = 59) or E2 and fenretinide 200 mg/day (n = 56). Sequential medroxyprogesterone acetate 10 mg/day was given in each group. After 12 months, there was a statistically significant effect of the route of administration of hormone replacement therapy (HRT) on fibrinogen levels; the median percentage change being -5.7% with CEE and -1.1% with E2 (p = 0.012). Total cholesterol decreased in all arms (p < 0.0001). HDL-C decreased significantly with transdermal E2 (p = 0.006) compared to oral CEE and with fenretinide relative to placebo (p<0.001). Triglycerides exhibited an opposite modulation in the HRT route, with a 21.4% median increase with oral CEE and an 8.6% reduction with transdermal E2 (p < 0.0001). Antithrombin-III showed a 4% borderline significant reduction in the fenretinide arm relative to placebo, irrespective of the HRT administration route (p = 0.055). CONCLUSIONS: Our data indicate that transdermal E2 may be preferable to oral CEE based on its safer cardiovascular risk profile. Fenretinide modified some cardiovascular risk biomarkers and confirmed a safer profile compared to other retinoids.

Jagged-1 mutation analysis in Italian Alagille syndrome patients.

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations. The two novel missense mutations were clustered in the 5' region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype.