Genetic Variants of ANGPT1, CD39, FGF2 and MMP9 Linked to Clinical Outcome of Bevacizumab Plus Chemotherapy for Metastatic Colorectal Cancer.

Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30; 95% CI: 1.52-7.14; p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.

UDP-glucuronosyltransferase genetic variation in North African populations: a comparison with African and European data.

BACKGROUND: Genetic variation in glucuronosyltransferases (UGT) is crucial in drug metabolism and risk of some diseases. AIM: To examine genetic variation in UGT in North African populations. SUBJECTS AND METHODS: Allele frequencies of SNPs UGT1A424Thr, UGT1A448Val, UGT2B1585Tyr, UGT2B15523Thr and UGT2B17 CNV deletion from Morocco, Algeria, Tunisia and Libya were compared to European and Sub-Saharan populations. RESULTS: North Africans are the group with the highest genetic heterogeneity given by internal differences in the occurrence of UGT2B17 deletion, UGT1A448Val and UGT1A4 haplotypes. UGT2B15 SNPs differentiate Sub-Saharans from the rest of the populations. CONCLUSION: North African populations show a high frequency of carriers of UGT2B15523Thr, a variant linked to an increased risk of prostate cancer. High Atlas Moroccans and Algerians show low frequency of UGT2B17del, a variant associated with high concentrations of testosterone and oestradiol.

HER2 and BARD1 Polymorphisms in Early HER2-Positive Breast Cancer Patients: Relationship with Response to Neoadjuvant Anti-HER2 Treatment.

The addition to chemotherapy of anti-HER2 drugs such as trastuzumab or pertuzumab has improved outcomes in HER2-positive breast cancer patients. However, resistance to these drugs in some patients remains a major concern. This study examines the possible association between the response to neoadjuvant anti-HER2 treatment in breast cancer patients and the presence of 28 SNPs in 17 genes involved in different cell processes (PON1, CAT, GSTP1, FCGR3, ATM, PIK3CA, HER3, BARD1, LDB2, BRINP1, chr6 intergenic region, RAB22A, TRPC6, LINC01060, EGFR, ABCB1, and HER2). Tumor samples from 50 women with early breast cancer were genotyped using the iPlex®Gold chemistry and MassARRAY platform, and patients were classified as good responders (Miller-Payne tumor grades 4-5) and poor responders (Miller-Payne tumor grades 1-3), as assessed upon surgery after 6 months of treatment. Proportions of patients with the HER2Ala1170Pro (rs1058808) SNP double mutation were higher in good (58.62%) than poor (20%) responders (p = 0.025). Similarly, proportions of patients carrying the synonymous SNP rs2070096 (BARD1Thr351=) (wv + vv) were higher in patients showing a pathological complete response (46.67%) than in those not showing this response (15.15%) (p = 0.031). The SNPs rs1058808 (HER2Ala1170Pro) and rs2070096 (BARD1Thr351=) were identified here as potential biomarkers of a good response to anti-HER2 treatment.

Usefulness of autosomal STR polymorphisms beyond forensic purposes: data on Arabic- and Berber-speaking populations from central Morocco.

BACKGROUND: This work describes, for the first time, the profile of Middle Atlas Berbers and Arabic-speaking central Moroccans for 15 autosomal STR loci widely used in forensic sciences. AIM: The main objectives were to determine the degree of heterogeneity among different Moroccan samples to identify geographic or linguistic patterns and to evaluate the usefulness of forensic STRs in anthropological studies. SUBJECTS AND METHODS: Blood samples were collected from 71 Arabic-speakers and 75 Berbers from the regions of Doukkala (central-west coast) and Khenifra (Middle Atlas), respectively. The AmpFlSTR Identifier kit was used to genotype 15 autosomal STR in both samples. RESULTS: Middle Atlas Berbers showed slightly higher genetic variation values compared to Arabic-speakers, both in the number of alleles and heterozygosity. In order to assess population relationships, data from Morocco, Algeria, Tunisia, Libya, Egypt, Kuwait, Qatar, Palestine, Syria, South-Spain and Turkey were included in the analysis. Within Morocco, genetic distances followed a clear geographic pattern. In the Arabic-speaking sample the genetic proportion of 'Arabian' admixture was estimated in 13%. CONCLUSION: The low value of admixture suggests that the Arabization of Morocco had a reduced demographic impact, which should be taken with caution because it is based on autosomal STRs with low inter-population variation levels.

Polymorphisms influencing muscle phenotypes in North-African and Spanish populations.

AIM: The purpose of this study was to determine the allelic and genotypic frequency distribution of the C34T mutation in the muscle isoform of the adenosine monophosphate deaminase 1 (AMPD1) gene and of the missense substitution K153R in the myostatin (GDF8) gene in one Spanish and two North African populations. METHOD: One sample of 98 individuals was genotyped from the South of Spain (Alpujarra) and two samples from Morocco (77 Berbers and 78 Arabs). RESULTS: The frequency of the AMPD1 C34T mutation was lower in Berbers (0.071) compared with the Alpujarra cohort (0.153, p = 0.018). The GDF8 K153R substitution showed little variability among the three cohorts. CONCLUSIONS: Studies with larger cohorts and other ethnic groups are needed to corroborate that there does not exist any major variability in the genotype distribution of genes associated with muscle phenotypes in the South-Eastern Mediterranean area.

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer.

HER2-positive breast cancer (BC) is an aggressive subtype that affects 20-25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC have dramatically improved since the introduction of anti-HER2 antibodies such as trastuzumab (TZ) and/or pertuzumab (PZ) added to chemotherapy. This study sought to examine whether correlation exists between copy number variations (CNVs) in several genes related to the PI3K/AKT pathway (HER2, FGFR1, PIK3CA, AKT3 and MDM2) and the efficacy of anti-HER2 neoadjuvant treatment in patients with early HER2-positive BC. Forty-nine patients received TZ or PZ/TZ and chemotherapy as neoadjuvant treatment. Gene CNVs were determined by quantitative polymerase chain reaction on paraffin-embedded biopsy specimens. The response to 6 months of therapy was assessed by Miller-Payne grading of the tumor on surgical resection; grades 4 and 5, indicating >90% tumor reduction, were defined as a good response. A good response was shown by 64.5% and a pCR by 31.2% of patients. When stratified by anti-HER2 antibody received and gene CNV, it was found that patients with FGFR1 gene amplification or those with FGFR1 amplification treated with TZ alone showed a poor response (p = 0.024 and p = 0.037, respectively). In the subset of patients treated with TZ/PZ combined, the pCR rate was significantly lower among those showing FGFR1 amplification (p = 0.021). Although based on a small sample size, our findings suggest that patients with FGFR1 amplification might benefit less from anti-HER2 antibody therapy.

Genetic differences among North African Berber and Arab-speaking populations revealed by Y-STR diversity.

Y-chromosome STR polymorphisms are inherited in a haploid state which makes them a powerful tool for easy tracing of paternal lineage and for use in human population evolutionary studies. North-African Y chromosomal diversity has traditionally been studied in order to find genetic and geographic associations as well as to test how natural and cultural barriers have affected the degree of genetic flow not only within North Africa but also in a wider Mediterranean context. The degree of Berber/Arab genetic differentiation in the Moroccan population has been tested for a complete set of forensic markers as sixteen Y-chromosomal short tandem repeats (STRs) (DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1). The results suggest considerable population heterogeneity in North Africa.

Role of Chromodomain-Helicase-DNA-Binding Protein 4 (CHD4) in Breast Cancer.

Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4-the core component of the nucleosome remodeling and deacetylase (NuRD) complex-may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either 'deleterious', 'probably/possibly damaging' or as 'high/medium pathogenic'; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

miR-7, miR-10a and miR-143 Expression May Predict Response to Bevacizumab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer.

PURPOSE: Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor A. It is currently used in combination with chemotherapy to treat metastatic colorectal cancer. This therapy is not equally effective in every patient; in some, mechanisms of resistance arise that remain poorly understood. The aim of the present work was to determine whether the expression of 26 miRNAs could be associated with the effectiveness of bevacizumab plus chemotherapy, with progression-free survival (PFS), and with overall survival (OS) in metastatic colorectal cancer. PATIENTS AND METHODS: Paraffin-embedded biopsies from 76 patients with metastatic colorectal cancer were collected to isolate miRNAs. The expression of 26 miRNAs was analyzed by quantitative RT-PCR. For the purpose of analysis, patients were classified as either "responders" (PFS ≥6 months since beginning treatment) or "non-responders" (PFS <6 months). For the analysis of PFS and OS, patients were classified into two groups using the median gene expression value as the cut-off point ("high" [≥50% percentile] or "low" [<50% percentile]). Time-to-event data were analyzed using the Kaplan-Meier method and compared by the log rank test. Cox regression was used to estimate hazard ratios (HR) and their 95% confidence intervals. RESULTS: miR-7-5p and miR-10a-5p were more strongly expressed in non-responders than responders (p=0.049 and p=0.043, respectively), and OS was poorer in patients showing these higher expression levels (HR=2.54, 95% CI 1.42-4.55, p=0. 001, and HR=1.81, 95% CI 1.02-3.20, p=0.039, respectively). The overexpression of miR-143-3p, however, was associated with a better prognosis and significantly better PFS (HR=0.57; 95% CI: 0.33-0.96; p=0.033). CONCLUSION: High expression values for miR-7-5p and miR-10a-5p might be considered markers of a poorer prognosis in patients with metastatic colorectal cancer treated with bevacizumab plus chemotherapy, while the same for miR-143-3p might be a marker of better outcomes.

STR genetic diversity in a Mediterranean population from the south of the Iberian Peninsula.

Sixteen Y-chromosomal short tandem repeats (STRs) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1) were typed in DNA samples from 52 unrelated men and 15 autosomal STRs (CSF1PO, D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, FGA, TH01, TPOX, vWA) were also studied for a group of 90 individuals (men and women) from the same population (Andalusians from La Alpujarra, South of Spain). The Alpujarrenian population represents an example of an isolated population with remarkable geographical, cultural and historical characteristics. High haplotype diversities were observed for the studied polymorphisms, 0.98 and 1 for YSTRs and autosomal STRs, respectively. Population comparisons for the autosomal STR allele distributions revealed remarkable levels of global homogeneity among samples geographically related.

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer.

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: Six case reports.

BACKGROUND: In metastatic colorectal cancer (mCRC), the anti-vascular endothelial growth factor drug bevacizumab (BVZ) plus chemotherapy significantly improves progression-free survival compared to chemotherapy (CT) alone. This benefit is not, however, observed in all patients. While increased chemokine CXCL5 gene expression promoting angiogenesis has been proposed as a prognostic mCRC biomarker, few studies have examined its relationship with drug efficacy. This study sought to analyze tumor CXCL5 gene expression in six patients with different efficacy of BVZ-containing CT in terms of the tumor response to treatment. CASE SUMMARY: We report six cases of stage IV KRAS-mutated mCRC. Patients were given first line treatment with BVZ-containing chemotherapy in University Hospital of Fuenlabrada. The six patients differed in terms of primary tumor location (right/left side), tumor burden (mostly hepatic and peritoneal disease) and clinical disease course. Before treatment onset, total RNA was isolated from paraffinated tumor biopsy specimens and CXCL5 gene expression quantified through conventional RT-qPCR procedures. Our main finding was that CXCL5 expression levels were several times higher in three patients with lower progression free survival (under 6 mo) from the start of treatment. CONCLUSION: A higher expression of CXCL5 was observed in the three patients showing worse tumor response to treatment.

Differential expression of PMCA2 mRNA isoforms in a cohort of Spanish patients with breast tumor types.

The present study examined the mRNA expression levels of different isoforms of the plasma membrane calcium ATPase 2 (PMCA2) gene generated by alternative splicing at the first intracellular loop (site A) and C-terminal region (site C) in 85 human breast cancer tumor and 69 adjacent non-tumor tissues. Associations were identified between the expression of PMCA2 splice isoforms and the following clinical variables: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, tumor size, staging and histological classification, and lymph node status. Transcripts including splice site A or splice site C were amplified by reverse transcription-quantitative polymerase chain reaction using PMCA2 isoform-specific primers. Tumor and adjacent tissues were determined to express the different PMCA2 splice isoforms 2w, 2× and 2z (site A), and 2b (site C). The mRNA levels for these variants indicated high biological variability, but increased expression was observed in breast tumor tissues, compared with in adjacent tissues. Significantly increased PMCA2×/b expression levels were detected in breast tumor tissues histologically classified as lobulillar, compared with in ductal-types breast tumor tissues (P<0.028). Furthermore, PMCA2z expression was significantly associated with PR status (P<0.024, compared with in PR-negative tumor tissues), and PMCA2w expression was significantly associated with ER status (P<0.048, increased in ER-positive tumor tissues, compared with ER-negative tumor tissues). Finally, PMCA2b was overexpressed in HER2-positive tumor tissues, compared with in HER2-negative tumor tissues (P<0.014). The data demonstrated the differential mRNA expression of a number of splice site A and C variants of PMCA2 in breast tumor and adjacent tissues, depending on tumor hormone receptor status and histological classification. In agreement with previous data, PMCA2b was overexpressed in HER2-positive tumor tissues, indicating that high mRNA levels of this variant could be a marker of poor prognosis.

Cytochrome and sulfotransferase gene variation in north African populations.

AIM: To describe the diversity of four cytochrome and four sulfotransferase polymorphisms in six north African samples. Scarce data have been compiled for these samples despite the rich genetic background of north African populations. MATERIALS & METHODS: CYP3A4*1B, CYP3A4*17, CYP3A4*3, CYP3A5*3, SULT1A1*2, SULT1A2*2, SULT1A2*3 and SULT1E1*2 polymorphisms were explored in 556 individuals from Morocco, Algeria, Tunisia and Libya. RESULTS: Allele frequencies in our samples largely exceeded the variation ranges described for European populations, especially for CYP3A4*1B, SULT1A1*2 and SULT1A2*3. CONCLUSION: North African populations are heterogeneous, genetically diverse and show a considerable sub-Saharan African contribution for markers associated with increased risk of prostate cancer and with differential drug metabolism.

Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients.

Tamoxifen is used to prevent and treat estrogen-dependent breast cancer. It is described as a prodrug since most of its antiestrogen effects are exerted through its hydroxylated metabolites 4-OH-tamoxifen and endoxifen. In prior work, we correlated optimal plasma levels of these metabolites with certain genotypes of CYP2D6 and SULT1A2. This descriptive study examines correlations between concentrations of tamoxifen's glucuronide metabolites and genotypes UGT1A4 Pro24Thr, UGT1A4 Leu48Val, UGT2B7 His268Tyr, UGT2B15 Asp85YTyr UGT2B15 Lys523Thr and UGT2B17del in 132 patients with estrogen receptor-positive breast cancer under treatment with tamoxifen. Patients were genotyped by real-time and conventional PCR-RFLP. The glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide were isolated from blood plasma and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Individuals who were homozygous for UGT1A448VAL showed significantly lower mean concentrations of both glucuronide metabolites compared to subjects genotyped as wt/wt plus wt/48Val (p=0.037 and p=0.031, respectively). Women homozygous for UGT2B7268Tyr also showed mean substrate/product ratios of 4-OH-tamoxifen/4-OH-tamoxifen-O-glucuronide and 4-OH-tamoxifen/4-OH-tamoxifen-N-glucuronide indicative of reduced glucuronidase activity compared to wt homozygotes or to heterozygotes for the polymorphism (p=0.005 and p=0.003, respectively). In contrast, UGT2B15 Lys523Thr and UGT2B17del were associated with possibly increased enzyme activity. Patients with at least one variant allele UGT2B15523Thr showed significantly higher 4-OH-tamoxifen-O-glucuronide and endoxifen-glucuronide levels (p=0.023 and p=0.025, respectively) indicating a variant gene-dose effect. Higher 4-OH-tamoxifen-N-glucuronide levels observed in UGT2B17del genotypes (p=0.042) could be attributed to a mechanism that compensates for the greater expression of other genes in UGT2B17 del/del individuals. Our observations suggest that patients carrying mutations UGT1A448Val, UGT2B7268Tyr or with wt genotypes for UGT2B17nodel and UGT2B15523Lys could be the best candidates for a good response to tamoxifen therapy in terms of eliciting effective plasma active tamoxifen metabolite levels. However, additional studies examining the effects of UGT genotype on overall patient response to TAM are needed to further examine the role of UGT polymorphisms in the therapeutic efficacy of TAM.

Genetic diversity of CYP3A4 and CYP3A5 polymorphisms in North African populations from Morocco and Tunisia.

The genes CYP3A4 and CYP3A5 form part of a cluster of cytochrome P450 genes involved in drug metabolism reactions. The allelic variants of these genes CYP3A4*1B, CYP3A4*3, CYP3A4*17 and CYP3A5*3 have been linked both to the reduced catalytic activity of cytochromes and to prostate cancer risk in whites, though scarce data exist for North African populations. The main objective of this study was to describe CYP3A4*3, CYP3A4*17, CYP3A4*1B and CYP3A5*3 allele frequencies and haplotype variation in Moroccan Berbers and the general Tunisian population. The data obtained for the Tunisian participants were consistent with the European allele frequency ranges described, while Moroccan Berbers showed high frequencies of CYP3A4*17 (1.8%), CYP3A4*3 (8.5%) and the CYP3A4*1B/CYP3A5*3 haplotype (18.4%). This haplotype, linked to an increased risk of prostate cancer, was detected at a much higher frequency compared with the present Tunisian population (8.4%) or with reported frequencies for populations such as whites (0.6%) or African Americans (5.3%).

Tamoxifen therapy in breast cancer: do apolipoprotein E genotype and menopausal state affect plasma lipid changes induced by the drug?

OBJECTIVE: This study examines the lipid profile change produced in response to tamoxifen (TAM) treatment, and its possible relationship with both apolipoprotein E genotype and menopausal state in patients with breast cancer. METHODS: Blood samples were collected from 86 Spanish women with breast cancer before initiating TAM treatment and in the following 6, 12 and 18 months of treatment. Plasma lipid levels (total cholesterol, triglycerides, HDL-cholesterol and LDL-cholesterol) were determined using an automatic analyzer. Genotypes for apolipoprotein E (ApoE) were identified by PCR-RFLP using the HhaI enzyme. RESULTS: In all patients, significant reductions in total cholesterol and LDL-cholesterol concentrations and a significant increase in triglyceride concentrations were observed after 6, 12, and 18 months of TAM treatment compared to baseline (p<0.01 for each time point). In the subset of APOE4-negative patients, triglyceride concentrations also significantly increased after 6, 12, and 18 months of treatment (p=0.019, p=0.045, p=0.001, respectively), while APOE4-positive patients showed no significant lipid changes at 12 and 18 months. However, after 18 months of TAM treatment the overall triglyceride concentrations had risen by 24.75% in APOE4-negative patients vs 29.9% in APOE4-positive patients. In postmenopausal women, significant reductions in total cholesterol, LDL-cholesterol and LDL/HDL ratios were observed at each time point (p<0.020 for each). CONCLUSIONS: TAM treatment induced similar plasma triglyceride increases in patients with positive or negative APOE genotype. Compared to premenopausal patients, postmenopausal breast cancer patients showed a more beneficial lipid profile change in response to treatment.

Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.