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Articles by H Brauch
Total Records ( 3 ) for H Brauch
  H Brauch , T. E Murdter , M Eichelbaum and M. Schwab
 

Background: Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor–positive breast cancer.

Content: Tamoxifen requires enzymatic activation by cytochrome P450 (CYP) enzymes for the formation of active metabolites 4-hydroxytamoxifen and endoxifen. As compared with the parent drug, both metabolites have an approximately 100-fold greater affinity for the estrogen receptor and the ability to inhibit cell proliferation. The polymorphic CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence the plasma concentrations of active tamoxifen metabolites and the outcomes of tamoxifen-treated patients. In particular, nonfunctional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 alleles are associated with higher recurrence rates.

Summary: Accordingly, CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) genotyping before treatment to predict metabolizer status may open new avenues for individualizing endocrine treatment, with the maximum benefit being expected for extensive metabolizers. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, which are used to treat hot flashes, should be avoided because they severely impair formation of the active metabolites.

  G Hennig , M Gehrmann , U Stropp , H Brauch , P Fritz , M Eichelbaum , M Schwab and W. Schroth
  BACKGROUND:

There is an increasing need for the identification of both DNA and RNA biomarkers from pathodiagnostic formalin-fixed paraffin-embedded (FFPE) tissue samples for the exploration of individualized therapy strategies in cancer. We investigated a fully automated, xylene-free nucleic acid extraction method for the simultaneous analysis of RNA and DNA biomarkers related to breast cancer.

METHODS:

We copurified both RNA and DNA from a single 10-µm section of 210 paired samples of FFPE tumor and adjacent normal tissues (1–25 years of archival time) using a fully automated extraction method. Half of the eluate was DNase I digested for mRNA expression analysis performed by using reverse-transcription quantitative PCR for the genes estrogen receptor 1 (ESR1), progesterone receptor (PGR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2), epoxide hydrolase 1 (EPHX1), baculoviral IAP repeat-containing 5 (BIRC5), matrix metallopeptidase 7 (MMP7), vascular endothelial growth factor A (VEGFA), and topoisomerase (DNA) II alpha 170kDa (TOP2A). The remaining undigested aliquot was used for the analysis of 7 single-nucleotide polymorphisms (SNPs) by MALDI-TOF mass spectrometry.

RESULTS:

In 208 of 210 samples (99.0%) the protocol yielded robust quantification-cycle values for both RNA and DNA normalization. Expression of the 8 breast cancer genes was detected in 81%–100% of tumor tissues and 21%–100% of normal tissues. The 7 SNPs were successfully genotyped in 91%–97% of tumor and 94%–97% of normal tissues. Allele concordance between tumor and normal tissue was 98.9%–99.5%.

CONCLUSIONS:

This fully automated process allowed an efficient simultaneous extraction of both RNA and DNA from a single FFPE section and subsequent dual analysis of selected genes. High gene expression and genotyping detection rates demonstrate the feasibility of molecular profiling from limited archival patient samples.

  R. L Milne , J Benitez , H Nevanlinna , T Heikkinen , K Aittomaki , C Blomqvist , J. I Arias , M. P Zamora , B Burwinkel , C. R Bartram , A Meindl , R. K Schmutzler , A Cox , I Brock , G Elliott , M. W. R Reed , M. C Southey , L Smith , A. B Spurdle , J. L Hopper , F. J Couch , J. E Olson , X Wang , Z Fredericksen , P Schurmann , M Bremer , P Hillemanns , T Dork , P Devilee , C. J van Asperen , R. A. E. M Tollenaar , C Seynaeve , P Hall , K Czene , J Liu , Y Li , S Ahmed , A. M Dunning , M Maranian , P. D. P Pharoah , G Chenevix Trench , J Beesley , kConFab Investigators , N. N Antonenkova , I. V Zalutsky , H Anton Culver , A Ziogas , H Brauch , C Justenhoven , Y. D Ko , S Haas , P. A Fasching , R Strick , A. B Ekici , M. W Beckmann , G. G Giles , G Severi , L Baglietto , D. R English , O Fletcher , N Johnson , I dos Santos Silva , J Peto , C Turnbull , S Hines , A Renwick , N Rahman , B. G Nordestgaard , S. E Bojesen , H Flyger , D Kang , K. Y Yoo , D. Y Noh , A Mannermaa , V Kataja , V. M Kosma , M Garcia Closas , S Chanock , J Lissowska , L. A Brinton , J Chang Claude , S Wang Gohrke , C. Y Shen , H. C Wang , J. C Yu , S. T Chen , M Bermisheva , T Nikolaeva , E Khusnutdinova , M. K Humphreys , J Morrison , R Platte , D. F Easton and on behalf of the Breast Cancer Association Consortium
  Background

A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.

Methods

2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.

Results

We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P ≥ .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).

Conclusion

The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

 
 
 
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