PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8 
Background
Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy.
Methods
A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism.
Findings
The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05–5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95–2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3–5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86–6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03–2.30).
Conclusion
In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.
doi:10.1158/1078-0432.CCR-12-2153
PMCID: PMC3548984  PMID: 23213055
Tamoxifen; CYP2D6; metabolism; anastrozole; breast cancer; estrogen receptor
2.  Decentral gene expression analysis for ER+/Her2− breast cancer: results of a proficiency testing program for the EndoPredict assay 
Virchows Archiv  2012;460(3):251-259.
Gene expression profiles provide important information about the biology of breast tumors and can be used to develop prognostic tests. However, the implementation of quantitative RNA-based testing in routine molecular pathology has not been accomplished, so far. The EndoPredict assay has recently been described as a quantitative RT-PCR-based multigene expression test to identify a subgroup of hormone–receptor-positive tumors that have an excellent prognosis with endocrine therapy only. To transfer this test from bench to bedside, it is essential to evaluate the test–performance in a multicenter setting in different molecular pathology laboratories. In this study, we have evaluated the EndoPredict (EP) assay in seven different molecular pathology laboratories in Germany, Austria, and Switzerland. A set of ten formalin-fixed paraffin-embedded tumors was tested in the different labs, and the variance and accuracy of the EndoPredict assays were determined using predefined reference values. Extraction of a sufficient amount of RNA and generation of a valid EP score was possible for all 70 study samples (100%). The EP scores measured by the individual participants showed an excellent correlation with the reference values, respectively, as reflected by Pearson correlation coefficients ranging from 0.987 to 0.999. The Pearson correlation coefficient of all values compared to the reference value was 0.994. All laboratories determined EP scores for all samples differing not more than 1.0 score units from the pre-defined references. All samples were assigned to the correct EP risk group, resulting in a sensitivity and specificity of 100%, a concordance of 100%, and a kappa of 1.0. Taken together, the EndoPredict test could be successfully implemented in all seven participating laboratories and is feasible for reliable decentralized assessment of gene expression in luminal breast cancer.
doi:10.1007/s00428-012-1204-4
PMCID: PMC3306560  PMID: 22371223
Breast cancer; Prognosis; mRNA; Quality control
3.  Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse 
The Journal of Clinical Investigation  2011;121(5):2000-2012.
In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.
doi:10.1172/JCI44751
PMCID: PMC3083794  PMID: 21540548
4.  Gene expression of PMP22 is an independent prognostic factor for disease-free and overall survival in breast cancer patients 
BMC Cancer  2010;10:682.
Background
Gene expression of peripheral myelin protein 22 (PMP22) and the epithelial membrane proteins (EMPs) was found to be differentially expressed in invasive and non-invasive breast cell lines in a previous study. We want to evaluate the prognostic impact of the expression of these genes on breast cancer.
Methods
In a retrospective multicenter study, gene expression of PMP22 and the EMPs was measured in 249 primary breast tumors by real-time PCR. Results were statistically analyzed together with clinical data.
Results
In univariable Cox regression analyses PMP22 and the EMPs were not associated with disease-free survival or tumor-related mortality. However, multivariable Cox regression revealed that patients with higher than median PMP22 gene expression have a 3.47 times higher risk to die of cancer compared to patients with equal values on clinical covariables but lower PMP22 expression. They also have a 1.77 times higher risk to relapse than those with lower PMP22 expression. The proportion of explained variation in overall survival due to PMP22 gene expression was 6.5% and thus PMP22 contributes equally to prognosis of overall survival as nodal status and estrogen receptor status. Cross validation demonstrates that 5-years survival rates can be refined by incorporating PMP22 into the prediction model.
Conclusions
PMP22 gene expression is a novel independent prognostic factor for disease-free survival and overall survival for breast cancer patients. Including it into a model with established prognostic factors will increase the accuracy of prognosis.
doi:10.1186/1471-2407-10-682
PMCID: PMC3018461  PMID: 21159173
5.  Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer 
BMC Cancer  2009;9:367.
Background
In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy.
Methods
Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values < 0.05 were considered to indicate statistical significance.
Results
Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter.
Conclusion
Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.
doi:10.1186/1471-2407-9-367
PMCID: PMC2770076  PMID: 19835621

Results 1-5 (5)