Tamoxifen (TAM) is effective in estrogen receptor positive (ER+) patients, reducing the risk of recurrence and death in all age groups. However, 25% of ER+/progesterone receptor positive (PR+) and ...66% of ER+/PR- tumors do not respond to TAM, emphasizing the need for additional predictive markers. The aim of this study was to develop a predictive gene expression profile for TAM response in high-risk, lymph node positive (N+) patients employing technique directly transferable to a routine molecular diagnostic laboratory. Thirty patients with recurrent disease (average time to relaps 2.96 years) were matched to 30 patients without recurrence. All patients were high-risk ER+ patients, paired according to lymph node status (N), malignancy grade, tumor size, WHO diagnosis and duration of TAM treatment. All patients were post-menopausal and all but one pair had a N+ status at time of diagnosis. All patients were treated with TAM as monotherapy for an average of 1.8 years. The average follow-up time was 13.7 years (range: 7.2-17.8). Total RNA was purified from primary frozen tumors and the gene expression of 59 endocrine treatment-related target genes were investigated. The target genes were normalized to 4 averaged reference genes, previously identified to be optimal for studying ER+ breast cancer samples. The gene expression was investigated by a novel qRT-PCR technique termed Low Density Arrays. Using a paired Wilcoxon rank sum test, we found more genes with low p-values than one can expect under chance conditions. Using a permutation test to adjust for multiple testing, two genes showed a significant difference at the 5% level. Among the 18 genes with p<0.15, 16 were down-regulated in patients with recurrent disease. Results of a cross validated forward logistic regression modelling indicated that up to 81% of all pairs could be correctly classified using combinations of 2 or 3 genes. Using the normalized values for 2 genes enabled correct classification of 87% of all pairs. Spearman correlations successfully indicated very few genes with distinctive pairwise correlations, suggesting dysregulation in different estrogen related pathways. The stringent case-control experimental set-up eliminates the danger of identifying genes as predictive, when they are in fact just correlated to the aggressive nature of the tumor. The identified 18 genes distinguishing TAM responders from non-responders are clearly promising, in that they provide independent information (low pairwise correlations). Furthermore, a higher number of genes than expected were found with p<0.15. In addition, the combination of 2 or 3 genes seems to allow classification of over 80% of the patient-pairs correctly in future applications. Further investigation is ongoing.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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