Project description:Breast cancer arising in young women has a poorer prognosis, is less likely to be hormone sensitive, and represents a particularly challenging clinical entity. The biology driving the aggressive nature of breast cancer arising in young women has yet to be defined. Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <= 45 years; older >= 65 years), 411 eligible patients (n = 200 < 45 years; n = 211 >= 65 years) with clinically-annotated Affymetrix microarray data were identified. Gene set enrichment analyses, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. In comparing deregulation of oncogenic pathways between age groups, a statistically higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in the tumors of younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with activation of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15; p = 0.008). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with a poorer outcome (HR = 2.7; p = 0.006). Similar pathway differences were identified using gene set enrichment analysis. Importantly, in multivariate analyses including clinico-pathologic variables, genomic clusters of pathway deregulation were identified to be independent predictors of disease-free survival. Finally, a significant relationship (p = 0.02) between anthracycline sensitivity and genomic clusters was observed among women aged >= 65 years. Submitters do not have approval to publish the .CEL files Experiment Overall Design: n=78
Project description:This SuperSeries is composed of the following subset Series: GSE4335: Norway/Stanford Breast Tumors GSE4336: Breast Tumors Abstract: Characteristic patterns of gene expression measured by DNA microarrays have been used to classify tumors into clinically relevant subgroups. In this study, we have refined the previously defined subtypes of breast tumors that could be distinguished by their distinct patterns of gene expression. A total of 115 malignant breast tumors were analyzed by hierarchical clustering based on patterns of expression of 534 "intrinsic" genes and shown to subdivide into one basal-like, one ERBB2-overexpressing, two luminal-like, and one normal breast tissue-like subgroup. The genes used for classification were selected based on their similar expression levels between pairs of consecutive samples taken from the same tumor separated by 15 weeks of neoadjuvant treatment. Similar cluster analyses of two published, independent data sets representing different patient cohorts from different laboratories, uncovered some of the same breast cancer subtypes. In the one data set that included information on time to development of distant metastasis, subtypes were associated with significant differences in this clinical feature. By including a group of tumors from BRCA1 carriers in the analysis, we found that this genotype predisposes to the basal tumor subtype. Our results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities. Refer to individual Series
Project description:Changes in cellular lipid metabolism are a common feature in most solid tumors, which occur already in early stages of the tumor progression. However, it remains unclear if the tumor-specific lipid changes can be detected at the level of systemic lipid metabolism. The objective of this study was to perform comprehensive analysis of lipids in breast cancer patient serum samples. Lipidomic profiling using an established analytical platform was performed in two cohorts of breast cancer patients receiving neoadjuvant chemotherapy. The analyses were performed for 142 patients before and after neoadjuvant chemotherapy, and the results before chemotherapy were validated in an independent cohort of 194 patients. The analyses revealed that in general the tumor characteristics are not reflected in the serum samples. However, there was an association of specific triacylglycerols (TGs) in patients' response to chemotherapy. These TGs containing mainly oleic acid (C18:1) were found in lower levels in those patients showing pathologic complete response before receiving chemotherapy. Some of these TGs were also associated with estrogen receptor status and overall or disease-free survival of the patients. The results suggest that the altered serum levels of oleic acid in breast cancer patients are associated with their response to chemotherapy.
Project description:Breast cancer arising in young women has a poorer prognosis, is less likely to be hormone sensitive, and represents a particularly challenging clinical entity. The biology driving the aggressive nature of breast cancer arising in young women has yet to be defined. Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <= 45 years; older >= 65 years), 411 eligible patients (n = 200 < 45 years; n = 211 >= 65 years) with clinically-annotated Affymetrix microarray data were identified. Gene set enrichment analyses, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. In comparing deregulation of oncogenic pathways between age groups, a statistically higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in the tumors of younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with activation of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15; p = 0.008). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with a poorer outcome (HR = 2.7; p = 0.006). Similar pathway differences were identified using gene set enrichment analysis. Importantly, in multivariate analyses including clinico-pathologic variables, genomic clusters of pathway deregulation were identified to be independent predictors of disease-free survival. Finally, a significant relationship (p = 0.02) between anthracycline sensitivity and genomic clusters was observed among women aged >= 65 years. Submitters do not have approval to publish the .CEL files Keywords: Retrospective analyses