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Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.

ABSTRACT: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights.Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t test and gene set analysis were used to identify differentially expressed genes and pathways.The ER and HER2 status based on mRNA expression remained stable in all but two cases, and there were no changes in proliferation metrics (Ki67 and proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3%), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g., fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial-mesenchymal transition or cancer stem cell signatures.Our data indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer.

SUBMITTER: Gonzalez-Angulo AM

PROVIDER: S-EPMC3288822 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.

Gonzalez-Angulo Ana M AM Iwamoto Takayuki T Liu Shuying S Chen Huiqin H Do Kim-Anh KA Hortobagyi Gabriel N GN Mills Gordon B GB Meric-Bernstam Funda F Symmans W Fraser WF Pusztai Lajos L

Clinical cancer research : an official journal of the American Association for Cancer Research 20120110 4

<h4>Purpose</h4>To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights.<h4>Methods</h4>Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class ...[more]

PMID: 22235097

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Project description:Observational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown.We assessed the effect of IER (two days of 65 % energy restriction per week) for one menstrual cycle on breast tissue gene expression using Affymetrix GeneChips, adipocyte size by morphometry, and systemic metabolism (insulin resistance, lipids, serum and urine metabolites, lymphocyte gene expression) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised and supervised analyses of matched pre and post IER biopsies in 20 subjects were performed, whilst liquid and gas chromatography mass spectrometry assessed corresponding changes in serum and urine metabolites in all subjects after the two restricted and five unrestricted days of the IER.Women lost 4.8 % (±2.0 %) of body weight and 8.0 % (±5.0 %) of total body fat. Insulin resistance (homeostatic model assessment (HOMA)) reduced by 29.8 % (±17.8 %) on the restricted days and by 11 % (±34 %) on the unrestricted days of the IER. Five hundred and twenty-seven metabolites significantly increased or decreased during the two restricted days of IER. Ninety-one percent of these returned to baseline after 5 days of normal eating. Eleven subjects (55 %) displayed reductions in energy restriction-associated metabolic gene pathways including lipid synthesis, gluconeogenesis and glycogen synthesis. Some of these women also had increases in genes associated with breast epithelial cell differentiation (secretoglobulins, milk proteins and mucins) and decreased collagen synthesis (TNMD, PCOLCE2, TIMP4). There was no appreciable effect of IER on breast gene expression in the other nine subjects. These groups did not differ in the degree of changes in weight, total body fat, fat cell size or serum or urine metabolomic markers. Corresponding gene changes were not seen in peripheral blood lymphocytes.The transcriptional response to IER is variable in breast tissue, which was not reflected in the systemic response, which occurred in all subjects. The mechanisms of breast responsiveness/non-responsiveness require further investigation.ISRCTN77916487 31/07/2012.

Project description:Neoadjuvant chemotherapy has been shown to be equivalent to post-operative treatment for breast cancer, and allows for assessment of chemotherapy response. In a pilot trial of docetaxel (T) and capecitabine (X) neoadjuvant chemotherapy for Stage II/III BC, we assessed correlation between baseline gene expression and tumor response to treatment, and examined changes in gene expression associated with treatment. Patients received four cycles of TX. Tumor tissue obtained from Mammotome core biopsies pretreatment (BL) and post-cycle 1 (C1) of TX was FLash frozen and stored at -70 degrees C until processing. Gene expression analysis utilized Affymetrix HG-U133 Plus 2.0 GeneChip arrays. Statistical analysis was performed using BRB Array Tools after RMA normalization. Gene ontology (GO) pathway analysis used random variance t tests with a significance level of P\0.005. For gene categories identified byGO pathway analysis as significant, expression levels of individual genes within those pathways were compared between classes using univariate t tests; those genes with significance level of P\0.05 were reported. PAM50 analyses were performed on tumor samples to investigate biologic subtype and risk of relapse (ROR). Using GO pathway analysis, 39 gene categories discriminated between responders and non-responders,most notably genes involved in microtubule assembly and regulation. When comparing pre- and post-chemotherapy specimens, we identified 71 differentially expressed gene categories, including DNA repair and cell proliferation regulation. There were 45 GO pathways in which the change in expression after one cycle of chemotherapy was significantly different among responders and nonresponders. The majority of tumor samples fell into the basal like and luminal B categories. ROR scores decreased in response to chemotherapy; this change was more evident in samples from patients classified as responders by clinical criteria. GO pathway analysis identified a number of gene categories pertinent to therapeutic response, and may be an informative method for identifying genes important in response to chemotherapy. Larger studies using the methods described here are necessary to fully evaluate gene expression changes in response to chemotherapy.

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Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.

Publications

Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.

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