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CancerSpectrum Knowledge Environment 01/2013; · 14.07 Impact Factor
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The Oncologist 01/2013; 18(4):e11-2. · 3.91 Impact Factor
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ABSTRACT: The aims of this study were to compare the performance of six different genomic prognostic markers to predict long-term survival and chemotherapy response on the same patient cohort and assess if clinicopathological variables carry independent prognostic and predictive values. We examined seven clinical variables and six previously described prognostic signatures on 228 tumors from patients who received homogeneous preoperative chemotherapy and had long-term follow-up information for survival. We used the area under the receiver operator characteristic curve (AUC) to compare predictors and also performed univariate and multivariate analyses including the genomic and clinical variables and plotted Kaplan-Meir survival curves. All genomic prognostic markers had statistically similar AUCs and sensitivity to predict 5-year progression-free survival (PFS, sensitivities ranged from 0.591 to 0.773, and AUCs: 0.599-0.673), overall survival (OS, sensitivities: 0.590-0.769, AUCs: 0.596-0.684) and pathologic complete response (pCR, sensitivities: 0.596-0.851, AUCs: 0.614-0.805). In multivariate analysis, the genomic markers were not independent from one another; however, estrogen receptor (Odds Ratio [OR] 7.63, P < 0.001) and HER2 status (OR: 0.37, P = 0.021) showed significant independent predictive values for pCR. Nodal status remained an independent prognostic, but not predictive, variable (OR for PFS: 2.77, P = 0.021, OR for OS: 3.62, P = 0.01). There was moderate to good agreement between different prediction results in pair-wise comparisons. First-generation prognostic-gene signatures predict both chemotherapy response and long-term survival. When multiple predictors are applied to the same case discordant risk prediction frequently occurs.
Breast Cancer Research and Treatment 08/2011; 130(1):155-64. · 4.43 Impact Factor
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Takayuki Iwamoto, Giampaolo Bianchini,
Yuan Qi,
Massimo Cristofanilli,
Anthony Lucci,
Wendy A Woodward,
James M Reuben,
Junji Matsuoka,
Yun Gong,
Savitri Krishnamurthy,
Vicente Valero,
Gabriel N Hortobagyi,
Fredika Robertson,
W Fraser Symmans,
Lajos Pusztai,
Naoto T Ueno
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ABSTRACT: The goal of this study was to determine whether gene expression differences exist between inflammatory breast cancers (IBC) and T stage-matched non-IBC patients stratified by hormone receptor and HER2 status. We used Affymetrix GeneChips to analyze 82 tumor samples (25 T4d patients, and 57 T4a-c patients) of newly diagnosed breast cancers. Genes that were differentially expressed between the IBC and non-IBC specimens were identified using the t test, and differential expression of gene sets was assessed using gene set analysis. Three distinct clinical subtypes of IBC and non-IBC were compared: ER-positive/HER2-normal, HER2-amplified, and ER-negative/HER2-normal. When we compared expression data from all IBC with all non-IBC, we found no significant differences after adjusting for multiple testing. When IBC and non-IBC tumors were compared by clinical subtype, however, significant differences emerged. Complement and immune system-related pathways were overexpressed in ER-positive/HER2-normal IBC. Protein translation and mTOR signaling were overexpressed in HER2-amplified IBC. Apoptosis-, neural-, and lipid metabolism-related pathways were overexpressed in ER-negative/HER2-normal IBC compared with non-IBC of the same receptor phenotype. In this T stage-matched case-control study, the survival curves of patients with IBC and non-IBC were similar for all three clinical subtypes. IBC tumors can be divided into molecular and clinical subtypes similar to those of non-IBC. Clinical subtypes of IBC show molecular differences compared with similar subtypes of non-IBC.
Breast Cancer Research and Treatment 02/2011; 125(3):785-95. · 4.43 Impact Factor
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Takayuki Iwamoto, Giampaolo Bianchini,
Daniel Booser,
Yuan Qi,
Charles Coutant,
Christine Ya-Hui Shiang,
Libero Santarpia,
Junji Matsuoka,
Gabriel N Hortobagyi,
William Fraser Symmans,
Frankie A Holmes,
Joyce O'Shaughnessy,
Beth Hellerstedt,
John Pippen,
Fabrice Andre,
Richard Simon,
Lajos Pusztai
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ABSTRACT: We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers.
We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost all known biological processes. Gene set analysis was performed on gene expression data from three cohorts of 234, 170, and 175 patients with HER2-normal lymph node-negative breast cancer who received no systemic adjuvant therapy to identify gene sets associated prognosis and three additional cohorts of 198, 85, and 62 patients with HER2-normal stage I-III breast cancer who received preoperative chemotherapy to identify gene sets associated with pathological complete response to therapy. These analyses were performed separately for estrogen receptor (ER)-positive and ER-negative breast cancers. Interaction between gene sets and survival and treatment response by breast cancer subtype was assessed in individual datasets and also in pooled datasets. Statistical significance was estimated with permutation test. All statistical tests were two-sided.
For ER-positive cancers, from 370 to 434 gene sets were associated with prognosis (P ≤ .05) and from 209 to 267 gene sets were associated with chemotherapy response in analysis by individual dataset. For ER-positive cancers, 131 gene sets were associated with prognosis and 69 were associated with pathological complete response (P ≤.001) in pooled analysis. Increased expression of cell cycle-related gene sets was associated with poor prognosis, and B-cell immunity-related gene sets were associated with good prognosis. For ER-negative cancers, from 175 to 288 gene sets were associated with prognosis and from 212 to 285 gene sets were associated with chemotherapy response. In pooled analyses of ER-negative cancers, 14 gene sets were associated with prognosis and 23 were associated with response. Gene sets involved in sphingolipid and glycolipid metabolism were associated with better prognosis and those involved in base excision repair, cell aging, and spindle microtubule regulation were associated with chemotherapy response.
Different biological processes were associated with prognosis and chemotherapy response in ER-positive and ER-negative breast cancers.
CancerSpectrum Knowledge Environment 02/2011; 103(3):264-72. · 14.07 Impact Factor
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Charles Coutant,
Roman Rouzier,
Yuan Qi,
Jacqueline Lehmann-Che, Giampaolo Bianchini,
Takayuki Iwamoto,
Gabriel N Hortobagyi,
W Fraser Symmans,
Serge Uzan,
Fabrice Andre,
Hugues de Thé,
Lajos Pusztai
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ABSTRACT: Estrogen receptor-positive (ER+) and -negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers.
We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER- cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER- cancers, respectively.
External validation to predict p53 status (n = 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n = 277, HR = 2.43, P < 0.0001) but it was not prognostic in ER- cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER- cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER-, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER- cancers. It also had no chemotherapy response predictive value in ER- or ER+ cancers.
P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer.
Clinical Cancer Research 01/2011; 17(8):2591-601. · 7.74 Impact Factor
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ABSTRACT: Predictive biomarkers capable of discriminating individuals who will benefit from a given therapy from those who will not are key to personalized medicine. New drugs are developed in patients with advanced disease, when ethical and practical shortcomings limit the collection of tumor specimens. The neoadjuvant setting offers a unique opportunity for overcoming these limitations. Tumor samples are collected at diagnosis and posttreatment surgery as part of a routine therapeutic approach. Pathological complete response has been consistently associated with long-term survival and may be useful as an intermediate endpoint in developing and evaluating predictive, as well as surrogate, biomarkers. In window-of-opportunity studies, new drugs are administered shortly before planned surgery, and the effect of the intervention can be assessed by comparing diagnostic biopsy with the surgical specimen. Until now, clinically useful and validated predictive markers for targeted therapy are rare, but appropriate investigations in neoadjuvant studies will likely change this.
JNCI Monographs 01/2011; 2011(43):91-4.
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ABSTRACT: Oncotype DX breast cancer assay (Genomic Health, Redwood City, Calif) stratifies patients with early breast cancer according to risk of distant recurrence. The authors hypothesized that the test is ordered when clinicopathological variables yield equivocal risk estimates. The current study also showed how often the test clarifies clinically ambiguous risk status.
The authors examined clinical/pathological characteristics and calculated risk of recurrence with Adjuvant! for 309 consecutive patients who underwent Oncotype DX testing at M. D. Anderson Cancer Center.
Of the patients comprising this study, most had stage I/II (n = 306, 99%) and grade I/II tumors (n = 236, 76%). The median risk of recurrence by Adjuvant! was 16% (IQR 11.2 to 20.4). Oncotype DX stratified 52% (n = 160), 40% (n = 122) and 9% (n = 27) of this clinically intermediate risk population into low, intermediate, and high risk groups, respectively. Correlation between projected risk of recurrence by Adjuvant! (Adjuvant!, online software and website) and Oncotype DX was minimal (r = 0.13). Recurrence score (P < .0001), but not age or tumor size, was higher in patients who received adjuvant chemotherapy. In all 3 grade subsets, recurrence score was higher in those who received chemotherapy compared with those who did not (P = .02, P < .0001, and P = .0009, respectively). All lobular carcinomas (n = 40) were classified as low/intermediate risk.
Oncotype DX yielded potentially informative risk assignments in patients considered indeterminate risk by routine clinical variables. However, 40% of the time test results reflected intermediate risk, with widely used recurrence score thresholds. This proportion increased to 66% using revised thresholds implemented by National Cancer Institute's Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx.
Cancer 11/2010; 116(22):5161-7. · 4.77 Impact Factor
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Ke Liang,
Francisco J Esteva,
Constance Albarracin,
Katherine Stemke-Hale,
Yang Lu, Giampaolo Bianchini,
Ching-Yi Yang,
Yong Li,
Xinqun Li,
Chun-Te Chen,
Gordon B Mills,
Gabriel N Hortobagyi,
John Mendelsohn,
Mien-Chie Hung,
Zhen Fan
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ABSTRACT: We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
Cancer cell 11/2010; 18(5):423-35. · 25.29 Impact Factor
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Giampaolo Bianchini,
Yuan Qi,
Ricardo H Alvarez,
Takayuki Iwamoto,
Charles Coutant,
Nuhad K Ibrahim,
Vicente Valero,
Massimo Cristofanilli,
Marjorie C Green,
Laszlo Radvanyi,
Christos Hatzis,
Gabriel N Hortobagyi,
Fabrice Andre,
Luca Gianni,
W Fraser Symmans,
Lajos Pusztai
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ABSTRACT: The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers.
We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients.
We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value.
Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.
Journal of Clinical Oncology 10/2010; 28(28):4316-23. · 18.37 Impact Factor
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Giampaolo Bianchini,
Takayuki Iwamoto,
Yuan Qi,
Charles Coutant,
Christine Y Shiang,
Bailang Wang,
Libero Santarpia,
Vicente Valero,
Gabriel N Hortobagyi,
W Fraser Symmans,
Luca Gianni,
Lajos Pusztai
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ABSTRACT: Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER(-)/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype.
Cancer Research 10/2010; 70(21):8852-62. · 7.86 Impact Factor
