Publications

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    ABSTRACT: SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. However, little is known regarding its role in breast cancer (BC). We conducted a pooled analysis of publically available datasets, in which BC patients who received no systemic therapy or received neoadjuvant chemotherapy were eligible. Patients were assigned to molecular subtypes using PAM-50. We computed a SPARC module (SPARC7), composed of genes with an absolute correlation with SPARC >0.7. In the systemically untreated cohort, we evaluated 1) expression of SPARC/SPARC7 according to breast cancer subtype, 2) association between SPARC/SPARC7 and biological processes related to proliferation, immune and stroma, and 3) association between SPARC/SPARC7 and relapse-free survival in a Cox model in all patients and in the different molecular subtypes adjusted for tumor size, nodal status, histological grade, and age. In the neoadjuvant cohort, we evaluated the association between SPARC and pCR in a logistic regression model, adjusted for the same clinicopathologic factors. 948 (10 datasets), and 791 (8 datasets) patients were included in the systemically untreated and neoadjuvant cohorts, respectively. High SPARC expression was associated with small tumor size, low histological grade and luminal-A tumors (all p<0.0001). There was a positive correlation between SPARC and stroma-related modules but negative correlation with proliferation modules. High SPARC expression was associated with poor prognosis in patients with basal and HER2+ breast cancer even after adjusting for clinicopathologic parameters. In the neoadjuvant cohort, a subgroup analysis suggested that high SPARC is associated with low rates of pCR in the HER2 subtype. Same results were observed on replacing SPARC by SPARC7. This analysis suggests a potential role of SPARC in determining prognosis and response to primary chemotherapy in early BC. This information could guide further development of albumin-bound cytotoxics in BC.
    PLoS ONE 12/2013; 8(4):e62451. · 3.53 Impact Factor
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    ABSTRACT: CD4+ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4+ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4+ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4+ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4+ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4+ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.
    The Journal of clinical investigation 06/2013; · 15.39 Impact Factor
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    ABSTRACT: The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.
    PLoS ONE 01/2013; 8(1):e53292. · 3.53 Impact Factor
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    ABSTRACT: Cancer Res; 72(24 Suppl.) December 15, 2012
    San Antonio Breast Cancer Symposium 2012; 12/2012
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    ABSTRACT: Background The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC.Methods Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS).ResultsA total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR(GG3 vs GG1) 5.6 (2.1-15.3); P < 0.001] and OS [HR(GG3 vs GG1) 7.2, 95% CI (1.6-32.2); P = 0.01].ConclusionsGG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status.
    Annals of Oncology 10/2012; · 7.38 Impact Factor
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    ABSTRACT: To investigate the association between chemotherapy response and gene expression modules describing important biologic processes and druggable oncogenic pathways in breast cancer (BC) subtypes. We searched for publicly available gene expression studies evaluating anthracycline with or without taxane-based neoadjuvant chemotherapy and identified eight studies with 996 patients. We computed 17 gene modules and calculated odds ratios (ORs) for pathologic complete response (pCR) for one-unit increases in scaled modules with and without adjustment for clinicopathologic characteristics. Added predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) and integrated discrimination index (IDI). We used the false discovery rate (FDR) to adjust for multiple testing. High immune module scores were associated with increased pCR probability in all BC subtypes. High module scores of chromosomal instability, phosphatase and tensin homolog (PTEN) loss, and E2F3 transcription factor were associated with increased pCR probability in estrogen receptor (ER) -negative/human epidermal growth factor receptor 2 (HER2) -negative and ER-positive/HER2-negative but not in HER2-positive tumors (interactions between HER2 and each of these modules for their association with pCR: P < .05; FDR, 0.17; trend for interaction between HER2 and PTEN). High values of insulin-like growth factor 1 activation module were associated with increased pCR probability only in ER-positive/HER2-negative tumors (interaction between insulin-like growth factor 1 and ER: P = .002; FDR, 0.03). When adding the immune module to clinicopathologic characteristics, we observed substantial increases in predictive accuracy for pCR in the HER2-positive subtype (IDI, 0.093; P = .004; increase in AUC from 0.760 to 0.836). Different processes and pathways are associated with pCR in different BC subtypes.
    Journal of Clinical Oncology 04/2012; 30(16):1996-2004. · 18.04 Impact Factor
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    ABSTRACT: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age. Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER(-)/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model. A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER(-)/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER(+)/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334). Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.
    Clinical Cancer Research 03/2012; 18(5):1341-51. · 7.84 Impact Factor
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    ABSTRACT: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance. We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets. This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients. Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease.
    Clinical Cancer Research 02/2012; 18(4):1004-14. · 7.84 Impact Factor
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    ABSTRACT: Purpose: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Since the pioneer work of Allinen et al. suggested that during breast cancer progression striking changes occur in CD10+ stromal cells, we aimed to better characterize this cell population and its clinical relevance. Experimental design: We developed a CD10+ stroma gene expression signature (using HG U133 Plus 2.0) based on the comparison of CD10 cells isolated from tumoral (n=28) and normal (n=3) breast tissue. We further characterized the CD10+ cells by co-culture experiments of representative breast cancer cell lines with the different CD10+ stromal cell types (fibroblasts, myoepithelial and mesenchymal stem cells (MSC)). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis and prediction of efficacy of chemotherapy using publicly available datasets. Results: This 12-gene CD10+ stroma signature includes among others genes involved in matrix remodeling (MMP11, MMP13, COL10A1) and genes related to osteoblast differentiation (periostin). The co-culture experiments demonstrated all three CD10+ cell types contribute to the CD10+ stroma signature, although MSCs have the highest CD10+ stroma signature score. Of interest, this signature demonstrated an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2+ subpopulation of breast cancer only, and potentially in non-response to chemotherapy for those patients. Conclusions: Our results highlight the importance of CD10+ cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2+ breast cancer disease.
    Clinical Cancer Research. 01/2012;
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    ABSTRACT: Background: Invasive lobular carcinoma (ILC) represent the second most common breast cancer (BC) histotype, but little information is available about its molecular features. We sought to perform a comprehensive molecular classification of ILC and to investigate the molecular features that can differentiate ILC from invasive ductal carcinoma (IDC). Methods: A consecutive series of 174 ILC tumors from three different centers with mininum 5-year follow-up was selected. Gene expression data were generated using Affymetrix U133 Plus 2.0 arrays. Data were analyzed by using frozen robust multiarray analysis (Matthew et al. 2009). ILC tumors were classified into BC molecular subtypes using the PAM50 classifier. Invasive Disease Free Survival (IDFS) was defined as the interval between the date of surgery and the date of any invasive recurrence or death. Multivariate analyses for 10-y IDFS containing classical clinico-pathologic characteristics were performed for different gene signatures, which were scaled so that 2.5 and 97.5% percentiles equal −1 and 1. A cohort of 90 IDC tumor samples, normalised with the same method, was used to compare expression data between ILC and IDC. Results: ILCs were mainly characterized as luminal A (LA: 76%, n=133) and luminal B (LB:; 20%, n=34) followed by a minority of HER2−positive (2%, n=3), basal (1%, n=2) and normal-like (1%, n=2) based on Perou's classification. LB had inferior 10-y IDFS than LA in univariate cox regression analysis (HR = 1.99, 95% CI, 1.08−3.67, p=0.026). The EMT gene module was significantly higher expressed in ILC as compared to IDC (p < 0.001). Adjusted hazard ratios (HR) for different gene modules investigated are detailed in the table below. Graphic Conclusions: ILC is mainly composed of luminal tumors and a minority of HER2−positive tumors. Similarly to IDC, proliferation remains a statistically significant prognostic factor for ILC. ILC tumors were enriched with an EMT phenotype, which is not observed among IDC luminals. Of interest IGF signaling, which is known to be associated with poor prognosis in ER-positive BC, added prognostic value in this population which may open new therapeutics avenues for ILC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-05.
    Thirty-Fourth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 6‐10, 2011; San Antonio, TX; 12/2011
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    ABSTRACT: The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10-14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10-14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.
    Endocrine Related Cancer 10/2011; 18(6):721-30. · 5.26 Impact Factor
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    ABSTRACT: Breast cancer is a molecularly, biologically and clinically heterogeneous group of disorders. Understanding this diversity is essential to improving diagnosis and optimizing treatment. Both genetic and acquired epigenetic abnormalities participate in cancer, but the involvement of the epigenome in breast cancer and its contribution to the complexity of the disease are still poorly understood. By means of DNA methylation profiling of 248 breast tissues, we have highlighted the existence of previously unrecognized breast cancer groups that go beyond the currently known 'expression subtypes'. Interestingly, we showed that DNA methylation profiling can reflect the cell type composition of the tumour microenvironment, and in particular a T lymphocyte infiltration of the tumours. Further, we highlighted a set of immune genes having high prognostic value in specific tumour categories. The immune component uncovered here by DNA methylation profiles provides a new perspective for the importance of the microenvironment in breast cancer, holding implications for better management of breast cancer patients.
    EMBO Molecular Medicine 09/2011; 3(12):726-41. · 7.80 Impact Factor
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    ABSTRACT: Circulating Tumor Cells (CTCs) detection and phenotyping are currently evaluated in Breast Cancer (BC). Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging. Spiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch®. Based on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluorescence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI) 0-8.4%) whereas 4.1% (95%CI 1.4-11.4%) of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS) had 1 HER2-positive CTC/22.5 mL, 7.9%, (95%CI 4.1-14.9%) of 101 women with non metastatic (M0) BC had ≥1 HER2-positive CTC/22.5 mL (median 1 cell, range 1-3 cells) and 35.9% (95%CI 22.7-51.9%) of 39 patients with metastatic BC had ≥1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1-42 cells). In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2-positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03). HER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies.
    PLoS ONE 01/2011; 6(1):e15624. · 3.53 Impact Factor

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