Gene Expression Profiles of Primary Breast Carcinomas from Patients at High Risk for Local Recurrence after Breast-Conserving Therapy

Kreike, Bas; Halfwerk, Hans; Kristel, Petra; Glas, Annuska M.; Peterse, Hans; Bartelink, Harry; Vijver, Marc J. van de

doi:10.1158/1078-0432.ccr-06-0805

Cited by 54 publications

(30 citation statements)

References 44 publications

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“…Our results are in good agreement with published microarray gene expression studies in breast cancer. For example, expression of IGFBP-rP1 is reduced in local recurrence (15) and is significantly lower in cancers with nodal metastasis (16). Furthermore, reduced expression is predictive of clinical resistance to taxanes (17) and we have shown in the present study that methylation in IGFBP-rP1 and IGFBPL1 is predictive of poor response to anthracycline/taxane-containing adjuvant chemotherapy.…”

Section: Discussionsupporting

confidence: 60%

Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes

Smith

Nicholson

Syed

et al. 2007

Clinical Cancer Research

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Purpose: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer. Experimental Design:We have investigated the expression and epigenetic regulation of IGFBPrP1and IGFBPL1in human breast cancer cell lines and primary and metastatic carcinomas. Results: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P = 0.008) and disease-free survival (DFS) following surgery (P = 0.04) and worse DFS following adjuvant chemotherapy (P = 0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P = 0.10) and decreased DFS (P = 0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P = 0.001) and DFS (P < 0.0001). Methylation in either IGFBP-rP1or IGFBPL1was significantly associated with nodal disease (P < 0.001).Conclusions: Expression of IGFBP-rP1and IGFBPL1is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy. Insulin-like growth factor (IGF) binding proteins (IGFBP) andIGFBP-related proteins (IGFBP-rP) are members of the IGFBP superfamily of proteins that affect the expression and function of IGF-I and IGF-II. Increased levels of IGF-I are associated with many cancers, including breast cancer. In many instances, the increase in IGF-I expression is associated with decreased expression of one or more members of the IGFBP superfamily.In addition to modulating IGF bioactivity, IGFBP family members have biological actions independent of their abilities to bind IGFs, including binding to a variety of extracellular and cell surface molecules, with consequent effects on processes such as growth arrest of breast cancer cells (1).There are 6 known IGFBPs (IGFBP-1 to IGFBP-6) and 10 IGFBP-rPs (IGFBP-rP1 to ref. 2). In addition, Cai et al. (3) have reported the identification of a novel member of the IGFBP superfamily, which they have designated IGFBP-RP4.[In order not to confuse IGFBP-RP4 with IGFBP-rP4, we will refer to this protein by the alternative name, IGFBPL1 (The Human Genome Browser at the University of California at San Francisco)].6 IGFBP-rP1 [also known as IGFBP-7 (4), mac25 (5), TAF (6), PSF (7), and angiomodulin (8)] has properties consistent with a tumor suppressor function. For example, IGFBP-rP1 expression is increased in senescent human mammary epithelial cells (9) and down-regulated in a variety of human cancers, including breast cancer (10), although the me...

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Section: Discussionsupporting

confidence: 60%

Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes

Smith

Nicholson

Syed

et al. 2007

Clinical Cancer Research

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“…It has been shown that gene expression profiling of primary breast carcinomas using microarray technology is a potent tool for predicting distant metastases and overall survival in breast cancer (23)(24)(25)(26)(27). Recently, we have attempted to use this technique to develop a gene expression profile predictive for LR (28,29). It has been shown that there is not a large difference between the overall gene expression profiles of primary tumors that recur locally and those that do not (28).…”

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confidence: 99%

“…Recently, we have attempted to use this technique to develop a gene expression profile predictive for LR (28,29). It has been shown that there is not a large difference between the overall gene expression profiles of primary tumors that recur locally and those that do not (28). We previously identified a group of genes associated with LR; this gene set was based on an in vitro model of wound response that proved to be predictive for metastasis development (30).…”

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confidence: 99%

Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients

Kreike

Halfwerk

Armstrong

et al. 2009

Clinical Cancer Research

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Purpose: The majority of patients with early-stage breast cancer are treated with breastconserving therapy (BCT). Several clinical risk factors are associated with local recurrence (LR) after BCT but are unable to explain all instances of LR after BCT. Here, gene expression microarrays are used to identify novel risk factors for LR after BCT. Experimental Design: Gene expression profiles of 56 primary invasive breast carcinomas from patients who developed a LR after BCT were compared with profiles of 109 tumors from patients who did not develop a LR after BCT. Both unsupervised and supervised methods of classification were used to separate patients into groups corresponding to disease outcome. In addition, for 15 patients, the gene expression profile in the recurrence was compared with that of the primary tumor. Results: The two main clusters found by hierarchical cluster analysis of all 165 primary invasive breast carcinomas revealed no association with LR. Predefined gene sets (molecular subtypes and "chromosomal instability" signature) are associated with LR (P = 0.0002 and 0.003, respectively). Significant analysis of microarrays revealed an association between LR and cell proliferation, not captured by histologic grading. Class prediction analysis constructed a gene classifier, which was successfully validated, cross-platform, on an independent data set of 161 patients (log-rank P = 0.041). In multivariate analysis, young age was the only independent predictor of LR. Conclusions: We have constructed and cross-platform validated a gene expression profile predictive for LR after BCT, which is characterized by genes involved in cell proliferation but not a surrogate for high histologic grade.Local treatment for early-stage breast cancer can consist of mastectomy or breast-conserving therapy (BCT). Several randomized controlled trials have shown no difference in survival rates after BCT or mastectomy for stage I and II breast cancer (1-3). Unfortunately, BCT is associated with a higher rate of local recurrence (LR) compared with mastectomy (1-3). A LR rate of <1% per annum is generally considered as clinically acceptable for T1-2 N0-1 breast cancers. The choice for the primary treatment modality is therefore often based on risk factors for LR.Several of these risk factors for LR after BCT have been identified: involvement of the surgical margins by invasive carcinoma [hazard ratio (HR), 2.8-3.9] and/or extensive ductal carcinoma in situ (DCIS; HR, 2.5-4.2), vascular invasion (HR, 2.0-2.9), young age (HR, 2.4-9.2), and tumor multicentricity (HR,. The addition of a radiation boost after whole-breast irradiation and adjuvant systemic therapy reduces LR rates by 40% to 60%, especially in younger patients (9,11,16,17,19,20).The importance of preventing LR is illustrated by the updated analyses of the Early Breast Cancer Trialists' Collaborative Group showing that LR is associated with poorer survival (21) and by Voogd et al. (22) who suggest that early detection of LR could improve survival. Thus, robust r...

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“…So far, very little is known about the differential or similarity of the pan-genomic expression or nature of both new primaries and IBTRs. Kreike et al (2006) reported a gene expression analysis of 18 000 cDNAs on nine pairs of primary breast cancer with their ipsilateral breast recurrences in women who were younger than 51 years old at the time of their initial breast-conserving therapy. Paired-data analysis showed no set of genes that was consistently different in expression between primary tumours and local recurrences.…”

Section: Discussionmentioning

confidence: 99%

Are ipsilateral breast tumour invasive recurrences in young (⩽40 years) women more aggressive than their primary tumours?

Sigal‐Zafrani

Antoni

et al. 2007

Br J Cancer

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The characteristics of ipsilateral breast tumour recurrences (IBTRs) relative to those of their primary tumours (PTs) remain scarcely studied. Of 70 young (p40 years) premenopausal women with IBTRs, we studied a series of 63 with paired histological data. Median follow-up since IBTR was 10 years. Rates of histological types, grades or hormonal receptors were not significantly different in PTs and in IBTRs. The concordance between IBTRs and their PTs was good for histological types. IBTRs with conserved histological types tended to occur more locally, but not significantly sooner than others. These IBTRs had good concordance for hormone receptors. In discordant cases there were as many losses as appearances of the receptors. The concordance was weak for grades, with equivalent numbers of IBTRs graded lower as higher than their PTs. The 10-year overall survival rate was 70%. Neither the conservation of histological type, location, nor of the two combined were associated with deaths. Early (o2 years) IBTRs, tended to be associated with poorer survival (HR ¼ 2.24 (0.92 -5.41); P ¼ 0.08). IBTRs did not display features of higher aggressiveness than PTs. Neither clinical nor histological definition of a true recurrence could be established other than the conservation of the histological type. British Journal of Cancer (2007) Breast-conserving treatments of early stage breast cancer exposes the patient to the risk of ipsilateral breast tumour recurrence (IBTR). The most important prognostic factor for local recurrence is the young age of the patient (Vrieling et al, 2003) and this remains true among young (o40 years old), premenopausal women treated either by surgery first (Bollet et al, 2007) or by neoadjuvant chemotherapy (Oh et al, 2006). Many questions remain unanswered concerning the real nature of these ipsilateral breast tumour recurrences. We shall examine how different they are from primary tumours and whether there are clinical or histological factors to help distinguish between a re-growth of malignant cells not removed by surgery and not killed by radiotherapy (also called a true recurrence, TR) and a de novo malignancy arising from mammary epithelial cells of residual breast tissues (also known as new primary tumours, NP) (Haffty et al, 1993). Some have implied that ipsilateral breast tumour recurrences should display features of, at least as much aggressiveness (differentiation (Huang et al, 2002), ploidy (Haffty et al, 1993) and percentage of invasiveness (Haffty et al, 1993;Smith et al, 2000;Huang et al, 2002)) to qualify as true recurrences. We shall see whether biological evidence can be found to support this definition. Finally, we shall investigate whether the characteristics of ipsilateral breast tumour recurrences are associated with prognosis. PATIENTS AND METHODSOut of a previously described series of 209 premenopausal women, younger than 40 years old, treated at the Institut Curie between 1985 and 1995 for early breast cancers (clinical T1-2, N0-1 ; Sobin and Wittekind, 2002) with primary brea...

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Gene Expression Profiles of Primary Breast Carcinomas from Patients at High Risk for Local Recurrence after Breast-Conserving Therapy

Abstract: Purpose: Several risk factors for local recurrence of breast cancer after breast-conserving

Cited by 54 publications

References 44 publications

Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes

Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes

Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients

Are ipsilateral breast tumour invasive recurrences in young (⩽40 years) women more aggressive than their primary tumours?

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