Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy

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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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

“…Nuyten and colleagues (33) and Kreike and colleagues (40) did not identify a specific geneset predicting risk of recurrence after BCT, though a gene profile based on the wound response signature was described as being of independent prognostic value. Later, the same group developed a 111-gene signature (35), but it did not show independent prognostic value in multivariate analysis, and lost prognostic impact when tested in independent cohorts (34,41 Time after treatment (years) identify patients developing LRR despite radiotherapy after BCT, could not be validated in other cohorts (35,36,41), and the most recent study by Sabatier and colleagues (36) did not succeed in determining a robust prognostic signature of LRR.…”

Section: Discussionmentioning

confidence: 99%

“…[33][34][35][36] and after mastectomy (37) have been published previously, but none of them have been successfully validated. The study by Cheng and colleagues (37) identified 34 genes with significant association with LRR.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort

Tramm

Mohammed

Myhre

et al. 2014

Purpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into “high LRR risk” and “low LRR risk” groups. PMRT significantly reduced risk of LRR in “high LRR risk” patients, whereas “low LRR risk” patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. Clin Cancer Res; 20(20); 5272–80. ©2014 AACR.

“…Results have been contradictory. The most recent and largest study, by Kreike and colleagues (10), is for a series of 165 young ( 50 years old) premenopausal Dutch patients using the Human Genome Oligo Set version 3.0 array (Operon) and did not confirm previous classifiers, namely, those based on the wound response signature (8) and that defined by Nim eus-Malmstr€ om and colleagues (9). Kreike and colleagues were able to construct a local recurrence classifier based on the expression of 111 genes and validate this profile on an independent data set of 161 consecutive patients with breast cancer treated by BCT who used a different microarray platform (10).…”

Section: Introductionmentioning

confidence: 99%

“…The fact that (young) age is the single most important risk factor, independent of all others (5), suggests that some unrevealed biologic characteristics of the primary breast cancer may be associated with a higher risk of developing a true local recurrence, that is, regrowth of clonogenic cells that were not removed by surgery or killed by radiotherapy (6). Gene expression profiling of primary breast carcinomas using microarray technology has already been used to try and discover a signature associated with a higher risk of developing true recurrence after BCT (7)(8)(9)(10). Results have been contradictory.…”

Section: Introductionmentioning

confidence: 99%

Search for a Gene Expression Signature of Breast Cancer Local Recurrence in Young Women

Servant

Bollet

Halfwerk

et al. 2012

Purpose: A gene expression signature, predictive for local recurrence after breast-conserving treatment, has previously been identified from a series of 165 young patients with breast cancer. We evaluated this signature on both another platform and an independent series, compared its performance with other published gene-sets, and investigated the gene expression profile of a larger data set.Experimental Design: Gene expression tumor profiles were obtained on 148 of the initial 165 Dutch patients and on an independent validation series of 195 French patients. Both unsupervised and supervised classifications were used to study the gene expression profile of the 343 breast cancers and to identify subgroups that differ for their risk of local recurrence.Results: The previous local recurrence signature was validated across platforms. However, when applied to the French patients, the signature did not reproduce its reported performance and did not better classify the patients than other published gene sets. Hierarchical clustering of all 343 breast cancers did not show any grouping reflecting local recurrence status. Genes related to proliferation were found differentially expressed between patients with or without local recurrence only in triple-negative tumors. Supervised classification revealed no significant gene set predictive for local recurrence or able to outperform classification based on clinical variables.Conclusions: Although the previously identified local recurrence signature was robust on another platform, we were neither able to validate it on an independent data set, nor able to define a strong gene expression classifier for local recurrence using a larger data set. We conclude that there are no significant differences in gene expression pattern in tumors from patients with and without local recurrence after breastconserving treatment.