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

Abstract

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.

Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer

“…It included 343 patients with early-stage breast cancer treated with BCS and postoperative radiotherapy (23). Gene expression from an additional dataset (Wang) consisting of patients with lymph node-negative breast cancer who were treated with BCS (219 patients) or mastectomy (67 patients) from 1980 to 1995 (24).…”

“…All patients from both datasets were used in the analysis, and complete patient and cohort characteristics are included in the Supplementary Tables S2 and S3 for each dataset. Specimen characteristics and handling were described previously (23,24). Data are presented in accordance with the REMARK guidelines, and no patients from these studies were excluded from these analyses.…”

Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer

“…Previous attempts to identify radiation-specific signatures to predict likelihood of benefit to adjuvant radiotherapy have either failed independent validation or have not been disease-specific resulting in inconsistent performance in independent cohorts (8)(9)(10)(11)(12). A recent study demonstrated the feasibility of this approach in the postmastectomy setting using patient-derived gene expression data from the DBCG82bc trials (13).…”

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

“…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.…”