Gene Expression Profiling in Primary Breast Cancer
Gene Expression Profiling in Primary Breast Cancer
Introduction: Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.
Methods: We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.
Results: Within the estrogen receptor-positive (ER) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER/ER).
Conclusion: A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.
The addition of postoperative radiotherapy to breast-conservation surgery in patients with lymph node-negative breast cancer has been shown to reduce the 10-year risk of local recurrence from 29.2% to 10%. However, more than half of the patients will never develop local recurrence whether given radiotherapy or not and a small proportion of the patients will develop local recurrence despite being given radiotherapy. Besides tumor-involved margins, generally accepted risk factors for the development of local recurrence are young age and multicentricity. A number of other risk factors have been reported (for example, extensive intraductal component, family history, lymphovascular invasion, lobular cancer, and estrogen receptor-negative (ER) status), but their clinical usefulness so far is limited. If the patients who develop local recurrence despite radiotherapy can be identified, other treatment strategies should be considered. No factor hitherto has been found to be clinically useful for the identification of patients developing local recurrence after radiotherapy.
Gene expression analyses have been found to be useful for molecular subclassification of breast cancer and also have shown promising results for predicting distant recurrence. Concerning prediction of local recurrence, only a few studies have been reported. Cheng and colleagues demonstrated two sets of gene expression profiles to be associated with local recurrence after mastectomy. Today, however, the majority of patients with breast cancer are operated on with breast-conservation surgery. As conventional risk factors for local recurrence after mastectomy differ from those after breast-conservation surgery, these findings may not be applicable when using less extensive surgery. Two recent studies included only patients treated with breast-conservation surgery: one was unable to find a distinguishing gene expression profile, whereas the other could only separate patients developing local recurrence after radiotherapy from patients not developing local recurrence by means of a predefined gene list, the wound-response signature. This signature has been suggested to provide a possible link between cancer progression and wound healing and originally was defined as the fibroblast core serum response. The material in the study by Nuyten and colleagues was heterogeneous with regard to margin status, ER status, lymph node status, adjuvant systemic treatment (47% with and 53% without), and radiotherapy (including both standard and boost treatment). This heterogeneity might be the reason for not finding a significant gene profile in this study when using the whole set of genes. As far as the importance of considering ER status in gene expression analyses, today it is generally accepted that ER and ER breast tumors have remarkably distinct gene expression profiles and this subdivision of ER status has been successfully applied when predicting distant recurrence.
Our study aimed at elucidating whether gene expression analysis is useful in predicting tumor sensitivity to radiotherapy and capacity to develop local recurrence in a patient material homogenous with regard to tumor-free margins, lymph node status, and radiotherapy (only standard doses). A predictive gene expression profile might impact the choice of both surgery and radiotherapy. A hypothetical clinical routine scheme, demonstrating three treatment options, is outlined in Figure 1. After a preoperative analysis of the gene expression profile, the first step is to identify the patients who will develop local recurrence despite radiotherapy. For this group, mastectomy might be a better choice. The second step is to separate those patients with no capacity to develop local recurrence and therefore not in need of radiotherapy after breast-conservation surgery from those with a capacity to develop local recurrence and in need of radiotherapy.
(Enlarge Image)
Figure 1.
A hypothetical clinical routine scheme for the choice of surgery and radiotherapy after preoperative gene expression analysis.
Abstract and Introduction
Abstract
Introduction: Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.
Methods: We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.
Results: Within the estrogen receptor-positive (ER) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER/ER).
Conclusion: A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.
Introduction
The addition of postoperative radiotherapy to breast-conservation surgery in patients with lymph node-negative breast cancer has been shown to reduce the 10-year risk of local recurrence from 29.2% to 10%. However, more than half of the patients will never develop local recurrence whether given radiotherapy or not and a small proportion of the patients will develop local recurrence despite being given radiotherapy. Besides tumor-involved margins, generally accepted risk factors for the development of local recurrence are young age and multicentricity. A number of other risk factors have been reported (for example, extensive intraductal component, family history, lymphovascular invasion, lobular cancer, and estrogen receptor-negative (ER) status), but their clinical usefulness so far is limited. If the patients who develop local recurrence despite radiotherapy can be identified, other treatment strategies should be considered. No factor hitherto has been found to be clinically useful for the identification of patients developing local recurrence after radiotherapy.
Gene expression analyses have been found to be useful for molecular subclassification of breast cancer and also have shown promising results for predicting distant recurrence. Concerning prediction of local recurrence, only a few studies have been reported. Cheng and colleagues demonstrated two sets of gene expression profiles to be associated with local recurrence after mastectomy. Today, however, the majority of patients with breast cancer are operated on with breast-conservation surgery. As conventional risk factors for local recurrence after mastectomy differ from those after breast-conservation surgery, these findings may not be applicable when using less extensive surgery. Two recent studies included only patients treated with breast-conservation surgery: one was unable to find a distinguishing gene expression profile, whereas the other could only separate patients developing local recurrence after radiotherapy from patients not developing local recurrence by means of a predefined gene list, the wound-response signature. This signature has been suggested to provide a possible link between cancer progression and wound healing and originally was defined as the fibroblast core serum response. The material in the study by Nuyten and colleagues was heterogeneous with regard to margin status, ER status, lymph node status, adjuvant systemic treatment (47% with and 53% without), and radiotherapy (including both standard and boost treatment). This heterogeneity might be the reason for not finding a significant gene profile in this study when using the whole set of genes. As far as the importance of considering ER status in gene expression analyses, today it is generally accepted that ER and ER breast tumors have remarkably distinct gene expression profiles and this subdivision of ER status has been successfully applied when predicting distant recurrence.
Our study aimed at elucidating whether gene expression analysis is useful in predicting tumor sensitivity to radiotherapy and capacity to develop local recurrence in a patient material homogenous with regard to tumor-free margins, lymph node status, and radiotherapy (only standard doses). A predictive gene expression profile might impact the choice of both surgery and radiotherapy. A hypothetical clinical routine scheme, demonstrating three treatment options, is outlined in Figure 1. After a preoperative analysis of the gene expression profile, the first step is to identify the patients who will develop local recurrence despite radiotherapy. For this group, mastectomy might be a better choice. The second step is to separate those patients with no capacity to develop local recurrence and therefore not in need of radiotherapy after breast-conservation surgery from those with a capacity to develop local recurrence and in need of radiotherapy.
(Enlarge Image)
Figure 1.
A hypothetical clinical routine scheme for the choice of surgery and radiotherapy after preoperative gene expression analysis.
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