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© 2000 American Society for Clinical Oncology High Local Recurrence Risk After Breast-Conserving Therapy in Node-Negative Premenopausal Breast Cancer Patients Is Greatly Reduced by One Course of Perioperative Chemotherapy: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group StudyFrom the Departments of Clinical Oncology, Surgery, Pathology, and Medical Statistics, Leiden University Medical Center, Leiden; Department of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; and European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group (Data Center, Brussels, Belgium, and member institutions). Address reprint requests to Marc J. van de Vijver, Department of Pathology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; email mvijver{at}nki.nl
PURPOSE: Patients with invasive breast cancer may develop a local recurrence (LR) after breast-conserving therapy (BCT). Younger age has been found to be an independent risk factor for LR. Within a group of premenopausal node-negative breast cancer patients, we studied risk factors for LR and the effect of perioperative chemotherapy (PeCT) on LR. PATIENTS AND METHODS: The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare surgery followed by one course of PeCT (fluorouracil, doxorubicin, and cyclophosphamide) with surgery alone. From patients treated on this trial, we selected premenopausal patients with node-negative breast cancer who were treated with BCT to examine whether histologic characteristics and the expression of various proteins (estrogen receptor, progesterone receptor, p53, Ki-67, bcl-2, CD31, c-erbB-2/neu) are risk factors for subsequent LR. Also, the effect of one course of PeCT on the LR risk (LRR) was studied. RESULTS: Using multivariate analysis, age younger than 43 years (relative risk [RR], 2.75; 95% confidence interval [CI], 1.46 to 5.18; P = .002), multifocal growth (RR, 3.34; 95% CI, 1.27 to 8.77; P = .014), and elevated levels of p53 (RR, 2.14; 95% CI, 1.13 to 4.05; P = .02) were associated with higher LRR. Also, PeCT was found to reduce LRR by more than 50% (RR, 0.47; 95% CI, 0.25 to 0.86; P = .02). Patients younger than 43 years who received PeCT achieved similar LR rates as those of patients younger than 43 years who were treated with BCT alone. CONCLUSION: In premenopausal node-negative patients, age younger than 43 years is the most important risk factor for LR after BCT; this risk is greatly reduced by one course of PeCT. The main reason for administering systemic adjuvant treatment is to improve overall survival. The important reduction of LR after BCT is an additional reason for considering systemic treatment in young node-negative patients with breast cancer.
LOCAL RECURRENCE (LR) after breast-conserving therapy (BCT) is assumed to arise from tumor cells that are left in the breast after local excision. Radiotherapy administered after local excision is aimed at eradicating these remaining tumor cells and is of major importance.1 With the combined modality of surgery followed by radiotherapy, the LR rate at 5 years varies from 4% to 10%.2-5 Chemotherapy has been shown to reduce the LR rate, whether it is used as a single adjuvant treatment after surgery6 or in combination with radiotherapy.1,7-9 When chemotherapy and radiotherapy are used in combination, lower LR rates are achieved than when either modality is used alone.7,9 The LR rate after BCT is inversely related to age.5 Young patients are at relatively high risk for LR2,4,5; particularly, patients who are younger than 35 years are at high risk. In this age group, 10-year local relapse rates of 30% or greater are reported.4,5,10 It is of great clinical value to have prognostic factors in order to select patients who are at high risk for LR; for these patients, more intense local treatment or mastectomy can then be considered. In addition to the negative psychologic effects of LR, a subgroup of patients may develop distant metastasis as a result of LR.5,11-14 For this reason, continuing efforts to identify patients who are at increased risk of LR after BCT are of major importance. Many studies have focused on risk factors for LR after BCT. In most studies, young age remains an independent risk factor. Unfortunately, within this group of younger women, we are still unable to select the patients who are at high risk for LR. A recent overview of perioperative polychemotherapy trials in patients with early breast cancer has shown that perioperative chemotherapy (PeCT) significantly decreases LR rates.15 This effect was observed in lymph node–negative patients who received only PeCT and also in lymph node–positive patients who received prolonged courses of chemotherapy in addition to PeCT. It was also found that younger patients benefit more from PeCT. We studied histologic characteristics and expression of various proteins as risk factors for LR in 361 premenopausal lymph node–negative patients treated with BCT. Before surgery, all patients were randomized to surgery followed by one course of perioperative polychemotherapy (fluorouracil, doxorubicin, and cyclophosphamide) or to surgery alone as part of a European Organization on Research and Treatment of Cancer (EORTC) trial. After surgery, all patients received radiotherapy as an integral part of the BCT. Also, the influence of one course of PeCT on the LR risk (LRR) was studied. We previously reported on a cohort of 441 lymph node–negative, premenopausal patients at a median follow-up of 49 months (range, 3 to 85 months) from the same trial.16 These patients were treated with BCT or mastectomy. Here we restrict our report to the subgroup of patients who underwent BCT, which comprises 361 patients with a median of 84 months (range, 33 to 117 months) of follow-up.
Patient Selection From May 1986 to March 1991, a total of 2,795 women with early breast cancer were enrolled onto EORTC trial 10854, which compared surgery followed by one course of perioperative polychemotherapy with surgery alone. The eligibility criteria and trial entry criteria have been described previously.17 At the time of randomization, patient axillary status was unknown. Further treatment was administered according to local procedures in each randomizing institute, and most premenopausal patients with positive axillary nodes continued with prolonged chemotherapy after surgery. Limiting our study to the subset of node-negative patients allowed us to compare patients who received PeCT to patients who received no further systemic treatment. We had previously collected paraffin-embedded tumor specimens from 441 premenopausal lymph node–negative patients who were randomized at the large reference centers. Of this patient group, a total of 361 patients had been treated with BCT.
Treatment
Follow-Up
Histology Review
Immunohistochemistry
Briefly, p53 accumulation was detected using Do-7 monoclonal antibody (Novacostra, Newcasle on Tyne, United Kingdom) and a semiquantitative system based on the sum of the mean staining intensity (0 to 3; none to strong) and an estimation of the percentage of positive cell nuclei (0 to 4; 0% to > 75%); this allowed a sum score of 0 to 7, with staining Results were scored independently by at least two investigators (P.C.C., M.J.v.d.V., and H.-J.v.S.)16,20; in the event of any differences, an agreement had to be reached among investigators. During the evaluation of the results, the investigators were unaware of the clinical outcome of the patients. All histologic variables could be studied. Of 361 tumor blocks, 357 (99%) were adequate to be used for ER status using the immunohistochemistry method, 355 (98%) for PR status, 360 (99%) for p53 expression, 360 (99%) for c-erbB-2 expression, 356 (99%) for determining the percentage of Ki-67 positive cells, 349 (97%) for bcl-2 expression, 281 (78%) for determining the MVD, and 361 (100%) for counting the number of mitoses. Also, for 328 tumors (91%), ER was studied using the biochemical assay.
Statistics
The statistic analyses were performed using SAS software (SAS Institute, Cary, NC). Survival curves were estimated using the Kaplan-Meier technique and compared using a two-sided log-rank test.23 Estimates of hazards ratios, their 95% confidence intervals, and P values were calculated using the Cox proportional hazards regression model.23 All P values were two-sided; P values
Patient Characteristics Characteristics of 361 premenopausal node-negative patients who were treated with BCT are listed in Table 1. The majority of the clinical and pathologic characteristics were equally balanced between the two treatment arms. Two patients were 63 years old, one on each treatment arm. These patients were reported as being premenopausal at time of randomization and are therefore included in the statistical analysis. In total, 45 LRs occurred as first events. Fifteen patients developed subsequent distant metastasis. The LRR for the whole cohort was 9% at 5 years and 15% at 8 years. At the time of analysis, 324 patients were still alive; their median follow-up was 84 months (range, 33 to 117 months). A total of 37 patients had died, with a median follow-up of 47 months (range, 18 to 100 months).
Prognostic Variables for LRR Univariate analysis. For all factors, the association with LR was studied at 8 years of follow-up. As can be seen in Table 2, the following factors showed a statistically (marginal) significant association with a higher LRR: no PeCT, age younger than 43 years, multifocal growth, negative ER status, and elevated levels of p53. PeCT was associated with a significantly lower LRR (P = .013); this will be further discussed in the next section (see Response to Chemotherapy). Young age, which is a well-known risk factor for LR, was also found to be significant in this study. Previously,16 we found that age younger than 43 years was a risk factor for poor disease-free survival. Patients who were younger than 43 years had an almost three-fold LRR compared with patients who were 43 years of age or older (23% v 8%; relative risk [RR], 2.82; 95% confidence interval [CI], 1.57 to 5.09; P = .0006). Tumors with multifocal growth were associated with a higher LRR (P = .03); the LRR for patients with multifocal tumor growth was 2.66 (95% CI, 1.04 to 6.81) compared with that of patients with a nonmultifocal tumor. Patients with a negative ER status as detected by the biochemical assay had an almost two-fold increased LRR compared with ER-positive patients (P = .04). Positive p53 staining was associated with a higher LRR (RR, 2.45; 95% CI, 1.17 to 5.13; P = .02).
The DCIS component in and around the invasive tumor was assessed, as well as the histologic type. EDCIS was associated with an increased LRR (RR, 1.47; 95% CI, 0.51 to 4.26) as compared with patients with none, small, or moderate amounts of DCIS in the tumor. A large component of DCIS around the tumor was found to be associated with an RR of 1.63 (95% CI, 0.59 to 4.46) as compared with patients with none to moderate amounts of DCIS around the tumor. These differences were not of statistical significance. Although poorly differentiated DCIS was associated with a higher LRR (RR, 1.50; 95% CI, 0.69 to 3.28), this also did not reach statistical significance. There was a trend for an association of c-erbB2/neu overexpression with a higher LRR (RR, 2.05; 95% CI, 0.88 to 4.80; P = .10).
The following factors were not associated with a higher LRR: tumor size ( Multivariate analysis. From the prognostic factors that were found to be significant in the univariate analysis, we first performed a stepwise multivariate analysis for the biologic factors: age, multifocal growth, and p53 staining (Table 3). ER status (according to biochemical staining) was not included in this multivariate model because of the many missing values (n = 33). Young age was determined to be the most significant risk factor for LR; multifocal growth and positive p53 staining were also found to have independent significant prognostic value for LRR.
Next, multivariate analysis was performed with PeCT treatment included in the analysis (Table 4). Again, by stepwise selection, young age was determined to be the most significant risk factor for LR. Younger patients (< 43 years) were found to have an almost three-fold higher LRR compared with older patients (P = .001). PeCT treatment was found to be very important in achieving a lower LRR. The LRR in patients treated with PeCT was found to be reduced by more than 50% as compared with patients who did not receive this treatment (P = .02). Positive p53 staining and multifocal growth were both found to be marginally significant predictors of LRR (P = .05 and P = .06, respectively), after the selection of age and treatment.
Response to Chemotherapy As indicated in the previous paragraph, patients who received PeCT were at decreased risk for LR; patients who did not receive PeCT had an 8-year LRR of 20%, whereas patients who received PeCT had an 8-year LRR of 10% (RR, 0.48; 95% CI, 0.27 to 0.86; P = .013) (Table 2 and Fig 1). We wanted to determine whether there were specific subgroups of patients within the PeCT group that benefited more from PeCT with respect to the reduction of the LRR. We therefore investigated the effects of PeCT on LR in the subgroups that were formed on the basis of the factors discussed in the previous paragraph (histologic factors and expression of various proteins). It was found that all subgroups of patients receiving PeCT showed a similar reduction of the LR rate. No subgroups could be identified that benefited more from this treatment (data not shown).
Because age as well as PeCT treatment were found to be of importance for the LRR, we studied these variables in combination with Kaplan-Meier curves. This is shown in Fig 2. It was found that PeCT reduces the LRR in older patients as well as in younger patients, with the benefit of PeCT being greater in patients who are younger than 43 years than in older patients. In the group of patients who were younger than 43 years, the risk of LR at 8 years was reduced from 31% to 15% by PeCT (P = .07). In the older patients (  43 years), the risk of LR at 8 years was reduced from 10% to 5% (P = .10) by PeCT. When young patients are given one course of PeCT, their LR is similar to that of older patients not receiving this treatment (P = .49)
Overall Survival To place these findings on LR in perspective, overall survival (OS) was evaluated. At 8 years of follow-up, a total of 37 patients had died. For patients treated without PeCT, OS at 8 years was 86% compared with 91% for patients treated with PeCT. Although a trend was seen for better OS for patients treated with PeCT, at the time of analysis this did not reach statistical significance (RR, 0.62; 95% CI, 0.33 to 1.19; P = .15) (Fig 3).
We have studied histologic and biologic factors as predictors for local recurrence after BCT in premenopausal lymph node–negative breast cancer patients. In addition, we studied the effect of one course of PeCT on the LRR. Many of the factors that can be assessed using paraffin-embedded tumor material were studied. The following independent risk factors for LR after BCT were found: age younger than 43 years, elevated levels of p53, and multifocal growth. The superior cosmetic results achieved with BCT have been shown to improve quality of life; this aspect seems to be particularly important to young patients.24 For this reason, it is important to offer these patients BCT whenever possible. However, numerous studies have shown that young age is a risk factor for LR after BCT.2,4,5,10 Given the relatively high LR rate in the whole group of young patients, it is of great clinical importance to identify additional risk factors for LR to guide clinical decision making. However, also in the present study, young age was the strongest risk factor for LR, independent of other factors. Although a relatively young patient group was studied (median age, 43 years), a strong effect of young age on LR was still seen. Patients who were younger than 43 years had an LR rate at 8 years of 23% compared with 8% for patients who were 43 years of age or older, which makes the LRR of these younger patients almost three times higher than that of older patients. This is in agreement with the gradual decrease in LR rate with increasing age, as was seen in studies that we performed earlier.5,25 From in vitro experiments, it seems that induction of apoptosis by radiation therapy is at least in part dependent on an intact p53 gene.26 In the present study, p53 protein accumulation reflecting p53 mutation is associated with a higher LRR. In view of the in vitro data, this may be the result of decreased sensitivity to radiotherapy of tumor cells that contain p53 gene alterations. Recently, Degeorges et al27 also reported p53 overexpression to be a risk factor for LR after BCT in lymph node–negative patients. However, the influence of p53 and other genes involved in apoptosis regulation and response to anticancer treatment is by no means clear. Tumor multifocality (defined as foci of invasive carcinoma separated from the dominant mass by normal tissue) was found to be a risk factor for LR in the present study, which is in line with previous reports by others.28-30 The increased risk of LR that is associated with multifocal tumors is most likely related to a significant residual tumor burden. In pathologic studies conducted at the University of Pennsylvania,31 residual tumor was identified in two or more quadrants of the breast in 46% of the patients with gross multifocal disease who were treated with mastectomy. In general, when gross multifocal disease is suspected by clinical or mammographic appearance, a patient should not be offered BCT. EDCIS has been found to be associated with LR in many studies.32-37 However, when tumor excisions are performed with clear margins removing all of the DCIS, similar LR rates are achieved for patients with and without EDCIS.38-40 In this study we found EDCIS to be associated with a higher LRR, although this did not reach statistical significance. This may in part be due to the small number of patients with EDCIS (n = 35) included on our study; such patients comprised only 10% of the study population. Poorly differentiated DCIS compared with intermediately and well-differentiated DCIS was associated with increased LRR, but again, this association did not reach statistical significance. Others have found a statistically significant association of poorly differentiated DCIS with LR.34 In the past decades, adjuvant chemotherapy in early breast cancer has been studied in many randomized trials. In this EORTC study, PeCT was investigated based on the hypothesis that tumor cells that are released into the circulation by surgery would be killed, and systemic therapy would be given at a time when the tumor load is small. Also, the surgical removal of tumors can induce cytokinetic changes in terms of an increased labeling index of residual tumor; an effect which can theoretically be decreased by PeCT.41,42 A recent overview by Clahsen et al15 of 6,093 patients who were treated with PeCT showed that PeCT prolongs disease-free survival. However, at the time of analysis, no significant improvement of OS was seen. In this overview, it was shown that the LR rate in patients receiving PeCT was decreased by 30%. This effect was seen in lymph node–negative patients treated with conservative surgery and postoperative radiotherapy alone, as well as lymph node–positive patients treated with prolonged adjuvant chemotherapy. Also in the present study, a trend was seen for improved OS with PeCT, although this did not reach statistical significance. However, PeCT greatly decreased the risk for LR. At 8 years of follow-up, a patient’s risk for LR is decreased with PeCT by more than 50%, as compared with that of patients not receiving this treatment. This effect of PeCT seemed to be stronger in younger women. Patients younger than 43 years who were treated with PeCT had an LRR at 8 years of 15% compared with 31% for patients who did not receive this treatment. It was also found that the LRR of patients younger than 43 years after one course of PeCT was comparable to the LRR of older patients who were treated with BCT alone. The risk of LR after BCT in young patients is high but seems to be more acceptable if perioperative systemic therapy is added. The optimal sequencing of chemotherapy and radiotherapy after BCT is still a subject of debate. The addition of chemotherapy to radiotherapy after BCT is known to reduce LRR7-9 when it is given concomitantly or after radiotherapy. However, the risk for local and distant relapse is dependent on partly different tumor variables. This results in the fact that patients with high risk for distant relapse are frequently treated with adjuvant chemotherapy first, despite the fact that it is known that higher LR rates are found when radiotherapy is delayed.42-44 Because of the impressive impact of one course of PeCT on LRR, we believe that the addition of PeCT can be quite useful to lower LRR, especially in high-risk young patients. PeCT can be given when a patient’s axillary status is yet unknown. Because PeCT is given directly after surgery, no delay is necessary for radiotherapy treatment. In young patients with high LRR after BCT, PeCT should be further studied to achieve acceptable LR rates. The main reason for systemic adjuvant treatment is to improve OS. The important reduction of LR after PeCT is an additional reason for considering systemic treatment in patients with node-negative breast cancer, especially young patients.
Cooperating investigators include the following: Christian Duval and Jean Pierre Julien, Centre Henri Becquerel, Rouen; Claude Pallud, Centre René Huguenin, St. Cloud; Anne-Marie Mandard, Centre François Baclesse, Caen; and Alice Delobelle-Deroide, Centre Oscar Lambret, Lille, France.
Supported by the Dutch Cancer Society (Koningin Wilhelmina Fonds).
Presented at the European Cancer Conference ECCO 10, September 1999, Vienna, Austria.
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ABSTRACT
INTRODUCTION
.01 were considered to be significant, and P values between .01 and .05 were considered to be marginally significant. 
