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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2028-2037 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3273 Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Five National Surgical Adjuvant Breast and Bowel Project Node-Positive Adjuvant Breast Cancer Trials
From the National Surgical Adjuvant Breast and Bowel Project Operations Office and Biostatistical Center; Department of Biostatistics, University of Pittsburgh Graduate School of Public Health; Allegheny General Hospital, Pittsburgh, PA; Stanford University School of Medicine, Stanford, CA; Aultman Cancer Center and Northeastern Ohio Universities College of Medicine, Canton, OH; and Cancer Research Network, Plantation, FL. Address reprint requests to Irene L. Wapnir, MD, Stanford University School of Medicine, 300 Pasteur Dr H-3625, Stanford, CA 94305-5655; e-mail: wapnir{at}stanford.edu
PURPOSE: Locoregional failure after breast-conserving surgery is associated with increased risk of distant disease and death. The magnitude of this risk in patients receiving chemotherapy has not been adequately characterized. PATIENTS AND METHODS: Our study population included 2,669 women randomly assigned onto five National Surgical Adjuvant Breast and Bowel Project node-positive protocols (B-15, B-16, B-18, B-22, and B-25), who were treated with lumpectomy, whole-breast irradiation, and adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated. Kaplan-Meier curves were used to estimate distant–disease-free survival (DDFS) and overall survival (OS) after IBTR or oLRR. Cox models were used to model survival using clinical and pathologic factors jointly with IBTR or oLRR as time-varying predictors. RESULTS: Four hundred twenty-four patients (15.9%) experienced locoregional failure; 259 (9.7%) experienced IBTR, and 165 (6.2%) experienced oLRR. The 10-year cumulative incidence of IBTR and oLRR was 8.7% and 6.0%, respectively. Most locoregional failures occurred within 5 years (62.2% for IBTR and 80.6% for oLRR). Age, tumor size, and estrogen receptor status were significantly associated with IBTR. Nodal status and estrogen and progesterone receptor status were significantly associated with oLRR. The 5-year DDFS rates after IBTR and oLRR were 51.4% and 18.8%, respectively. The 5-year OS rates after IBTR and oLRR were 59.9% and 24.1%, respectively. Hazard ratios for mortality associated with IBTR and oLRR were 2.58 (95% CI, 2.11 to 3.15) and 5.85 (95% CI, 4.80 to 7.13), respectively. CONCLUSION: Node-positive breast cancer patients who developed IBTR or oLRR had significantly poorer prognoses than patients who did not experience these events.
Results from randomized clinical trials have provided consistent evidence that survival of early-stage breast cancer patients treated with breast-conserving surgery and breast radiotherapy is equivalent to survival after mastectomy.1-7 In the pivotal National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial, outcomes of women treated with lumpectomy and breast radiotherapy have remained statistically equivalent to those of women treated with mastectomy with 20 years of follow-up. These results occurred despite a cumulative ipsilateral breast tumor recurrence (IBTR) rate of 14.3%.1 Moreover, distant relapse rates and overall survival (OS) rates have not been affected significantly by the higher IBTR rates in the group that underwent lumpectomy alone.7 Since these results were reported, much attention has been focused on identifying the clinical and pathologic factors associated with IBTR and on the development of strategies that could decrease local failure after breast-conserving surgery. In 1991, Fisher et al8 reported an adjusted relative risk of developing distant disease after IBTR of 3.41. In 1995, Veronesi et al9 noted that the hazard of distant relapse was 4.62 in patients who developed IBTR compared with patients who did not. Others have reported 5-year OS rates after IBTR ranging from 45% to 79%. These studies have identified IBTR as an independent predictor of distant metastases and poor survival.10-16 In this report, we examine cumulative IBTR rates and the effect of IBTR on the risk of distant disease and death in node-positive patients treated with lumpectomy, radiation therapy, and adjuvant systemic therapy in five more recent NSABP adjuvant trials. We also examine distant disease rates and mortality rates after other locoregional recurrences (oLRR) in the same patient population and compare distant–disease-free survival (DDFS) and OS after IBTR and oLRR according to clinical and pathologic variables.
Study Population Node-positive patients treated on NSABP clinical trials B-15, B-16, B-18, B-22, or B-25 were used to derive the cohort for this analysis. The study population for this report includes the subgroup of all eligible patients in these five studies who had follow-up information, had postoperative systemic therapy, and were treated by lumpectomy plus level I or II axillary node dissection from 1984 to 1994. Of note, the patients included from protocol B-18 represent only the subset of node-positive patients treated with postoperative systemic chemotherapy. Patients in this analysis had tumor-free lumpectomy margins and received postoperative radiotherapy consisting of 50 Gy to the whole breast. Regional nodal radiation was not administered, and data were not collected to ascertain how much of the axilla was included in the radiation fields. Chemotherapy was administered to all groups included in this analysis, with the exception of patients in one arm of protocol B-16, who received tamoxifen alone. Written informed consent was required from each patient according to federal and institutional guidelines. Demographic information and pathologic features were recorded in the NSABP database as submitted to the NSABP Biostatistical Center (University of Pittsburgh, Pittsburgh, PA). Summaries of the five protocols used for this analysis are listed in Table 1. Details are available in the original reports of each individual study.17-21
Definitions of End Points IBTR was defined as recurrent tumor (excluding lobular carcinoma-in-situ) occurring after lumpectomy plus radiotherapy in either the breast parenchyma or skin of the ipsilateral breast in the absence of regional or distant metastatic disease. Metastatic disease in the internal mammary, supraclavicular, infraclavicular, or ipsilateral axillary nodes was classified as a regional recurrence. For this analysis, regional nodal recurrence and recurrence in the nonbreast skin of the ipsilateral chest wall were classified as oLRR. All other sites of tumor recurrence and other cancers were classified as distant treatment failures. DDFS was censored in cases when death as a result of other causes was recorded. Recurrences and other treatment failures were documented by clinical examination, radiologic studies, and/or pathology assessment. Participating investigators were not required to provide details of treatment after the documentation of in-breast recurrences or locoregional failures. All deaths were included for the analyses of the OS end point.
Statistical Methods The second set of analyses involved characterizing how IBTR, oLRR, and other clinical and demographic factors influenced mortality or the occurrence of distant disease. The Kaplan-Meier method was used to estimate survival and DDFS after the occurrence of IBTR or oLRR.25 For these analyses, survival and DDFS times were reported using the times from first clinical failure event until death or distant disease, respectively. Five-year results are reported for these end points. However, when we compared the effect of early versus late IBTR and oLRR on mortality and distant disease, we administratively censored the data after 3 years. This was done to minimize the bias associated with the decreased time at risk for mortality and distant disease for patients who had later IBTR and oLRR compared with patients with earlier events. Finally, when directly relating IBTR or oLRR to mortality, we considered them to be time-dependent variables, as was done previously.8,26 The findings presented in this report pertain to all eligible lumpectomy patients in the five studies who had follow-up information that had been received at the NSABP Biostatistical Center as of December 31, 2003.
A total 10,010 women were entered onto the five studies. Of these, 2,669 underwent breast-conserving surgery and were eligible with a median time on study of 13.3 years. This group constitutes our population at risk for IBTR or oLRR. Patient and tumor characteristics are listed in Table 2. The proportion of T1 lesions was lowest in the B-18 patients because palpable primary disease was required in that study. The distribution of patients according to the number of involved axillary lymph nodes was similar across protocols, with approximately two thirds of patients having one to three involved nodes.
As of December 31, 2003, 259 (9.7%) of the 2,669 patients in our study population had developed IBTR as a first event (Table 3). oLRRs had occurred in 165 (6.2%; 47 axillary, 81 supraclavicular, 13 chest wall, seven scar only, and 17 other or multiple local or regional sites). Of the 259 IBTRs, 161 (62.2%) occurred within 5 years of the initial surgery, and 229 (88.4%) occurred within 10 years after surgery. Of the 165 oLRRs, 133 (80.6%) occurred within 5 years, and 158 (95.8%) within 10 years after initial surgery. The 10-year cumulative incidence was 8.7% for IBTR and 6.0% for oLRR. The lowest percentage of IBTR was observed in protocol B-16 (6.5%), in which all patients were 50 years of age or older and received tamoxifen (with or without chemotherapy). The highest percentage of IBTR was 12.2% in protocol B-15, in which the majority of patients were under the age of 50 years and none received tamoxifen. However, an age-adjusted Cox regression analysis indicates that no statistically significant variation in the incidence of IBTR existed across protocols (P = .50).
Cumulative Incidence of IBTR and oLRR by Age Women younger than 50 years of age at trial entry had a significantly higher cumulative incidence of IBTR than those  50 years of age (P < .0001; Fig 1A). For women younger than 50, 50 to 59, and 60 years old, the 10-year cumulative incidence of IBTR was 11.1%, 6.1%, and 5.1%, respectively. By comparison, such differences were not observed in the incidence of oLRR (Fig 2A).
Cumulative Incidence of IBTR and oLRR by Nodal Status The cumulative incidence of IBTR was not significantly associated with the number of positive nodes (P = .53; Fig 1B). However, the cumulative incidence of oLRR was significantly associated with the number of positive nodes (P < .0001; Fig 2B). At 10 years, the cumulative incidence of oLRR was 4.4% for women with one to three positive nodes, 7.2% for women with four to nine positive nodes, and 14.6% for women with 10 positive nodes.
Cumulative Incidence of IBTR and oLRR by Tumor Size
Cumulative Incidence of IBTR and oLRR by Hormone Receptor Status
DDFS and Survival After IBTR and oLRR
IBTR and clinical factors were used to model OS (Table 4). Patients who developed IBTR had an increased risk of death compared with patients who did not (hazard ratio [HR] = 2.58; 95% CI, 2.11 to 3.15). Other predictors of mortality included age at entry, number of positive nodes, clinical tumor size, and ER status. Women in this cohort who were 60 years old had a 26% higher likelihood of death than women who were  49 years old (Table 4). Similarly, larger tumors and nodal involvement were significantly associated with elevated mortality. Patients with an oLRR had an increased risk of death compared with those who did not, with an HR of 5.85 (95% CI, 4.80 to 7.13; Table 5). All of the clinical factors mentioned above were again significant predictors of mortality. Similar results held for the relationship between IBTR and oLRR with distant disease (adjusted HRs for occurrence of distant disease after IBTR and oLRR were 2.72 and 6.68, respectively; analyses not shown).
Time to oLRR We also examined the effect of early versus late IBTR and oLRR on mortality and distant disease (Table 6). The results indicate that even when different cutoffs are used for defining late versus early IBTR, patients with a later IBTR had more than a 40% reduction in 3-year mortality risk after recurrence compared with those who had an earlier IBTR. The relative risks for 3-year mortality and distant disease after late versus early oLRR were similar to those observed for IBTR. However, mortality after oLRR was much worse than after an IBTR; the 3-year OS rate for patients who had an oLRR within 2 years of their original cancer was only 15.3%.
Locoregional failure after mastectomy has long been recognized as a harbinger of metastatic disease. However, the extent to which IBTR, in contrast to oLRR, forecasts distant disease has been debated for nearly two decades.10,14,27,28 To address this issue, we conducted an across-protocol analysis in five node-positive randomized clinical trials. Although these studies were not designed for cross-protocol analysis, such an exercise can provide useful information to generate new hypotheses for future clinical trials. In 1991, Fisher et al8 examined the biologic relationship between IBTR as a first event and the risk of subsequent metastatic disease based on results from NSABP protocol B-06, which compared total mastectomy with lumpectomy with or without breast radiation in patients with operable breast cancer. IBTR emerged as an independent predictor of distant disease, conferring a 3.41-fold increased risk. Additionally, patients who experienced an early IBTR had worse DDFS than those who experienced a later IBTR. Our present findings reinforce the previous results from B-06 and corroborate IBTR as an indicator of poor prognosis. Five years after an IBTR, only 51.4% of patients were free of distant disease. The average annual death and distant disease rates in the first 5 years after IBTR were 10.2% and 14.9%, respectively. Prognosis after oLRR is much worse than after IBTR. Five years after oLRR, only 18.8% (95% CI, 13.0% to 27.4%) of patients remained free of distant disease. The average annual death and distant disease rates in the 5 years after oLRR were 28.8% and 45.7%, respectively. The time to IBTR has been proposed as an additional prognostic factor of survival.8,13,14,29 Moran and Haffty30 observed better survival in patients when IBTR occurred after 5 years. Among patients with recurrences in the breast within 5 years of initial therapy, the 5-year OS rate was 65% and the 5-year distant–recurrence-free survival rate was 61%. In contrast, the 5-year OS rate was 81% and the 5-year distant–recurrence-free survival rate was 80% in patients who developed IBTR 5 or more years after diagnosis. This finding suggests that a higher proportion of late IBTRs represents metachronous second primaries in the breast rather than recurrence of the index lesion. In our study, the incidence of these events was greatest in the first 3 years after cancer surgery, and the majority of recurrences occurred in the first 5 years after the initial diagnosis. Age, pathologic tumor size, and ER status have been shown in several studies as significant discriminants for IBTR,9,31-34 similar to what we report here. Nodal status in our patient cohort was not a significant predictor of IBTR, which is similar to what was noted in other comprehensive reports.32,34,35 In contrast, nodal status was a highly significant predictor for oLRR, along with age and hormone receptor status. Young age has been singled out as a significant predictor of higher IBTR in several studies.34-39 This was also noted in an analysis of NSABP protocol B-06, in which age was an independent discriminant for IBTR.40 Higher local recurrence rates in premenopausal versus postmenopausal women have also been reported.7,31,41 Tamoxifen therapy has been shown to reduce rates of IBTR in ER-positive disease, so analysis of age as a predictor for IBTR may be confounded in studies in which premenopausal patients with ER-positive cancer were not treated with tamoxifen. In the studies included in this report, premenopausal women did not receive tamoxifen therapy, irrespective of a positive ER status.19-21 However, differences in the IBTR HRs between studies in our report disappeared when age-adjusted analyses were performed (P = .50). Many studies have examined the effects of surgical margins on disease recurrence.5,42-45 In these five NSABP studies, patients had to have negative margins to be considered eligible, and consequently, margin status was not identified as a risk factor for distant failure or survival, as others have reported.46 Most IBTRs occur in the vicinity of the index tumor and present primarily as intraparenchymal lesions.36,47,48 Less than 10% are inoperable because of diffuse breast or skin involvement.49-52 Recurrences elsewhere in the ipsilateral breast or second primaries in the ipsilateral breast may truly have different biologic behavior because, theoretically, the second primaries represent de novo disease rather than persistent, radioresistant, drug-insensitive disease. Molecular markers, as reported by Smith et al,51 have been used to distinguish a tumor recurrence associated with the index lesion from a second primary cancer. Genomic and molecular profiling could characterize these recurrences more accurately in the future. Mastectomy is the most common surgical treatment for IBTR. Several investigators have reported acceptable long-term local control rates after repeat lumpectomy with or without additional radiotherapy.53-57 The role of chemotherapy in the management of IBTR and oLRR remains uncertain. Although the use of hormonal therapy has been shown to be effective,58,59 the benefit of chemotherapy in decreasing rates of distant metastatic disease and improving survival after IBTR and oLRR has not been adequately evaluated in prospective randomized trials.12 Recently, a large international multicenter trial by the International Breast Cancer Study Group and the NSABP was initiated (http://www.nsabp.pitt.edu; http://www.ibcsg.org) to address this issue. Given the poor prognosis of this patient population, it is clear that new strategies are needed for their management.
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank the investigators who enrolled patients onto National Surgical Adjuvant Breast and Bowel Project trials B-15, B-16, B-18, B-22, and B-25 (listed in appendices of the initial reports of those studies). We are grateful to B.C. Good, PhD, and W.L. Rea for editorial assistance.
Supported by Public Health Service Grant Nos. U10-CA-12027, CA-69651, CA-37377, and CA-69974 from the National Cancer Institute, Department of Health and Human Services. Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
