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© 2001 American Society for Clinical Oncology Risk Factors for Recurrence and Metastasis After Breast-Conserving Therapy for Ductal Carcinoma-In-Situ: Analysis of European Organization for Research and Treatment of Cancer Trial 10853From the Departments of Radiation Oncology and Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; EORTC Data Center, Brussels, Belgium; Departments of Surgery and Pathology, Centre Henri Becquerel, Rouen, Department of Pathology, C.R.L.C. Val D’Aurelle, Montpellier, and Department of Pathology, Institut Bergonié, Bordeaux, France; Clinical Oncology Unit, Guy’s Hospital, London, United Kingdom; and Department of Pathology, Istituto Nazionale dei Tumori, Milano, Italy. Address reprint requests to Johannes L. Peterse, MD, Department of Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
PURPOSE: In view of the increasing number of patients treated with breast-conserving treatment (BCT) for ductal carcinoma-in-situ (DCIS), risk factors for recurrence and metastasis should be identified. PATIENTS AND METHODS: Clinical and pathologic characteristics from patients with DCIS in the European Organization for Research and Treatment of Cancer trial 10853 (excision with or without radiotherapy) were related to the risk of recurrence. Pathologic features were derived from a central review of 863 of the 1,010 randomized cases (85%). The median follow-up was 5.4 years.
RESULTS: Factors associated with an increased risk of local recurrence in the multivariate analysis were young age ( CONCLUSION: Patients with poorly differentiated DCIS have a high risk of distant metastasis after invasive local recurrence. Margin status is the most important factor in the success of BCT for DCIS; additionally, young age and symptomatic detection of DCIS have negative prognostic value.
CONTROVERSY EXISTS concerning breast-conserving treatment (BCT) for ductal carcinoma-in-situ (DCIS). BCT has proven to be an equivalent alternative to mastectomy in invasive breast cancer. However, whereas ablative treatment for DCIS can almost invariably achieve cure, BCT for DCIS implies a risk of residual disease that might progress into invasive carcinoma, thereby increasing the risk of death from metastatic disease. Two randomized clinical trials have shown that radiotherapy reduces the risk of local recurrence after local excision of DCIS.1-3 Even with radiotherapy, however, recurrence rates of about 10% at 5 years were observed in both trials. The assessment of clinical and pathologic factors that are associated with the risk of recurrence would enable the identification of subgroups of patients for whom ablative treatment should be preferred to BCT, and subgroups that may be treated by local excision without radiotherapy. DCIS forms a heterogeneous group of lesions in which various morphologic subtypes can be recognized. In recent years, several classification systems of DCIS have been proposed.4-7 Nonrandomized studies have suggested that well-differentiated (or low-grade) DCIS is associated with a low risk of recurrence, whereas poorly differentiated (or high-grade) DCIS has a high risk of recurrence and progression to invasion.8-13 In addition to the histologic type, the extent of the lesion and the width of the tumor-free margin play a role in local control after BCT for DCIS.13-18 At present, it is unknown which factors are associated with the risk of distant metastasis and death. The first results of the European Organization for Research and Treatment of Cancer (EORTC) 10853 study were published recently.1 In this phase III randomized clinical trial, 1,010 patients with DCIS were randomized between no further treatment and external irradiation (50 Gy in 25 fractions to the whole breast) after microscopic complete excision of the lesion. The trial included a central pathology review to evaluate the diagnosis and classification of the lesion. Here we report the results of this pathology review and relate clinical and pathologic factors with local recurrence, distant metastasis, and survival.
Between January 1986 and July 1996, 1,010 women from 46 institutes were enrolled in the EORTC DCIS study. Detailed information about study design, eligibility criteria, follow-up procedures, and identification of endpoints have been described elsewhere.1 Patients were selected on the basis of the diagnosis of the local pathologist; diagnostic requirements were DCIS without invasion and uninvolved margins. The pathology protocol advised to sample extensively, preferably directed by a lamellated specimen mammogram, both from grossly and from mammographically abnormal areas, including all inked margins. The pathology review was performed by one of the authors (J.L.P.) and focused on the diagnosis and classification of the lesion. The centers were either requested to send slides and pathology reports or were site-visited by the reviewer. In case of discordant diagnoses, a third pathologist’s (M.V.) opinion was requested to obtain a final diagnosis. The slides of 889 patients were available for review. These slides were collected through 35 participating institutes, from over 50 pathology laboratories in Europe. In 20 cases, inadequate material was sent and in six cases the quality of the slides did not allow a reliable diagnosis, leaving 863 cases (85%) for analysis. The distribution of the clinical characteristics including age, method of detection, and number of recurrences per treatment arm was similar for reviewed and nonreviewed cases (data not shown). In 57%, all slides were available for review, and for these the median number was 17 (range, five to 66). In the remaining 43%, a selection of slides was sent. Therefore, the extent of the lesion and the width of the tumor-free margin could not reliably be assessed by review of the histologic slides.
Thus, the pathology reports were reviewed for the extent of the lesion and the margin status. For the size, only those measurements that were mentioned in the Microscopy section and/or in the Conclusion of the report were used. For margin status, it was recorded whether it was reported; whether it was considered free (> 1 mm), close ( The protocol only allowed the enrollment of patients with DCIS, without evidence of (micro) invasion. In the review, invasion was defined as a focus with the common features of invasive carcinoma of at least 1 mm outside the periductal stromal cuff. For cases of DCIS, the following histologic features were assessed: cytonuclear grade (low, moderate, or high), necrosis (none or moderate/marked), and the main architectural growth pattern (clinging, micropapillary, cribriform, or solid/comedo). Eighteen intracystic papillary carcinomas were included in the category of cribriform growth pattern. All cases were classified according to Holland et al5 into well-differentiated, intermediately differentiated, and poorly differentiated subtypes. Initially, necrosis was not scored separately. After publication of the Van Nuys classification,4 necrosis was recorded in the histology review. The Van Nuys classification was applied for the 559 cases in which both nuclear grade and the presence of necrosis were scored.
At the time of analysis, the median duration of follow-up was 5.4 years. Univariate analyses stratified for treatment were performed for the age of the patient, method of detection, and all histologic variables in order to assess their prognostic value for local recurrence separately. For these analyses, cases with benign proliferative lesions and lobular carcinoma in situ (LCIS) have been pooled, as well as the invasive lesions with the cases that showed suspicion of invasion. Age was dichotomized ( The Cox proportional hazards model was fitted for each of these variables with treatment as a stratification factor, and the comparison between the different levels of the variable was made on the basis of the likelihood ratio test. The hazard ratios are presented with the level of the variable considered best as the baseline. Only overall tests over the two treatment arms are performed because too few events are available to test in the treatment subgroups separately or to test for interaction between the treatment and the prognostic factor. A Cox proportional hazards regression model19 was fitted for the multivariate analysis of local recurrence, using variables with significant P values (P < .05) in the univariate analysis. Since nuclear grade and histologic type were highly correlated, only the histologic type was included in the multivariate analysis. The presence of necrosis and the Van Nuys classification were not used in the multivariate analysis because they were applied for only a subset of patients. For the multivariate analysis, all categories with free margins were grouped, and the close/involved margins were categorized with the nonspecified margins. The likelihood ratio test was used for testing the effect of each of the variables after adjusting for the other variables in the multivariate model. Finally, the association between variables used in the multivariate analysis was tested by the likelihood ratio test. Statistical analyses were performed using the SAS software (SAS Institute, Cary, NC).
Pathology Review The diagnosis of DCIS was confirmed in 775 of 863 lesions (90%). In 45 cases (5%), benign proliferative lesions were diagnosed, consisting of 22 cases with epithelial hyperplasia without atypia and 23 with complex sclerosing lesions. Invasive growth was found in 27 cases (3%), and in another 13 (1.5%) there was suspicion of invasion. In three cases, the lesion was classified as LCIS. The pathology reports described a diameter in 178 cases (25%). Size was reported to be smaller than 1 cm in 121 (68%), between 1 and 2 cm in 41 (23%), and larger than 2 cm in 16 cases (9%). The pathology reports did not specify margin status in 88 cases (12%). Margins were reported "free" without further specification in 350 cases (49%), an exact distance was given in 36 cases (5%), no residual DCIS was found at surgical re-excision in 147 (21%), and the margins were reported close/involved in 62 cases (9%). At review, of 775 cases of DCIS, 284 (37%) were classified as well-differentiated DCIS, 198 (25%) as intermediately differentiated, and 293 (38%) as poorly differentiated.
Local Recurrence
Other factors significantly related to the risk of local recurrence were age, method of detection, nuclear grade, histologic type of DCIS, architecture, presence of necrosis, Van Nuys classification, margin status, and treatment (Table 1). The multivariate analysis shows that young age, symptomatic detection, cribriform or solid/comedo architecture, nonspecified or close/involved margins, and local excision without radiotherapy are all risk factors for local recurrence ( Table 2).
Some of the variables used in the multivariate analysis were correlated: patients presenting with clinical symptoms showed a trend toward more extensive lesions (P < .01), and 19% of those symptomatically detected lesions were reported larger than 20 mm, compared with 6% of the mammographically detected lesions. Young patients had a significantly higher rate of symptomatically detected lesions compared with older patients (63% v 24%,  2 P = .001). Young age was not related to the nuclear grade of DCIS. The group with a re-excision without residual DCIS had an 18% local recurrence rate when treated with excision alone (Table 1); when treated with excision and radiotherapy, the recurrence rate was reduced to 7%. Kaplan-Meier20 curves for treatment related to margin status are presented in Fig 1. Although patients with involved/nonspecified margins had a longer median local recurrence-free interval when treated with radiotherapy compared with local excision alone, a high local recurrence rate is still observed in the group treated with radiotherapy (16 of 81 [20%]).
DCIS Recurrence, Invasive Recurrence, Distant Metastasis, and Survival Table 3 shows the histologic type of DCIS related to DCIS and invasive recurrence, distant metastasis, and death for all patients and for the two treatment arms separately. The histologic type is significantly related to the risk of DCIS recurrence (P = .0002), but is not related to the risk of invasive recurrence. For all three types, a similar rate (7% to 9%) of invasive recurrence was found. The outcome after invasive local recurrence is, however, different for the three subtypes. Of 60 patients with an invasive local recurrence, 14 developed distant metastases; one of 20 (5%) patients with well-differentiated DCIS, two of 13 (15%) with intermediately differentiated DCIS, and 11 of 27 (41%) with poorly differentiated DCIS. Patients with poorly differentiated DCIS had a significantly higher risk of developing distant metastases (P = .0133). Also, the risk of death was significantly related to the histologic type (P = .0087) (Table 3).
Since histologic type and architecture showed significant overlap ( Table 4), similar results can be expected with respect to outcome. However, in the group with a micropapillary/clinging growth pattern, a small number of invasive recurrences was observed (five of 204 [2%]) ( Table 5).
Within the group of well-differentiated DCIS, we separately analyzed the association between architecture and recurrence. There is a significantly different recurrence rate in well-differentiated DCIS with a clinging, a micropapillary, and a cribriform architecture (0% v 7% v 18%, respectively) ( Fig 2).
When the group of patients with well-differentiated DCIS is analyzed without the cases of clinging lesions, 28 of 225 patients (12%) developed a local recurrence, with nine (4%) being a DCIS recurrence, and 20 (9%) an invasive carcinoma (one patient first developed a DCIS recurrence and subsequently an invasive recurrence). The analysis of histologic type according to local recurrence did not change significantly (P = .05), nor did the analysis according to DCIS (P = .003) or to invasive recurrence (P = .70).
BCT for DCIS should result in a low local recurrence rate and should not lead to higher rates of distant metastasis and death compared with mastectomy. Nonrandomized studies have shown that long-term survival of patients treated with mastectomy is about 98% to 99%.21 The results of two randomized clinical trials show that radiotherapy and local excision reduces the risk of local recurrence compared with local excision alone. However, in the radiotherapy group, a recurrence rate of 9% was still observed at 4 years in the EORTC 10853 trial,1 and 10% at 5 years in the National Surgical Breast and Bowel Project (NSABP) B-17 trial.2 Therefore, we aimed to identify subgroups of patients with different risks of recurrence and metastasis. In 10%, the diagnosis of DCIS could not be confirmed. The rate of 3% missed invasive foci is comparable with the NSABP B-17 trial, where 2% invasive lesions were found.22 Furthermore, 45 lesions (5%) were at review classified as benign proliferative lesions. The distinction of DCIS from benign intraductal proliferative epithelial lesions can cause diagnostic problems. Even experienced breast pathologists show a high interobserver variability in these groups of lesions.23 In light of this, it is not surprising to find a number of benign proliferative lesions in this series. In contrast to the NSABP B-17, where 7% of the cases were classified as atypical ductal hyperplasia (ADH),22 we did not find any lesions that fulfilled the diagnostic criteria of ADH. The criteria of Page et al to distinguish ADH from DCIS is that ADH "may be recognized as indicating the very least (minimal) examples of low-grade (noncomedo) DCIS.. . . "24 Tavassoli et al25 defined such lesions as ADH if the size was smaller than 2 mm. In the present series, only one lesion of 1 mm was found, but this was an intermediately differentiated DCIS. A low recurrence rate was observed in patients with well-differentiated DCIS with a clinging architecture: none of these 59 cases developed a recurrence. Eusebi et al26 found that, at a mean follow-up of 17.5 years, only two out of 32 cases of clinging well-differentiated DCIS recurred, and in that case as well-differentiated DCIS. Others have not classified these lesions as DCIS, but as "columnar alteration with prominent apical snouts and secretion"27 or "atypical ductal cells with apocrine snouts."28 It seems justified to distinguish these lesions as a separate entity and to offer patients close follow-up after local excision only. A low rate of invasive recurrence was also found in well-differentiated DCIS with a micropapillary growth pattern, whereas in well-differentiated cribriform DCIS the rate was similar to that in poorly differentiated DCIS. This indicates that these architectural patterns reflect a spectrum of development from relatively innocent clinging lesions to those with a fully developed cribriform DCIS; lesions with a micropapillary growth pattern can be considered an intermediate in this pathway. We have identified factors that were associated with an increased risk of recurrence; these risk factors can be grouped as treatment-, patient-, and tumor-related. Involved, close, or nonspecified margins and treatment without radiotherapy were significantly related to the risk of recurrence. In Table 1 it can be seen that radiotherapy reduces the risk of recurrence in all subgroups. Although the numbers of events are too small for testing the effect of the treatment on the different variables, the risk of recurrence with radiotherapy is particularly low in low-grade lesions (4%) or in lesions without necrosis (4%). On the other hand, even with radiotherapy, high recurrence rates are observed in the worst subgroups (ie, 18% in high nuclear grade, 16% in the presence of necrosis, 17% in clinically detected cases). In the updated analysis of the NSABP B-17 study, the cumulative probability of recurrence among patients with moderate/marked necrosis and treated with radiotherapy was about 10% at 5 years.29 The width of the tumor-free margin is considered one of the most important prognostic factors in BCT for DCIS.13-15 Silverstein et al14 recently showed that with a margin width of 10 mm or more, the risk of local recurrence is very low (2% at a mean follow-up of 81 months), and suggested that these cases might have no additional benefit from adjuvant radiotherapy. However, their data are derived from a nonrandomized series of patients, with different lengths of follow-up for the different treatment groups, and with a selection for treatment derived from important risk factors such as size, margin status, and histologic type. Our study does not allow the identification of a safe margin width for treatment without radiotherapy, since the trial eligibility criteria did not require reporting of the margin width. Recurrence rates of 24% were observed in cases with close/involved margins, and even higher when the margin status was not mentioned (up to 28%). Radiotherapy cannot compensate for involved margins, as even with the application of irradiation the recurrence rate was 20% in this group. Obtaining a microscopic complete excision is therefore mandatory in BCT for DCIS. However, even in the group of DCIS for which margins could be considered optimal (ie, those patients who underwent a surgical re-excision in which no residual DCIS was found), a local recurrence rate of 18% was observed when these patients were treated with surgery alone. A re-excision was defined as a second surgical procedure, without definition of the extent of the surgical procedure. The high incidence of recurrences suggests that a re-excision often did not include the entire operated area. Two additional clinical risk factors for local recurrence were found: young age and symptomatic presentation of DCIS. The presence of symptoms as a risk factor has been reported previously.11,13 The fact that more extensive lesions give increase to symptoms may explain this finding. Women younger than 40 were at higher risk of recurrence than older women, with 18 of the 51 young patients (35%) developing a recurrence. Several studies have shown that young age is associated with an increased risk of local recurrence in BCT for invasive breast cancer.30-33 Recently, the same has been reported for DCIS in two retrospective studies,15,34 with reported recurrence rates of 47% in 15 patients younger than 40 years, and of 26% in 31 patients younger than 45 years. In our study, young patients often had symptomatically detected lesions. However, young patients did not have higher grade DCIS compared with older patients, which is in concordance with the two other reports.15,34 Several, often nonrandomized, studies have shown that nuclear grade and the presence of (comedo type) necrosis, both separately or combined in a classification system, are predictive factors for local recurrence.8-13,29 In the present series, there was a relation between the histologic type and the risk of DCIS recurrence, but the risk of an invasive recurrence, which is clinically more important, was independent of the histologic type. We found a significant relation between the histologic type of DCIS and the risk of metastasis and death after invasive recurrence, with 41% of the patients with an invasive local recurrence after poorly differentiated DCIS developing distant metastasis. This supports the theory that DCIS predicts the grade of invasive carcinoma, that genetic modifications differ for different subtypes of DCIS, and that progression from well-differentiated to poorly differentiated DCIS is not common.35,36 Long-term follow-up will be required to evaluate outcome of invasive recurrence after well-differentiated DCIS, but our findings emphasize the clinically different impact of an invasive local recurrence after well and poorly differentiated DCIS. Treatment should therefore especially be focused on the prevention of recurrence in patients with poorly differentiated DCIS.
APPENDIX
We thank all pathology laboratories that made the pathology review possible.
1. Julien JP, Bijker N, Fentiman IS, et al: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: First results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355: 528-533, 2000[Medline]
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Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 328: 1581-1586, 1993 3. Fisher B, Dignam J, Wolmark N, et al: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16: 441-452, 1998[Abstract] 4. Silverstein MJ, Poller DN, Waisman JR, et al: Prognostic classification of breast ductal carcinoma-in-situ. Lancet 345: 1154-1157, 1995[Medline] 5. Holland R, Peterse JL, Millis RR, et al: Ductal carcinoma in situ: A proposal for a new classification. Semin Diagn Pathol 11: 167-180, 1994[Medline] 6. Poller DN, Silverstein MJ, Galea M, et al: Ideas in pathology: Ductal carcinoma in situ of the breast—A proposal for a new simplified histological classification association between cellular proliferation and c-erbB-2 protein expression. Mod Pathol 7: 257-262, 1994[Medline] 7. National Coordinating Group for Breast Screening Pathology : Pathology Reporting in Breast Cancer Screening. Sheffield, United Kingdom, NHSBSP Publications No 3, 1997, pp 22-27 8. Bellamy CO, McDonald C, Salter DM, et al: Noninvasive ductal carcinoma of the breast: The relevance of histologic categorization. Hum Pathol 24: 16-23, 1993[Medline] 9. Lagios MD, Margolin FR, Westdahl PR, et al: Mammographically detected duct carcinoma in situ: Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 63: 618-624, 1989[Medline] 10. Schwartz GF, Finkel GC, Garcia JC, et al: Subclinical ductal carcinoma in situ of the breast: Treatment by local excision and surveillance alone. Cancer 70: 2468-2474, 1992[Medline] 11. Ottesen GL, Graversen HP, Blichert-Toft M, et al: Ductal carcinoma in situ of the female breast: Short-term results of a prospective nationwide study—The Danish Breast Cancer Cooperative Group. Am J Surg Pathol 16: 1183-1196, 1992[Medline] 12. Solin LJ, Yeh IT, Kurtz J, et al: Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation: Correlation of pathologic parameters with outcome of treatment. Cancer 71: 2532-2542, 1993[Medline] 13. Sneige N, McNeese MD, Atkinson EN, et al: Ductal carcinoma in situ treated with lumpectomy and irradiation: Histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol 26: 642-649, 1995[Medline]
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Nixon AJ, Neuberg D, Hayes DF, et al: Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 12: 888-894, 1994
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Vicini FA, Kestin LL, Goldstein NS, et al: Impact of young age on outcome in patients with ductal carcinoma-in-situ treated with breast-conserving therapy. J Clin Oncol 18: 296-306, 2000 35. Millis RR, Barnes DM, Lampejo OT, et al: Tumour grade does not change between primary and recurrent mammary carcinoma. Eur J Cancer 34: 548-553, 1998 36. Goldstein NS, Murphy T: Intraductal carcinoma associated with invasive carcinoma of the breast: A comparison of the two lesions with implications for intraductal carcinoma classification systems. Am J Clin Pathol 106: 312-318, 1996[Medline] Submitted June 30, 2000; accepted January 4, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 years) (hazard ratio, 2.14; P = .02), symptomatic detection of DCIS (hazard ratio, 1.80; P = .008), growth pattern (solid and cribriform) (hazard ratios, 2.67 and 2.69, respectively; P = .012), involved margins (hazard ratio, 2.07; P = .0008), and treatment by local excision alone (hazard ratio, 1.74; P = .009). The risk of invasive recurrence was not related to the histologic type of DCIS (P = .63), but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS (hazard ratio, 6.57; P = .01). 
