Originally published as JCO Early Release 10.1200/JCO.2006.06.1366 on June 26 2006

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Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma-In-Situ: Ten-Year Results of European Organisation for Research and Treatment of Cancer Randomized Phase III Trial 10853—A Study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group

Nina Bijker, Philip Meijnen, Johannes L. Peterse, Jan Bogaerts, Irène Van Hoorebeeck, Jean-Pierre Julien, Massimiliano Gennaro, Philippe Rouanet, Antoine Avril, Ian S. Fentiman, Harry Bartelink, Emiel J. Th. Rutgers

From the Departments of Radiation Oncology, Surgery, and Pathology, Antoni van Leeuwenhoek Hospital, the Netherlands Cancer Institute, Amsterdam, the Netherlands; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Department of Surgery, Centre Henri Becquerel, Rouen; Department of Surgery, CRLC Val D'Aurelle, Montpellier; Department of Surgery, Institut Bergonié, Bordeaux, France; Department of Surgery, Istituto Nazionale dei Tumori, Milan, Italy; and the Department of Academic Oncology, Guy's Hospital, London, United Kingdom

Address reprint requests to Nina Bijker, MD, PhD, Department of Radiation Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: n.bijker{at}nki.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: The European Organisation for Research and Treatment of Cancer conducted a randomized trial investigating the role of radiotherapy (RT) after local excision (LE) of ductal carcinoma-in-situ (DCIS) of the breast. We analyzed the efficacy of RT with 10 years follow-up on both the overall risk of local recurrence (LR) and related to clinical, histologic, and treatment factors.

PATIENTS AND METHODS: After complete LE, women with DCIS were randomly assigned to no further treatment or RT (50 Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The median follow-up was 10.5 years.

RESULTS: The 10-year LR-free rate was 74% in the group treated with LE alone compared with 85% in the women treated by LE plus RT (log-rank P < .0001; hazard ratio [HR] = 0.53). The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P = .0065) respectively. Both groups had similar low risks of metastases and death. At multivariate analysis, factors significantly associated with an increased LR risk were young age ( 40 years; HR = 1.89), symptomatic detection (HR = 1.55), intermediately or poorly differentiated DCIS (as opposed to well-differentiated DCIS; HR = 1.85 and HR = 1.61 respectively), cribriform or solid growth pattern (as opposed to clinging/micropapillary subtypes; HR = 2.39 and HR = 2.25 respectively), doubtful margins (HR = 1.84), and treatment by LE alone (HR = 1.82). The effect of RT was homogeneous across all assessed risk factors.

CONCLUSION: With long-term follow-up, RT after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from RT.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Since the introduction of mammographic screening in the Western world, ductal carcinoma-in-situ (DCIS) has changed from being a rare disease to a lesion detected in up to 20% to 30% of breast cancers in screening programs.¹ Before the advent of screening, this preinvasive form of breast cancer was normally treated by mastectomy. After the proven success of radiotherapy (RT) in breast-conserving treatment (BCT) for invasive breast cancer,^2,3 in the mid and late 1980s, several randomized clinical trials in Europe and North America were initiated to evaluate optimal BCT for patients with DCIS. Three studies investigated the role of breast RT after local excision (LE) of the lesion.^4-6 In the European Organisation for Research and Treatment of Cancer (EORTC) 10853 study, more than 1,000 women were randomly allocated to RT to the whole breast or no further treatment after complete LE of DCIS. The early results, published in 2000,⁶ indicated an overall reduction of the risk of local recurrence (LR) as a result of RT. With this report, we analyzed the efficacy of RT with 10 years of follow-up on both the overall risk of LR and related to various clinical, histologic, and treatment factors.

	PATIENTS AND METHODS

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Women with DCIS of the breast were randomly assigned between RT and no further treatment after complete LE of the lesion. Extent of free margins was not specified other than that DCIS should not be present at microscopic examination of the margins. Patients with lesions up to 5 cm in diameter, without evidence of (micro)invasion or Paget's disease, were eligible for the study. The prescribed irradiation dose was 50 Gy in 25 fractions to the whole breast. No boost was advised (5% of the patients randomly assigned to RT received a boost). The use of tamoxifen was not recommended. The primary end points were both invasive and DCIS LR in the treated breast. Secondary end points included metastasis, death, and contralateral breast cancer (CLBC). Further information about study design, eligibility criteria, surgery and RT protocols, quality assurance, and follow-up procedures has been given previously.⁶

The data obtained from a general review, during which mammographic, surgical, histologic, and follow-up data were checked in the patients' medical files, served as a basis for the previous and current analyses. In the 16% for whom no detailed review data were available, the original data reported to the EORTC Data Center were used for the analyses.

All patients were required to have bilateral mammograms preoperatively and annually during follow-up. Although the protocol did not require postoperative mammograms, a specimen x-ray was made in 90% of the patients with nonpalpable DCIS.⁷

The trial included a central pathology review, available on 863 patients.⁸ For the current analysis, we have used the data of the pathology review for analyses related to the risk of recurrence. At pathology review, invasive growth was found in 27 cases, and in 13 there was suspicion of invasion. In 48 cases, benign proliferative lesions or lobular carcinoma in situ were diagnosed at review. These cases have been included in all analyses of the effect of RT on the primary and secondary end points. Analysis restricted to confirmed DCIS cases yielded the same results (data not shown).

Because the extent of the lesion and the width of the tumor-free margin could not reliably be assessed by review of the histologic slides, the pathology reports were reviewed. The size of the DCIS was mentioned in the pathology report in only 193 cases (25%). The margin status was considered free if it was reported free (> 1 mm), or if a re-excision was performed and no residual DCIS was found. When margins were reported to be close ( 1 mm) or involved, and when the margin status was not specified, the margin status was classified under not free. A previous analysis had shown that at a median follow-up of 5.4 years, the first groups, as well as the last three groups, had similar recurrence rates.⁸

All analyses are based on the intent-to-treat principle with recurrence-free intervals defined as the time between the date of random assignment and the date of recurrence. The time-to-recurrence curves were calculated using the Kaplan-Meier technique⁹ and compared using a two-sided log-rank test with 5% type I error.¹⁰ An estimate of the size of the treatment effect was calculated based on the hazard ratio (HR) and its 95% two-sided CI. The HRs are presented with the level of the variable considered best as the baseline. A Cox proportional hazards regression model¹¹ was fitted for the multivariate analysis of LR, using variables with significant P values (< 0.05) in the univariate analysis.

	RESULTS

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Between March 1986 and July 1996, 1,010 women were randomly assigned to no further treatment (503 patients) or to RT (507 patients) after LE. The previous report demonstrated that patient, tumor, and treatment characteristics according to treatment group were well balanced between the arms.⁶ The median age of the women was 53 years; 71% of them were mammographically detected. The present analysis was performed in August 2005, at a median duration of follow-up of 10.5 years.

LR-Free Interval
One hundred thirty-two patients developed LRs in the LE group and 75 in the LE + RT group. The risk of LR was reduced with 47% in the LE + RT group compared with that in the LE group (log-rank P < .0001), the 10-year LR-free rates were 85% and 74%, respectively (Table 1; Fig 1). One hundred three patients had LRs of DCIS, and 106 patients developed invasive LRs. Two patients with a DCIS LR subsequently developed an invasive LR. There was a similar reduction in the risk of DCIS and invasive LR. The 10-year DCIS LR-free rate was 93% in the LE + RT group versus 86% in the LE group (P = .0011); the 10-year invasive LR-free rates were 92% and 87%, respectively (P = .0065; Table 1; Fig 1).

View larger version (8K): [in this window] [in a new window]   Fig 1. (A) Time to local recurrence by treatment arm; (B) time to ductal carcinoma in situ recurrence by treatment arm; and (C) time to invasive recurrence by treatment arm. O, observed; N, number of patients; LE, local excision; RT, radiotherapy.

Other Events
Table 1 demonstrates no significant difference in the 10-year CLBC-free interval. The 10-year metastasis-free rate was the same in the two treatment arms (96%). In 25 patients, metastases originated from an invasive LR (15 in the LE group and 10 in the LE + RT group). Two patients (in the LE + RT group) developed metastases after a DCIS LR. In five patients, distant metastasis developed without a prior LR or CLBC, and in nine patients, metastatic disease was preceded by a CLBC. Two patients developed metastases simultaneously with a regional recurrence (without an LR).

Of the 59 deaths, 32 were breast cancer–related (15 in the LE group and 17 in the LE + RT group): 23 patients died as a result of metastatic disease after an LR, four patients from metastases as first event without prior LR, and another five patients after an invasive CLBC. Another malignancy was the cause of death in 13 patients, seven died as a result of cardiovascular disease, five because of various other causes, and for two patients the cause of death was unknown. The 10-year overall survival rate was 95% in both arms.

Risk Factors Associated With Recurrence
The analyses on risk factors were performed on 775 cases in which the diagnosis of DCIS was confirmed. Table 2 shows results of the univariate analysis. Women 40 years of age or younger were at high risk for developing an LR (34% at 10 years). In the LE group, 16 of 38 young women developed an LR (43% at 10 years). In the LE + RT group, seven of 27 women had an LR (23% at 10 years). Young women had a higher rate of symptomatically detected lesions (66%, compared with 25% of women older than 40), mostly because they were not in the screening age range. Twenty-seven percent (11 of 41) of the young patients had margins that were not free, compared with 22% (152 of 700) of the women older than 40 years of age. Of the younger patients, 37% had poorly differentiated lesions, compared with the 38% of patients older than 40 years of age.

Figure 2 shows in a Forrest plot that RT reduced the risk of LR in all subgroups, with the effect of RT being homogeneous across all risk factors.

View larger version (25K): [in this window] [in a new window]   Fig 2. Effect of radiotherapy on local control by subgroup. LE, local excision; RT, radiotherapy; HR, hazard ratio; CI, 95% CI.

	DISCUSSION

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Whereas in the EORTC study, at the first analysis a surprisingly higher rate of CLBCs was found in the RT arm,⁶ in the current update a significant difference could no longer be observed. As was assumed in the first analysis, this update seems to confirm that the original finding was a false positive.

Our analysis of risk factors for LR showed that young women ( 40 years of age) are at a particularly high risk for LR. A similar phenomenon is seen for invasive breast cancer.^15-18 Other studies have also found that young age is an adverse prognostic factor for LR after BCT for DCIS.^12,14,19,20 The cases of DCIS in the young age group are a mixture of lesions detected in high-risk women who underwent individual screening, and of symptomatic lesions, which have been shown to grow more extensively.²¹ Possible biologic differences of DCIS in young women are subject of research.²² In our study, the young women did not have a higher frequency of poorly differentiated DCIS compared with the older women.

The completeness of excision of the DCIS remains one of the most important predictors for LR. Many studies have shown that margin status is an independent factor for LR after BCT for DCIS.^12-14,20,23 The current trial required excision margins to be free of tumor for trial entry. Thus, by review of the medical files, strictly, patients with involved margins would have become ineligible. However, only seven patients were entered while the pathologist stated the margins to be involved with tumor. When margins are really involved with tumor, one can expect even higher LR rates. Therefore, the performance of a complete excision with tumor-free margins is one of the mainstays of BCT for DCIS. In 1999, a retrospective series suggested that with a margin width of at least 10 mm, the risk of LR was very low, with possibly a limited absolute additional benefit of RT in BCT of DCIS. Recently, a prospective study of 158 patients with small ( 2.5 cm) grade 1 or 2 DCIS, excised with margins of 10 mm or larger, still found a high LR rate after LE only of 12% at 5 years.²⁴ In our study, those patients who underwent a re-excision in which no residual DCIS was found (also considered 10 mm) did not have a lower LR rate compared with those who had free margins without further specification of the margin width. Currently, the Radiation Therapy Oncology Group (RTOG) 9804 study randomly assigns women with "good-risk" DCIS between RT plus tamoxifen and tamoxifen only.

The risk factor analysis of the NSABP study at 8 years of follow-up yielded the presence of comedo necrosis as the most important risk factor related to LR.²⁵ Although margin status was of borderline significance in this analysis, the authors still stressed the importance of a microscopic complete excision.

Current practice, to ensure complete removal of all microcalcifications, includes a postoperative mammogram that was not part of the protocol because, at the time this study was designed, there was limited experience with BCT for nonpalpable lesions.

Our analysis shows that well-differentiated DCIS had a lower risk of LR than intermediately and poorly differentiated subtypes. Nevertheless, also in the well-differentiated group, RT reduced the risk of LR (Fig 2). As can be seen in Table 4, well-differentiated DCIS had a lower risk of DCIS LR but not of invasive LR. From our data, high-grade DCIS does not seem to progress into invasive carcinoma more rapidly than low-grade DCIS. Table 4 shows that a higher number of women (n = 12) with poorly differentiated DCIS died as a result of invasive LR, compared with three women with a well and three with an intermediately differentiated DCIS.

The groups with an exceptionally low risk of recurrence were those with well-differentiated DCIS with a clinging or micropapillary growth pattern, with, in both groups, overall less than 10% LRs at 10 years. In these groups, although the relative benefit of RT is similar to that in the other groups, the absolute benefit of RT on the LR risk will become very small.

The reduced risk of LR caused by RT has, at 10 years of follow-up, not resulted in a survival difference between the two arms. The death rate attributable to metastasized breast cancer after an invasive LR is with 2% the same in both arms and is, with this time of follow-up, similar to death rates reported after mastectomy.²⁶ However, this study was not powered for finding a difference in metastasis or survival. Perhaps only long-term follow-up from combined clinical trials can give answer to these questions. For women with DCIS who are at a high risk of invasive LR, such as those 40 years of age or younger or those with lesions that cannot be excised with tumor-free margins, the subsequent risk of eventually dying from metastasized disease after an invasive LR could become unacceptably high.

Both the NSABP B-17 and the EORTC 10853 trials show relatively high 10-year LR rates of approximately 15% after RT. In the RT arms of these trials, the whole breast was irradiated to a dose of 50 Gy, without a boost dose administered to the original tumor bed. Recently, a large randomized trial has demonstrated that, in invasive breast cancer, an additional dose of 16 Gy directed at the tumor bed further reduced the risk of LR, with a HR of 0.59.²⁷ This additional dose to the tumor bed might also further reduce the risk of LR in DCIS.

The joint randomized trial NSABP B-39/RTOG 0413 compares whole-breast RT with partial breast RT in patients with early stage breast cancer, including DCIS. Because of the sometimes discontinuous spread of DCIS within the branching ducts, residual disease may not be in the immediate vicinity of the biopsy cavity. Therefore, women with DCIS might not be good candidates for partial-breast RT.

Two randomized trials have investigated tamoxifen in the treatment of DCIS.^5,28 The UKCCCR reported only a slight effect of tamoxifen on the reduction of DCIS LR and concluded that there is little evidence for treatment with tamoxifen in women with DCIS. The NSABP B-24 study showed a reduction of mainly invasive LRs and CLBCs caused by tamoxifen. In neither the UKCCCR nor the NSABP B-24 trial was information available on the estrogen receptor (ER) of the DCIS. Our data demonstrate that patients with a higher risk of metastases are those with a poorly differentiated DCIS. These lesions lack ER overexpression in 52% to 61%.^29-31 Tamoxifen is known to be ineffective for preventing recurrence in ER-negative breast tumors. The NSABP B-35 study, comparing tamoxifen with anastrozole in post menopausal women with DCIS, is ongoing.

In summary, the updated results of our trial confirm that, at long-term follow-up, the effectiveness of RT in BCT for DCIS persists. In addition, we have observed that RT reduced the risk of LR in all clinical and pathologic subgroups of patients, with a homogeneous treatment effect of RT across the levels of all factors considered. Hence, RT should be considered in all women treated with BCT for DCIS. However, some subgroups are at very low risk for LR; patients with clinging/micropapillary well-differentiated DCIS might be offered excision without additional irradiation in view of their excellent prognosis with surgery alone. In contrast, some women are, even after RT, at high risk of LR, such as young women and/or those with involved excision margins; in these patients, conservation of the breast should be weighted against a relatively high risk of developing distant metastases caused by an invasive LR from a curable disease.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The following institutions, listed with their principal investigators, participated to this study. Istituto Nazionale Dei Tumori, Milano, Italy (M. Gennaro), Institut Bergonié, Bordeaux, France (A. Avril), Center Henri Becquerel, Rouen, France (J.-P. Julien), CRCL Val D'Aurelle, Montpellier, France (P. Rouanet), Institut Jules Bordet, Brussels, Belgium (M. Coibion), University Hospital Gasthuisberg, Leuven, Belgium (J. Wildiers), Radiotherapeutisch Instituut, Arnhem, the Netherlands (A.H. Westenberg), the Netherlands Cancer Institute—Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands (E.J.T. Rutgers), Rotterdams Radiotherapeutisch Instituut, the Netherlands (P.C.M. Koper/C. Griep), Dr Bernard Verbeeten Instituut, Tilburg, the Netherlands (H.P. Hamers), Ospedale Civile, Genova, Italy (G. Canavese), Integraal Kankercentrum West, Leiden, the Netherlands (M.B. Lagaaij), Policlinico di Careggi, Florence, Italy (L. Cataliotti), University Hospital Leiden, the Netherlands (J.W.H. Leer), Maastro Clinic, Heerlen, the Netherlands (J.J. Jager), Guy's Hospital, London, England (I.S. Fentiman), Universitair Medisch Centrum St Radboud, Nijmegen, the Netherlands (T. Wobbes), Intergraal Kankercentrum Amsterdam, the Netherlands (H.W. Siebbeles), UMCU Utrecht, the Netherlands (H. Struikmans), Center Eugène Marquis, Rennes, France (C. Chenal), St Savas Hospital, Athens, Greece (I. Karydas), IPO, Porto, Portugal (J. Cardoso da Silva), Western Gerenal Hospital, Edinburgh, Scotland (U. Chetty/H.J. Stewart), Istituto Europeo di Oncologia, Milano, Italy (V. Sacchini), Center Georges-François Leclerc, Dijon, France (J.C. Horiot), Hôpital Jean Minjoz, Besançon, France (S. Schraub/J.F. Bosset), Academisch Medisch Centrum, Amsterdam, the Netherlands (C.W. Taat), Istituto de Ginecologia e Ostetrica, Torino, Italy (D. Katsaros), Universitätsklinik für Chirurgie, Graz, Austria (M.G. Smola), Marika Eliadi Hospital, Athens, Greece (S. Vassilaros), I Universitäts Klinik für Chirurgie, Innsbruck, Austria (M. Duenser), Radiotherapeutisch Instituut Friesland, Leeuwarden, the Netherlands (G. Botke), Policlinico di Borgo Roma, Verona, Italy (S. Modena), Ospedale de Noale, Italy (M. Bari), Instituto Oncologia San Sebastian, Spain (J.A. Alberro), Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands (K.J. Roozendaal), Diakonessenhuis, Utrecht, the Netherlands (J.W.R. Nortier), Ninewells Hospital, Dundee, Scotland (P.E. Preece), Erasmus MC, Rotterdam, the Netherlands (T.A.W. Splinter), Saint Lucas Andreas Ziekenhuis, Amsterdam, the Netherlands (R. Weller), Streekziekenhuizen Gooi-Noord, Blaricum, the Netherlands (M.A.N. Gerrits), Universitätsklinik, Göttingen, Germany (H. Rauschecker), Hôpital Cantonal de Genève, Switzerland (L. Perey), Tygerberg Hospital, South Africa (J. Van Zijl), Rambam Medical Center, Haïfa, Israël (A. Kuten), and CHU Vaudois, Lausanne, Switzerland (R. Mirimanoff).

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Ian S. Fentiman Provision of study materials or patients: Johannes L. Peterse, Jean-Pierre Julien, Massimiliano Gennaro, Philippe Rouanet, Antoine Avril, Harry Bartelink, Emiel J. Rutgers Collection and assembly of data: Nina Bijker, Philip Meijnen, Johannes L. Peterse, Jan Bogaerts, Irène Van Hoorebeeck, Jean-Pierre Julien, Massimiliano Gennaro, Harry Bartelink, Emiel J. Rutgers Data analysis and interpretation: Nina Bijker, Philip Meijnen, Johannes L. Peterse, Jan Bogaerts, Harry Bartelink, Emiel J. Rutgers Manuscript writing: Nina Bijker, Philip Meijnen, Johannes L. Peterse, Ian S. Fentiman, Harry Bartelink, Emiel J. Rutgers Final approval of manuscript: Nina Bijker, Philip Meijnen, Johannes L. Peterse, Jean-Pierre Julien, Massimiliano Gennaro, Philippe Rouanet, Harry Bartelink, Emiel J. Rutgers Other: Irène Van Hoorebeeck [data verification]

 

	NOTES

 
Supported by Grants No. 2U10 CA11488-16 through 5U10 CA11488-35 from the National Cancer Institute (National Institutes of Health, Bethesda, MD).

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. Ernster VL, Ballard-Barbash R, Barlow WE, et al: Detection of ductal carcinoma in situ in women undergoing screening mammography. J Natl Cancer Inst 94:1546-1554, 2002[Abstract/Free Full Text]

2. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002[Abstract/Free Full Text]

3. van Dongen JA, Voogd AC, Fentiman IS, et al: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92:1143-1150, 2000[Abstract/Free Full Text]

4. Fisher B, Land S, Mamounas E, et al: Prevention of invasive breast cancer in women with ductal carcinoma in situ: An update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28:400-418, 2001[CrossRef][Medline]

5. Houghton J, George WD, Cuzick J, et al: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: Randomised controlled trial. Lancet 362:95-102, 2003[CrossRef][Medline]

6. 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[CrossRef][Medline]

7. Bijker N, Rutgers EJ, Peterse JL, et al: Variations in diagnostic and therapeutic procedures in a multicentre, randomized clinical trial (EORTC 10853) investigating breast-conserving treatment for DCIS. Eur J Surg Oncol 27:135-140, 2001[CrossRef][Medline]

8. Bijker N, Peterse JL, Duchateau L, et al: 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 10853. J Clin Oncol 19:2263-2271, 2001[Abstract/Free Full Text]

9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

10. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

11. Cox DR: Regression models and life-tables. J R Stat Assoc B 34:187-220, 1972

12. Cutuli B, Cohen-Solal-Le Nir C, de Lafontan B, et al: Breast-conserving therapy for ductal carcinoma in situ of the breast: The French Cancer Centers' experience. Int J Radiat Oncol Biol Phys 53:868-879, 2002[CrossRef][Medline]

13. Silverstein MJ, Lagios MD, Groshen S, et al: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340:1455-1461, 1999[Abstract/Free Full Text]

14. Solin LJ, Fourquet A, Vicini FA, et al: Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breast. Cancer 103:1137-1146, 2005[CrossRef][Medline]

15. de la Rochefordiere A, Asselain B, Campana F, et al: Age as prognostic factor in premenopausal breast carcinoma. Lancet 341:1039-1043, 1993[CrossRef][Medline]

16. Elkhuizen PH, van de Vijver MJ, Hermans J, et al: Local recurrence after breast-conserving therapy for invasive breast cancer: High incidence in young patients and association with poor survival. Int J Radiat Oncol Biol Phys 40:859-867, 1998[CrossRef][Medline]

17. 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[Abstract/Free Full Text]

18. Vrieling C, Collette L, Fourquet A, et al: Can patient-, treatment- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients? Eur J Cancer 39:932-944, 2003[CrossRef][Medline]

19. Van Zee KJ, Liberman L, Samli B, et al: Long term follow-up of women with ductal carcinoma in situ treated with breast-conserving surgery: The effect of age. Cancer 86:1757-1767, 1999[CrossRef][Medline]

20. Vargas C, Kestin L, Go N, et al: Factors associated with local recurrence and cause-specific survival in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy or mastectomy. Int J Radiat Oncol Biol Phys 63:1514-1521, 2005[CrossRef][Medline]

21. Walker RA, Dearing SJ, Brown LA: Comparison of pathological and biological features of symptomatic and mammographically detected ductal carcinoma in situ of the breast. Hum Pathol 30:943-948, 1999[CrossRef][Medline]

22. Rodrigues NA, Dillon D, Carter D, et al: Differences in the pathologic and molecular features of intraductal breast carcinoma between younger and older women. Cancer 97:1393-1403, 2003[CrossRef][Medline]

23. Fisher ER, Costantino J, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17: Intraductal carcinoma (ductal carcinoma in situ)—The National Surgical Adjuvant Breast and Bowel Project Collaborating Investigators. Cancer 75:1310-1319, 1995[CrossRef][Medline]

24. Wong JS, Kaelin CM, Troyan SL, et al: Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 24:1031-1036, 2006[Abstract/Free Full Text]

25. Fisher ER, Dignam J, Tan-Chiu E, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: Intraductal carcinoma. Cancer 86:429-438, 1999[CrossRef][Medline]

26. Ernster VL, Barclay J, Kerlikowske K, et al: Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program. Arch Intern Med 160:953-958, 2000[Abstract/Free Full Text]

27. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378-1387, 2001[Abstract/Free Full Text]

28. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999[CrossRef][Medline]

29. Bijker N, Peterse JL, Duchateau L, et al: Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ. Br J Cancer 84:539-544, 2001[CrossRef][Medline]

30. Ringberg A, Anagnostaki L, Anderson H, et al: Cell biological factors in ductal carcinoma in situ (DCIS) of the breast-relationship to ipsilateral local recurrence and histopathological characteristics. Eur J Cancer 37:1514-1522, 2001[CrossRef][Medline]

31. Warnberg F, Nordgren H, Bergkvist L, et al: Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. Br J Cancer 85:869-874, 2001[CrossRef][Medline]

Submitted February 15, 2006; accepted April 27, 2006.

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