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Originally published as JCO Early Release 10.1200/JCO.2007.11.4686 on November 5 2007 © 2007 American Society of Clinical Oncology. Significance of Multifocality in Ductal Carcinoma In Situ: Outcomes of Women Treated With Breast-Conserving Therapy
From the Departments of Radiation Oncology and Pathology, Toronto-Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences Centre; and the Centre for Research in Women's Health, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada Address reprint requests to Eileen Rakovitch, MD, MSc, FRCPC, Toronto-Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5; e-mail: eileen.rakovitch{at}sunnybrook.ca
Purpose There is concern that women with multifocal ductal carcinoma in situ (DCIS; confined to one quadrant) who are treated with breast-conserving surgery face a high risk of local recurrence; therefore, many are treated with mastectomy. The objective of this study is to evaluate the significance of multifocality and the outcomes of women with multifocal DCIS treated with breast-conserving therapy. Methods The records of patients treated with breast-conserving surgery for DCIS between 1982 and 2000 were reviewed. Multivariate analyses were performed to evaluate the effects of multifocality and other prognostic factors on the rate of local recurrence. Results Of 615 cases of DCIS reviewed, 310 (41%) received breast-conserving surgery and 305 (40%) received breast-conserving surgery plus radiation (n = 260 with multifocality, n = 314 without multifocality, and n = 31 focality unreported). On multivariate analysis, multifocality (hazard ratio [HR] = 1.80; 95% CI, 1.15 to 2.80; P = .01), radiation treatment (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.74; 95% CI, 1.03 to 2.92; P = .04), and high nuclear grade (HR = 1.65; 95% CI, 1.02 to 2.65; P = .04) were associated with risk of local recurrence. The detrimental effect of multifocality was limited to women who did not receive radiotherapy; the local recurrence–free survival rate at 10 years was 59% for women with multifocal disease and 80% for women without multifocality (P = .02). Among women treated with breast-conserving surgery plus radiation, there was no difference in 10-year local recurrence–free survival (80% v 87%; P = .35). There was no association between multifocality and the development of invasive recurrence. Conclusion Multifocality is a significant predictor of local recurrence in women who receive breast-conserving surgery for DCIS without radiotherapy; however, low recurrence rates can be achieved if adjuvant radiation is administered.
Ductal carcinoma in situ (DCIS) is a noninvasive form of breast cancer and is defined by the presence of malignant epithelial cells confined to the breast ductule.1 The increased utilization of screening mammography during the last 20 years has lead to a dramatic rise in the incidence of DCIS, and now DCIS represents 20% to 40% of all breast cancers diagnosed by screening mammography.2 The prognosis of DCIS is excellent, with 10-year survival rates in excess of 95%.3-5 The goal of treatment is to excise the entire lesion, leaving negative resection margins, to minimize the risk of further recurrence (in situ or invasive) and to avoid further surgery, hormone therapy, and chemotherapy (in the event of an invasive recurrence). Before the era of mammographic screening, the treatment of DCIS was largely by mastectomy, because DCIS was usually extensive at diagnosis, often involving most of the breast.1 The advent of screening mammography has led to a significant decrease in the median size of DCIS lesions at presentation.6 Today, most cases of DCIS can be treated with breast-conserving surgery, providing a good cosmetic outcome. Nevertheless, approximately one third of women with DCIS are treated with mastectomy,7,8 and this raises the possibility that in some cases, mastectomy may be unnecessary. Recently, we studied the factors associated with the use of mastectomy, versus breast-conserving surgery, among women diagnosed with DCIS in the Ontario Breast Screening Program.8 The presence of multifocal DCIS was the strongest predictor of mastectomy. On multivariate analysis, women with multifocal DCIS were three times more likely to receive a mastectomy compared with women without multifocality (odds ratio = 3.5; 95% CI, 1.7 to 7.1; P = .0005). However, it is not clear to what extent, if any, multifocality is an independent predictor of recurrence in women treated with breast-conserving therapy. Hence, the need for treating all women with multifocal DCIS by mastectomy is unproven. The objectives of this study are to evaluate the risk of local recurrence risk among women with multifocal DCIS treated with breast-conserving therapy and to determine whether multifocality is an independent risk factor for local recurrence.
Patients The records of all patients with a diagnosis of DCIS (with or without microinvasion) who were referred to a single regional cancer center between 1982 and 2000 were reviewed. Cases treated with mastectomy were excluded (n = 145). The charts of all patients treated with breast-conserving surgery were reviewed (N = 615). Baseline data were collected on patient age, characteristic pathologic features, and treatments received. An axillary nodal dissection was performed in 60 (9.8%) of 615 patients, and 41 women (6%) received tamoxifen. The medical charts were reviewed for the presence of recurrent disease. Information on patients who had not attended the cancer center in the last 12 months was obtained through correspondence with the primary physician or surgeon.
Radiation Therapy
Pathology Multifocality refers to the presence of multiple foci of DCIS within the same duct system. Although there are various definitions of multifocality in the literature, we applied the definition used by Sikand et al10 because of its clarity and ease of reproducibility. Multifocality was a pathologic feature defined as more than one distinct focus of DCIS, with at least 5 mm of intervening healthy tissue confined to a single quadrant of the breast.10 For cases with multifocal DCIS, the size of the largest focus was recorded. Missing pathologic data that could not be obtained by pathology review or from the original pathology report were coded as "not reported." All treatments and outcomes were validated by review of pathology and operative reports.
Statistical Analysis
Patients From 1982 to 2000, 760 cases of DCIS were referred to a single regional cancer center; 145 (19%) were treated by mastectomy and were excluded from this analysis. The remaining 615 cases were eligible for the study. There were 310 (50%) patients treated with breast-conserving surgery alone and 305 (50%) patients treated with breast-conserving surgery plus radiation. Patient and pathologic characteristics are listed in Table 1. The median age was 56 years (range, 25 to 93 years) for women treated with breast-conserving surgery alone and 54 years (range, 23 to 81 years) for those treated with breast-conserving surgery plus radiation. The median follow-up time was 6.9 years (range, 0.06 to 19.6 years) for the group that received breast-conserving surgery alone and 4.9 years (range, 0.06-17.6 years) for the group that received breast-conserving surgery plus radiation (P < .01).
Outcomes Among the women treated with breast-conserving surgery alone, 65 women (21%) developed local recurrence (31 DCIS and 30 invasive). Among cases treated with breast-conserving surgery plus radiation, 26 women (9%) developed local recurrence (19 DCIS and six invasive). The 5-year actuarial local recurrence–free survival rates were 85% among cases treated with breast-conserving surgery alone and 93% for those treated with breast-conserving surgery plus radiation. The 10-year actuarial local recurrence–free survival rates were 72% among cases treated with breast-conserving surgery alone and 82% for those treated with breast-conserving surgery plus radiation. The 5-year actuarial invasive local recurrence–free survival rates were 95% for cases treated with breast-conserving surgery alone and 99% for those treated with breast-conserving surgery plus radiation. The 10-year actuarial invasive local recurrence–free survival rates were 85% for cases treated with breast-conserving surgery alone and 92% for those treated with breast-conserving surgery plus radiation. The median time to local recurrence was 4.2 years (range, 0.3 to 16.7 years) after breast-conserving surgery alone and 3.0 years (range, 0.6 to 8.7 years) after breast-conserving surgery plus radiation.
Predictors of Local Recurrence
Multivariate analysis. On multivariate analysis, multifocality was the strongest predictor of local recurrence (DCIS or invasive; HR = 1.8; 95% CI, 1.2 to 2.8; P = .01; Table 3). Other predictive factors were radiotherapy (HR = 0.46; 95% CI, 0.29 to 0.74; P = .001), margin width 4 mm or smaller (HR = 1.7; 95% CI, 1.0 to 2.9; P = .04), and high nuclear grade (HR = 1.6; 95% CI, 1.0 to 2.7; P = .04). Among the subset of patients with negative resection margins, the presence of multifocality remained a significant predictor of local recurrence (HR = 1.97; 95% CI, 1.23 to 3.15; P = .005; Table 3).
Age was not a statistically significant predictor of local recurrence, although there were only 31 cases diagnosed at younger than 40 years (16 treated with breast-conserving surgery alone, 15 treated with breast-conserving surgery plus radiation), and there was little power to detect a significant difference associated with choice of treatment in young women.
Impact of Multifocality
In contrast, there was no significant impact of multifocality among women who received radiation. The actuarial local recurrence–free survival rates at 5 years were 92% and 94%, for those with multifocal and unifocal disease, respectively (P = .4) and at 10 years were 81% and 84% years for those with and without multifocality, respectively (P = .40; Fig 2). There was no significant association between multifocality and the development of invasive breast cancer (Table 4).
There were 26 cases of DCIS and microinvasion (six were treated with breast-conserving surgery and 20 were treated with breast-conserving surgery and radiation). Because there were few cases, we did not stratify the cohort between cases of pure DCIS and those with microinvasion.
The results of this study indicate that multifocality is an independent predictor of local recurrence among women treated with breast-conserving surgery alone for DCIS. This does not imply that mastectomy is necessary for all women with multifocal disease; low recurrence rates were observed after breast-conserving surgery and radiation, provided that the margins of resection were negative. The tendency to recommend mastectomy to women with multifocal DCIS may be the result of the interpretation of previous studies that report on the presence of residual disease in mastectomy specimens after excision of the index lesion.1,11,12 Physicians may be concerned that the presence of residual disease will inevitably lead to local recurrence.13 For example, in a study of 60 cases of DCIS diagnosed from 1980 to 1987, 11 cases (18%) had two or more foci of DCIS separated by a gap of more than 5 mm.14 In another study of 32 cases of DCIS diagnosed from 1980 to 1982 (in which half were > 4 cm in size), one case had foci of DCIS extending 4 cm beyond the visible lesion.11 However, these studies were conducted before the era of mammographic screening, and the cases may not be representative of the current population of patients, most of whom have mammographically detected DCIS. In our study, women known to have extensive DCIS were treated by mastectomy. We included women who were selected for breast-conserving surgery and were found postoperatively to have multifocal disease. For these patients, breast-conserving surgery and radiation may be a valid alternative to mastectomy. Previous clinical studies have shown that, despite the presence of residual disease, breast-conserving surgery and radiation can lead to low recurrence rates.4,15-18 This suggests that not all occult residual disease will manifest as a local recurrence and that postoperative radiotherapy is effective in controlling residual disease. We found that multifocality was a risk factor for local recurrence only among patients who did not receive adjuvant radiation. There is currently no agreement on the precise definition of multifocality. To some extent, this may explain why its significance has been poorly understood. Multifocality has been defined at various times as the following: small tumor foci extending over an area of 5 cm11; a discontinuous pattern of DCIS involving at least two foci of tumor separated by uninvolved tissue measuring less than 4 cm14; the presence of tumor within or close to the same quadrant as the index lesion19 or the presence of more than one focus of tumor separated by at least 5 mm of intervening normal tissue.10 In most randomized trials and cohort studies of DCIS, multifocality has not been routinely evaluated.20 Multifocality was not identified to be an independent predictor of recurrence in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B17 trial, although it was associated with the presence of positive resection margins.21 It is well documented that the presence of negative resection margins is associated with a lower risk of local recurrence. In this study, the risk of local recurrence was significantly less with margin width greater than 4 mm. This does not imply that a minimum margin of 4 mm is required in all women, and further studies may help to identify the optimal width of the resection margin. In summary, the results of our study indicate that multifocality is an independent risk factor for the development of local recurrence after breast-conserving surgery for DCIS. Nevertheless, breast preservation is a valid option for many women with multifocal DCIS. Low recurrence rates can be achieved provided that the disease is completely excised with negative resection margins and that adjuvant radiation is administered. Mastectomy may be reserved for women with multicentric DCIS (defined by the presence of DCIS in multiple quadrants of the breast) or for cases where complete surgical excision (with negative resection margins) cannot be achieved with an acceptable cosmetic result. Additional research is required to confirm the outcomes observed in this study.
The author(s) indicated no potential conflicts of interest.
Conception and design: Eileen Rakovitch Manuscript writing: Eileen Rakovitch, Jean-Philippe Pignol, Steven Narod Final approval of manuscript: Jean-Philippe Pignol, Wedad Hanna, Steven Narod, Jacqueline Spayne, Sharon Nofech-Mozes, Carole Chartier, Lawrence Paszat
published online ahead of print at www.jco.org on November 5, 2007. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Holland R, Hendriks JH, Vebeek AL, et al: Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet 335:519-522, 1990[CrossRef][Medline] 2. 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 3. Bijker N, Meijnen P, Peterse JL, et al: 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. J Clin Oncol 24:3381-3387, 2006 4. 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] 5. 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] 6. Lagios MD: Duct carcinoma in situ: Biological implications for clinical practice. Semin Oncol 23:6-11, 1996 (suppl)[Medline] 7. Baxter NN, Virnig BA, Durham SB, et al: Trends in the treatment of ductal carcinoma in situ of the breast. J Natl Cancer Inst 96:443-448, 2004 8. Rakovitch E, Pignol JP, Hanna W, et al: The management of ductal carcinoma in situ of the breast: A screened population-based analysis. Breast Cancer Res Treat 101:335-347, 2007[CrossRef][Medline] 9. 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] 10. Sikand K, Lee AH, Pinder SE, et al: Sections of the nipple and quadrants in mastectomy specimens for carcinoma are of limited value. J Clin Pathol 58:543-545, 2005 11. Holland R, Veling SH, Mravunac M, et al: Histologic multifocality of Tis, T1-2 breast carcinomas Implications for clinical trials of breast-conserving surgery. Cancer 56:979-990, 1985[CrossRef][Medline] 12. Rosen PP, Fracchia AA, Urban JA, et al: "Residual" mammary carcinoma following simulated partial mastectomy. Cancer 35:739-747, 1975[CrossRef][Medline] 13. Sanders ME, Schuyler PA, Dupont WD, et al: The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer 103:2481-2484, 2005[CrossRef][Medline] 14. Faverly DR, Burgers L, Bult P, et al: Three dimensional imaging of mammary ductal carcinoma in situ: Clinical implications. Semin Diagn Pathol 11:193-198, 1994[Medline] 15. 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] 16. Jacobson JA, Danforth DN, Cowan KH, et al: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332:907-911, 1995 17. 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] 18. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002 19. Fisher ER, Sass R, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (protocol 6): II, Relation of local breast recurrence to multicentricity. Cancer 57:1717-1724, 1986[CrossRef][Medline] 20. 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 21. 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] Submitted March 6, 2007; accepted August 7, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests and mean differences for continuous variables by t tests. To study prognostic factors, univariate and multivariate survival analyses were performed using the Cox proportional hazards model. The model evaluated the relationship between patient and tumor characteristics (ie, tumor size, nuclear grade, comedonecrosis, nuclear grade, presence of multifocality, presence of microinvasion, margin status, and width of resection margin) and outcome (ie, local recurrence). Because nuclear grade and the presence of comedonecrosis were correlated (P < .0001), they were not entered into the model simultaneously. Log (-log SF) curves were plotted and compared for cases treated with breast-conserving surgery alone and breast-conserving surgery with radiation to ensure that the assumptions of the Cox proportional hazards model were not violated. Local recurrence was defined as invasive or DCIS recurrences that occurred in the ipsilateral breast at least 6 months after the diagnosis of DCIS. Patients were excluded at the time of last follow-up. If patients were lost to follow-up visit, they were excluded at time of last visit. 
4 mm) resection margins (HR = 2.5; 95% CI, 1.2 to 5.6; P = .02). 
