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Originally published as JCO Early Release 10.1200/JCO.2005.04.4610 on February 6 2006 © 2006 American Society of Clinical Oncology.
Is Excision Alone Adequate Treatment for Low-Risk Ductal Carcinoma-in-Situ of the Breast?University of Pennsylvania, Philadelphia, PA The diagnosis of ductal carcinoma-in-situ (DCIS; intraductal carcinoma) of the breast presents a dilemma for both the patient and the treating physician. DCIS is a nonobligate precursor of invasive carcinoma and occupies a position on the spectrum of neoplasia between benign and malignant.1 Some patients with DCIS will develop a true malignancy over time, but some patients will not, and current prognostic capabilities cannot predict the natural history for individual patients. When DCIS is diagnosed, patients and physicians often pursue treatment in an attempt to prevent a subsequent malignant lesion from developing because malignant transformation carries well-known risks for the patient from invasive carcinoma. Treatment with radiation and tamoxifen can reduce the risk of recurrence, including invasive recurrence, but for the overall population of patients with DCIS, such risk reduction comes with the knowledge that the majority of patients are overtreated. Compounding this dilemma, most DCIS lesions are detected in asymptomatic patients on routine screening mammography, and virtually no patient dies from an index DCIS lesion. Can some patients with DCIS be adequately treated with excision alone? One of the major clinical questions surrounding the management of DCIS is whether there is an identifiable cohort of patients with sufficiently low risk of recurrence such that further treatment beyond excision (lumpectomy) is not required. In this issue, Wong et al2 report the results of a well-designed and well-conducted single-arm study in which the authors attempted to identify prospectively a cohort of DCIS patients with a sufficiently low risk of local recurrence after excision so that no additional treatment with radiation or tamoxifen was required. The importance of this study is that it is one of the first reported attempts to identify prospectively a low-risk subgroup of patients with DCIS who could be adequately treated with excision alone.
The criteria for entry onto this study were based on commonly accepted clinical parameters for defining low-risk DCIS, including tumor size It is noteworthy that the study by Wong et al2 failed to identify prospectively a low-risk cohort of patients suitable for treatment with excision alone. Given the small total number of patients in this study, many subsets contained too few patients for meaningful analysis. As a result, the study provides no substantive clues to improve patient selection in the future. In a similar prospective, single-arm trial of wide excision alone with a minimum negative margin width of 10 mm, Rampaul et al3 reported that the crude local recurrence rate was 11% (28 of 256 patients) after a median follow-up of 7.2 years.
Attempts have been made at least as far back as the 1980s to identify a low-risk cohort of DCIS patients who do not require further treatment after excision.4,5 Numerous retrospective studies have analyzed selected patient populations to suggest criteria to define a low-risk subgroup, and many different criteria have been proposed. Most attempts have been based on clinical and pathologic criteria such as mammographic detection, small size (for example, Retrospective studies are hypothesis generating, not hypothesis testing, and form the basis for prospective studies. In the setting of DCIS, the subgroup of patients for whom radiation can be omitted has not been prospectively and reproducibly identified in clinical trials.6 In retrospective studies of excision alone for selected patients with DCIS, 10-year local recurrence rates have been reported as 20% to 44%.7-12 An acceptable level of risk for local recurrence after treatment with excision alone has not been established and likely varies from patient to patient and from physician to physician. Three randomized trials of radiation for patients with DCIS have been reported to date.13-18 All three trials demonstrated that the risk of local recurrence, including invasive local recurrence, was reduced when definitive breast radiation was administered after excision compared with excision alone. Two of these trials used the straightforward random assignment of excision alone compared with excision plus radiation.13-17 In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B17 trial, the 12-year risk of local recurrence was reduced with the addition of radiation from 31.7% to 15.7% (P < .000005).14 The European Organization for Research and Treatment of Cancer 10853 trial reported that the 4-year local recurrence rate was 16% for patients treated with excision alone compared with 9% for patients treated with radiation after excision (P = .005).16 The third trial from the United Kingdom, Australia, and New Zealand (UK/ANZ) used a 2 x 2 design.18 In the analysis limited to radiation, the local recurrence rate was reduced with the addition of radiation from 14% to 6% (P < .0001). Subset analyses from two of these randomized trials failed to identify any subset of patients who did not benefit from radiation.15,17 Retrospective, nonrandomized studies also have demonstrated that the addition of radiation after lumpectomy reduces the risk of local recurrence.9,12 In addition, using Surveillance, Epidemiology, and End Results data, Baxter et al19 reported that the 8-year rate of invasive local recurrence after lumpectomy was reduced from 6.2% without radiation to 2.7% with radiation (adjusted hazard ratio = 0.43). The results of the value of radiation for DCIS from the three randomized trials, as well as from retrospective studies, are all remarkably similar; the addition of radiation after excision reduces the risk of local recurrence by approximately 50%. The value of tamoxifen in the management of DCIS has been reported in two randomized studies.14,18,20 In the NSABP B24 study, the 7-year risk of local recurrence in the treated breast after lumpectomy plus radiation was reduced from 11.1% without tamoxifen to 7.7% with tamoxifen (P = .02), and the risk of all breast cancer events (ipsilateral plus contralateral) was reduced from 16.9% to 10.0% (P = .0003).14 In contrast, the UK/ANZ trial demonstrated a nonsignificant reduction in all breast events with the addition of tamoxifen from 18% to 14% (P = .13).18 However, the UK/ANZ trial had a shorter follow-up (median, 4.4 years) than the NSABP B24 trial (median, 6.9 years), and there was an approximately 22% relative risk reduction in all breast cancer events with the addition of tamoxifen in the UK/ANZ trial. Thus, it is reasonable to speculate that the UK/ANZ trial might well demonstrate a statistically and clinically significant benefit for treatment with tamoxifen with longer follow-up and a larger number of events. Similar to invasive carcinoma, tamoxifen is beneficial only for hormone receptor–positive DCIS.21 Clinical trials are currently testing newer agents (for example, aromatase inhibitors) that have the potential to reduce recurrence even further. No study of DCIS has yet demonstrated that adding radiation or tamoxifen improves overall survival. However, all of the reported randomized trials were powered to evaluate for differences in either local control or all breast cancer events and were underpowered to evaluate for differences in breast cancer deaths and overall survival. In the Early Breast Cancer Trialists' Collaborative Group overview (meta-analysis) of randomized trials of radiation for invasive breast carcinoma, improving local control with the addition of radiation after breast conservation surgery was associated with a reduction in breast cancer deaths and an improvement in overall survival.22,23 Although improvement in local control was seen in individual randomized trials, reduction in breast cancer deaths and improvement in overall survival could be established only by combining the randomized trials in the overview, thereby resulting in large numbers of patients, large numbers of events after treatment, and long-term follow-up. Approximately half of all local recurrences after initial breast conservation treatment for DCIS are invasive.9,13-18,20,24 Thus, on the basis of the current evidence, one cannot conclude that the addition of radiation or tamoxifen does not lead to a reduction in breast cancer deaths for patients with DCIS of the breast.
Cooperative group studies are continuing the attempt to prospectively identify a low-risk subgroup of DCIS patients. These studies should enhance the knowledge of the best treatment strategies for DCIS. In the Eastern Cooperative Oncology Group registration trial E5194, patients were prospectively identified for treatment using excision alone without radiation, with optional tamoxifen. The criteria for entry were mammographic detection, excision with a minimum negative margin width of 3 mm or greater, negative postbiopsy mammogram, and either the combination of grade 1 or 2 plus tumor size So, can some patients with DCIS be adequately treated with excision alone? Intuitively, there should be some subsets of DCIS patients with a sufficiently low risk of recurrence that omitting adjuvant radiation or tamoxifen (if hormone receptor positive) is reasonable; however, such a subset of patients has not been prospectively identified. The study by Wong et al2 provides a strong cautionary warning that undertreatment by omission of adjuvant therapy can lead to an unacceptably high rate of local recurrence. Given the current evidence, one must conclude that, after excision, all patients with DCIS (except for the patient with a short life expectancy or substantial comorbid conditions) should be seriously considered for adjuvant treatment with radiation and tamoxifen to minimize the risk of local recurrence. Although the data for radiation are strong and consistent, the recommendations for adjuvant tamoxifen must be viewed in light of the differences in reported outcomes from the two randomized trials of adjuvant tamoxifen (NSABP B24 and UK/ANZ). For now and the near future, there is no well-defined, low-risk subgroup of patients with DCIS after excision who can reasonably forego adjuvant therapy. The results of ongoing trials will add valuable information but will likely not be definitive. Because of the absence of definitive information, patients and physicians will need to acknowledge the dilemma of managing DCIS of the breast and must carefully weigh the currently available data when making individual patient management decisions. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
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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] 19. Baxter NN, Virnig BA, Durham SB, et al: Radiation after lumpectomy for DCIS to reduce the risk of invasive breast cancer: A population-based study. J Clin Oncol 23:8s, 2005 (suppl 1; abstr 516) 20. 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] 21. Allred DC, Bryant J, Land S, et al: Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: Findings from NSABP protocol B-24. Breast Cancer Res Treat 76:S36, 2002 (suppl 1, abstr) 22. 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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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2.5 cm, predominant nuclear grade 1 or 2, removal of all suspicious calcifications, and importantly, widely negative margins of resection (defined as a minimum negative margin width of 1 cm or a re-excision with no tumor). The reported annual risk of local recurrence was 2.4% per year, with an estimated 5-year local recurrence rate of 12%. This rate was higher than the predetermined acceptable rate of local recurrence, and therefore, the trial was closed to accrual early. 
