|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2001 American Society for Clinical Oncology
Ductal Carcinoma-In-SituByFrom the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA. Address reprint requests to D. Lawrence Wickerham, MD, National Surgical Adjuvant Breast and Bowel Project, 4 Allegheny Center/East Commons Professional Bldg, Pittsburgh, PA 15212.
OVER THE PAST 25 years in the United States, the number of women diagnosed with ductal carcinoma-in-situ (DCIS) has increased dramatically. It is estimated that 12% to 15% of all newly diagnosed breast cancers today (approximately 25,000 to 30,000 cases annually) are DCIS.1 The increase in reported incidence of this once uncommon disease is thought to be a direct result of the widespread use of screening mammography. Ninety percent of DCIS is identified by mammograms.2 For years the traditional surgical management of DCIS was mastectomy, with or without axillary dissection. Given the demonstration that breast-conserving surgery is an effective option in the treatment of invasive breast cancer, and the perceivedly favorable prognosis of mammographically detected DCIS, the need for mastectomy was called into question.3
National Surgical Adjuvant Breast and Bowel Project (NSABP) researchers designed Protocol B-17 to evaluate the use of lumpectomy with and without breast irradiation in women with DCIS (Fig 1). Between October 1985 and December 1990, 818 women with DCIS who had been treated by local excision and who had clear tumor margins were randomly assigned to receive no further treatment or breast irradiation. Eight years of follow-up showed that lumpectomy plus radiation was more beneficial than lumpectomy alone in these women with localized, fully excised DCIS.4,5 The incidence of invasive ipsilateral breast tumor (IBT) recurrence was reduced from 13.4% to 3.9% (P< .001), and the incidence of noninvasive IBT was reduced from 13.4% to 8.2% (P = .007). All cohorts benefited from radiation regardless of clinical or mammographic tumor characteristics.6,7 The incidence of local-regional and distant events was similar in both groups, and there were no differences in overall survival.
The European Organization for Research and Treatment of Cancer conducted a similar trial.8 Between 1986 and 1996, 1,111 women with mammographically detected DCIS measuring  5 cm were treated by complete local excision and then randomly assigned to either no further treatment or breast irradiation. At a median follow-up of 4.25 years, radiation therapy was shown to reduce the overall number of both invasive and noninvasive recurrences in the ipsilateral breast in these women. An additional interesting finding surfaced in the NSABP B-17 trial after 8 years. In those women who had been treated with lumpectomy and breast irradiation, the risk of invasive breast cancer in the contralateral breast was remarkably similar to the risk of invasive breast cancer in the ipsilateral breast (contralateral 3.5% v ipsilateral 3.9%). A second NSABP DCIS trial, B-24, evaluated the worth of tamoxifen, which had demonstrated a substantial benefit in the adjuvant treatment of breast cancer,9 in reducing the incidence of both ipsilateral and contralateral invasive breast cancer (Fig 2). Patients with DCIS treated with lumpectomy and breast irradiation were randomly assigned to receive either tamoxifen 20 mg/d or a placebo for a 5-year period.10 The NSABP had completed adjuvant therapy trials evaluating tamoxifen in both node-positive and node-negative patients.11,12 In one of these trials, B-14, patients with node-negative, estrogen receptor–positive breast cancers were randomly assigned to receive either placebo or tamoxifen.13-15 Not only was there a benefit for the tamoxifen-treated patients in disease-free and overall survival, there was also a substantial reduction in contralateral breast cancers, a finding that led to the NSABP’s first breast cancer prevention trial, P-1.16 This observation, along with preclinical evidence that tamoxifen inhibits both the initiation and the promotion of tumors in experimental animals,17,18 made tamoxifen an attractive therapy for patients with DCIS treated with lumpectomy and breast irradiation.
Between May 1991 and April 1994, 1,804 women were randomized onto the B-24 trial to evaluate tamoxifen for the reduction of ipsilateral and contralateral invasive breast cancer. At 5 years, the incidence of subsequent invasive and noninvasive breast cancers at any site was reduced by 37% with tamoxifen (13.4 v 8.2; P < .001). The incidence of invasive breast cancer events was reduced from 7.2% in the placebo group to 4.1% in the tamoxifen (P = .004). There was a significant reduction in the incidence of all contralateral breast cancer in the tamoxifen-treated women (Table 1). The side effects and toxicities of tamoxifen demonstrated in B-24 were in keeping with those noted in the larger P-1 Breast Cancer Prevention Trial. The most common side effects were hot flashes and vaginal discharge, and there was an expected increase in both endometrial cancer and thromboembolic events.
The prognosis of women with DCIS treated by lumpectomy and breast irradiation is quite good, and although the benefit of adding tamoxifen is statistically significant, the absolute magnitude of benefit only approaches 5% at 5 years. Are there subgroups of patients who can be identified who may have a greater or lesser benefit from tamoxifen treatment? Efforts are underway in B-24 to determine whether the estrogen receptor status of the DCIS predicts response. At present, there are no data that address this question. The benefit in reduction in contralateral breast cancer, however, may prove to be independent of the receptor status of the primary tumor.
Experience with tamoxifen from the NSABP P-1 Breast Cancer Prevention Trial showed that women younger than 50 years of age at entry, most of whom were premenopausal, had little or no excess risk of endometrial cancer or thromboembolic events. In addition, although the effects of tamoxifen in reducing subsequent invasive breast cancer events both in the P-1 study and in B-24 were of a similar magnitude in younger (< 50 years) and older (
Can tamoxifen be given to women with DCIS treated with lumpectomy who choose to avoid breast irradiation? There are ongoing randomized clinical trials to assess this question prospectively. The results of NSABP Trial B-21, although not directly comparable, showed that, in patients with invasive breast cancers In summary, the reported incidence of DCIS has increased dramatically as a consequence of the increased use of screening mammography. Randomized clinical trials have demonstrated that breast-conserving surgery followed by breast irradiation is an option in the management of this disease. DCIS has also been shown to be indicator of risk for contralateral breast cancer. After lumpectomy and breast irradiation, the addition of tamoxifen reduces the incidence of overall breast events, including a reduction in contralateral breast cancer. The decision to take tamoxifen as adjuvant therapy for DCIS at present is based largely on clinical assessments of potential benefits and risks. Research currently under way is examining the relationship between estrogen receptor levels and tamoxifen benefit. Future work is likely to focus on the development of more effective therapies with less toxicity. The molecular characterization of DCIS tumors should assist us in being able to more accurately predict prognosis and to judge more astutely what the response to targeted therapies will be in a given woman.
Supported by Public Health Service grant nos. U10CA12027 and U10CA37377 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. I thank Sandra M. Swain, MD, and Victor G. Vogel, MD, MHS.
1. Sakorafas GH, Tsiotou AG: Ductal carcinoma in situ (DCIS) of the breast: Evolving perspectives. Cancer Treat Rev 26: 103-125, 2000[Medline] 2. Winchester DP, Strom EA: Standards for diagnosis and management of ductal carcinoma in situ (DCIS) of the breast. CA Cancer J Clin 48: 108-128, 1998[Abstract] 3. Fisher B, Bauer M, Margolese R, et al: Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 312: 665-673, 1985[Abstract]
4.
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 5. 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] 6. 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[Medline] 7. 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[Medline] 8. Julien JP, Biijker 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] 9. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451-1467, 1998 10. 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[Medline] 11. Fisher B, Redmond C, Brown A, et al: Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 305: 1-6, 1981[Abstract] 12. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8: 1005-1018, 1990[Abstract] 13. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor–positive tumors. N Engl J Med 320: 479-484, 1989[Abstract] 14. Fisher B, Redmond C, Wickerham DL, et al: Systemic therapy in patients with node-negative breast cancer: A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials. Ann Intern Med 111: 703-712, 1989
15.
Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93: 684-690, 2001
16.
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90: 1371-1388, 1998 17. Jordan VC: Effect of tamoxifen (ICI 46, 474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12: 419-424, 1976 18. Jordan VC, Allen KE: Evaluation of the antitumor activity of the nonsteroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16: 239-251, 1980 19. Wolmark N, Dignam J, Margolese R, et al: The role of radiotherapy and tamoxifen in the management of node negative invasive breast cancer -1.0 cm treated with lumpectomy: Preliminary results of NSABP Protocol B-21. Proc Am Soc Clin Oncol 19:70a, 2000 (abstr 271)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
INTRODUCTION
NATIONAL SURGICAL ADJUVANT...
50 years of age) women, the cumulative benefit is expected to be greater in the younger group, because such benefit is a function of time at risk for subsequent events. 
