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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1395-1396 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1432
Evolution of Breast-Conserving Therapy for Localized Breast CancerDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA It has been almost 25 years since the 1983 Journal of Clinical Oncology (JCO) article, "Clinical-Pathologic Study of Early Breast Cancer Treated by Primary Radiation Therapy," by Harris et al.1 We are pleased that this article has been selected to be highlighted in JCO's 25th anniversary series because it gives us the opportunity to assess how the science has evolved since then and to consider what broader lessons can be learned from these studies. At the time of publication, the use of breast-conserving therapy (BCT), consisting of breast-conserving surgery and postoperative breast irradiation (RT), was gradually increasing in the United States. It is remarkable now to consider that during the early years of BCT, pathologic evaluation of margins of the breast-resection specimens was not routine practice. The prevailing theory was that the surgeon had to remove the gross disease and that moderate-dose RT would eradicate residual "subclinical disease" while preserving the cosmetic result. Implicit in this theory was the assumption that the extent of "subclinical disease" was limited and similar in all patients. Our initial published reports on the use of BCT showed promising results, but with short follow-up. With longer follow-up, we began to observe a higher rate of local recurrence (local recurrence here refers to a recurrence of breast cancer in the parenchyma or, rarely, the skin of the ipsilateral-treated breast). In an attempt to understand the reasons for local recurrence, a series of collaborative clinicopathologic studies were undertaken. Detailed (and laborious) assessment of the pathologic characteristics of the resected breast specimens was undertaken, and the pathologic features were correlated with clinical outcome, focusing on local recurrence. Our 1983 article was one of the earliest such studies. The results of that study indicated that local recurrence was mainly seen in patients whose tumors showed what we called an extensive intraductal component (EIC), defined then as the constellation of moderate or marked intraductal carcinoma (ductal carcinoma in situ [DCIS]) in the tumor, intraductal carcinoma in the adjacent tissue, and high nuclear grade. With additional patients and longer follow-up (and more local recurrences), the definition of EIC evolved to encompass either invasive cancers that showed both prominent DCIS within the confines of the invasive tumor (typically occupying at least 25% of the tumor) and DCIS in the grossly normal adjacent breast tissue, or lesions composed primarily of DCIS with one or more foci of invasive carcinoma. The 5-year results for our patients treated between 1968 and 1982 are summarized in Table 1. EIC-positive cancers were noted to be more common in premenopausal than postmenopausal patients. "Other" recurrences in Table 1 were predominantly at distant sites, whereas local recurrences were mainly at or near the primary site in the breast. Table 1 indicates that local recurrence was uncommon in patients with EIC-negative cancers and common in patients with EIC-positive cancers. It was interesting to note that EIC-positive cancers were not a biologically more aggressive form of breast cancer; if anything, patients with EIC-positive breast cancer had a lower rate of "other" recurrences than patients with EIC-negative cancers. Patients with EIC-positive cancers also did not have a higher rate of contralateral-breast cancer than patients with EIC-negative cancers (data not shown here). This suggested to us that the problem with EIC-positive cancers was in the segment of the primary disease.
We eventually began to ink and microscopically evaluate the margins of resected breast specimens and encouraged our surgical colleagues to perform re-excisions if the margins were positive. We subsequently found and reported that EIC-positive cancers commonly had considerable residual DCIS on re-excision, whereas EIC-negative cancers uncommonly had considerable residual disease.2 We also collaborated with Roland Holland, MD, who had performed whole-organ studies of mastectomy specimens in patients with breast cancer, documenting the presence, type, and extent of additional microscopic disease beyond the tumor mass. Together, we found that EIC-positive cancers frequently had extensive additional microscopic disease (mainly DCIS), whereas EIC-negative cancers uncommonly had extensive additional disease.3 Figure 1 is taken from our 1990 JCO article, which reported the results of this collaboration. It shows the percentage of cases with prominent additional intraductal cancer as a function of the distance from the edge of the tumor, separately for EIC-positive and EIC-negative cancers. EIC-positive cases consistently had a significantly greater amount of "residual" disease at each distance beyond the edge of the tumor.
About this time, mammography was improving and breast-imaging experts were noting that some cancers had extensive associated microcalcifications, typically arranged in a segmental fashion. Working together, we found that this mammographic pattern was common in EIC-positive cancers.4 Importantly, we found that when careful breast imaging (to make certain that all suspicious mammographic calcifications had been resected) was combined with careful pathologic assessment (to ensure that the margins of resection were negative), the rate of local recurrence after BCT in patients with EIC-positive cancers was similar to that in patients with EIC-negative cancers.5 A separate serendipitous development was that adjuvant systemic therapy (both hormonal therapy and chemotherapy), developed to reduce distant metastases, was found to interact favorably with RT in reducing local recurrence with BCT.6-8 Whereas long-term follow-up of our early cohort of patients showed a 10-year local recurrence rate of 20%, recent series of patients treated with BCT show 10-year local recurrence rates of approximately 5%. Of critical importance, of course, was that randomized clinical trials comparing breast-conserving therapy and mastectomy all showed equivalent long-term survival. What lessons can be learned from this experience? First, short-term follow-up of trials of innovative approaches to BCT should be viewed cautiously. (This is true not only regarding efficacy, but also regarding safety.) This lesson is applicable to the promising, but still early, results seen with accelerated partial-breast irradiation. Second, this work illustrates the value of collaborative clinico-pathologic studies using well-annotated clinical data sets. Although this study focused on the morphologic features of the cancers, current studies focus more heavily on the molecular features of the cancers. Third, although the pitfalls in retrospective studies (bias, misclassification, confounding, use of multiple comparisons, and so on) are well known, such studies can still be useful, particularly to evaluate "problems" (such as local recurrence or complications) using a clinical intervention. By the identification of such problems, it is possible to improve outcomes, as occurred here in the use of BCT. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Jay R. Harris, Stuart J. Schnitt Provision of study materials or patients: Jay R. Harris, Stuart J. Schnitt Collection and assembly of data: Jay R. Harris, Stuart J. Schnitt Data analysis and interpretation: Jay R. Harris, Stuart J. Schnitt Manuscript writing: Jay R. Harris, Stuart J. Schnitt Final approval of manuscript: Jay R. Harris, Stuart J. Schnitt
REFERENCES 1. Harris JR, Connolly JL, Schnitt SJ, et al: Clinical-pathologic study of early breast cancer treated by primary radiation therapy. J Clin Oncol 1:184-189, 1983[Abstract] 2. Schnitt SJ, Connolly J, Khettry U, et al: Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment with primary radiation therapy. Cancer 59:675-681, 1987[CrossRef][Medline] 3. Holland R, Connolly JL, Gelman R, et al: The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 8:113-118, 1990 4. Sadowsky NL, Semine A, Harris JR: Breast imaging: A critical aspect of breast conserving treatment. Cancer 65:2113-2118, 1990[CrossRef][Medline] 5. Schnitt SJ, Abner A, Gelman R, et al: The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 74:1746-1751, 1994[CrossRef][Medline] 6. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002 7. Fyles AW, McCready DR, Manchul LA, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963-970, 2004 8. Fisher B, Dignam J, Mamounas EP, et al: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: Eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14:1982-1992, 1996 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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4 cm, P = 5 x 10–8. Reprinted from Holland R et al.
