In late 1972, a 54-year-old woman underwent an

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1 ORIGINAL ARTICLE Ductal Carcinoma In Situ: Recent History and Areas of Controversy Michael D. Lagios, MD,* and Melvin J. Silverstein, MD, *Breast Cancer Consultation Service, Tiburon, California; Breast Service, Hoag Memorial Hospital Presbyterian, Newport Beach, California; Keck School of Medicine, University of Southern California, Los Angeles, California n Abstract: The authors provide a perspective on the rapidly evolving field of prognostic analyses designed to quantify the risk of local recurrence in conservatively treated ductal carcinoma in situ (DCIS). These include morphologic features variously defined, nomograms, algorithms and multi-gene expression assays-all of which have completed against the perceived conclusions of the randomized trials of irradiation and Tamoxifen for DCIS: all subsets benefit. At present the majority of newly diagnosed DCIS can be adequately treated with surgery alone. A number will require irradiation to achieve acceptable local control, and a minority will require mastectomy regardless of adjuvant treatments. Differences in the definition of prognostic factors and in the methods used to establish them is a major reason for the lack of consensus in treatment recommendation. n Key Words: breast conservation, DCIS, local control, radiation therapy, tamoxifen IN THE BEGINNING In late 1972, a 54-year-old woman underwent an open surgical biopsy for a palpable left breast mass. No breast imaging was performed. Frozen section revealed what the pathologist called at that time intraductal carcinoma. When she awoke, she had undergone a radical mastectomy. Final pathology revealed that the palpable mass was some fibrocystic variant. The intraductal carcinoma was an inadvertent 9 mm focus of what would be called today grade 2 ductal carcinoma in situ with focal necrosis. No other abnormalities were found upon routine sampling of the mastectomy specimen. Thirty-two lymph nodes were negative. Five years later, she was alive and well and thankful there had been no recurrence of breast cancer. She was markedly deformed. She thought about breast cancer every day for the rest of her life when she dressed. The advent of mammography in the mid-1970s had multiple major impacts on the size and stage at which Address correspondence and reprint requests to: Michael D. Lagios, MD, The Breast Cancer Consultation Service, St. Mary Hospital & Medical Center Pathology, 450 Stanyan Street, San Francisco, CA 94117, USA, or mlagios@aol.com DOI: /tbj Wiley Periodicals, Inc., X/15 The Breast Journal, Volume 21 Number 1, new invasive breast cancers were detected. It also introduced the problem of small mammographically detected, clinically silent foci of ductal carcinoma in situ (DCIS), a type of lesion previously unknown. We were soon inundated with a lesion we knew little about nor how to treat. A common initial experience was for the frequency of DCIS to increase three- to five-fold within as many years, eventually growing to represent as much as 20 25% of all new breast cancers (1). There were no established guidelines for appropriate treatment. Virtually all such patients were initially treated by radical or modified radical mastectomy with Level I and II axillary lymph node dissection. One of us (MDL), in 1975, had begun utilizing Robert Egan s serial subgross technique to examine mastectomy specimens to assess the frequency of multifocal and multicentric carcinomas (2). Among patients with mammographically detected DCIS, such thorough examination permitted the extent of a particular patient s DCIS to be mapped out and occult foci of invasion to be detected (3). It soon became apparent that the vast majority of such patients were unifocal without invasion or metastases to axillary nodes and many were under 25 mm in extent (3). After many such modified radical mastectomies, a colleague, Dr. Phillip Westdahl,

2 22 lagios and silverstein MD, and MDL began to question whether every patient with mammographically detected DCIS of this size required a modified radical mastectomy. We began a clinical study of excision alone for DCIS with a laundry list of entry qualifications. At this time (1977), there was no literature on radiation therapy for excised DCIS but that would come 5 years later (4). Moreover, we speculated that mammographically detected DCIS might have a biology or risk comparable to LCIS this clearly reflecting our ignorance at the time. As part of the pathologic examination of needlelocalized segmental resections, an intact x-ray and an x-ray of the resection sectioned into consecutive mm thick slices was prepared on each case and the entire specimen processed sequentially a method also adopted by our brother group in Van Nuys, California (5,6), and subsequently strongly recommended as a routine procedure by the College of American Pathologists in 2009 (7,8). It was this methodology of tissue processing and the histologic examination of the entire specimen which permitted us to document the approximate size and margin width, in a prospective manner (9). This also allowed us to exclude microinvasion given the limitations of sectioning. THE RANDOMIZED TRIALS The first prospective randomized trial comparing segmental resection of a lesion plus radiation therapy with mastectomy was not published until 1981 (10). But this trial was for patients with invasive breast cancer. Patients with DCIS were excluded. Breast conservation was slow to catch on in the United States. Fisher et al. published NSABP B-06 in 1985 (11) and by the late 1980s, breast conservation had become a real choice but only for invasive breast cancer. The treatment of DCIS lagged behind. Patients with a more advanced form of the disease, invasive breast cancer, were allowed to save their breasts, while patients with an earlier form of the disease, DCIS, were offered mastectomy. In 1986, the National Surgical Adjuvant Breast and Bowel Project initiated a formal randomized trial of radiation therapy versus lumpectomy alone for ductal carcinoma in situ (NSABP B-17). The results of this trial were not published until 1993 (12). B-17 and trials similar to it (13 15) (EORTC 10853, UK/ANZ, SWE DCIS) all have clearly shown a 50% reduction in local recurrence rate effected by radiation therapy. Unfortunately, the trials were not powered to analyze size, margin width, and grade, and these data were not retrievable retrospectively. Therefore, it was not possible to provide subset analyses using these factors individually or together to project risk based on local recurrences. The 15-year follow-up of NSABP-B17 cites an ipsilateral local invasive recurrence rate of 19.6%, and a total (invasive and in situ) local recurrence rate of 35% without irradiation. The total local recurrence rate with irradiation is 19.8% (16). However, the trial data cannot address what the local recurrence rate would be for an 8 mm low-grade, widely excised focus of DCIS in a 65-year old. The legacy of the randomized trials is mixed: Clearly radiation therapy provided a major benefit for local control, but with potential morbidities related to radiation for a disease which, in large part, is nonlethal and employing a therapy which can only be used once. In addition, many patients who undergo radiation therapy could achieve equivalent local control with re-excision alone (5,17 19). A related legacy of the randomized trials is that they are perceived to represent Level I evidence and, therefore, a mantra of radiation and tamoxifen for all shades of gray has evolved from their results. But this ignores the evidence of nonrandomized prospective studies (6,9,18 21) which can address questions of the local recurrence risk using prospectively established prognostic features. At this point in time, in 2015, we should be utilizing identifiable prognostic factors to counsel patients with DCIS on appropriate therapeutic choices. To paraphrase a colleague, There should be a moratorium on the use of simplistic data from these early trials which would result in many patients being significantly overtreated. A CHANCE MEETING In the early 1980s, at a national meeting dealing with breast cancer, the two authors of this paper met. In 1979, MJS had started the first freestanding breast center in the United States in Van Nuys, California. MJS allegedly knew a lot about breast cancer but he knew little to nothing about DCIS. In fact, he had never treated a case with anything less than a mastectomy. After that meeting, the two became friends and colleagues, publishing dozens of papers together. MJS became an aggressive breast preserver for patients

3 DCIS, History, and Controversies 23 with DCIS. At first, using excision plus radiation therapy whenever possible and by the late 1980s, excision alone. ALGORITHMS AND NOMOGRAMS The University of Southern California/Van Nuys Prognostic Index (USC/VNPI) is an algorithm, which can reproducibly stratify risk of local recurrence and establish subsets of patients who can be spared radiation and tamoxifen (18,19). The USC/VNPI is based on five prognostic factors, including age, tumor extent, margin width, and the combination of nuclear grade and necrosis (Van Nuys Pathologic Classification) (22). The USC/VNPI should be contrasted with MSKCC nomogram (23) and that of Kerlikowske et al. (24). The MSKCC nomogram represents retrospective data on DCIS but excludes extent (size) as a variable since this was not collected prospectively, dichotomizes grade and margin analysis: ink on tumor or <2 mm versus >2 mm (23). In addition, the various items in a nomogram are heavily weighed by specific therapeutic interventions. In fact, most of the scoring derives from whether patient had radiation and/or tamoxifen. In contrast, the VNPI evaluates prognostic factors to assess whether radiation and tamoxifen are of any benefit. Kerlikowske et al retrieved 1162 DCIS cases from multiple institutions (24). These slides were reviewed to confirm an initial DCIS diagnosis. All had subsequent local recurrences. There was no standard pathology protocol utilized between the separate institutions and the majority of cases had only been sampled as opposed to completely and sequentially processed. The most significant factor predicting an invasive recurrence was palpability as opposed to mammographic detection. Certain immunohistochemical markers were found to be significant but only 143 of 1162 cases had sufficient tissue for immunohistochemistry of any type (12.3%). GENE SIGNATURE ASSAY FOR DCIS Oncotype DCIS was validated with archival material from ECOG-E5194, a registration trial designed to identify DCIS subsets for whom breast conservation without irradiation could be achieved (25). The trial in part was modeled on earlier studies, which employed rigid entry criteria (9,20). ECOG-E5194 employed a maximum 25 mm size for low/intermediate grade DCIS, and 10 mm for high-grade DCIS (26). Resections were completely processed, and a 3 mm minimal margin was required; however, 65% or more of the patients had 10 mm margins. The results of the study showed that grade clearly made a difference in local recurrence rate, but other variables (size and margin status) were rigidly controlled. The Oncotype DCIS gene signature assay was validated on the basis of E5194, and the results should be valid for DCIS patients who otherwise meet the strict eligibility criteria of that study (25,26). In other words, to use this test, a minimum three mm margin is required. If a DCIS lesion is transected and Oncotype DCIS testing yields a low score, it is meaningless until the lesion has been re-excised to clear margin of at least 3 mm. The Oncotype DCIS assay is akin to a genetic grade and does not take into account well-established prognostic factors, such as size, patient age, and precise margin width margins from 3 to 10 mm are equivalent. In practice, many order the assay and rely on the recurrence score, oblivious to the fact that size and/or margin status may have excluded the case from E5194 criteria. Two recent examples from our practice illustrate the problems: 1 A 64-year old with a 5 mm focus of intermediate grade (nuclear grade II with necrosis) DCIS exhibits final margins of mm. Her VNPI is calculated as follows: Grade = 2, size = 1, margins = 1, age = 1, and total score 5. An Oncotype DCIS was performed and reveals a DCIS score of 63 (high risk), and a projected 10-year total local recurrence rate of 25%, 15% of which is projected to be invasive. In contrast, the USC/VNPI score of 5 results in a total average local recurrence rate of 7.2% at 12 years of followup, half of which (3.6%) is projected to be invasive carcinoma without breast irradiation and/or tamoxifen. 2 A 41-year old was found to have an intermediate grade DCIS 32 mm in size with focal margin width of 2 mm. Her USC/VNPI can be calculated as: Grade = 2, size = 2, age = 2, and margins = 2, for a total score of 8. This score results in a projected total local recurrence rate without radiation therapy of 60%. Re-excision could potentially reduce the patient s score to 7, which in conjunction with a 3 mm minimum margin results in a 14% total local recurrence rate at 12 years. Oncotype DX analysis,

4 24 lagios and silverstein however, resulted in a recurrence score of 10 and a total local recurrence rate of 11%, but the results of the test do not apply because the patient would be ineligible by criteria of E5194 based on large tumor size (32 mm) and inadequate margin width (2 mm). These cases and others like them suggest that the value of Oncotype DCIS is uncertain, but in any case can only be applied if the patient s other prognostic features are taken into account and meet the criteria of the ECOG-E5194 registration trial on which the assay was validated. INK ON TUMOR No ink on tumor has recently become the standard for a clear margin in patients with invasive cancer who are going to be treated with radiation therapy (27). A consensus paper was recently published simultaneously by three societies representing surgical, medical and radiation oncologists, although no vote was taken by any society members regarding the definition of a clear margin (27). Although the differences between margins for invasive carcinomas can be minimized by irradiation especially when comparing all margins 2 mm versus all those >2 mm, the same does not apply to DCIS in which an effort is made to avoid radiation therapy. In fact, there is a progressive increase in risk of local recurrence from DCIS as margins narrow and this is particularly evident in margins which are not transected but measure <1 mm. Margins must be measured by ocular micrometry in DCIS for patients to avoid over-treatment. TAMOXIFEN AS AN ADJUVANT AGENT IN DCIS Two-randomized trials testing the efficacy of tamoxifen as an adjuvant agent for local control in patients with DCIS treated by breast conservation have recently been updated (16,28), and have elicited some pointed commentary (29,30). NSABP-B24 randomized patients to tamoxifen or placebo after all had undergone lumpectomy and irradiation. Immunohistochemical identification of estrogen receptor was not available at the time the trial was initiated, so that the ER status of the patients treated was originally unknown. Allred et al. (31) was able to retrospectively document ER status in 732 of 1804, B24 cases (31). The differences between ER positive patients treated by tamoxifen versus placebo were small and no paired comparison (e.g., ipsilateral invasive or in situ, contralateral invasive, etc.) achieved a p 0.5. The numerical difference in the ipsilateral invasive carcinoma group on the basis of tamoxifen was six patients, and for ipsilateral in situ recurrences two patients. Wapnir et al. (16) has shown that in the entire trial (including patients with unknown ER status) that there was a small benefit for local control for ipsilateral invasive events, representing a difference of 22 patients (81 invasive recurrence ipsilaterally without tamoxifen, 59 with tamoxifen). Tellingly, however, the update of the UK/ANZ trial in which there was a four-way randomization (to lumpectomy alone, lumpectomy plus radiation, lumpectomy plus tamoxifen, and lumpectomy plus both tamoxifen and radiation) demonstrated no benefit whatever for tamoxifen among irradiated patients. Warrick and Allred in an editorial note that tamoxifen is probably overused, and advocate more selective use (30). Given the morbidities associated with tamoxifen in postmenopausal patients, that SERM should be avoided in such patients, particularly those with low-grade disease regardless of ER status. It is worth remembering that B24 employed the same pathology protocol as B17 (12,32,33). Resections were only sampled and margins were not properly identified, and likely some microinvasive disease was left unrecognized; i.e., undocumented invasive cancer may have existed in some of the cases and been treated inadvertently by tamoxifen administration. CONCLUSIONS We have come a long way in the last 35 years in our understanding of the biology and risks associated with specific subsets of DCIS. We have established reproducible methods of grading and sizing and assessment of margins. The VNPI is an algorithm based on prospectively accumulated data and can consistently and significantly delineate subsets at different levels of risk. In 2015, we should not be recommending radiation and tamoxifen for all patients with DCIS. Radiation therapy provides no survival advantage for mammographically detected small foci of DCIS. It should not be employed when surgical re-excision alone can achieve an equal degree of local control. Local recurrences in DCIS can be managed by adequate re-excision alone when the recurrence is in situ and with surgical re-excision and radiation for invasive events. The latter option is precluded by prior

5 DCIS, History, and Controversies 25 prophylactic use of irradiation. The legacy of the randomized trials initiated some 30 years ago is no longer pertinent for the management of the larger number of currently detected small foci of DCIS. These trials are noninformative for DCIS as is currently analyzed with specific grade, size, and margin status. Ductal carcinoma in situ is a heterogeneous group of lesions with varying malignant potential. Some lesions will progress to invasive cancer, some will not and at present we have no reliable means of predicting the type of local recurrence invasive or in situ for a particular patient. There is much talk in the recent literature about the overdiagnosis and overtreatment of breast cancer. We agree with much of this. Nevertheless, when a lesion is discovered on breast imaging and biopsy reveals DCIS, we are generally required to do something about it. 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