Is DCIS breast cancer, and how do I treat it?

1 23

���������� ���������������������������� �������������������������������������������� !"���������

��������� ���� ������ �������������� �����

��!���� ���!����� ���!��������� ��!��!���������������!��!���!� �����

1 23

Your article is protected by copyright and allrights are held exclusively by Springer Science+Business Media New York. This e-offprint isfor personal use only and shall not be self-archived in electronic repositories. If youwish to self-archive your work, please use theaccepted author’s version for posting to yourown website or your institution’s repository.You may further deposit the accepted author’sversion on a funder’s repository at a funder’srequest, provided it is not made publiclyavailable until 12 months after publication.

Current Treatment Options in OncologyDOI 10.1007/s11864-012-0217-1

Breast Cancer (CI Falkson, Section Editor)

Is DCIS Breast Cancer, and HowDo I Treat it?N. Bijker, MD, PhD1,*

M. Donker, MD2

J. Wesseling, MD, PhD3

G. J. den Heeten, MD, PhD4

E. J. Th. Rutgers, MD, PhD2

Address1,*Department of Radiation Oncology,Academic Medical Center,P.O. Box 22700, 1100DE Amsterdam, The NetherlandsEmail: [email protected] of Surgical Oncology,Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital,Plesmanlaan 121, 1066CX Amsterdam, The NetherlandsEmail: [email protected]: [email protected] of Pathology, Netherlands Cancer Institute, Antoni vanLeeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam,The NetherlandsEmail: [email protected] of Radiology/Biomedical Engineering and Physics,Academic Medical Center,P.O. Box 22660, 1100 DD Amsterdam, The NetherlandsEmail: [email protected]

* Springer Science+Business Media New York 2012

KeywordsDuctal carcinoma in situ I DCIS I Breast cancer I Breast conserving therapy I Surgery radiotherapy I Mammogram IMRI

Opinion statement

Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer with a hetero-geneous clinical behaviour. Since the introduction of mammographic screening pro-grammes, the incidence of DCIS has shown a dramatic increase. Treatment shouldfocus on the prevention of progression to invasive disease. If progression occurs, poor-ly differentiated DCIS frequently gives rise to grade III invasive breast cancer, whereaswell differentiated DCIS more often recurs as grade I invasive disease. However, atpresent, validated diagnostic test are lacking to predict progression accurately. Themajority of women with DCIS are suitable for breast conserving therapy. Obtaining clearsurgical margins is the most important goal of a local excision. Radiotherapy is effec-tive in reducing the risk of local recurrence with about 50 % in all subgroups ofpatients with DCIS. (Breast cancer specific) survival of women with DCIS is excellent,and radiotherapy does not further improve this. Future research should be directed in

Author's personal copy

enabling to select women who have a high risk of—invasive—recurrence, so in whichradiotherapy should be standard part of the breast conserving approach, and thosewomen with a more indolent lesion, in which after surgery a watchful waiting approachcan be followed.

Is DCIS breast cancer?IntroductionBreast cancer is the leading type of cancer for womenin western countries, affecting approximately one outof nine women during her lifetime. Most, if not all, in-vasive breast cancers have a preinvasive stage definedas carcinoma in situ. Ductal carcinoma in situ (DCIS)is a proliferation of malignant epithelial cells thatare confined to the ductal and/or lobules without in-vasive growth into the surrounding stroma. Conse-quently, DCIS does not harbor metastasisingcapacity, and therefore, adequate treatment of DCISleads to cure.

Lesions currently diagnosed as DCIS were firstrecognised in 1893. Bloodgood described “come-do-adenocarcinoma” as an entity of “…a benign tu-mor of the breast…, with on its surface manygreyish-white, granular cylinders, which I called atthat time comedos” [1]. The lymph nodes werenot involved and with surgery the patient wascured from her disease. The concept of noninvasivebreast carcinoma was introduced in 1911 by Mac-Carty. He demonstrated that abnormal cells in theducts were cytologically identical to the cells of in-vasive carcinoma, and therefore, he wondered if itwas “necessary to wait for the penetration of thebasement membrane before making a diagnosis ofcarcinoma [2]. The term carcinoma in situ as firstintroduced in 1932 by Broders [3].

Although DCIS is the precursor of invasivebreast cancer, probably not all DCIS lesions willprogress into invasive carcinoma. Little is knownabout the natural history of DCIS, if left untreated.Autopsy series show DCIS in 6–18 % of breasts ofwomen who died of causes unrelated to breast can-cer [4–6]. This suggests that a considerable numberof DCIS lesions will never become invasive tumors.The natural course of the disease has been evaluat-ed in a few studies in cases picked up by review ofthe histology of breast biopsies for lesions thatwere originally interpreted as benign. These studiesfound small numbers of women with misdiag-

nosed, therefore untreated, CIS and report ratesof subsequent invasive breast cancer from 14–53 %, after long follow-up periods ranging 18–30 years [7, 8]. Morphologically different types ofDCIS can be recognized: DCIS with a well-differen-tiated cell type, resembling that of normal breasttissue, is more easily misdiagnosed than DCIS witha poorly differentiated cell type. The majority ofthe cases of misdiagnosed, untreated DCIS werewell-differentiated lesions; the natural course ofpoorly differentiated DCIS might very well be dif-ferent.

As a result of population-based mammographicscreening programs, the incidence of DCIS has in-creased dramatically. A systematic review gave anestimated incidence of DCIS of 5.8 per 100,000in 1975, which had risen to 32.5/100,000 in2004 [9]. Data from the Surveillance Epidemiologyand End Results (SEER) program showed that ap-proximately 15-20 % of all detected breast cancersin screening programs are DCIS [10]. A systematicreview from data from the United States showedthat although the incidence of more aggressive“comedo”-type DCIS remains stable over recentyears, the incidence of the considered more indo-lent non-comedo type has increased [9]. Data fromthe Dutch National Cancer Registry showed that in1989, 5 % of all breast malignancies in the Nether-lands was DCIS; in 2000, this was 9 % and in re-cent years the figure has increased to 13 % [11].In the Netherlands, the percentage of DCIS wasboosted further by the introduction of digitalscreening with an extra 15 % to 20 % of allscreen-detected carcinomas in 2010. A recent Dutchstudy found that the transition to digital mammog-raphy improved the detection of breast cancer,whereas it did not result in a disproportionate in-crease in low-grade DCIS lesions [12].

The high number of DCIS cases detected as a re-sult of screening mammography has raised ques-

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

tions about the clinical significance of theselesions. It has been proved that screening reducesthe mortality from breast cancer [13, 14•]. This re-duction is achieved by the detection and adequatetreatment of 1) early-stage invasive carcinomas,and 2) DCIS, not yet invasive. It is, however, notclear which cases of DCIS contribute to this mortal-ity reduction. A proportion of DCIS may neverhave become invasive during the lifetime of the pa-tient, if these had not been detected. At present,identification of those lesions that are likely to be-come invasive is not possible. Therefore, treatmentof every detected case of DCIS is indicated andshould aim to avoid the progression to invasivebreast cancer.

Types of DCISDuctal carcinoma in situ forms a group of hetero-geneous lesions with different clinical behavior.The traditional classification of DCIS was basedon the predominant architectural pattern in whichcomedo, solid, cribriform, micropapillary growthpatterns were recognized [9]. This classificationlacked reproducibility, mainly because several dif-ferent patterns are frequently present within thesame tumor [15]. In the past decades, severalnew classifications for DCIS have been introduced,mainly based on nuclear grade. Also, attemptshave made to introduce the concept ductal intrae-pithelial neoplasia (DIN), similar to cervical can-cer, to replace the term DCIS [16]. However, thishas not been generally accepted. Holland et al.have based their classification on a combinationof cytonuclear differentiation and cell polarizationand divides DCIS into three types: well, intermedi-

ate, and poorly differentiated [17]. This systemapproaches the generally applied Bloom andRichardson grading system adapted by Elston andEllis for invasive breast cancer [18]. In tumorswhere both a DCIS and an invasive componentare present, the grade of the invasive tumor corre-lates well with the histologic type of the DCIS,i.e., well-differentiated DCIS is associated withgrade I invasive ductal carcinoma (IDC), and poor-ly differentiated DCIS with grade III IDC [19]. Thesame holds true for progression from DCIS to IDC,implying that dedifferentiation is a very rare eventin breast cancer [20, 21].

Immunohistochemistry and molecular featuresAs in invasive breast cancer, well-differentiated DCISoften expresses positive estrogen (ER) and progester-one receptors (PR), whereas in poorly differentiatedDCIS this is only seen in 30–40 % of the cases[21–23]. A remarkably high rate of HER2/neu over-expression is seen in DCIS, especially in poorly dif-ferentiated DCIS, in which up to 70 % of the lesionsshow HER2/neu overexpression [22–24]. Expressionof Ki67 and p53 are seen and also correlate withthe histologic type of the lesion [22, 25].

Microarray gene-profiling of invasive breast cancerhas identified different subtypes, including luminalA, luminal B, HER2-overexpressing, and basal-likegroups. In invasive breast cancer, these different pro-files are strongly predictive for recurrence and survival.Evidence emerges that DCIS can be classified in a sim-ilar manner [26], and recent data suggest a role forgene profiling to predict the risk of invasive recurrence[27].

How do I treat DCIS?

Like every woman with breast cancer, treatment of a patient with (suspected)DCIS requires a multidisciplinary approach. The involved breast teamshould at least have a radiologist, surgeon, specialized nurse, pathologist,radiation oncologist, and medical oncologist. Preferably, a plastic surgeonshould be part of the team.

ImagingDCIS typically presents as microcalcifications on the mammogram. Thesecalcifications develop either in necrotic areas of the lesion or inspissated

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy

secretion of the cells. Approximately 70-80 % of the lesions present as anonpalpable lesion with microcalcifications of the mammogram being theonly abnormality [28]. The remaining cases give rise to nipple discharge or apalpable mass.

Depending on the Breast Imaging-Reporting and Data System (BIRADS)classification of mammographic microcalcifications, the risk of malignancyvaries with 18 % of BIRADS 3 being malignant to 91 % of women withBIRADS 5 calcifications [29]. The type and distribution pattern of the calci-fications correlates with the type of DCIS [17], a segmental distributionpattern of linear, casting-type calcifications being strongly predictive forpoorly differentiated DCIS, whereas fine granular clustered microcalcifica-tions more often are seen in well-differentiated lesions.

The quality of the mammogram is important for evaluation of the typeand extension of the microcalcifications and additional spot compressionand magnification views could be helpful in the precise assessment of theextent of the lesion. However, many (parts of) DCIS do not contain detect-able calcifications and therefore will be mammographically occult. It isknown that the diameter of the area of calcifications underestimates thehistological extent of the DCIS [30].

Role of magnetic resonance imagingIn magnetic resonance imaging (MRI), enhancement of breast tumors dependson the presence of tumor-induced angiogenesis. An increased density of mi-crovasculature will increase blood flow, thereby causing contrast enhancement.In addition, tumor-induced microvessels often demonstrate structural abnor-malities, which give rise to leakage of the contrast agent. This causes the char-acteristic malignant contrast enhancement during time (kinetics), the so-calledwashout phenomenon. In DCIS, neovascularization occurs; however, the ves-sels formed aremoremature than vessels in invasive carcinomas [31]. Therefore,the typical washout patterns, indicative ofmalignancy, often are absent. Instead,subtler asymmetric enhancement patterns can be seen. In high-grade DCIS,microvessel density is higher and consequently enhancement is stronger.Therefore, these lesions are more easily identified on MRI than are low-gradeDCIS. A recent, prospective study investigating the role ofMRI in detectingDCISfound that MRI detected 92 % of the lesions compared with only 56 % bymammography [32•]. Mammography was falsely negative in 44 %, whereasMRIwas falsely negative in 8%.MRI especially detectedmorehigh-grade lesionsthan mammography. Furthermore, several studies have found that size mea-surement of DCIS onMRI was more reliably predictive of the histopathologicalsize compared with mammography [33•]. However, overestimation due tocyclus-related and benign proliferative lesions does frequently occur, and theidentification of more extensive disease on MRI could give rise to unnecessaryinterventions. To date, there is no evidence that the use of MRI improves out-come in patients with DCIS.

SurgeryWide local excision

A local excision of the microcalcifications should aim at a complete re-moval of the lesion. Because the lesion is not palpable, this is not always

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

easy to achieve. Whereas for invasive breast cancer the rate of incompleteexcisions at first attempt in the Netherlands is approximately 9.5 %, forDCIS this is 28.5 % [34]. One study has shown that more experiencedsurgeons achieve a higher rate of complete excision in impalpable breastlesions, and ultimately a higher rate of breast conservation [35]. Thereare several techniques for preoperative tumor localization. Wire locali-zation is currently the standard for surgical excision of nonpalpablebreast lesions. The placement of wires are needed to guide the surgeon,and the use of more than one wire helps to obtain 3D assessment of themicrocalcifications in the breast, which is associated with a higher rate ofcomplete excisions. Another localization technique that is increasinglybeing used is radioguided localization in which a liquid radioactivetracer (Tc-99) or radioactive iodine seed (I-125) is inserted into the tu-mor. This localization method allows a more flexible surgical approachto the lesion, is more patient-friendly, and preferred by surgeons [36,37•], In a recent, systematic review on radioguided surgery, a lower rateof positive margins was reported, leading to less re-excisions and im-proved cosmetic outcome [38].

Role of the sentinel nodeThe risk of an isolated lymph node recurrence is very small in DCIS, i.e.,1–3 % in RCTs [39–41, 42••]. From the SEER data, it is known that inthe United States 18 % of women with DCIS have had a sentinel lymphnode biopsy (SN) [43]. The risk of a positive SN with pure DCIS is small(7-9 %) and most of the metastases found are micrometastases or iso-lated tumor cells, detected by immunohistochemistry [44, 45]. Thechoice to perform an SN procedure therefore should be based to theunderlying risk of invasion. This invasive breast cancer underestimationrate is reported to be 20-38 % and is increased with a present palpablemass, an associated density on the mammogram, poorly differentiatedDCIS in the biopsy, younger age, and a larger extent of the microcalci-fications [46–48]. Performing a sentinel node procedure should beweighed against the risk of morbidity [49–53]. In general, a sentinelnode procedure is usually performed if there is an associated mass or ifan ablative treatment is chosen. A recent study showed the additionalvalue of the MRI in women with DCIS at core biopsy [54]. It was foundthat, if there was suspicious enhancement on MRI, the absence of a latetype I enhancement was predictive for the absence of invasion.

Pathologic evaluationEvaluation of the specimen by the pathologist requires a close collabo-ration between the surgeon, radiologist, and pathologist. The surgeonshould aim to perform wide local excision in one complete specimenand mark the specimen for the pathologist. The specimen needs to be x-rayed to confirm the gross presence of the microcalcifications in twodimensions. A sliced radiograph of the serially sectioned breast specimenis the preferred method of tissue processing to determine extent andmargin status optimally [55•].

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy

MastectomyBecause DCIS does not bare a risk for distant metastasis, completeremoval of the whole breast tissue will lead to cure. Breast cancer-specific survival rates after mastectomy for DCIS are reported to be 98-99 % [56, 57].

Missed invasive foci due to inadequate sampling at the time of sur-gery are considered the origin of the incidentally observed distant me-tastases after ablative treatment. A local—chest wall—recurrence aftermastectomy is extremely rare, but reported [58]. In these cases, mostlikely, breast tissue was left subcutaneously containing part of an (ex-tensively growing) DCIS.

Mastectomy is, however, overtreatment for many screen-detectedDCIS lesions of—often—limited extent. Although no randomized, clini-cal trial has ever been performed to compare mastectomy with breast-conserving therapy, nowadays breast-conserving therapy for DCIS is agenerally accepted and applied treatment with approximately 60-70 % ofwomen being suitable for breast-conserving therapy.

Mastectomy is the preferred treatment when a complete surgical removalof the area of DCIS is not possible. An immediate reconstruction of thebreast can then be offered to the patient, because radiotherapy to the chestwall will not be required.

Breast-conserving therapy (BCT)Results of breast-conserving therapy (BCT) for women with invasive breastcancer cannot be directly extrapolated to patients with DCIS. In thepatient with invasive breast cancer, the prognosis, both after BCT and mas-tectomy, depends to a large extent on the risk of metastatic disease, which ismainly related to the stage and the tumour characteristics. In DCIS, theprognosis is entirely based on the risk of—invasive—local recurrence. Severalstudies have shown a poor survival after an invasive local recurrence [42••,59–62].

Breast-conserving surgery should be aimed to remove the complete areaof DCIS. Obtaining clear margins is the most important factor in reducingthe risk of local recurrence [63•, 64–66, 67••]. Ample research has been doneto investigate the optimal with of the tumor-free margin, most in a non-randomized, observational, and often retrospective manner. Reported re-quired margins range from 1, 2, to 5 mm, and one study suggested that witha tumor-free margin of at least 10 mm the risk of local recurrence is so lowthat adjuvant treatment may not be necessary [64]. To date, randomizedtrials have not confirmed this. A meta-analysis suggested that 2 mm is asufficient margin in breast-conserving surgery, although this has to be con-firmed in prospective studies [63•].

RadiotherapyFour, randomized, clinical trials have been performed to investigate therole of radiotherapy in BCT for DCIS [40, 42••, 68••, 69]. All trialsrandomized women with DCIS, after a complete local excision of thelesion, between no further treatment and radiotherapy to the whole

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

breast, 50 Gy. None of the trials prescribed a boost to the tumor bed;the United Kingdom DCIS trial had a 4!4 factorial design in whichwomen also could be randomized to tamoxifen [68••]. In all four trials,the surgical margins had to be free; none of them prescribed a minimaltumor-free margin.

The Early Breast Cancer Trialists Collaborative Group (EBCTCG) pub-lished in 2010 a meta-analysis of these trials [67••]. The results show thatradiotherapy consistently resulted in a 50 % reduction in the risk of localrecurrence. In the pooled group of 1,851 patients treated with excision alone,approximately 28.1 % developed a local recurrence with a median follow-upof 10 years. In the group of 1,878 women treated with excision followedby radiotherapy, this rate was 12.9 %, an absolute reduction of 15.2 %. Inboth the group treated with and without radiotherapy, approximately half ofthe recurrences were again DCIS and half of them recurred as an invasivecarcinoma. Further analysis showed that radiotherapy was effective to reducethe risk of local recurrence in all analyzed subgroups of patients,egardless of age, clinical presentation, grade, and type of DCIS.

Risk factors for recurrenceWomen who present with clinical symptoms, such as a palpable mass ornipple discharge, have a higher risk of local recurrence than those havinga screen-detected, nonpalpable lesion [67••]. Such as with invasivebreast cancer, young age is a clear risk factor for local recurrence, withhazard rates of approximately 2 for developing a local recurrence com-pared with older women [66, 67••, 69–71]. Definition of young age andreported higher local recurrence risk varies from younger than age 40 toyounger than age 45 years. This factor is independent from other riskfactors, and from whether or not radiotherapy is applied. Reported ratesof local recurrence are up to 23 % at 10 years for women younger thanage 40 years, treated with surgery and radiotherapy [40].

Although an optimal width of the tumor-free margin has not fullybeen established, many studies have shown that involved margins areassociated with an increased risk of local recurrence. Also, with ra-diotherapy high rates of local recurrence are reported up to 24 % incase of involved margins [67••]. Margins therefore should always befree; 50-Gy radiotherapy does not compensate for involved margins.Several studies have reported a higher recurrence when margins wereG1 mm [40, 63•]. One retrospective study showed in these cases that aboost might be effective in reducing the risk of recurrence [72].

SurvivalDespite the effect of radiotherapy to reduce the risk of local recurrence, itdoes not influence overall survival or breast cancer-specific survival.Reported survival rates after BCT for DCIS are excellent, with BCS survivalrates of 96 % at 10 years [67••]. In these figures, mortality from contralateralbreast cancer events is included.

Radiotherapy is known to have potential harmful side effects, such asincreased risk of cardiotoxicity and induction of second malignancieswith long-term follow-up. In the EBCTCG overview data, there was a

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy

nonsignificantly slightly higher risk of mortality from heart disease(mortality rate ratio 1.11) [67••]. At 10 years follow-up, there was noevidence that radiotherapy had any effect on the incidence of secondarycancers.

Treatment with surgery onlyBecause of the lack of survival benefit of radiotherapy and of reportedside effects, several studies were performed to investigate whether womenwith DCIS can be safely treated with conserving surgery alone. TheEastern Cooperative Oncology Group (ECOG) conducted a non-randomized prospective study with 670 patients with either low/inter-mediate grade DCIS up to 2.5 cm or high grade DCIS of maximum 1 cmwho underwent complete excision with microscopic margins of at least 3 mm[73•]. At a median follow-up of 6.7 years, the low/intermediate group (whichcomprised the majority of patients, namely 565 patients) had a 10.5 % riskof local relapse. Half of these recurrences were DCIS. The high-grade lesions didmuch worse, with 18 % recurrence at 7 years, of which 35 % were invasive.

Another prospective, single-arm study investigated conservative sur-gery only in women with DCIS of grade 1 or 2 with an extent ofmax 2.5 cm with final margins minimal 1 cm [74]. Of 158 patients,the 5-year local recurrence rate was 12 %, of which 69 % were re-currence of DCIS. The study was closed prematurely, because the re-currence rate exceeded the predetermined stopping rules. It isnoteworthy that a total of only 4 of 158 women developed an inva-sive recurrence at 5 years.

Although there is a general feeling that treating every woman withDCIS with postexcision radiotherapy implies overtreatment, so far,we have failed to identify a subgroup of women with DCIS whoserisk of recurring as an invasive breast cancer is so low that we couldabandon such a treatment. Future studies should aim to better un-derstand the progression of a preinvasive lesion to an invasive breastcancer and to identify groups of DCIS who have a higher risk ofprogression. Recently, the Oncotype DX assay was used to predictwhich women, treated with local excision only, are a higher risk forrecurrence. Future clinical trial should incorporate these molecularbiologic studies [27].

Role of systemic treatmentData of two randomized, clinical trials are available that investigated therole of tamoxifen in DCIS. The NSABP B-24 trial investigated the benefitof tamoxifen for 5 years in women who were treated with breast-con-serving surgery, including radiotherapy. At a median follow-up of13.6 years, tamoxifen reduced the risk of local recurrence with 32 %[42••]. Tamoxifen did not influence overall mortality, and a significantexcess of endometrial cancer and thromboembolic events was observedin the tamoxifen group. Tamoxifen was given to all women with DCIS;a posthoc analysis of ER status showed that tamoxifen was only effectivein the 77 % of DCIS cases with ER-positive disease. Tamoxifen alsowas effective to reduce the risk of contralateral breast cancer (32 % risk

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

reduction). The U.K. DCIS had a 4!4 factorial design in which therole of tamoxifen also was investigated. This trial showed that tamoxifenreduced the incidence recurrent ipsilateral DCIS and contralateraltumors but had no effect on ipsilateral invasive disease [68••]. Becauseof these equivocal results and the fact that tamoxifen can causeserious toxicity, the role of this endocrine adjuvant treatment in DCISremains uncertain.

Alternatives in radiotherapy dose and techniqueIn all randomized trials, the dose delivered was 50 Gy without an ad-ditional boost to the tumor bed. In invasive breast cancer, it has beenshown that a boost can further reduce the risk of local recurrence by afactor of 2 [75]. To date, no randomized trial has been published in-vestigating the value of adding a boost dose in DCIS, but a study fromthe Rare Cancer Network suggests the value of a boost in DCIS, espe-cially in younger women [72]. In this study, 373 women aged 45 yearsor younger with DCIS were retrospectively analyzed concerning theinfluence of radiotherapy. Fifteen percent had no radiotherapy, 45 %had whole-breast irradiation without a boost, and 40 % had whole-breast irradiation with a boost. With a median follow-up of72 months, the 10-year local relapse-free survival rates were 47 %,72 %, and 86 %, respectively. The hazard ratio for local recurrence was0.33 with 50 Gy, and 0.15 with 50 Gy plus boost, indicating a dose–effect relationship. An international phase III study is forthcoming in-vestigating the role of the boost in women with DCIS (TROG 07.01,BIG 3–07, EORTC 22085–10083).

In recent years, (accelerated) partial breast irradiation (APBI) hasmade its mark as an alternative approach in breast-conserving therapyfor early breast cancer. The fact that the majority of local recurrencesoccur at the vicinity of the original tumor bed serves as the basis totreat the surgical cavity alone instead of irradiating the whole breast.APBI can be delivered through multiple techniques, The first results ofa randomized trial that investigated targeted intraoperative radiotherapyfor small invasive breast cancers are promising, although follow-up isstill very short [76]. Currently, several clinical trials (NSABP B-39,RAPID) are being conducted to investigate APBI in early-stage breastcancer and include women with DCIS. One should keep in mindthat reported recurrence rates after BCT for DCIS tend to be higherthan for invasive breast cancer. The often discontinuous growth ofDCIS, with frequently observed “gaps” of uninvolved breast tissue, maybe in part responsible for this observation [30]. Therefore, it isadvised to use APBI for DCIS only within clinical trials and awaittheir results before considering this procedure safe in general clinicalpractice.

Although all randomized, clinical trials investigating the role of radio-therapy in DCIS prescribed conventionally fractionated radiotherapy,50 Gy in 25 fractions, nowadays, there is ample evidence that hypo-fractionated radiotherapy yields similar results in early breast cancer,both in terms of tumor control as in cosmetic outcome [77, 78]. The

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy

trials investigating hypofractionated radiotherapy did not include womenwith DCIS; however, from radiobiological perspective, there is no reasonto assume that hypofractionation would be less effective in DCIS. TheTROG 07.01 trial, investigating the role of the boost in DCIS is currentlyongoing, and also allocates women to either conventional or hypofrac-tionated radiotherapy.

Conclusions

DCIS is a heterogeneous disease, and successful treatment of DCISrequires a multidisciplinary approach. Future studies should adapt researchquestions and treatment strategies on the heterogeneity of the disease withdistinguish lesions with an indolent behavior from those with a higherrisk of progression to invasive breast cancer. At present, no well-estab-lished tests are available for DCIS to predict this clinical behavior; there-fore, all cases should be adequately treated.

DisclosureNo potential conflicts of interest relevant to this article were reported.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Bloodgood JC. Comedo carcinoma (or comedo-adeno-ma) of the female breast. Am J Cancer. 1934;22:842–53.

2. MacCarty WC. Carcinoma of the breast. TransactSouth Surg Gynaecol Assoc. 1911;23:262–70.

3. Broders AC. Carcinoma in situ contrasted with benignpenetrating epithelium. JAMA. 1932;99:1670–4.

4. Alpers CE, Wellings SR. The prevalence of carcinomain situ in normal and cancer-associated breasts. HumPathol. 1985;16:796–807.

5. Nielsen M. Autopsy studies of the occurrence ofcancerous, atypical and benign epithelial lesions inthe female breast. APMIS Suppl. 1989;10:1–56.

6. Bhathal PS, Brown RW, Lesueur GC, Russell IS. Fre-quency of benign and malignant breast lesions in207 consecutive autopsies in Australian women. Br JCancer. 1985;51:271–8.

7. Eusebi V, Feudale E, Foschini MP, et al. Long-termfollow-up of in situ carcinoma of the breast. SeminDiagn Pathol. 1994;11:223–35.

8. Sanders ME, Schuyler PA, Dupont WD, Page DL. Thenatural history of low-grade ductal carcinoma in situof the breast in women treated by biopsy only

revealed over 30 years of long-term follow-up. Can-cer. 2005;103:2481–4.

9. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductalcarcinoma in situ of the breast: a systematic review ofincidence, treatment, and outcomes. J Natl CancerInst. 2010;102:170–8.

10. Ernster VL, Ballard-Barbash R, Barlow WE, et al. De-tection of ductal carcinoma in situ in women un-dergoing screening mammography. J Natl CancerInst. 2002;94:1546–54.

11. Dutch Cancer Registry hosted by IKNL ©: Inci-dence breast cancer/DCIS, Available at http://cijfersoverkanker.nl. Accessed October 2012.

12. Bluekens AM, Holland R, Karssemeijer N, BroedersMJ, den Heeten GJ. Comparison of Digital ScreeningMammography and Screen-Film Mammography inthe Early Detection of Clinically Relevant Cancers: AMulticenter Study. Radiology. 2012 Oct 2. [Epubahead of print] PubMed PMID: 23033499.

13. Schopper D, deWolf C. How effective are breast cancerscreening programmes by mammography? Review ofthe current evidence. Eur J Cancer. 2009;45:1916–23.

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

14.• Broeders M, Moss S, Nystromm L, et al. The impactof mammographic screening on breast cancer mor-tality in Europe: a review of observational studies. JMed Screen. 2012;19:33–41.

In this systematic review of observational studies investigat-ing the impact of mammographic screening on breast cancermortality, a European estimate of breast cancer mortalityreduction of 38-48% for screened women was found.15. Quinn CM, Ostrowski JL. Cytological and architec-

tural heterogeneity in ductal carcinoma in situ of thebreast. J Clin Pathol. 1997;50:596–9.

16. Tavassoli FA. Breast pathology: rationale for adoptingthe ductal intraepithelial neoplasia (DIN) classifica-tion. Nat Clin Pract Oncol. 2005;2:116–7.

17. Holland R, Peterse JL, Millis RR, et al. Ductal carci-noma in situ: a proposal for a new classification.Semin Diagn Pathol. 1994;11:167–80.

18. Elston CW, Ellis IO. Pathological prognostic factors inbreast cancer. I. The value of histological grade in breastcancer: experience from a large study with long-termfollow-up. Histopathology. 1991;19:403–10.

19. Lampejo OT, Barnes DM, Smith P, Millis RR. Evalu-ation of infiltrating ductal carcinomas with a DCIScomponent: correlation of the histologic type of thein situ component with grade of the infiltratingcomponent. Semin Diagn Pathol. 1994;11:215–22.

20. Millis RR, BarnesDM, LampejoOT, et al. Tumour gradedoes not change between primary and recurrentmammary carcinoma. Eur J Cancer. 1998;34:548–53.

21. Bijker N, Peterse JL, Duchateau L, et al. Histologicaltype and marker expression of the primary tumourcompared with its local recurrence after breast-con-serving therapy for ductal carcinoma in situ. Br JCancer. 2001;84:539–44.

22. Zafrani B, Leroyer A, Fourquet A, et al. Mammograph-ically-detected ductal in situ carcinoma of the breastanalyzedwith a new classification. A study of 127 cases:correlation with estrogen and progesterone receptors,p53 and c-erbB-2 proteins, and proliferative activity.Semin Diagn Pathol. 1994;11:208–14.

23. Meijnen P, Peterse JL, Antonini N, et al. Immuno-histochemical categorisation of ductal carcinoma insitu of the breast. Br J Cancer. 2008;98:137–42.

24. van de Vijver MJ, Peterse JL, Mooi WJ, et al. Neu-protein overexpression in breast cancer. Associationwith comedo-type ductal carcinoma in situ andlimited prognostic value in stage II breast cancer NEngl J Med. 1988;319:1239–45.

25. Bobrow LG, Happerfield LC, Gregory WM, et al. Theclassification of ductal carcinoma in situ and its as-sociation with biological markers. Semin DiagnPathol. 1994;11:199–207.

26. Clark SE, Warwick J, Carpenter R, et al. Molecularsubtyping of DCIS: heterogeneity of breast cancerreflected in pre-invasive disease. Br J Cancer.2011;104:120–7.

27. Solin LJ. A Quantitative Multigene RT-PCR Assay forPredicting Recurrence Risk after Surgical ExcisionAlone without Irradiation for Ductal Carcinoma InSitu (DCIS): A Prospective Validation Study of theDCIS Score from ECOG E5194 [abstract S4-6]. Pre-sented at the 34th Annual San Antonio Breast CancerSymposium 2011.

28. Bijker N, Rutgers EJ, Peterse JL, et al. Variations indiagnostic and therapeutic procedures in a multi-centre, randomized clinical trial (EORTC 10853) in-vestigating breast-conserving treatment for DCIS. EurJ Surg Oncol. 2001;27:135–40.

29. Muller-Schimpfle M, Wersebe A, Xydeas T, et al.Microcalcifications of the breast: how does radiologicclassification correlate with histology? Acta Radiol.2005;46:774–81.

30. Holland R, Hendriks JH, Vebeek AL, et al. Extent,distribution, and mammographic/histological corre-lations of breast ductal carcinoma in situ. Lancet.1990;335:519–22.

31. Rice A, Quinn CM. Angiogenesis, thrombospondin,and ductal carcinoma in situ of the breast. J ClinPathol. 2002;55:569–74.

32.• Kuhl CK, Schrading S, Bieling HB, et al. MRI for di-agnosis of pure ductal carcinoma in situ: a prospec-tive observational study. Lancet. 2007;370:485–92.

In this large observational study the sensitivity of MRI indetecting DCIS is compared with that of mammography.33.• Schouten van der Velden AP, Schlooz-Vries MS,

Boetes C, Wobbes T. Magnetic resonance imaging ofductal carcinoma in situ: what is its clinical applica-tion? A review. Am J Surg. 2009;198:262–9.

In this review, the value but also the limitations of the role ofMRI for DCIS are highlighted.34. van der Heiden-van der Loo, de Munck L, Visser O, et

al. Variation between hospitals in surgical marginsafter first breast-conserving surgery in the Nether-lands. Breast Cancer Res Treat. 2012;131:691–8.

35. Dixon JM, Ravisekar O, Cunningham M, et al. Factorsaffecting outcome of patients with impalpable breastcancer detected by breast screening. Br J Surg.1996;83:997–1001.

36. Rampaul RS, Bagnall M, Burrell H, et al. Randomizedclinical trial comparing radioisotope occult lesionlocalization and wire-guided excision for biopsy ofoccult breast lesions. Br J Surg. 2004;91:1575–7.

37.• Lovrics PJ, Goldsmith CH, Hodgson N, et al. Amulticenter, randomized, controlled trial compar-ing radioguided seed localization to standard wirelocalization for nonpalpable, invasive and in situbreast carcinomas. Ann Surg Oncol.2011;18:3407–14.

A randomized, controlled trial comparing ROLL with wire lo-calization for nonpalpable breast cancers shows that the ROLLprocedure is shorter, with less rankedpain for thepatientswhilethe rate of complete excisions is similar in the two groups.

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy

38. Lovrics PJ, Cornacchi SD, Vora R et al. Systematicreview of radioguided surgery for non-palpablebreast cancer. Eur J Surg Oncol 2011.

39. Emdin SO, Granstrand B, Ringberg A, et al. SweDCIS:radiotherapy after sector resection for ductal carci-noma in situ of the breast. Results of a randomisedtrial in a population offered mammography screen-ing. Acta Oncol. 2006;45:536–43.

40. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserv-ing treatment with or without radiotherapy in ductalcarcinoma-in-situ: ten-year results of European Or-ganisation for Research and Treatment of Cancerrandomized phase III trial 10853–a study by theEORTC Breast Cancer Cooperative Group andEORTC Radiotherapy Group. J Clin Oncol.2006;24:3381–7.

41. Solin LJ, Fourquet A, Vicini FA, et al. Salvage treat-ment for local or local-regional recurrence after ini-tial breast conservation treatment with radiation forductal carcinoma in situ. Eur J Cancer.2005;41:1715–23.

42.•• Wapnir IL, Dignam JJ, Fisher B, et al. Long-termoutcomes of invasive ipsilateral breast tumor recur-rences after lumpectomy in NSABP B-17 and B-24randomized clinical trials for DCIS. J Natl CancerInst. 2011;103:478–88.

The NSABP B-17 is one of the randomized, clinical trials toinvestigate the role of radiotherapy in breast-conservingtherapy for DCIS that published its results here with long-term follow-up of 207 months. It is a combined publicationwith the results of the NSABP B-24 trial, which analyzed therole of tamoxifen in BCT for DCIS.43. Zujewski JA, Harlan LC, Morrell DM, Stevens JL.

Ductal carcinoma in situ: trends in treatment overtime in the US. Breast Cancer Res Treat.2011;127:251–7.

44. Leidenius M, Salmenkivi K, von Smitten K, HeikkilaP. Tumour-positive sentinel node findings in patientswith ductal carcinoma in situ. J Surg Oncol.2006;94:380–4.

45. Moore KH, Sweeney KJ, Wilson ME, et al. Outcomesfor women with ductal carcinoma-in-situ and apositive sentinel node: a multi-institutional audit.Ann Surg Oncol. 2007;14:2911–7.

46. Meijnen P, Oldenburg HS, Loo CE, et al. Risk of in-vasion and axillary lymph node metastasis in ductalcarcinoma in situ diagnosed by core-needle biopsy.Br J Surg. 2007;94:952–6.

47. Yen TW, Hunt KK, Ross MI, et al. Predictors of in-vasive breast cancer in patients with an initial diag-nosis of ductal carcinoma in situ: a guide to selectiveuse of sentinel lymph node biopsy in managementof ductal carcinoma in situ. J Am Coll Surg.2005;200:516–26.

48. Goyal A, Douglas-Jones A, Monypenny I, et al. Isthere a role of sentinel lymph node biopsy in ductalcarcinoma in situ? Analysis of 587 cases. BreastCancer Res Treat. 2006;98:311–4.

49. Mansel RE, Fallowfield L, Kissin M, et al. Random-ized multicenter trial of sentinel node biopsy versusstandard axillary treatment in operable breast cancer:the ALMANAC Trial. J Natl Cancer Inst.2006;98:599–609.

50. Giuliano AE, Hunt KK, Ballman KV, et al. Axillarydissection vs no axillary dissection in women withinvasive breast cancer and sentinel node metasta-sis: a randomized clinical trial. JAMA.2011;305:569–75.

51. Land SR, Kopec JA, Julian TB, et al. Patient-reportedoutcomes in sentinel node-negative adjuvant breastcancer patients receiving sentinel-node biopsy or ax-illary dissection: National Surgical Adjuvant Breastand Bowel Project phase III protocol B-32. J ClinOncol. 2010;28:3929–36.

52. Ashikaga T, Krag DN, Land SR, et al. Morbidityresults from the NSABP B-32 trial comparing sentinellymph node dissection versus axillary dissection. JSurg Oncol. 2010;102:111–8.

53. Wang Z, Wu LC, Chen JQ. Sentinel lymph node bi-opsy compared with axillary lymph node dissectionin early breast cancer: a meta-analysis. Breast CancerRes Treat. 2011;129:675–89.

54. Deurloo EE, Sriram JD, Teertstra HJ, et al. MRI of thebreast in patients with DCIS to exclude the presenceof invasive disease. Eur Radiol. 2012;22:1504–11.

55.• Grin A, Horne G, Ennis M, O'Malley FP. Measuringextent of ductal carcinoma in situ in breast excisionspecimens: a comparison of 4 methods. Arch PatholLab Med. 2009;133:31–7.

This study shows that the serial sequential sampling methodis the preferred method in accurately measuring extent ofDCIS cases.56. Chadha M, Portenoy J, Boolbol SK, et al. Is there a

role for postmastectomy radiation therapy in ductalcarcinoma in situ? Int J Surg Oncol. 2012;2012:423–520.

57. Silverstein MJ, Barth A, Poller DN, et al. Ten-yearresults comparing mastectomy to excision and radi-ation therapy for ductal carcinoma in situ of thebreast. Eur J Cancer. 1995;31A:1425–7.

58. Kim JH, Tavassoli F, Haffty BG. Chest wall relapseafter mastectomy for ductal carcinoma in situ: a re-port of 10 cases with a review of the literature. CancerJ. 2006;12:92–101.

59. Silverstein MJ, Lagios MD, Martino S, et al. Outcomeafter invasive local recurrence in patients with ductalcarcinoma in situ of the breast. J Clin Oncol.1998;16:1367–73.

60. Romero L, Klein L, Ye W, et al. Outcome after inva-sive recurrence in patients with ductal carcinoma insitu of the breast. Am J Surg. 2004;188:371–6.

61. Lee LA, Silverstein MJ, Chung CT, et al. Breast cancer-specific mortality after invasive local recurrence inpatients with ductal carcinoma-in-situ of the breast.Am J Surg. 2006;192:416–9.

Breast Cancer (CI Falkson, Section Editor)

Author's personal copy

62. Voogd AC, van Oost FJ, Rutgers EJ, et al. Long-termprognosis of patients with local recurrence afterconservative surgery and radiotherapy for early breastcancer. Eur J Cancer. 2005;41:2637–44.

63.• Dunne C, Burke JP, Morrow M, Kell MR. Effect ofmargin status on local recurrence after breast con-servation and radiation therapy for ductal carcinomain situ. J Clin Oncol. 2009;27:1615–20.

A meta-analysis of randomized and nonrandomized clinicalstudies was performed to investigate the effect of marginstatus on the risk of recurrence in BCT with radiotherapy forDCIS. It was concluded that margins should be negative inBCT for DCIS. More specifically, a margin threshold of 2 mmseems to be as good as a larger margin width.64. Silverstein MJ, Lagios MD, Groshen S, et al. The in-

fluence of margin width on local control of ductalcarcinoma in situ of the breast. N Engl J Med.1999;340:1455–61.

65. Sahoo S, Recant WM, Jaskowiak N, et al. Definingnegative margins in DCIS patients treated with breastconservation therapy: the University of Chicago ex-perience. Breast J. 2005;11:242–7.

66. Solin LJ, Fourquet A, Vicini FA, et al. Mammographi-cally detected ductal carcinoma in situ of the breasttreated with breast-conserving surgery and definitivebreast irradiation: long-term outcome and prognosticsignificance of patient age and margin status. Int JRadiat Oncol Biol Phys. 2001;50:991–1002.

67.•• Correa C, McGale P, Taylor C, et al. Overview of therandomized trials of radiotherapy in ductal carcino-ma in situ of the breast. J Natl Cancer Inst Monogr.2010;2010:162–77.

This paper presents the meta-analysis of randomized,clinical trials performed by the Early Breast Cancer Tria-lists’ Collaborative Group investigating the effect of ra-diotherapy on the risk of recurrence in breast-conservingtherapy for DCIS.68.•• Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen

and radiotherapy in women with locally excisedductal carcinoma in situ: long-term results from theUK/ANZ DCIS trial. Lancet Oncol. 2011;12:21–9.

The long-term results of theU.K. DCIS trial are presented in thispaper. At amedian follow-up of 12.7 years, the beneficial effectof radiotherapy in BCT to reduce the risk of local recurrence isconfirmed and is shown that tamoxifen reduces both the re-duction of the risk of ipsilateral DCIS recurrence and contra-lateral breast cancer.69. Holmberg L, Garmo H, Granstrand B, et al. Absolute

risk reductions for local recurrence after postoperative

radiotherapy after sector resection for ductal carcinomain situ of the breast. J Clin Oncol. 2008;26:1247–52.

70. Alvarado R, Lari SA, Roses RE et al.. Biology, treat-ment, and outcome in very young and older womenwith DCIS. Ann Surg Oncol. 2012.

71. Vicini FA, Recht A. Age at diagnosis and outcome forwomen with ductal carcinoma-in-situ of the breast: acritical review of the literature. J Clin Oncol.2002;20:2736–44.

72. Omlin A, Amichetti M, Azria D, et al. Boost ra-diotherapy in young women with ductal carcino-ma in situ: a multicentre, retrospective study ofthe Rare Cancer Network. Lancet Oncol.2006;7:652–6.

73.• Hughes LL, Wang M, Page DL, et al. Local excisionalone without irradiation for ductal carcinoma insitu of the breast: a trial of the Eastern Coopera-tive Oncology Group. J Clin Oncol.2009;27:5319–24.

The ECOG 5194 trial is the largest prospective, non-randomized trial in which 670 women with DCIS weretreated with breast-conserving surgery without radiotherapy.It shows that small low- or intermediate-grade DCIS excisedwith wide tumor-free margins have a LR risk of 6.1 % at 5years. High-grade lesions did much worse with a 5-year LRrisk of 15.3 %.74. Wong JS, Kaelin CM, Troyan SL, et al. Prospective

study of wide excision alone for ductal carcinoma insitu of the breast. J Clin Oncol. 2006;24:1031–6.

75. Bartelink H, Horiot JC, Poortmans PM, et al. Impactof a higher radiation dose on local control and sur-vival in breast-conserving therapy of early breastcancer: 10-year results of the randomized boost ver-sus no boost EORTC 22881–10882 trial. J ClinOncol. 2007;25:3259–65.

76. Vaidya JS, Joseph DJ, Tobias JS, et al. Targetedintraoperative radiotherapy versus whole breastradiotherapy for breast cancer (TARGIT-A trial):an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376:91–102.

77. Whelan TJ, Pignol JP, Levine MN, et al. Long-termresults of hypofractionated radiation therapy forbreast cancer. N Engl J Med. 2010;362:513–20.

78. Bentzen SM, Agrawal RK, Aird EG, et al. The UKStandardisation of Breast Radiotherapy (START) TrialA of radiotherapy hypofractionation for treatment ofearly breast cancer: a randomised trial. Lancet Oncol.2008;9:331–41.

Is DCIS Breast Cancer, and How Do I Treat it? Bijker et al.

Author's personal copy