Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com)

Current Trends in the Management of Ductal Carcinoma In Situ Review Article [1] | September 15, 2016 | Oncology Journal [2], Breast Cancer [3], Breast Cancer Year in Review 2016 [4] By Tristen S. Park, MD [5] and E. Shelley Hwang, MD, MPH [6] This review will summarize the current trends in the diagnosis and management of DCIS and will highlight ongoing trials that are shaping future management of this entity.

Introduction Ductal carcinoma in situ (DCIS) was once an uncommon breast lesion, but now comprises 20% to 30% of new breast cancer diagnoses detected on mammography. In the United States, over 50,000 patients are diagnosed with DCIS annually.[1,2] This is in large part due to the widespread implementation of screening mammography, where DCIS most commonly presents as microcalcifications in the absence of other clinical findings. DCIS is traditionally considered to be a precursor to invasive disease; however, this paradigm has been challenged by the fact that although the incidence and treatment of DCIS have risen, there has not been a concomitant decline in the incidence of invasive breast cancer.[3] Additionally, molecular similarities found between in situ and invasive cancers within histologic grades have shaped the theory that breast cancer develops by progressive accumulation of genetic abnormalities along two parallel pathways. Precursor lesions along the low-grade pathway lead to low-grade DCIS and subsequently to low-grade invasive breast cancers, while the high-grade pathway results in high-grade DCIS and high-grade invasive lesions.[4] Biomarkers, such as estrogen receptor (ER) status and Ki-67, have also been shown to play a role in distinguishing between these two pathways.[5] Therefore, DCIS is currently viewed as a nonobligate precursor to invasive disease. Progression to invasive carcinoma is not definite, and this process is thought to be the result of biologic interplay between the accumulation of genetic events and a permissive microenvironment.[6,7] Although some lesions will likely remain clinically insignificant over an individual’s lifetime, there are more aggressive lesions with invasive components that require urgent intervention. The clinical and molecular discriminants between low-risk DCIS and high-risk DCIS are under active investigation. Models of clinical, pathologic, and molecular prognostic factors are currently being explored and validated. Ideally, better risk stratification would allow patients with low-risk DCIS to be treated with a more minimalistic approach, including omission of radiation therapy (RT) or surgery in favor of active surveillance. Aggressive treatment would then be limited to those individuals with high-risk disease. In addition to the added morbidity that can be avoided by omitting surgery/RT in low-risk DCIS, the cost to the US healthcare system of overtreatment from such a risk-driven approach could be reduced.

Imaging Mammography The vast majority of DCIS cases are diagnosed as asymptomatic microcalcifications on screening mammography, with 80% presenting as microcalcifications alone and 20% as other suspicious mammographic findings, including masses and focal nodular patterns.[8] Only 5% of DCIS cases are associated with a palpable finding,[9] making DCIS largely an unintended consequence of increased breast cancer surveillance. The morphology of microcalcifications can often indicate the likelihood of a DCIS diagnosis. The highest risk for DCIS is associated with heterogeneous/fine pleomorphic morphology with a clustered or grouped distribution (Figure 1), as compared with coarse calcifications, which indicate a lower likelihood of DCIS.[10] Morphology may also predict prognosis: in a recent single-institution study, fine linear branching microcalcifications were associated with a higher rate of local recurrence.[11,12] Page 1 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) Digital mammography has been shown to be more sensitive for detection of DCIS compared with film screen mammography.[13-15] Of note, one study demonstrated that digital mammography was better than plain film mammography for detection of high-grade DCIS compared with low-grade lesions, and was also more sensitive for detection of DCIS in both premenopausal and perimenopausal populations.[14] The addition of tomosynthesis to digital mammography was approved for breast cancer screening in 2011. This combined modality has been shown to increase detection of invasive cancers and reduce callback rates, but has not resulted in an increase in detection of DCIS.[16] MRI The role of MRI in the management of DCIS is not clearly established. Theoretically, MRI findings could aid in guiding treatment by informing decisions for breast conservation therapy (BCT) or mastectomy, and by evaluation of the contralateral breast. Currently, MRI is better at detecting multicentricity than mammography.[17-19] Since multicentricity is a contraindication to BCT, the use of MRI may be a valuable adjunct in surgical decision making. In addition to multicentricity, MRI can potentially provide more precise information about the size and extent of DCIS lesions, thereby guiding extent of excision. However, there is limited consensus regarding the ability of MRI to more accurately estimate the size of DCIS lesions compared with mammography. Studies have shown that MRI can both underestimate and overestimate extent of disease.[20-22] MRI can be used to screen the contralateral breast, resulting in identification of contralateral cancer in 2.6% of patients.[21] Other potential advantages that MRI offers include reduced re-excision rates and decreased local recurrence. However, this has not been validated in published studies, which show no reduction in re-excision rates in women undergoing lumpectomy following MRI compared with those who did not undergo preoperative MRI.[23,24] There is evidence that supports potential disadvantages of MRI in this setting, including increases in cost, patient anxiety, and mastectomy rate, regardless of the results found on MRI.[21,25,26] Additionally, since MRI can overestimate the extent of disease, this may lead to patients receiving more extensive procedures than necessary.

Pathology DCIS of the breast is characterized by malignant epithelial cells confined to the ductal system of the breast without evidence of invasion through the basement membrane.[27] Histologic parameters most established in evaluating DCIS include nuclear grade and architectural subtype/necrosis. Nuclear grade has been shown to correlate best with clinical outcomes and was emphasized in the 2009 College of American Pathologists/American Society of Clinical Oncology protocol for reporting DCIS lesions. These guidelines recommend that nuclear grade of DCIS lesions be defined as low grade (grade 1), intermediate grade (grade 2), and high grade (grade 3). Grade is determined by nuclear features, including size, cellular proliferation, presence and size of nucleoli, and frequency of mitotic figures (Figure 2). Architectural subtypes include comedo and noncomedo patterns, with the comedo pattern defined by high-grade cells, central necrosis, and pleomorphic calcifications, and noncomedo patterns divided into cribriform, micropapillary, solid, and papillary subtypes. This distinction is of particular clinical relevance, since comedo DCIS has been shown to have a higher rate of local recurrence than noncomedo lesions.[10] Foci of microinvasion are often found in larger DCIS lesions. Microinvasion is rarely found in lesions smaller than 2 cm, but can be detected in up to 44% to 75% of lesions that are 5 to 7 cm.[28] Challenges can occur in distinguishing between low-grade DCIS and atypical ductal hyperplasia, as well as between comedo-type DCIS lesions and the pleomorphic subtype of lobular carcinoma in situ lesions. Margin assessment also poses a challenge because of the presence of skip lesions, particularly in low-grade lesions.[29] This difficulty is reflected in a study by Elmore et al, which looked at diagnostic concordance among pathologists interpreting breast biopsy specimens. Although there was a 96% concordance rate with invasive cancer specimens, there was 85% concordance for DCIS, with 13% of cases being underinterpreted.[30]

Surgery Currently, National Comprehensive Cancer Network guidelines for the treatment of DCIS include excision of all disease to negative margins with either mastectomy or, alternatively, BCT with or without RT.[31] Sentinel lymph node biopsy (SLNB) is also indicated in selected cases. Although local Page 2 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) recurrence rates with mastectomy are lower than those for BCT with RT (1%–2% vs 10%–15%), this has not translated into a difference in breast cancer–specific mortality.[32-36] Surgical decision making has been influenced by a variety of factors, including comorbidities, age at diagnosis, and desire to avoid repeat procedures and to prevent local recurrence. Risk models, genetic testing, and molecular profiling of tumors have also guided decision making and will be increasingly important in the future management of this disease.[37] Mastectomy One-third of patients diagnosed with DCIS in the United States will be treated with mastectomy. Factors that have traditionally played a role in deciding on mastectomy include diffuse multicentric disease; contraindication to RT (including prior history of RT); and concurrent collagen vascular disease, such as lupus and scleroderma. Retrospective studies of mastectomy in patients with DCIS report 10-year breast cancer–specific survival rates of greater than 98%. Of note, the acceptance of BCT with RT in the 1990s had led to a decrease in the rate of mastectomy; however, the most recent study of 212,936 patients from 1998 to 2011 demonstrated an increasing trend. Mastectomy rates initially declined from 1998 (36%) to 2004 (28%), but then increased to 33% in 2011. Younger patient age, high tumor grade, greater distance from a treatment facility, and treatment at an academic center were associated with higher use of mastectomy.[37,38] The trend of contralateral prophylactic mastectomy for the treatment of DCIS has also increased, and was associated with younger age, BRCA positivity, and a family history of ovarian cancer.[39] Nipple and skin sparing mastectomies have been increasingly used in the setting of DCIS. Although initially the concept of preserving the nipple-areola complex (NAC) was concerning for both increased local recurrence rates as well as ischemic complications, careful patient selection and advances in technique have resulted in good oncologic outcomes and acceptably low complication rates. The largest series involving 111 DCIS patients observed a 2% rate of local recurrence at 3 years, with no NAC or skin recurrences.[40-42] Breast conservation therapy Two-thirds of patients diagnosed with DCIS undergo surgical treatment with BCT. RT following BCT for DCIS is currently standard of care for most patients with higher-risk disease, including those with larger extent of calcifications, high grade, and close margins. Five large prospective trials have demonstrated that adjuvant RT decreased ipsilateral breast cancer events by approximately 50% after BCT. Of these recurrent events, half were invasive disease and half were DCIS (Table).[32-36] These landmark prospective randomized studies have established that adjuvant RT decreases the rate of local recurrence. However, these trials have failed to show that this reduction translates into an overall survival benefit. Thus, several trials have evaluated whether omission of RT after BCT in carefully selected populations could yield acceptably low local recurrence rates to consider lumpectomy alone in some clinical subgroups. The Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) 5194 trial was a single-arm prospective study of two clinical cohorts undergoing BCT for DCIS: cohort 1—low risk (grade 1/2 DCIS, ≤ 2.5 cm; 19% with tumor size > 10 mm) and cohort 2—high risk (high-grade DCIS, ≤ 1.0 cm; 14% with tumor size > 10 mm). Both groups had negative margins of at least 3 mm. The 12-year rates for the development of local recurrence were 14.4% for cohort 1 and 24.6% for cohort 2 (P = .003). The 12-year rates for the development of invasive local recurrence were 7.5% and 13.4%, respectively (P = .08). For patients with low-risk DCIS treated with BCT without RT, the risks of developing local recurrence and invasive local recurrence increased through 12 years of follow-up, without evidence of a plateau. High-risk patients had a much higher rate of local failure without RT.[43] A single-institution study conducted at the Harvard University–affiliated hospitals followed 158 low-risk DCIS patients (grade 1/2, ≤ 2.5 cm with margins ≥ 1 cm) and found that the 10-year estimated local recurrence rate was 15.6%, with about one-third of these being invasive. Thus, even in low-risk patients with wide excision margins there was a substantial risk of local recurrence with omission of RT.[44] The most recent trial to evaluate excision alone in a low-risk population is the Radiation Therapy Oncology Group (RTOG) 9804 trial, which randomized 636 patients with low- and intermediate-grade DCIS, tumor size ≤ 2.5 cm and ≥ 3-mm margins, to either whole-breast radiation or observation after BCT. At 7 years of follow-up, 6.7% in the observation group developed local recurrence, compared with 0.9% of the RT group.[32] Together, these studies in a low-risk DCIS subset indicate that a clinically favorable DCIS group may be identified, and the decision for adjuvant RT should be Page 3 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) discussed in the setting of negligible mortality benefit, particularly in this clinically favorable subset. TO PUT THAT INTO CONTEXT

A. Marilyn Leitch, MD The University of Texas Southwestern Medical Center Dallas, Texas What Are the Current Controversies in Managing DCIS? This article highlights the controversies regarding ductal carcinoma in situ (DCIS) that have been heating up over the last few years. Several factors are contributing to this: the significant proportion of newly diagnosed cancers that are DCIS; the trend of increasing bilateral mastectomies; the development of genomic assays for prognostication; and the proliferation of literature regarding overdiagnosis and overtreatment of DCIS. There is tension between the desire for early detection of breast cancer and concern for overtreatment. The 2015 article by Narod et al, derived from Surveillance, Epidemiology, and End Results (SEER) data, concluded that breast cancer mortality for women treated for DCIS is only 3.3% at 20 years, and that use of radiotherapy does not reduce that mortality.[1] A New York Times article interpreted this study as confirmation of overdiagnosis and unnecessary treatment.[2] Dr. Narod was quoted as saying, “I think the best way to treat DCIS is to do nothing.” Patients responded to these articles with varied opinions, indicative of their differing priorities and concerns about the risk of invasive cancer without treatment. How Can Clinicians Handle Patient Concerns Regarding Undertreatment and Overtreatment of DCIS? Physicians must recognize the spectrum of risk posed by DCIS and utilize the newly available prognostic tools to assess an individual’s risk for development of invasive breast cancer to guide management. Clinical trials are key in defining the best strategies for management of DCIS. When considering management of lower-risk DCIS with observation alone, physicians should advise their patients to participate in clinical trials that are in progress to evaluate both oncologic outcomes and the patient’s quality of life with observation alone. REFERENCES 1. Narod SA, Iqbal J, Giannakeas V, et al. Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. 2015;1:888-96. 2. Kolata G. Doubt is raised over value of surgery for breast lesion at earliest stage. New York Times. http://www.nytimes.com/2015/08/21/health/breast-cancer-ductal-carcinoma-in-situ-study.html. Accessed August 15, 2016. Financial Disclosure: Dr. Leitch has served in an advisory role in a limited capacity (< 1 day) for Castle BioScience and Genomic Health. For patients undergoing BCT, either with or without radiation, a key factor associated with durable locoregional control is negative margin status. Recently, a multidisciplinary consensus panel reviewed multiple data sources including a meta-analysis of margin width for DCIS.[45] The panel concluded that a margin of 2 mm should be achieved in the setting of adjuvant external beam radiation, since smaller margins were strongly associated with a higher rate of ipsilateral breast tumor recurrence. However, re-excision should be considered after taking into account the full context of an individual patient’s presentation. Accelerated partial breast irradiation Outcomes for DCIS patients (as well as those with invasive cancer) treated with accelerated partial breast irradiation (APBI) have now been published. Currently, the American Society for Radiation Oncology consensus panel guidelines list DCIS lesions of ≤ 3 cm as cautionary for off-protocol use of Page 4 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) APBI.[46] Prior smaller series have shown excellent outcomes, with the rate of ipsilateral local recurrence ranging from 2% to 3.4%, with follow-up periods ranging from 9 to 60 months.[47-49] The largest series to date looked at 300 patients who were either part of the American Society of Breast Surgeons MammoSite registry trial or at the William Beaumont Hospital. These studies found similar rates of ipsilateral local recurrence at 5 years between patients who underwent APBI vs standard RT (2.6% vs 3.1%; P = .90).[50] This suggests that APBI may be a viable option, but would require follow-up in larger series. Sentinel lymph node biopsy Current practice guidelines recommend that SLNB be offered to patients with DCIS when mastectomy is performed. The possibility of finding an invasive cancer in the breast and subsequent disruption of lymphatics, which precludes a subsequent SLNB, drives this recommendation. In contrast, SLNB is not routinely recommended for patients with DCIS treated with BCT. However, some guidelines indicate that SLNB may be considered when physical exam or imaging shows a mass lesion highly suggestive of cancer or if the area of DCIS is large (> 5 cm).[51] In unselected DCIS, the rate of positive sentinel lymph node involvement ranges from 5% to 10% and is mostly comprised of isolated tumor cells or micrometastases. Outcomes in patients with DCIS and low-volume nodal disease have not differed from those in patients with DCIS and negative nodes.[52-56] In addition, a large single-institution study suggested that increased interventions were associated with positive SLNB findings, generally in the form of micrometastases. The authors note that this supports the benign translocation theory, according to which benign mechanical transport of cells through lymphatics due to preoperative manipulation of the primary tumor can lead to positive SLNB findings.[52] This further argues against routine SLNB for DCIS without invasion except in the setting of mastectomy for DCIS.

Endocrine Therapy Several trials have evaluated the use of tamoxifen in DCIS. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial found that the use of tamoxifen after BCT with RT reduced local recurrence. Tamoxifen decreased both ipsilateral and contralateral invasive breast cancer events by 32% (hazard ratio: 0.68; 95% CI, 0.50–0.98).[57] The majority of DCIS is ER-positive, and the benefit was conferred to patients with estrogen or progesterone receptor (PR)-positive DCIS only. Comparable reductions were seen in the United Kingdom/Australia/New Zealand (UK/ANZ) trial, with a significant reduction in the overall breast cancer event rate (24.6% to 18.1% at 12 years; P = .002).[58] Studies investigating aromatase inhibitors as adjuvant therapy for DCIS have also been recently completed. The NSABP B-35 trial randomized patients undergoing lumpectomy and RT to tamoxifen or the aromatase inhibitor anastrozole, and found that anastrozole resulted in significantly fewer breast cancer events at 9 years compared with tamoxifen. These benefits were only seen in postmenopausal patients younger than 60 years.[59] Lower rates of thromboembolic and uterine cancer events were seen in the anastrozole group, at a cost of more osteoporotic fractures and myalgia. There were no differences in overall survival, but this study suggests that anastrozole may be a viable alternative to tamoxifen in postmenopausal women.

Prognostic Models Clinical, pathologic, and molecular factors have been studied for their predictive value for recurrence after BCT. Several models have been published and are currently being validated in independent patient populations. The goal of these models is to delineate the patient populations that can be considered low risk, as well as to help guide management, including the decision to omit RT. Van Nuys Prognostic Index The Van Nuys Prognostic Index (VNPI) was the first prognostic index proposed for DCIS based on outcomes from a large, prospective, single-institution DCIS registry. The VNPI includes four factors: size, margin, nuclear grade with necrosis, and age. Each variable is assigned a score of 1 to 3, with a total score ranging from a low of 4, indicating the lowest likelihood of recurrence, to a high of 12, indicating the highest likelihood.[60] The VNPI recommends that patients with a total score of 4, 5, 6, or 7 with at least 3-mm margins undergo excision alone. Patients with a score of 8 or 9 with a close margin, or scores of 10, 11, or 12, are recommended mastectomy. Those with scores of 7 with close Page 5 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) margins, or 8 or 9 with negative margins, are recommended RT along with BCT. Memorial Sloan Kettering Cancer Center nomogram An alternative approach to evaluating the risk of local recurrence in patients with DCIS after local excision is the Memorial Sloan Kettering Cancer Center nomogram. Using 10 clinical, pathologic, and treatment variables, this nomogram predicts the probability of local recurrence at 5 and 10 years after BCT. The factors include age at diagnosis, family history, presentation (radiologic vs clinical), adjuvant RT, adjuvant endocrine therapy, nuclear grade, necrosis, margins, number of surgical excisions, and year of surgery.[61] However, Yi et al assessed this nomogram independently in 794 patients, and it was found to have imperfect calibration and discrimination, with a concordance index of 0.63.[62] Validation in other independent datasets would be useful to assess the general utility of this nomogram in different patient populations. Oncotype DX DCIS Score Substantial effort has been put into developing multigene assays to help delineate low-risk patient populations. The Oncotype DX DCIS Score is a 12-gene expression assay for DCIS that estimates the 10-year risk of any local recurrence (DCIS or invasive) following treatment with BCT without RT. Among 327 patients who were enrolled in the ECOG-ACRIN 5194 study, the DCIS score was shown to predict an individual’s risk of developing local recurrence. For DCIS low-, intermediate-, and high-risk groups, the 10-year risk of an ipsilateral breast event were 10.6%, 26.7%, and 25.9%, respectively. For invasive cancer events, the risks were 3.7%, 12.3%, and 19.2%, respectively. The authors concluded that RT may be omitted in the low- and intermediate-risk groups, but should be included in the treatment of the high-risk group.[63] These findings were confirmed in a larger patient population–based cohort by Rakovitch et al, who correlated the Oncotype DX DCIS Score with outcomes in a study of 3,320 patients. The study demonstrated that the Oncotype DX DCIS Score correlated with local recurrence risk (low, 12.7%; intermediate, 33%; high, 27.8%), albeit with less discrimination than was seen with the ECOG-ACRIN 5194 dataset. Compared with the population in the ECOG-ACRIN 5194 trial, this larger, more diverse patient population was higher risk, and was comprised of 32% high-grade DCIS and 45% with margin width between 1 mm and 3 mm. Despite these differences, the risks of local recurrence in each prespecified DCIS risk group were strikingly similar between the two studies.[64] These results demonstrate that multigene assays may have a promising role in stratifying risk for DCIS patients and will likely play a prominent role in future management. To date, other prognostic biomarkers have shown limited ability to discriminate between low- and high-risk DCIS. Advances in the field have been hampered by a lack of consensus on what constitutes the most meaningful outcome, with many studies focused on predictors of ipsilateral breast recurrence, but other more recent studies targeting markers of invasive progression. Single markers such as ER, Ki-67, and human epidermal growth factor receptor 2 (HER2) have shown some correlation with outcome.[65] Moreover, combined marker sets such as Ki-67, COX-2, and p16,[66] as well as constructed tumor phenotype,[67] will likely show some prognostic value but will require validation in independent datasets.

Active Surveillance The appreciation of the wide heterogeneity of DCIS with variable malignant potential has generated interest in delineating which patients should be treated aggressively vs safely, or followed with close monitoring. It is clear that high-grade DCIS is more biologically aggressive and can lead to invasive cancer, in addition to harboring occult malignancy. Low- and intermediate-grade DCIS accounts for 30% of screen-detected DCIS, and its malignant potential is less assured. Thus, there are studies now underway to define the feasibility of adopting surveillance, rather than a surgical approach, for biologically favorable DCIS. The “low risk” (LORIS) DCIS trial is a phase III, randomized, noninferiority trial of surgery vs active monitoring in low-risk DCIS patients, which was initiated in Europe in 2014.[68] It randomizes patients with low- or intermediate-grade DCIS to either surgery or active surveillance without endocrine therapy. The primary objective of the study is the comparison of ipsilateral and invasive disease–free survival time between the active monitoring and surgery arms. Secondary objectives will include overall survival and time to development of ipsilateral and contralateral cancers. In the United States, this question will also be addressed by the COMET (Comparison of Operative vs Medical Endocrine Therapy for Low-Risk DCIS) trial. Eligibility for the study will be limited to low- and Page 6 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) intermediate-grade DCIS that is ER- and/or PR-positive and HER2-negative (Figure 3). Participants will be randomized to receive either standard guideline-concordant care with usual follow-up, or active surveillance with a mammogram of the index breast every 6 months for 5 years. Patients in the active surveillance arm will be strongly encouraged to pursue endocrine therapy. A third study of low-risk DCIS sponsored by the European Organisation for Research and Treatment of Cancer, the LORD (LOw Risk DCIS) study, is scheduled to begin in the second half of 2016. All three studies are based on the high sensitivity of modern mammographic surveillance, as well as the excellent long-term outcomes of DCIS patients, even for those who develop early-stage invasive cancer. Together, these trials will provide valuable evidence showing whether a surveillance approach compromises survival after diagnosis of DCIS. An additional important aspect of these trials will be the collection of patient-reported outcomes, which will determine whether such a surveillance strategy could be acceptable to patients. Important metrics to assess in both the treatment and surveillance arms are the long-term effects on psychological and physical quality of life associated with the different management approaches for DCIS. Ultimately, patients and providers will be able to use this evidence to determine whether the trade-offs of one approach vs another align with an individual patient’s health and quality-of-life goals.

Cost vs Value Thus far, the only study to look at the cost burden of overtreatment of DCIS was published by Ong et al, which looked at the estimated national expense of overtreating DCIS, as well as of false-positive mammograms.[69] The authors estimated the cost of DCIS overdiagnosis by applying the average cost of DCIS treatment ($12,369) to the published DCIS overdiagnosis rate (86%), with the total resulting in $243 million annually. Of note, this was also thought to be an underestimate, since the authors specifically looked at DCIS ICD-9 codes to determine this figure and they believed that some cases of DCIS could have been misclassified as invasive cancer. Other factors that may change this estimate include the overdiagnosis rate and re-excision rate, which is more common for DCIS patients. The overdiagnosis rate was based on a series of small studies of patients who were previously misdiagnosed with benign disease, did not receive treatment, and were subsequently diagnosed with DCIS. In the largest of these series, 14% went on to develop invasive cancer.[70] In addition, because obtaining negative margins for DCIS is more challenging due to skip lesions, it has been reported that up to 40% of women with DCIS require a second operation, at an average cost of $11,000 per re-excision.[24] Although provocative, these estimates only provide a general calculation of the cost of overtreatment, and must be balanced against the trade-offs of continued surveillance, possible anxiety, and diagnosis of subsequent invasive cancer. One model of cancer progression indicates that the cost of such trade-offs are highly dependent on patient factors such as age at diagnosis; in the future, these considerations will further help refine management of DCIS.[71]

Conclusion The significant rise in the incidence of DCIS since the implementation of routine screening mammography has resulted in the appreciation of the vast biologic heterogeneity of this disease entity. Moving forward, the traditional approach of surgery, RT, and endocrine therapy will need to be revisited as the active investigation into risk stratification using molecular and clinical parameters continues. Development of personalized therapy based on risk assessment is the future goal to reduce morbidity, psychological impact, and healthcare burden of this disease. Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Oncology (Williston Park). 30(9):823–831.

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Figure 1. Morphologic Differences Between Microcalcifications on Mammo...

Table. Summary of Prospective Randomized Trials and Prospective Single...

Figure 2. Histologic Characteristics of Atypical Ductal Hyperplasia (A... References: 1. Sumner WE 3rd, Koniaris LG, Snell SE, et al. Results of 23,810 cases of ductal carcinoma-in-situ. Ann Surg Oncol. 2007;14:1638-43. 2. Baxter NN, Virnig BA, Durham SB, Tuttle TM. Trends in the treatment of ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2004;96:443-8. 3. Ozanne EM, Shieh Y, Barnes J, et al. Characterizing the impact of 25 years of DCIS treatment. Breast Cancer Res Treat. 2011;129:165-73. 4. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, et al. Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010;57:171-92. 5. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869-74. 6. Giussani M, Merlino G, Cappelletti V, et al. Tumor-extracellular matrix interactions: Identification of Page 8 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) tools associated with breast cancer progression. Semin Cancer Biol. 2015;35:3-10. 7. Acerbi I, Cassereau L, Dean I, et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb). 2015;7:1120-34. 8. Ikeda DM, Andersson I. Ductal carcinoma in situ: atypical mammographic appearances. Radiology. 1989;172:661-6. 9. Sundara Rajan S, Verma R, Shaaban AM, et al. Palpable ductal carcinoma in situ: analysis of radiological and histological features of a large series with 5-year follow-up. Clin Breast Cancer. 2013;13:486-91. 10. Pang JM, Gorringe KL, Fox SB. Ductal carcinoma in situ—update on risk assessment and management. Histopathology. 2016;68:96-109. 11. Rauch GM, Hobbs BP, Kuerer HM, et al. Microcalcifications in 1657 patients with pure ductal carcinoma in situ of the breast: correlation with clinical, histopathologic, biologic features, and local recurrence. Ann Surg Oncol. 2016;23:482-9. 12. Holmberg L, Wong YN, Tabar L, et al. Mammography casting-type calcification and risk of local recurrence in DCIS: analyses from a randomised study. Br J Cancer. 2013;108:812-9. 13. Del Turco MR, Mantellini P, Ciatto S, et al. Full-field digital versus screen-film mammography: comparative accuracy in concurrent screening cohorts. AJR Am J Roentgenol. 2007;189:860-6. 14. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med. 2005;353:1773-83. 15. Bluekens AM, Holland R, Karssemeijer N, et al. Comparison of digital screening mammography and screen-film mammography in the early detection of clinically relevant cancers: a multicenter study. Radiology. 2012;265:707-14. 16. Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA. 2014;311:2499-507. 17. Hwang ES, Kinkel K, Esserman LJ, et al. Magnetic resonance imaging in patients diagnosed with ductal carcinoma-in-situ: value in the diagnosis of residual disease, occult invasion, and multicentricity. Ann Surg Oncol. 2003;10:381-8. 18. Menell JH, Morris EA, Dershaw DD, et al. Determination of the presence and extent of pure ductal carcinoma in situ by mammography and magnetic resonance imaging. Breast J. 2005;11:382-90. 19. Santamaria G, Velasco M, Farrus B, et al. Preoperative MRI of pure intraductal breast carcinoma—a valuable adjunct to mammography in assessing cancer extent. Breast. 2008;17:186-94. 20. Schouten van der Velden AP, Boetes C, Bult P, Wobbes T. The value of magnetic resonance imaging in diagnosis and size assessment of in situ and small invasive breast carcinoma. Am J Surg. 2006;192:172-8. 21. Lehman CD, Gatsonis C, Kuhl CK, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007;356:1295-303. 22. Allen LR, Lago-Toro CE, Hughes JH, et al. Is there a role for MRI in the preoperative assessment of patients with DCIS? Ann Surg Oncol. 2010;17:2395-400. 23. Pilewskie M, Olcese C, Eaton A, et al. Perioperative breast MRI is not associated with lower locoregional recurrence rates in DCIS patients treated with or without radiation. Ann Surg Oncol. 2014;21:1552-60. Page 9 of 13

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24. Davis KL, Barth RJ Jr, Gui J, et al. Use of MRI in preoperative planning for women with newly diagnosed DCIS: risk or benefit? Ann Surg Oncol. 2012;19:3270-4. 25. Itakura K, Lessing J, Sakata T, et al. The impact of preoperative magnetic resonance imaging on surgical treatment and outcomes for ductal carcinoma in situ. Clin Breast Cancer. 2011;11:33-8. 26. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-8. 27. Lester SC, Bose S, Chen YY, et al. Protocol for the examination of specimens from patients with ductal carcinoma in situ of the breast. Arch Pathol Lab Med. 2009;133:15-25. 28. Lagios MD, Westdahl PR, Margolin FR, Rose MR. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer. 1982;50:1309-14. 29. Siziopikou KP. Ductal carcinoma in situ of the breast: current concepts and future directions. Arch Pathol Lab Med. 2013;137:462-6. 30. Elmore JG, Longton GM, Carney PA, et al. Diagnostic concordance among pathologists interpreting breast biopsy specimens. JAMA. 2015;313:1122-32. 31. National Comprehensive Cancer Network (US). The complete library of NCCN clinical practice guidelines in oncology. Rockledge, PA: National Comprehensive Cancer Network; 2003. http://www.nccn.org/professionals/physician_gls/default.asp. Accessed August 4, 2016. 32. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33:709-15. 33. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast. J Clin Oncol. 2008;26:1247-52. 34. EORTC Breast Cancer Cooperative Group; EORTC Radiotherapy Group; Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853—a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;24:3381-7. 35. 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. 2003;362:95-102. 36. 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. 1998;16:441-52. 37. Worni M, Akushevich I, Greenup R, et al. Trends in treatment patterns and outcomes for ductal carcinoma in situ. J Natl Cancer Inst. 2015;107:djv263. 38. Rutter CE, Park HS, Killelea BK, Evans SB. Growing use of mastectomy for ductal carcinoma-in situ of the breast among young women in the United States. Ann Surg Oncol. 2015;22:2378-86. 39. Elsayegh N, Kuerer HM, Lin H, et al. Predictors that influence contralateral prophylactic mastectomy election among women with ductal carcinoma in situ who were evaluated for BRCA genetic testing. Ann Surg Oncol. 2014;21:3466-72. 40. Crowe JP, Patrick RJ, Yetman RJ, Djohan R. Nipple-sparing mastectomy update: one hundred Page 10 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com) forty-nine procedures and clinical outcomes. Arch Surg. 2008;143:1106-10; discussion 10. 41. Sakurai T, Zhang N, Suzuma T, et al. Long-term follow-up of nipple-sparing mastectomy without radiotherapy: a single center study at a Japanese institution. Med Oncol. 2013;30:481. 42. Warren Peled A, Foster RD, Stover AC, et al. Outcomes after total skin-sparing mastectomy and immediate reconstruction in 657 breasts. Ann Surg Oncol. 2012;19:3402-9. 43. Solin LJ, Gray R, Hughes LL, et al. Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-year results from the ECOG-ACRIN E5194 study. J Clin Oncol. 2015;33:3938-44. 44. Wong JS, Chen YH, Gadd MA, et al. Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal carcinoma in situ (DCIS). Breast Cancer Res Treat. 2014;143:343-50. 45. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. J Clin Oncol. 2016 Aug 15. pii: JCO683573 [Epub ahead of print] 46. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). J Am Coll Surg. 2009;209:269-77. 47. Benitez PR, Streeter O, Vicini F, et al. Preliminary results and evaluation of MammoSite balloon brachytherapy for partial breast irradiation for pure ductal carcinoma in situ: a phase II clinical study. Am J Surg. 2006;192:427-33. 48. Abbott AM, Portschy PR, Lee C, et al. Prospective multicenter trial evaluating balloon-catheter partial-breast irradiation for ductal carcinoma in situ. Int J Radiat Oncol Biol Phys. 2013;87:494-8. 49. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment efficacy with accelerated partial breast irradiation (APBI): final analysis of the American Society of Breast Surgeons MammoSite breast brachytherapy registry trial. Ann Surg Oncol. 2013;20:3279-85. 50. Vicini F, Shah C, Ben Wilkinson J, et al. Should ductal carcinoma-in-situ (DCIS) be removed from the ASTRO consensus panel cautionary group for off-protocol use of accelerated partial breast irradiation (APBI)? A pooled analysis of outcomes for 300 patients with DCIS treated with APBI. Ann Surg Oncol. 2013;20:1275-81. 51. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2014;32:1365-83. 52. Francis AM, Haugen CE, Grimes LM, et al. Is sentinel lymph node dissection warranted for patients with a diagnosis of ductal carcinoma in situ? Ann Surg Oncol. 2015;22:4270-9. 53. Tunon-de-Lara C, Chauvet MP, Baranzelli MC, et al. The role of sentinel lymph node biopsy and factors associated with invasion in extensive DCIS of the breast treated by mastectomy: the Cinnamome prospective multicenter study. Ann Surg Oncol. 2015;22:3853-60. 54. Dominguez FJ, Golshan M, Black DM, et al. Sentinel node biopsy is important in mastectomy for ductal carcinoma in situ. Ann Surg Oncol. 2008;15:268-73. 55. Moore KH, Sweeney KJ, Wilson ME, et al. Outcomes for women with ductal carcinoma-in-situ and a positive sentinel node: a multi-institutional audit. Ann Surg Oncol. 2007;14:2911-7. 56. Fraile M, Gubern JM, Rull M, et al. Is it possible to refine the indication for sentinel node biopsy in high-risk ductal carcinoma in situ? Nucl Med Commun. 2006;27:785-9. Page 11 of 13

Current Trends in the Management of Ductal Carcinoma In Situ Published on Cancer Network (http://www.cancernetwork.com)

57. Allred DC, Anderson SJ, Paik S, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24. J Clin Oncol. 2012;30:1268-73. 58. Cuzick J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol. 2011;12:21-9. 59. Margolese RG, Cecchini RS, Julian TB, et al. Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet. 2016;387:849-56. 60. Silverstein MJ, Poller DN, Waisman JR, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995;345:1154-7. 61. Rudloff U, Jacks LM, Goldberg JI, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol. 2010;28:3762-9. 62. Yi M, Meric-Bernstam F, Kuerer HM, et al. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. J Clin Oncol. 2012;30:600-7. 63. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013;105:701-10. 64. Rakovitch E, Nofech-Mozes S, Hanna W, et al. A population-based validation study of the DCIS score predicting recurrence risk in individuals treated by breast-conserving surgery alone. Breast Cancer Res Treat. 2015;152:389-98. 65. Buckley N, Boyle D, McArt D, et al. Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention. Oncotarget. 2015;6:43244-54. 66. Kerlikowske K, Molinaro AM, Gauthier ML, et al. Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst. 2010;102:627-37. 67. Williams KE, Barnes NL, Cramer A, et al. Molecular phenotypes of DCIS predict overall and invasive recurrence. Ann Oncol. 2015;26:1019-25. 68. Francis A, Thomas J, Fallowfield L, et al. Addressing overtreatment of screen detected DCIS; the LORIS trial. Eur J Cancer. 2015;51:2296-303. 69. Ong MS, Mandl KD. National expenditure for false-positive mammograms and breast cancer overdiagnoses estimated at $4 billion a year. Health Aff (Millwood). 2015;34:576-83. 70. Leonard GD, Swain SM. Ductal carcinoma in situ, complexities and challenges. J Natl Cancer Inst. 2004;96:906-20. 71. Ryser MD, Worni M, Turner EL, et al. Outcomes of active surveillance for ductal carcinoma in situ: a computational risk analysis. J Natl Cancer Inst. 2015;108. pii: djv372.

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