New approaches are needed to determine which ductal carcinoma in situ (DCIS) is at high risk for progression to invasive ductal carcinoma (IDC). We retrospectively studied DCIS patients who declined surgery (2002-2019), and received endocrine therapy (ET) and breast MRI. Baseline MRI and changes at 3 months and 6 months were analyzed by recursive partitioning to stratify IDC risk. Sixty-two patients (63 DCIS; 1 bilateral) with a mean follow-up of 8.5 years were included. Fifty-one percent remained on active surveillance (AS) without evidence of IDC, with a mean duration of 7.6 years. A decision tree based on MRI features of lesion distinctness and background parenchymal enhancement (BPE) at baseline and change after 3 months of ET stratified patients into low, intermediate, and high risk for progression to IDC. MRI imaging features in patients treated with ET and undergoing AS, may help determine which DCIS lesions are at low versus high risk for IDC.

Ductal carcinoma in situ (DCIS) incidence has risen rapidly with the introduction of screening mammography, yet it is unclear who benefits from both the amount and type of adjuvant treatment (radiation therapy, (RT), endocrine therapy (ET)) versus what constitutes over-treatment. Our goal was to identify the effects of adjuvant RT, or ET+/- RT versus breast conservation surgery (BCS) alone in a large multi-center registry of retrospective DCIS cases (N = 1,916) with median follow up of 8.2 years. We show that patients with DCIS who took less than 2 years of adjuvant ET alone have a similar second event rate as BCS. However, patients who took more than 2 years of ET show a significantly reduced second event rate, similar to those who received either RT or combined ET+RT, which was independent of age, tumor size, grade, or period of diagnosis. This highlights the importance of ET duration for risk reduction.

Ductal carcinoma in situ (DCIS) is a biologically heterogenous entity with uncertain risk for invasive ductal carcinoma (IDC) development. Standard treatment is surgical resection often followed by radiation. New approaches are needed to reduce overtreatment. This was an observational study that enrolled patients with DCIS who chose not to pursue surgical resection from 2002 to 2019 at a single academic medical center. All patients underwent breast MRI exams at 3- to 6-month intervals. Patients with hormone receptor–positive disease received endocrine therapy. Surgical resection was strongly recommended if clinical or radiographic evidence of disease progression developed. A recursive partitioning (R-PART) algorithm incorporating breast MRI features and endocrine responsiveness was used retrospectively to stratify risk of IDC. A total of 71 patients were enrolled, 2 with bilateral DCIS (73 lesions). A total of 34 (46.6%) were premenopausal, 68 (93.2%) were hormone-receptor positive, and 60 (82.1%) were intermediate- or high-grade lesions. Mean follow-up time was 8.5 years. Over half (52.1%) remained on active surveillance without evidence of IDC with mean duration of 7.4 years. Twenty patients developed IDC, of which 6 were HER2 positive. DCIS and subsequent IDC had highly concordant tumor biology. Risk of IDC was characterized by MRI features after 6 months of endocrine therapy exposure; low-, intermediate-, and high-risk groups were identified with respective IDC rates of 8.7%, 20.0%, and 68.2%. Thus, active surveillance consisting of neoadjuvant endocrine therapy and serial breast MRI may be an effective tool to risk-stratify patients with DCIS and optimally select medical or surgical management.Significance:A retrospective analysis of 71 patients with DCIS who did not undergo upfront surgery demonstrated that breast MRI features after short-term exposure to endocrine therapy identify those at high (68.2%), intermediate (20.0%), and low risk (8.7%) of IDC. With 7.4 years mean follow-up, 52.1% of patients remain on active surveillance. A period of active surveillance offers the opportunity to risk-stratify DCIS lesions and guide decisions for operative management.

The Breast JournalVolume 27, Issue 4 p. 406-408 COMMENTARY Accuracy of sentinel lymph node biopsy in invasive lobular carcinoma of the breast: Factors associated with false negatives Rita A. Mukhtar MD, Corresponding Author Rita A. Mukhtar MD rita.mukhtar@ucsf.edu orcid.org/0000-0001-8079-7846 Department of Surgery, University of California, San Francisco, CA, USA Correspondence Rita Mukhtar, 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA 94143. Email: rita.mukhtar@ucsf.eduSearch for more papers by this authorCase E. Brabham AB, Case E. Brabham AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorRuby Guo AB, Ruby Guo AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorMary Kathryn Abel AB, Mary Kathryn Abel AB Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorJasmine Wong MD, Jasmine Wong MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorCheryl Ewing MD, Cheryl Ewing MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorLaura J. Esserman MD, MBA, MD, Laura J. Esserman MD, MBA, MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorMichael Alvarado MD, Michael Alvarado MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this author Rita A. Mukhtar MD, Corresponding Author Rita A. Mukhtar MD rita.mukhtar@ucsf.edu orcid.org/0000-0001-8079-7846 Department of Surgery, University of California, San Francisco, CA, USA Correspondence Rita Mukhtar, 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA 94143. Email: rita.mukhtar@ucsf.eduSearch for more papers by this authorCase E. Brabham AB, Case E. Brabham AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorRuby Guo AB, Ruby Guo AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorMary Kathryn Abel AB, Mary Kathryn Abel AB Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorJasmine Wong MD, Jasmine Wong MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorCheryl Ewing MD, Cheryl Ewing MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorLaura J. Esserman MD, MBA, MD, Laura J. Esserman MD, MBA, MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorMichael Alvarado MD, Michael Alvarado MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this author First published: 24 January 2021 https://doi.org/10.1111/tbj.14161Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume27, Issue4April 2021Pages 406-408 RelatedInformation

Neoadjuvant therapy in breast cancer can downstage axillary lymph nodes and reduce extent of axillary surgery. As such, accurate determination of nodal status after neoadjuvant therapy and before surgery impacts surgical management. There are scarce data on the diagnostic accuracy of breast magnetic resonance imaging (MRI) for nodal evaluation after neoadjuvant therapy in patients with invasive lobular carcinoma (ILC), a diffusely growing tumor type. We retrospectively analyzed patients with stage 1–3 ILC who underwent pre-operative breast MRI after either neoadjuvant chemotherapy or endocrine therapy at our institution between 2006 and 2019. Two breast radiologists reviewed MRIs and evaluated axillary nodes for suspicious features. All patients underwent either sentinel node biopsy or axillary dissection. We evaluated sensitivity, specificity, negative and positive predictive values, and overall accuracy of the post-treatment breast MRI in predicting pathologic nodal status. Of 79 patients, 58.2% received neoadjuvant chemotherapy and 41.8% neoadjuvant endocrine therapy. The sensitivity and negative predictive value of MRI were significantly higher in the neoadjuvant endocrine therapy cohort than in the neoadjuvant chemotherapy cohort (66.7 vs. 37.9%, p = 0.012 and 70.6 vs. 40%, p = 0.007, respectively), while overall accuracy was similar. Upstaging from clinically node negative to pathologically node positive occurred in 28.0 and 41.7%, respectively. In clinically node positive patients, those with an abnormal post-treatment MRI had a significantly higher proportion of patients with ≥4 positive nodes on pathology compared to those with a normal MRI (61.1 versus 16.7%, p = 0.034). Overall, accuracy of breast MRI for predicting nodal status after neoadjuvant therapy in ILC was low in both chemotherapy and endocrine therapy cohorts. However, post-treatment breast MRI may help identify patients with a high burden of nodal disease (≥4 positive nodes), which could impact pre-operative systemic therapy decisions. Further studies are needed to assess other imaging modalities to evaluate for nodal disease following neoadjuvant therapy and to improve clinical staging in patients with ILC.

Abstract Purpose: Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision usually with radiation therapy or mastectomy and often endocrine therapy, treatments that are the same as for invasive cancer (IDC). It is clear, however that not all patients with DCIS will develop IDC and so the question is who benefits from early surgical intervention? Active Surveillance (AS) with endocrine risk reduction presents an opportunity to improve outcomes by identifying those lesions that can be managed with endocrine therapy alone without immediate surgical intervention. An active surveillance cohort of women who chose not to have surgery at diagnosis were followed with serial MRIs to identify the imaging features associated with successful AS and those with IDC. Methods: Patients with DCIS were enrolled in MRI surveillance studies between 2002 and 2019 and analyzed retrospectively with IRB approval. Per medical record review, these patients sought to avoid surgical intervention. Inclusion criteria included at least two breast MRIs performed for purposes of surveillance. The final cohort of patients included 64 cases with at least two breast MRIs, with 27 patients having more than 4 MRIs. All breast MRIs consisted of routine sequences, including both pre and post IV contrast images with at least 2 post-contrast time points. Lesion conspicuity, change in lesion, background parenchymal enhancement (BPE), change in BPE, and likelihood of invasive cancer at each MRI timepoint, were subjectively measured independently by two breast radiologists. A Likert scale was used to grade each imaging feature. Radiologists were blinded to the clinical outcome of whether the patient had IDC at surgery or not. Input variables included all imaging features collected and classification trees were trained and bootstrapped on 90% of the data using recursive partitioning to distinguish imaging features predictive of clinical outcome. Proportionality tests were conducted to test whether IDC was associated with age, menopausal status, and breast composition among other clinical variables.Results: Women in the cohort had a mean age of 53.6 years (range 29.8 to 78.9). 98.3% were HR+. Of the 64 cases in the cohort, 57 received endocrine therapy (89.1%). A total of 31 cases (48.4%) eventually had surgical excision and 33 (51.6%) remained on AS. At surgery, 17 patients had IDC (26.6%). Classification trees revealed that the most distinguishing features in the model correlating with IDC were if the lesion was distinct from background at MRI timepoint 1, an increase in BPE between MRI timepoints 1 and 2, and an increase in the lesion size or conspicuity between MRI timepoints 1 and 2. At diagnosis, 56.3% demonstrated a more diffuse pattern of enhancement where the DCIS lesion was not distinguishable above background. Of those with lesions that did not stand out above background at diagnosis and whose BPE did not increase, only 1 of 31 patients developed IDC (3%) with mean follow up of 4.62 years. Patients with IDC were proportionately older (>60) and post-menopausal (73% with IDC were postmenopausal), although only 57% were postmenopausal at diagnosis. Other variables such as breast composition were not enriched in either the IDC versus the non-IDC population. Conclusion: Our study suggests that imaging markers such as BPE and conspicuity of lesion enhancement may provide information to better understand and stratify the risk of DCIS and avoid overtreatment. Importantly, MRI may provide insight as to when a diagnosis of DCIS is more likely to be a global risk factor amenable to endocrine risk reduction, versus a lesion best treated with surgical excision. Pathology correlation is underway. We are currently developing methods to improve reproducibility and harmonization between radiologists, and performance on a validation set will be presented. Citation Format: Heather Greenwood, Rita Freimanis, Case Brabham, Rita Mukhtar, Gillian Hirst, Paul Kim, April Liang, Laura Esserman, Nola Hylton, Amrita Basu. Magnetic resonance imaging insights from an active surveillance cohort of women with DCIS [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-01.

Abstract Introduction: Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision with radiation and often endocrine therapy. However, not all DCIS progresses to invasive ductal carcinoma (IDC); thus, surgical intervention may constitute overtreatment for DCIS that has low risk for progressing to IDC. A period of active surveillance (AS) with magnetic resonance imaging (MRI) monitoring may offer the opportunity to stratify lesions with high and low risk for invasion and to avoid overtreatment of DCIS. The purpose of this study was to characterize the outcomes of a cohort of women who elected to go on AS to avoid surgical intervention and to identify whether clinical and imaging features would identify patients who should convert to operative management. Methods: The clinicopathologic variables and outcomes of patients with DCIS who prospectively enrolled in MRI monitoring studies between 2002 and 2019 were retrospectively analyzed with IRB approval. We included 64 cases among 63 women who declined standard operative management for DCIS and had at least two breast MRIs. Clinicopathologic data and physician recommendations regarding continuing surveillance versus converting to operative management were recorded from the medical record. Those who had surgical excision showing IDC were considered to have progressed; those with only DCIS at excision or no operative intervention were considered to have stable disease. Results: Women in the cohort were an average of 53.6 years (29.8 - 78.9) old, and nearly all cases of DCIS with estrogen receptor (ER) status were ER+ (98.3%). Of the 64 cases in the cohort, 57 received endocrine therapy (89.1%). Average length of time on AS was 2.7 years (.2 – 11.9) with a median of 3 (2 – 18) MRIs performed and mean follow-up time 5.6 years (0.9 – 15.3). A total of 31 cases (48.4%) eventually had surgical excision while 33 (51.6%) remained on AS. There were 17 cases with IDC at surgery (26.6%). The IDC was an average of 1.5 cm (0.1 – 9.0) and most commonly ER + (88.2%), HER2 + (53.3%), grade 2 (58.9%), and node negative (82.4%). Only 7 women did not take endocrine therapy, but 3 of those women had IDC (42.9%). In 15 of the 17 cases with IDC (88.2%), the physician noted concern for progression in their clinic note and recommended surgical excision. This occurred a mean of 1.9 years (0.2 – 6.5) from the start of AS, with 47%, 67%, and 87% of cases identified within 1, 2 and 3 years from the start of AS. Suspicion of progression was based on an increase in lesion size or prominence on MRI and/or increase in calcifications on mammography. Of those that were identified as good candidates to continue AS with no concern for progression (n = 49), 16 chose to undergo surgical excision (32.7%) and 2 had IDC (4.1%). Conclusion: After over a decade of following women who seek alternatives to surgery for DCIS, we have identified clinicopathologic and imaging features that discriminate good candidates for AS and endocrine risk reducing therapy from those best treated with surgical excision. In our cohort of mostly ER+ patients receiving endocrine therapy on AS, over half of the cohort (51.6%) avoided surgical intervention. Her2 status, Oncotype DCIS, and Mammaprint scores of IDC is in process and will be presented. Our data support the study of AS as a method to stratify the risk of IDC and avoid overtreatment. We will present a personalized AS algorithm (based on biology and imaging) that we intend to prospectively test in the ATHENA network and NCI funded MCL consortium. Table 1: Cohort CharacteristicsFull Cohort (n=64)No evidence of IDC (n=47)IDC at surgery (n=17)Age at Diagnosis (years)53.6 (29.8 - 78.9)52.9 (29.8 - 74.5)55.5 (41.9 - 78.9)Time on AS (years)2.7 (.2 - 11.9)2.8 (.2 - 11.9)2.2 (.3 -5.9)Follow-Up (years)5.6 (0.9 - 15.3)Menopausal StatusPremenopausal26 (40.6%)22 (46.8%)4 (23.5%)Postmenopausal35 (54.7%)24 (51.1%)11 (64.7%)Unknown3 (4.7%)1 (2.1%)2 (11.8%)Breast CompositionFatty4 (6.3%)3 (6.4%)1 (5.9%)Scattered14 (21.9%)9 (19.1%)5 (29.4%)Heterogeneous27 (42.2%)19 (40.4%)8 (47.1%)Extreme17 (26.5%)14 (29.8%)3 (17.6%)Unknown2 (3.1%)2 (4.3%)0 (0.0%)ER StatusPositive57 (89.1%)41 (87.2%)16 (94.1%)Negative1 (1.6%)0 (0.0%)1 (5.9%)Unknown6 (9.3%)6 (12.8%)0 (0.0%)PR StatusPositive50 (78.1%)36 (76.6%)14 (82.3%)Negative5 (7.8%)3 (6.4%)2 (11.8%)Unknown9 (14.1%)8 (17.0%)1 (5.9%)GradeHigh20 (31.3%)15 (31.8%)5 (29.4%)Intermediate32 (50.0%)21 (44.6%)11 (64.7%)Low10 (15.6%)9 (19.1%)1 (5.9%)Unknown2 (3.1%)2 (28.5%)0 (0.0%Hormone TherapyYes57 (89.1%)43 (91.5%)14 (82.4%)No7 (10.9%)4 (8.5%)3 (17.6%) Citation Format: Case Brabham, Rita Mukhtar, April Liang, Paul Kim, Gillian Hirst, Amrita Basu, Heather Greenwood, Rita Freimanis, Alexander Borowsky, Shelley Hwang, Rick Baehner, Gregor Krings, Nola Hylton, Laura Esserman. Active surveillance for DCIS: Clinical outcomes at 5.6 years mean follow-up [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-03.

e12604 Background: The safety of the sentinel lymph node biopsy procedure (SLNB) in the surgical management of breast cancer relies upon a false negative rate (FNR) being less than 10%. The accuracy of SLNB in invasive lobular carcinoma (ILC), the second most common type of breast cancer, has not been evaluated. Because of high rates of false negative imaging and the diffuse growth pattern in ILC, less accurate pre-operative staging and a potentially unreliable lymphatic drainage pattern may impact the accuracy of SLNB in this tumor type. We therefore sought to characterize the accuracy of SLNB in a cohort of patients with ILC. Methods: We queried an institutional database of 707 patients with ILC and identified 196 patients who underwent SLN mapping with excision of both sentinel and non-sentinel nodes. A false negative was defined as having negative sentinel lymph nodes and a positive non-sentinel node. We calculated the FNR and sensitivity of SLNB and evaluated clinicopathologic variables. Results: Of 196 cases, 183 were clinically node-negative, 9 were clinically node-positive, and 4 had unknown clinical node status. Of the 183 clinically node-negative patients, 69 (37.7%) patients had node-positive disease at surgery. Overall, 7 of 196 cases had false negative SLNB, yielding an FNR of 8.97%. The sensitivity of SLNB was 91%. Patients with a false negative SLNB were significantly older than patients without (mean age 63 versus 54.7 years, p = 0.041). Significantly fewer sentinel and non-sentinel nodes were removed in women aged 50 years or older compared to those under 50 (1.9 vs. 2.5 sentinel nodes, p = 0.0158; 4.7 vs. 7.9 non-sentinel nodes, p = 0.0077). There were no differences in tumor receptor subtype, grade, stage, presence of lymphovascular invasion, or receipt of neoadjuvant therapy in those with a false negative SLNB compared to those without. Conclusions: The high rate of nodal positivity in clinically node negative patients highlights the challenges of clinical nodal assessment in ILC. Despite this, the SLNB procedure had a FNR that fell within the acceptable range, supporting its use in ILC. The relationship between number of sentinel nodes removed and FNR deserves further study, particularly in older women where extent of nodal surgery continues to decline.

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 We are interested in identifying molecular and tumor immune microenvironment factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: We are conducting a retrospective pilot study (DEFENSE) of 10 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile to 10 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (>5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients will be divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunohistochemistry (mIHC) using three immune panels, and stromal profiling. Each profiling modality will be performed by a different institution included in the NIH Molecular Characterization of Screen-Detected Lesions (MCL) consortium. This pilot study will inform our decision to expand our study to a full-scale review of 200 patients (100 DCIS, 100 invasive cancer) among our institutions. Results: We have thus far demonstrated the feasibility of our pilot study with 10 blocks in total sent to and received by each institution. Whole exome DNA sequencing, SMART-3SEQ, mIHC, and stromal profiling work has begun and will be available for presentation, and we plan to make pathology, clinical and genomic data available through the MCL's collaborative partnership with the NASA Jet Propulsion Lab (JPL) cloud-based platform. Conclusions: We have successfully shown that a multi-institution collaborative can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that our data will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention. References: 1 Narod SA et al (2015). Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma in Situ. JAMA Oncol. 1(7): 888-96. Citation Format: Alexa Glencer, Olivier Harismendy, Alexander Borowsky, Gillian L. Hirst, Janet Stein, Mark Evans, Donald Weaver, Robert West, Case Brabham, Hidetoshi Mori, Laura J. Esserman. Understanding the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and the tumor immune microenvironment: The DEFENSE study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5440.

BackgroundThe safety of breast conservation therapy (BCT) has not been demonstrated in large ILC tumors, potentially contributing to the higher mastectomy rates seen in ILC.MethodsWe queried a prospectively maintained database to identify patients with ILC measuring ≥4 cm and evaluated difference in recurrence free survival (RFS) between those treated with BCT versus mastectomy using a multivariate model.ResultsOf 180 patients, 30 (16.7%) underwent BCT and 150 (83.3%) underwent mastectomy. Patients undergoing mastectomy were younger (56.6 vs. 64.3 years, p = 0.003) and had larger tumors (7.2 vs. 5.4 cm, p < 0.001). While tumor size, nodal stage, receptor subtype, and margin status were significantly associated with RFS, there was no difference in RFS at 5 (p = 0.88) or 10 (p = 0.65) years for individuals undergoing BCT versus mastectomy.ConclusionsFor patients with ILC ≥4 cm, BCT provides similar tumor control as mastectomy, provided that negative margins are achieved.