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Background: Ductal carcinoma in situ (DCIS) of the breast is an early stage of breast cancer, and preventing its progression to invasive ductal carcinoma (IDC) is crucial for the early detection and treatment of breast cancer. Although single-cell transcriptome analysis technology has been widely used in breast cancer research, the biological mechanisms underlying the transition from DCIS to IDC remain poorly understood., Results: We identified eight cell types through cell annotation, finding significant differences in T cell proportions between DCIS and IDC. Using this as a basis, we performed pseudotime analysis on T cell subpopulations, revealing that differentially expressed genes primarily regulate immune cell migration and modulation. By intersecting WGCNA results of T cells highly correlated with the subtypes and the differentially expressed genes, we identified six key genes: FGFBP2, GNLY, KLRD1, TYROBP, PRF1, and NKG7. Excluding PRF1, the other five genes were significantly associated with overall survival in breast cancer, highlighting their potential as prognostic biomarkers., Conclusions: We identified immune cells that may play a role in the progression from DCIS to IDC and uncovered five key genes that can serve as prognostic markers for breast cancer. These findings provide insights into the mechanisms underlying the transition from DCIS to IDC, offering valuable perspectives for future research. Additionally, our results contribute to a better understanding of the biological processes involved in breast cancer progression., (© 2024. The Author(s).)

Objective: To develop a nomogram that integrates clinical-pathologic and imaging variables to predict ipsilateral breast tumor recurrence (IBTR) in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)., Materials and Methods: This retrospective study included consecutive women with DCIS who underwent BCS at two hospitals. Patients who underwent BCS between 2003 and 2016 in one hospital and between 2005 and 2013 in another were classified into development and validation cohorts, respectively. Twelve clinical-pathologic variables (age, family history, initial presentation, nuclear grade, necrosis, margin width, number of excisions, DCIS size, estrogen receptor, progesterone receptor, radiation therapy, and endocrine therapy) and six mammography and ultrasound variables (breast density, detection modality, mammography and ultrasound patterns, morphology and distribution of calcifications) were analyzed. A nomogram for predicting 10-year IBTR probabilities was constructed using the variables associated with IBTR identified from the Cox proportional hazard regression analysis in the development cohort. The performance of the developed nomogram was evaluated in the external validation cohort using a calibration plot and 10-year area under the receiver operating characteristic curve (AUROC) and compared with the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram., Results: The development cohort included 702 women (median age [interquartile range], 50 [44-56] years), of whom 30 (4%) women experienced IBTR. The validation cohort included 182 women (48 [43-54] years), 18 (10%) of whom developed IBTR. A nomogram was constructed using three clinical-pathologic variables (age, margin, and use of adjuvant radiation therapy) and two mammographic variables (breast density and calcification morphology). The nomogram was appropriately calibrated and demonstrated a comparable 10-year AUROC to the MSKCC nomogram (0.73 vs. 0.66, P = 0.534) in the validation cohort., Conclusion: Our nomogram provided individualized risk estimates for women with DCIS treated with BCS, demonstrating a discriminative ability comparable to that of the MSKCC nomogram., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background/aim: Ductal carcinoma in situ is considered a local disease with no metastatic potential, thus sentinel lymph node biopsy (SLNB) may be deemed an overtreatment. SLNB should be reserved for patients with invasive cancer, even though the risk of upstaging rises to 25 %. We aimed to identify clinicopathological predictors of post-operative upstaging in invasive carcinoma., Methods: We retrospectively analyzed patients with a pre-operative diagnosis of DCIS subjected to breast surgery between January 2017 to December 2021, and evaluated at the Breast Unit of PTV (Policlinico Tor Vergata, Rome)., Results: Out of 267 patients diagnosed with DCIS, 33(12.4 %) received a diagnosis upstaging and 9(3.37 %) patients presented with sentinel lymph node (SLN) metastasis. In multivariate analysis, grade 3 tumor (OR 1.9; 95 % CI 1.2-5.6), dense nodule at mammography (OR 1.3; 95 % CI 1.1-2.6) and presence of a solid nodule at ultrasonography (OR 1.5; 95 % CI 1.2-2.6) were independent upstaging predictors. Differently, the independent predictors for SLNB metastasis were: upstaging (OR 2.1.; 95 % CI 1.2-4.6; p = 0.0079) and age between 40 and 60yrs (OR 1.4; 95 % CI 1.4-2.7; p = 0.027). All 9 patients with SLN metastasis received a diagnosis upstaging and were aged between 40 and 60 years old., Conclusion: We identified pre-operative independent predictors of upstaging to invasive ductal carcinoma. The combined use of different predictors in an algorithm for surgical treatments of DCIS could reduce the numbers of unnecessary SLNB., Competing Interests: Declaration of competing interest All the authors declare that they have no potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: As the benefits of intensive locoregional therapy for ductal carcinoma in situ (DCIS) are realized over time in older adults, life expectancy may help to guide treatment decisions. We examined whether life expectancy was associated with extent of locoregional therapy in this population., Patients and Methods: Women ≥ 70 years old with < 5 cm of DCIS diagnosed 2010-2015 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset and categorized by a life expectancy ≤ 5 or > 5 years, defined by a validated claims-based measure. Differences in locoregional therapy (mastectomy + axillary surgery, mastectomy-only, lumpectomy + radiation therapy (RT) + axillary surgery, lumpectomy + RT, lumpectomy-only, and no treatment) by life expectancy were assessed using Pearson chi-squared tests. Generalized linear mixed models were used to identify factors associated with receipt of lumpectomy-only., Results: Of 5346 women (median age of 75 years, range 70-97 years), 927 (17.3%) had a life expectancy ≤ 5 years. Of the 4041 patients who underwent lumpectomy, 710 (13.3%) underwent axillary surgery. More patients with life expectancy ≤ 5 years underwent lumpectomy-only (39.4% versus 27%), mastectomy-only (8.1% versus 5.3%), or no treatment (5.8% versus 3.2%; p < 0.001). On multivariable analysis, women with life expectancy ≤ 5 years had a significantly greater likelihood of undergoing lumpectomy-only [OR 1.90, 95% CI (1.63-2.22)]., Conclusions: Life expectancy is associated with lower-intensity locoregional therapy for older women with DCIS, yet a large proportion of patients with a life expectancy ≤ 5 years received RT and axillary surgery, highlighting potential overtreatment and opportunities to de-escalate locoregional therapy in older adults., (© 2024. Society of Surgical Oncology.)

Purpose: Ductal-carcinoma in situ (DCIS) is a pre-invasive form of breast cancer with good prognosis. Follow-up guidelines in the Netherlands are currently the same as for invasive breast cancer. Due to fear of invasive breast cancer or recurrence, it is hypothesized that follow-up for DCIS after treatment is more intense in practice resulting in potentially unnecessary high costs. This study investigates the follow-up in practice for patients with DCIS compared to the recommendations in order to inform clinicians and policy makers how to utilize these guidelines., Methods: Patients diagnosed with pure DCIS between 2004 and 2014 were followed up until 2018. Information on duration and frequency of follow-up visits, reasons and decision makers for shortening, and prolonging follow-up was collected. Prolonged follow-up was defined as deviation from the Dutch guideline: more than 5 years of follow-up and older than 60 years., Results: Of the 227 patients the mean number of visits per year was 1.4 and mean years of follow-up was 6.0. Thirty-three percent had prolonged follow-up and 26% shorter follow-up than recommended. A majority (78%) of decision for prolonged follow-up was being made by clinicians., Conclusion: Follow-up duration is in almost half of patients with DCIS according to guidelines and with most prolonged follow-up only up to a year longer than recommended. In most cases suspicious findings and the timing of the population screening program appeared to cause prolonged follow-up. If accepted by patients and clinicians, future DCIS specific guidelines should address these reasons and tailor to the individual risks., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Routine sentinel lymphadenectomy (SLNB) for early-stage HR+/HER2- breast cancer in women ≥70 is discouraged by Choosing Wisely, but whether SLNB can be routinely omitted in women ≥70 with DCIS undergoing mastectomy is unclear. This study aims to evaluate rates of axillary surgery and nodal positivity (pN+) in this population to determine the impact of axillary surgery on treatment decisions., Methods: Females ≥70 with DCIS undergoing mastectomy were identified from the National Cancer Database (2012-2020). The rate of upstaging to invasive cancer (≥pT1) or pN+ was assessed. Subset analyses were conducted for ER+ patients. Adjuvant therapies were evaluated among ≥pT1 patients after stratifying by nodal status., Results: Of 9,030 patients, 1,896 (21%) upstaged to ≥pT1. Axillary surgery was performed in 86% of patients, predominantly sentinel lymphadenectomy (SLNB, 65%). Post hoc application of Choosing Wisely criteria demonstrated that 93% of the entire cohort and 97% of ER+ DCIS patients could have avoided axillary surgery. Nodal positivity was 0.3% among those who didn't upstage, and 12% among those upstaging to ≥pT1, with <2% having pN2-3 disease, irrespective of receptor subtype. Node-positive patients had higher adjuvant therapy usage, but there was no recommendation for adjuvant chemotherapy or radiation for 71% and 66% of pN+ patients, respectively., Conclusions: Axillary surgery can be omitted for most patients ≥70 undergoing mastectomy for ER+ DCIS, aligning with recommendations for invasive cancer, and omission can be considered in those with ER- disease. Future guidelines incorporating preoperative imaging, as in the SOUND trial, may aid in identifying patients benefiting from axillary surgery., (© 2024. Society of Surgical Oncology.)

Traditionally, management of early-stage breast cancer has required adjuvant radiation therapy following breast conserving surgery, due to decreased local recurrence and breast cancer mortality. However, over the past decade, there has been an increasing emphasis on potential overtreatment of patients with early-stage breast cancer. This has given rise to questions of how to optimize deintensification of treatment in this cohort of patients while maintaining clinical outcomes. A multitude of studies have focused on identification of a subset of patients with invasive breast cancer who were at low risk of local recurrence based on clinicopathologic features and therefore suitable for RT omission. These studies have failed to identify a subset that does not from RT with respect to local control. Several ongoing trials are evaluating alternative approaches to deintensification while focusing on tumor biology. With regards to ductal carcinoma in situ (DCIS), the role of RT has been questioned since breast conservation was utilized. Paralleling invasive disease studies, studies have sought to use clinicopathologic features to identify low risk patients suitable for RT omission but have failed to identify a subset that does not from RT with respect to local control. Use of new assays in patients with DCIS may represent the ideal approach for risk stratification and appropriate deintensification. At this time, when considering deintensification, individualizing treatment decisions with a focus on shared decision making is paramount., Competing Interests: Disclosure The author Chirag Shah reported Consultant Impedimed, PreludeDX, and Videra Surgical as conflicts of interest. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Proliferative breast atypical lesions, including atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasms (LIN), represent benign entities that confer an elevated risk of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). However, the timing of disease progression is variable and risk factors associated with the trajectory of disease are unknown., Methods: Patients diagnosed with ADH or LIN from 1992 to 2017 at an academic center were identified. Early progression was defined as DCIS or IBC diagnosed within 5 years following the initial atypia diagnosis. Unadjusted cancer-free survival was estimated using the Kaplan-Meier method. Demographics, clinicopathologic features, and use of chemoprevention were compared between the early and late development groups., Results: Overall, 418 patients were included-73.7% with ADH and 26.3% with LIN. Over a median follow up of 92.1 months, 71/418 (17.0%) patients developed IBC (57.7%) or DCIS (42.3%). Almost half (47.9%, 34/71) were diagnosed within 5 years of their initial atypia diagnosis, and 52.1% (37/71) were diagnosed after 5 years. Patient and atypia characteristics were not associated with rate of events or time to events. There was a trend of early events being more often ipsilateral (76.5% early vs. 54.1% late; p = 0.13) versus contralateral., Conclusions: In a large cohort of patients with breast atypia and long-term follow up, 17% experienced subsequent breast events, with approximately half of the events occurring within the first 5 years following the initial atypia diagnosis. Clinical features were not associated with the trajectory to subsequent events, supporting that atypia signals both local and overall malignancy risk., (© 2024. Society of Surgical Oncology.)

Background: Consensus guidelines recommend ≥ 2 mm margins in patients undergoing partial mastectomy (PM) for ductal carcinoma in situ (DCIS). It is unknown whether the number or proximity of margins less than 2 mm is associated with an increased mastectomy rate in patients attempting breast conservation therapy (BCT) for DCIS. The aim of this study is to examine this relationship., Patients and Methods: An institutional database review identified 208 patients with DCIS who underwent PM at a tertiary referral center and community hospitals from July 2020 to June 2023. Patients with a history of breast cancer, previous surgery for breast cancer, ipsilateral invasive carcinoma, papillary carcinoma, Paget's disease, more lobular carcinoma in situ (LCIS) than DCIS present, initial mastectomy, no DCIS present, routine shave margins (of all vectors), and ≥ 2 mm margins of all six vectors were excluded. Selective intraoperative margin re-excisions were included., Results: A total of 208 patients who met inclusion criteria were retrospectively reviewed. 122 (25%) had one close/positive (< 2 mm) margin and 86 (18%) had two or more close/positive margins. Of the patients with one close/positive margin, 7% (9/122) eventually underwent mastectomy. Of the patients with two or more close/positive margins, 20% (17/86) eventually underwent mastectomy. Overall, no patients with opposing margins underwent mastectomy., Conclusions: Patients undergoing PM for DCIS have a mastectomy rate that is increased threefold, with two or more close/positive margins at initial PM, when compared with those with only one close/positive margin. The presence of opposing close/positive margins at initial PM did not increase the mastectomy rate and most were cleared with re-excision., (© 2024. Society of Surgical Oncology.)

Background: Early invasive ductal carcinoma (IDC) breast cancer often presents with a coexisting ductal carcinoma in situ (DCIS) component, while about 5 % of cases present with an extensive (>25 %) intraductal component (EIC). The impact of EIC on the genomic risk of recurrence is unclear., Methods: Patients with early hormone receptor-positive HER2neu-negative (HR + HER2-) IDC breast cancer and a known OncotypeDX Breast Recurrence Score® (RS) who underwent breast surgery at our institute were included. Using a rule-based text-analysis algorithm, we analyzed pathological reports and categorized patients into three groups: EIC, non-extensive DCIS (DCIS-L), and pure-IDC (NO-DCIS). Genomic risk was determined using OncotypeDX RS., Results: A total of 33 (4.6 %) EIC cases, 377 (57.2 %) DCIS-L cases and 307 (42.8 %) NO-DCIS cases were identified. Patients in the EIC group were younger and had lower tumor grades than other groups. The distribution of genomic risk varied between the groups, with EIC tumors significantly less likely to have a high RS (>25) compared to DCIS-L and No-DCIS tumors (3 % vs 20 % and 20 %, respectively; p = 0.03). When adjusted to age, tumor size, grade and LNs involvement, both DCIS-L and NO-DCIS groups were significantly correlated with a higher probability of high RS compared to the EIC group (OR 12.3 and OR 13.1, respectively; p < 0.02). Moreover, patients with EIC had a lower likelihood for adjuvant chemotherapy recommendation., Conclusions: In early HR + HER2- IDC, an EIC correlates with a reduced genomic recurrence risk. The impact on genomic risk seems to be influenced by the extent, not merely the presence, of DCIS., Competing Interests: Declaration of competing interest Y.Bar reports consulting fees from Eli lilly, Roche, Stemline and Gilead and travel fees from Gilead. A.Sonnenblick reports consulting fees from Eli lilly, Teva, Pfizer, Novartis, Roche, Gilead, MSD, Astra-Zenca, Progenetics and Rhenium; Travel fees from Neopharm, Celgene, Medison, Roche and MSD and grant support from Novartis and Roche, all outside the submitted work. I.Wolf reports research grants from MSD, BMS, Roche and Novartis; S. Strulov Shachar reports consulting fees from: Pfizer, Novartis, Roche, Medison, MSD, AstraZeneca, Eli Lilly, ProGenetics, Gilead and Stemline and travel fees from Pfizer, Roche, Gilead and AstraZeneca, all outside the submitted work. The rest of the authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: BreastScreen Australia, the population mammographic screening program for breast cancer, uses two-view digital screening mammography ± ultrasound followed by percutaneous biopsy to detect breast cancer. Secondary breast imaging for further local staging, not performed at BreastScreen, may identify additional clinically significant breast lesions. Staging options include further mammography, bilateral ultrasound, and/or contrast-based imaging (CBI) [magnetic resonance imaging (MRI) or contrast-enhanced mammography (CEM)]. CBI for local staging of screen-detected cancer was introduced at an academic hospital breast service in Melbourne, VIC, Australia. We report findings for otherwise occult disease and resulting treatment changes., Material and Methods: Patients staged using CEM between November 2018 and April 2022 were identified from hospital records. Data were extracted from radiology, pathology, and breast unit databases. CEM-detected abnormalities were documented as true positive (TP) for invasive cancer or ductal carcinoma in situ (DCIS), or otherwise false positive (FP). The impact on surgical decisions was assessed., Results: Of 202 patients aged 44-84 years, 60 (30%) had 74 additional findings [34 (46%) TP, 40 (54%) FP]. These were malignant in 29/202 (14%) patients (79% invasive cancers, 21% DCIS). CEM resulted in surgical changes in 43/202 (21%) patients: wider resection (24/43), conversion to mastectomy (6/43), contralateral breast surgery (6/43), additional ipsilateral excision (5/43), and bracketing (2/43). Additional findings were more common for patients with larger index lesions and for invasive cancer, but there was no significant variation by age, breast density, or index lesion grade., Conclusions: CEM for local staging of screen-detected breast cancers identified occult malignancy in 14% of patients. CEM improves local staging and may facilitate appropriate management of screen-detected breast cancers., (© 2024. Society of Surgical Oncology.)

Currently, there is no robust evidence demonstrating a clear association between Lynch syndrome and non-malignant breast pathology such as adenomyoepithelioma. We report a case of benign breast adenomyoepithelioma, which after recurrence was associated with ductal carcinoma in-situ (DCIS) in a 41-year-old woman with Lynch syndrome, who lacked significant family history of breast or ovarian cancer. Both, the adenomyoepithelioma and DCIS were found to have nuclear loss of MSH2/MSH6 by immunohistochemistry, while germline testing confirmed MSH2 gene mutation. Concordant loss of MSH2 in both lesions in the context of a MSH2 pathogenic variant in this patient with Lynch syndrome illustrates that the benign adenomyoepithelioma behaved as a likely precursor of DCIS. Our report provides a novel perspective that in some patients with Lynch syndrome adenomyoepithelioma may represent a pre-malignant precursor lesion of DCIS., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Current guidelines do not recommend routine sentinel node biopsy (SLNB) for ductal carcinoma in situ (DCIS), except in the setting of mastectomy or microinvasive disease. This study aimed to evaluate national SLNB utilization in women undergoing upfront mastectomy for DCIS, identify predictors of SLNB utilization, and determine the percentage with a positive SLNB., Methods: A retrospective cohort analysis was performed using the NCDB of women with clinical DCIS who underwent upfront mastectomy between 2012 and 2017. Demographic and clinicopathologic variables were compared between patients who underwent SLNB and those who did not. Multivariate logistic regression models were used to identify factors associated with SLNB utilization and positive SLNB., Results: About 38,973 patients met inclusion criteria: 34,231 (88%) underwent SLNB and 4742 (12%) had no surgical axillary staging. Most patients were age 50-69 (51%), non-Hispanic White (71%), with private insurance (66%). On multivariate analysis, older patients were less likely to receive SLNB (P < .01), while patients with higher grade DCIS were more likely to undergo SLNB (P < .01). In those who underwent SLNB (n = 34,231), only 1,149 (3.4%) had nodal involvement. Non-Hispanic Black patients had increased odds of a positive SLNB (P < .01), while those with estrogen receptor positive disease were less likely to be node positive (OR 0.68, P < .001)., Conclusions: While 88% of patients had a SLNB, only 3.4% were found to be node positive. Given this low rate, it is reasonable to consider SLNB omission in select patients with low grade, hormone receptor positive DCIS undergoing upfront mastectomy., Competing Interests: Disclosures All authors have no disclosures to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). The inability to accurately estimate an individual's risk of local recurrence (LR) and invasive LR using clinicopathologic factors (CPF) contributes to the overtreatment of DCIS. We examined the impact of the 12-gene DCIS Score (DS) and the 21-gene Recurrence Score (RS) on the accuracy of predicting LR and invasive LR., Methods: A population-based cohort diagnosed with pure DCIS treated with BCS ± RT from 1994 to 2003 was used. All patients had expert pathology review and assessment of the DS and RS. Predictive models (CPF alone, DS + CPF, and RS + CPF) were developed using multivariable Cox regression analyses to predict 10-year LR and invasive LR risks. Models were evaluated on the basis of c-statistic, -2log likelihood estimate (-2LLE), and Akaike information criterion. Calibration was performed using bootstrap resamples, with replacement., Results: The cohort includes 1,226 women treated with BCS; 712 received RT. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive. Models including the DS or RS performed better in predicting the 10-year risk of LR compared with models on the basis of CPF alone with excellent calibration. The two molecular-based models also performed better in predicting invasive LR compared with the CPF model but the model incorporating the RS did not perform better in the prediction of invasive LR compared with the DS-based model., Conclusion: Models incorporating the DS or RS more accurately predicted the 10-year risk of LR and invasive LR after BCS compared with models on the basis of CPF alone. Inclusion of the RS, compared with DS, did not improve the prediction of the 10-year risk of invasive LR.

Background: The heterogeneous biology of ductal carcinoma in situ (DCIS), as well as the variable outcomes, in the setting of numerous treatment options have led to prognostic uncertainty. Consequently, making treatment decisions is challenging and necessitates involved communication between patient and provider about the risks and benefits. We developed and investigated an interactive decision support tool (DST) designed to improve communication of treatment options and related long-term risks for individuals diagnosed with DCIS., Findings: The DST was developed for use by individuals aged > 40 years with DCIS and is based on a disease simulation model that integrates empirical data and clinical characteristics to predict patient-specific impacts of six DCIS treatment choices. Personalized risk predictions for each treatment option were communicated using icon arrays and percentages for each outcome. Users of the DST were asked before and after interacting with the DST about: (1) awareness of DCIS treatment options, (2) willingness to consider these options, (3) knowledge of risks associated with DCIS, and (4) helpfulness of the DST. Data were collected from January 2019 to April 2022. Users' median estimated risk of dying from DCIS in 10 years decreased from 9% pre-tool to 3% post-tool (p < 0.0001). 76% (n = 101/132) found the tool helpful., Conclusions: Information about DCIS treatment options and related risk predictions was effectively communicated, and a large majority participants found the DST to be helpful. Successfully informing patients about their treatment options and how their individual risks affect those options is a critical step in the decision-making process., Clinicaltrials: gov Identifier NCT02926911., (© 2024. The Author(s).)

Background: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated., Methods: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up., Results: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups., Conclusions: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women., (© 2024. The Author(s).)

Background: The first aim of this study was to examine trends in the risk of ipsilateral invasive breast cancer (iIBC) after breast-conserving surgery (BCS) of ductal carcinoma in situ (DCIS). A second aim was to analyse the association between DCIS grade and the risk of iIBC following BCS., Patients and Methods: In this population-based, retrospective cohort study, the Netherlands Cancer Registry collected information on 25,719 women with DCIS diagnosed in the period 1989-2021 who underwent BCS. Of these 19,034 received adjuvant radiotherapy (RT). Kaplan-Meier analyses and Cox regression models were used., Results: A total of 1135 patients experienced iIBC. Ten-year cumulative incidence rates of iIBC for patients diagnosed in the periods 1989-1998, 1999-2008 and 2009-2021 undergoing BCS without RT, were 12.6%, 9.0% and 5.0% (P < 0.001), respectively. For those undergoing BCS with RT these figures were 5.7%, 3.7% and 2.2%, respectively (P < 0.001). In the multivariable analyses, DCIS grade was not associated with the risk of iIBC., Conclusion: Since 1989 the risk of iIBC has decreased substantially and has become even lower than the risk of invasive contralateral breast cancer. No significant association of DCIS grade with iIBC was found, stressing the need for more powerful prognostic factors to guide the treatment of DCIS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: In up to 72 % of HER2+ invasive breast cancer (IBC), a ductal carcinoma in situ (DCIS) component is present. The presence of DCIS is associated with increased positive surgical margins after breast-conserving surgery (BCS). The aim of this study was to assess surgical margins, recurrence and survival in a nationwide cohort of HER2+ IBC with versus without a DCIS component, treated with neoadjuvant systemic therapy (NST) and BCS., Materials and Methods: Women diagnosed with HER2+ IBC treated with NST and BCS, between 2010 and 2019, were selected from the Netherlands Cancer Registry and linked to the Dutch Nationwide Pathology Databank. Kaplan-Meier and Cox regression analyses were performed to determine locoregional recurrence rate (LRR) and overall survival (OS) and associated clinicopathological variables. Surgical outcomes and prognosis were compared between IBC only and IBC+DCIS., Results: A total of 3056 patients were included: 1832 with IBC and 1224 with IBC+DCIS. Patients with IBC+DCIS had significantly more often positive surgical margins compared to IBC (12.8 % versus 4.9 %, p < 0.001). Five-year LRR was significantly higher in patients with IBC+DCIS compared to IBC (6.8 % versus 3.6 %, p < 0.001), but the presence of DCIS itself was not significantly associated with LRR after adjusting for confounders in multivariable analysis. Five-year OS did not differ between IBC+DCIS and IBC (94.9 % versus 95.7 %, p = 0.293)., Conclusion: The presence of DCIS is associated with higher rates of positive surgical margins, but not with LRR and lower OS when adjusted for confounders. Further research is necessary to adequately select IBC+DCIS patients for BCS after NST., Competing Interests: Declaration of competing interest Prof. Dr. Smidt reports grants from Nutricia and Servier Pharmaceuticals for microbiome research in colorectal cancer, and use of material from Illumina, not related to this study. Dr. T. van Nijnatten received institutional grant support from Bayer, and speaker honoraria from GE Healthcare and Bayer, not related to this study. L. Kooreman reports consulting fees from Novartis and educational fees from SCEM, not related to this study. All author authors report no declarations of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations., Methods: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations., Results: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria., Conclusions: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients., Trial Registration: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 )., (© 2024. The Author(s).)

Purpose: We aimed to update the trend of hypofractionated whole-breast irradiation (HF-WBI) use over time in the US and examine factors associated with lack of HF-WBI adoption for patients with early-stage invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) undergoing a lumpectomy., Methods and Materials: Among patients who underwent a lumpectomy, we identified 928,034 patients with early-stage IBC and 330,964 patients with DCIS in the 2004 to 2020 National Cancer Database. We defined HF-WBI as 2.5-3.33 Gy/fraction to the breast and conventionally fractionated WBI as 1.8-2.0 Gy/fraction. We evaluated the trend of HF-WBI utilization using a generalized linear model with the log link and binomial distribution. Factors associated with HF-WBI utilization were assessed using multivariable logistic regression in patients diagnosed between 2018 and 2020., Results: Among patients with IBC, HF-WBI use has significantly increased from 0.7% in 2004 to 63.9% in 2020. Similarly, HF-WBI usage among patients with DCIS has also increased significantly from 0.4% in 2004 to 56.6% in 2020. Black patients with IBC were less likely than White patients to receive HF-WBI (adjusted odds ratio [AOR] 0.81; 95% CI, 0.77-0.85). Community cancer programs were less likely to administer HF-WBI to patients with IBC (AOR, 0.80; 95% CI, 0.77-0.84) and to those with DCIS (AOR, 0.87; 95% CI, 0.79-0.96) than academic/research programs. Younger age, positive nodes, larger tumor size, low volume programs, and facility location were also associated with lack of HF-WBI adoption in both patient cohorts., Conclusions: HF-WBI utilization among postlumpectomy patients has significantly increased from 2004 to 2020 and can finally be considered standard of care in the US. We found substantial disparities in adoption within patient and facility subgroups. Reducing disparities in HF-WBI adoption has the potential to further alleviate health care costs while improving patients' quality of life., Competing Interests: Disclosures None., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: International guidelines recommend open surgery for atypical ductal hyperplasia (ADH) in the breast due to risk of underestimating malignant disease. Considering the ongoing randomized trials of active surveillance of low-risk ductal carcinoma in situ (DCIS), it seems reasonable to define a low-risk group of women with ADH where a conservative approach is appropriate. The aim here was to evaluate the management and risk for upgrade of lesions diagnosed as ADH in percutaneous breast biopsies in two Swedish hospitals., Methods: All women with a screen-detected or symptomatic breast lesion breast imaging-reporting and data system (BI-RADS) 2-4 and a percutaneous biopsy showing ADH between 2013 and 2022 at Sundsvall Hospital and Umeå University Hospital were included. Information regarding imaging, histopathology, clinical features, and management was retrieved from medical records. Odds ratio (OR) and 95% confidence intervals (CI) for upgrade to malignant diagnosis after surgery were calculated by logistic regression analysis., Results: Altogether, 101 women were included with a mean age 56.1 (range 36-93) years. Most women were selected from the national mammography screening program due to microcalcifications. Biopsies were performed with vacuum-assisted biopsy (60.4%) or core-needle biopsy (39.6%). Forty-eight women (47.5%) underwent surgery, of which 11 were upgraded to DCIS, and 7 to invasive breast cancer (upgrade rate 37.5%). Among the 53 women managed conservatively (median follow-up 74 months), one woman (1.9%) developed subsequent ipsilateral DCIS. The combined upgrade rate was 18.8%. No clinical variable statistically significantly correlating to risk of upgrade was identified., Conclusions: The upgrade rate of 37.5% in women undergoing surgery compared to an estimated 5-year risk of ipsilateral malignancy at 1.9% in women managed conservatively indicate that non-surgical management of select women with ADH is feasible. Research should focus on defining reproducible criteria differentiating high-risk from low-risk ADH., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose To determine whether time-dependent deep learning models can outperform single time point models in predicting preoperative upgrade of ductal carcinoma in situ (DCIS) to invasive malignancy at dynamic contrast-enhanced (DCE) breast MRI without a lesion segmentation prerequisite. Materials and Methods In this exploratory study, 154 cases of biopsy-proven DCIS (25 upgraded at surgery and 129 not upgraded) were selected consecutively from a retrospective cohort of preoperative DCE MRI in women with a mean age of 59 years at time of diagnosis from 2012 to 2022. Binary classification was implemented with convolutional neural network (CNN)-long short-term memory (LSTM) architectures benchmarked against traditional CNNs without manual segmentation of the lesions. Combinatorial performance analysis of ResNet50 versus VGG16-based models was performed with each contrast phase. Binary classification area under the receiver operating characteristic curve (AUC) was reported. Results VGG16-based models consistently provided better holdout test AUCs than did ResNet50 in CNN and CNN-LSTM studies (multiphase test AUC, 0.67 vs 0.59, respectively, for CNN models [ P = .04] and 0.73 vs 0.62 for CNN-LSTM models [ P = .008]). The time-dependent model (CNN-LSTM) provided a better multiphase test AUC over single time point (CNN) models (0.73 vs 0.67; P = .04). Conclusion Compared with single time point architectures, sequential deep learning algorithms using preoperative DCE MRI improved prediction of DCIS lesions upgraded to invasive malignancy without the need for lesion segmentation. Keywords: MRI, Dynamic Contrast-enhanced, Breast, Convolutional Neural Network (CNN) Supplemental material is available for this article. © RSNA, 2024.

Background: Retrospective observational studies suggest a potential role of beta-blockers as a protective strategy against progression and metastasis in invasive breast cancer. In this context, we investigated the impact of beta-blocker exposure on risk for progression to invasive breast cancer after diagnosis of ductal cancer in situ (DCIS)., Methods: The retrospective study population included 2535 women diagnosed with pure DCIS between 2006 and2012 in three healthcare regions in SwedenExposure to beta-blocker was quantified using a time-varying percentage of days with medication available. The absolute risk was quantified using cumulative incidence functions and cox models were applied to quantify the association between beta-blocker exposure and time from DCIS diagnosis to invasive breast cancer, accounting for delayed effects, competing risks and pre-specified confounders., Results: The median follow-up was 8.7 years. One third of the patients in our cohort were exposed to beta-blockers post DCIS diagnosis. During the study period, 48 patients experienced an invasive recurrence, giving a cumulative incidence of invasive breast cancer progression of 1.8% at five years. The cumulative exposure to beta-blocker was associated with a reduced risk in a dose-dependent manner, though the effect was not statistically significant., Conclusion: Our observational study is suggestive of a protective effect of beta-blockers against invasive breast cancer after primary DCIS diagnosis. These results provide rationales for experimental and clinical follow-up studies in carefully selected DCIS groups., (© 2024. The Author(s).)

The exact relationship between solid papillary carcinoma (SPC) and invasive breast carcinoma of no special type (IBC-NST) with neuroendocrine differentiation and SPC and mucinous carcinoma (MC) of the breast remains unclear. To clarify the relationship, we conducted a comparative study of morphological and neuroendocrine features between ductal carcinoma in situ (DCIS, 72 cases) and SPC in situ (35 cases), and IBC-NST (103 cases) and invasive SPC (92 cases). We also conducted the study between MC associated with and without SPC. Synaptophysin, chromogranin A, and INSM1 were employed for the immunohistochemical study. IBC-NST had occasionally a morphological similarity with invasive SPC. While 123 of 127 cases with SPC demonstrated diffuse staining with one or more of the neuroendocrine markers, the only one case of DCIS and none of IBC-NST showed it. Type B was observed in 16 of 18 cases of MC associated with SPC and in 13 of 33 cases of MC without it. All the cases of MC with SPC and 6 of 33 cases without it showed diffuse staining for at least one of the neuroendocrine markers. In conclusion, a careful distinction between invasive SPC and IBC-NST with neuroendocrine differentiation is required. We assume that SPC in situ is a potential candidate for precursor of IBC-NST with neuroendocrine differentiation. MC of the breast is suggested to have two pathogenetic pathways through SPC in situ or non-SPC in situ. SPC in situ is thought to be less common as a precursor of MC than non-SPC in situ., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Ductal carcinoma in situ (DCIS) is recognised by the World Health Organisation (WHO) Classification of Tumours (WCT) as a non-invasive neoplastic epithelial proliferation confined to the mammary ducts and lobules. This report categorises the references cited in the DCIS chapter of the 5th edition of the WCT (Breast Tumours) according to prevailing evidence levels for evidence-based medicine and the Hierarchy of Evidence for Tumour Pathology (HETP), identifying potential gaps that can inform subsequent editions of the WCT for this tumour., Methods and Results: We included all citations from the DCIS chapter of the WCT (Breast Tumours, 5th edition). Each citation was appraised according to its study design and evidence level. We developed our map of cited evidence, which is a graphical matrix of tumour type (column) and tumour descriptors (rows). Spheres were used to represent the evidence, with size and colour corresponding to their number and evidence level respectively. Thirty-six publications were retrieved. The cited literature in the DCIS chapter comprised mainly case series and were regarded as low-level. We found an unequal distribution of citations among tumour descriptors. 'Pathogenesis' and 'prognosis and prediction' contained the most references, while 'clinical features', 'aetiology' and 'diagnostic molecular pathology' had only a single citation each. 'Prognosis and prediction' had the greatest proportion of moderate- and high-levels of evidence., Conclusion: Our findings align with the disposition for observational studies inherent in the field of pathology. Our map is a springboard for future efforts in mapping all available evidence on DCIS, potentially augmenting the editorial process and future editions of WCTs., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: Breast-conserving surgery alone, breast-conserving surgery with adjuvant radiation treatment, and mastectomy are guideline-concordant treatments for ductal carcinoma in situ. The aim of this study was to compare survival outcomes between these treatment options., Methods: A stratified random sample of patients diagnosed with pure ductal carcinoma in situ between 2008 and 2014 was selected from 1330 sites in the USA. Data on diagnosis, treatment, and follow-up were abstracted by local cancer registrars. Population-averaged marginal estimates of disease-specific survival and overall survival for breast-conserving surgery alone, breast-conserving surgery with radiation treatment, and mastectomy were obtained by combining sampling and overlap weights., Results: A total of 18 442 women were included, with a median follow-up of 67.8 (interquartile range 46.1-93.5) months. A total of 35 women died from breast cancer, at a median age of 62 (interquartile range 50-74) years. Population-averaged 8-year rates of disease-specific survival were 99.6% or higher for all treatment groups, with no significant differences between groups (breast-conserving surgery alone versus breast-conserving surgery with radiation treatment, HR 1.19 (95% c.i. 0.29 to 4.85); and mastectomy versus breast-conserving surgery with radiation treatment, HR 1.74 (95% c.i. 0.53 to 5.72). There was no difference in overall survival between the patients who underwent a mastectomy and the patients who underwent breast-conserving surgery with radiation treatment (HR 1.09 (95% c.i. 0.83 to 1.43)). Patients who underwent breast-conserving surgery alone had lower overall survival compared with the patients who underwent breast-conserving surgery with radiation treatment (HR 1.29 (95% c.i. 1.00 to 1.67)). This survival difference vanished for all but one subgroup, namely patients less than 65 years (HR 1.86 (95% c.i. 1.15 to 3.00))., Conclusion: There was no statistically significant difference in disease-specific survival between women operated with breast-conserving surgery alone, breast-conserving surgery with radiation treatment, or mastectomy for ductal carcinoma in situ. Given the low absolute risk of disease-specific mortality, these results provide confidence in offering individualized locoregional treatment without fear of compromising survival., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients., (© 2024. The Author(s).)

Background: A better understanding of ductal carcinoma in situ (DCIS) is urgently needed to identify these preinvasive lesions as distinct clinical entities. Semaphorin 3F (SEMA3F) is a soluble axonal guidance molecule, and its coreceptors Neuropilin 1 (NRP1) and NRP2 are strongly expressed in invasive epithelial BC cells., Methods: We utilized two cell line models to represent the progression from a healthy state to the mild-aggressive or ductal carcinoma in situ (DCIS) stage and, ultimately, to invasive cell lines. Additionally, we employed in vivo models and conducted analyses on patient databases to ensure the translational relevance of our results., Results: We revealed SEMA3F as a promoter of invasion during the DCIS-to-invasive ductal carcinoma transition in breast cancer (BC) through the action of NRP1 and NRP2. In epithelial cells, SEMA3F activates epithelialmesenchymal transition, whereas it promotes extracellular matrix degradation and basal membrane and myoepithelial cell layer breakdown., Conclusions: Together with our patient database data, these proof-of-concept results reveal new SEMA3F-mediated mechanisms occurring in the most common preinvasive BC lesion, DCIS, and represent potent and direct activation of its transition to invasion. Moreover, and of clinical and therapeutic relevance, the effects of SEMA3F can be blocked directly through its coreceptors, thus preventing invasion and keeping DCIS lesions in the preinvasive state., (© 2024. The Author(s).)

Ductal carcinoma in situ (DCIS) accounts for approximately 30% of new breast cancer diagnoses. However, our understanding of how normal breast tissue evolves into DCIS and invasive cancers remains insufficient. Further, conclusions regarding the mechanisms of disease progression in terms of histopathology, genetics, and radiology are often conflicting and have implications for treatment planning. Moreover, the increase in DCIS diagnoses since the adoption of organized breast cancer screening programs has raised concerns about overdiagnosis and subsequent overtreatment. Active monitoring, a nonsurgical management strategy for DCIS, avoids surgery in favor of close imaging follow-up to de-escalate therapy and provides more treatment options. However, the two major challenges in active monitoring are identifying occult invasive cancer and patients at risk of invasive cancer progression. Subsequently, four prospective active monitoring trials are ongoing to determine the feasibility of active monitoring and refine the patient eligibility criteria and follow-up intervals. Radiologists play a major role in determining eligibility for active monitoring and reviewing surveillance images for disease progression. Trial results published over the next few years would support a new era of multidisciplinary DCIS care., Competing Interests: The author has no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Background: The density of tumour-infiltrating lymphocytes (TILs) could be prognostic in ductal carcinoma in situ (DCIS). However, manual TIL quantification is time-consuming and suffers from interobserver and intraobserver variability. In this study, we developed a TIL-based computational pathology biomarker and evaluated its association with the risk of recurrence and benefit of adjuvant treatment in a clinical trial cohort., Methods: In this retrospective cohort study, a computational pathology pipeline was developed to generate a TIL-based biomarker (CPath TIL categories). Subsequently, the signature underwent a masked independent validation on H&E-stained whole-section images of 755 patients with DCIS from the UK/ANZ DCIS randomised controlled trial. Specifically, continuous biomarker CPath TIL score was calculated as the average TIL density in the DCIS microenvironment and dichotomised into binary biomarker CPath TIL categories (CPath TIL-high vs CPath TIL-low) using the median value as a cutoff. The primary outcome was ipsilateral breast event (IBE; either recurrence of DCIS [DCIS-IBE] or invasive progression [I-IBE]). The Cox proportional hazards model was used to estimate the hazard ratio (HR)., Findings: CPath TIL-score was evaluable in 718 (95%) of 755 patients (151 IBEs). Patients with CPath TIL-high DCIS had a greater risk of IBE than those with CPath TIL-low DCIS (HR 2·10 [95% CI 1·39-3·18]; p=0·0004). The risk of I-IBE was greater in patients with CPath TIL-high DCIS than those with CPath TIL-low DCIS (3·09 [1·56-6·14]; p=0·0013), and the risk of DCIS-IBE was non-significantly higher in those with CPath TIL-high DCIS (1·61 [0·95-2·72]; p=0·077). A significant interaction (p interaction =0·025) between CPath TIL categories and radiotherapy was observed with a greater magnitude of radiotherapy benefit in preventing IBE in CPath TIL-high DCIS (0·32 [0·19-0·54]) than CPath TIL-low DCIS (0·40 [0·20-0·81])., Interpretation: High TIL density is associated with higher recurrence risk-particularly of invasive recurrence-and greater radiotherapy benefit in patients with DCIS. Our TIL-based computational pathology signature has a prognostic and predictive role in DCIS., Funding: National Cancer Institute under award number U01CA269181, Cancer Research UK (C569/A12061; C569/A16891), and the Breast Cancer Research Foundation, New York (NY, USA)., Competing Interests: Declaration of interests AM is an equity holder in Picture Health, Elucid Bioimaging, and Inspirata; serves on the advisory board of Picture Health and SimBioSys; currently consults for Takeda; serves as a member for the Frederick National Laboratory Advisory Committee; is involved in two different R01 grants with Inspirata; and has sponsored research agreements with AstraZeneca and Bristol Myers Squibb. AM's technology has been licensed to Picture Health and Elucid Bioimaging. MAT has received research funding from Genomic Health and Ventana Medical Systems. JC has received funding from AstraZeneca for the IBIS-II trial and receives royalties from Myriad for a patent on a prostate cancer biomarker. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In breast cancer (BC) pathogenesis models, normal cells acquire somatic mutations and there is a stepwise progression from high-risk lesions and ductal carcinoma in situ to invasive cancer. The precancer biology of mammary tissue warrants better characterization to understand how different BC subtypes emerge. Primary methods for BC prevention or risk reduction include lifestyle changes, surgery, and chemoprevention. Surgical intervention for BC prevention involves risk-reducing prophylactic mastectomy, typically performed either synchronously with the treatment of a primary tumor or as a bilateral procedure in high-risk women. Chemoprevention with endocrine therapy carries adherence-limiting toxicity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diagnosis of ductal carcinoma in situ (DCIS) represents about 25% of newly diagnosed breast cancers. There is debate about the benefit of sentinel lymph node biopsy (SLNB) for further staging and guidance of therapy in patients with DCIS. Current guidelines recommend SLNB for patients undergoing breast-conserving therapy (BCT) for DCIS. Utilizing superparamagnetic iron oxide (SPIO) nanoparticles as a tracer may allow for a delayed SLNB (d-SLNB), typically within a month of injection. We present our experience with a patient who due to complications from surgery could not complete her d-SLNB for 165 days. The SPIO tracer remained active in the lymph node and remained clinically useful for this five and a half month gap from time of injection. Further study is needed to determine the clinical longevity of SPIO in a lymph node., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia., Methods: NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival data were assessed., Results: A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alone had a nipple or areola recurrence., Conclusions: Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment., (© 2024. Society of Surgical Oncology.)

Objectives: To evaluate the added value of contrast-enhanced ultrasound (CEUS) on top of breast conventional imaging for predicting the upgrading of ductal carcinoma in situ (DCIS) to invasive cancer after surgery., Methods: This retrospective study enrolled 140 biopsy-proven DCIS lesions in 138 patients and divided them into two groups based on postoperative histopathology: non-upgrade and upgrade groups. Conventional ultrasound (US), mammography (MMG), CEUS and clinicopathological (CL) features were reviewed and compared between the two groups. The predictive performance of different models (with and without CEUS features) for histologic upgrade were compared to calculate the added value of CEUS., Results: Fifty-nine (42.1 %) lesions were histologically upgraded to invasive cancer after surgery. By logistic regression analyses, we found that high-grade DCIS at biopsy (P=0.004), ultrasonographic lesion size > 20 mm (P=0.007), mass-like lesion on US (P=0.030), the presence of suspicious calcification on MMG (P=0.014), the presence of perfusion defect (P=0.005) and the area under TIC>1021.34 ml (P<0.001) on CEUS were six independent factors predicting concomitant invasive components after surgery. The CL+US+MMG model made with the four predictors in the clinicopathologic, US and MMG categories yielded an area under the receiver operating curve (AUROC) value of 0.759 (95 % CI: 0.680-0.828) in predicting histological upgrade. The combination model built by adding the two CEUS predictors to the CL+US+MMG model showed higher predictive efficacy than the CL+US+MMG model (P=0.018), as the AUROC value was improved to 0.861 (95 % CI: 0.793-0.914)., Conclusions: The addition of contrast-enhanced ultrasound to breast conventional imaging could improve the preoperative prediction of an upgrade to invasive cancer from CNB -proven DCIS lesions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To assess the association between tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) samples and disease recurrence., Methods: This retrospective cohort study included women aged 18 years and older who underwent treatment between January 2007 and December 2020. Male patients, individuals diagnosed with invasive or microinvasive disease based on anatomopathological examination of surgical specimens, and those with a personal history of any other cancers were excluded. Additionally, the presence of "touching TILs" (lymphocytes in direct contact with tumor cells) and periductal desmoplasia were evaluated as complementary methods to represent the immunological microenvironment. The primary outcome was relapse-free survival based on TIL quantification adjusted for potential confounders. Pathologists assessed TILs in the sample with the highest tumor representation and quantified them as a percentage. Survival was evaluated using Kaplan‒Meier curves, log-rank tests, and Cox regression models., Results: A total of 191 patients met the eligibility criteria. The mean follow-up duration was 77.2 months, with a recurrence rate of 9.2%. Patients with TILs ≥ 17% had a greater risk of recurrence (HR 2.97, 95% CI 1.17-7.51; p = 0.02). Additionally, focal necrosis (HR 6.4, 95% CI 1.39-34.71; p = 0.018) or comedonecrosis (HR 4.53, 95% CI 1.34-15.28; p = 0.015) were associated with increased recurrence risk. According to the multivariate model, comedonecrosis and TILs ≥ 17% were significantly associated with recurrence (p = 0.034 and p = 0.035, respectively). Regarding the evaluations of "touching TILs" and periductal desmoplasia, no statistical significance was found when assessing their association with disease recurrence., Conclusion: In our cohort, a high percentage of TILs (≥ 17%) and the presence of comedonecrosis were independently associated with DCIS recurrence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The current standard of treatment for ductal carcinoma in situ (DCIS) is surgery with or without adjuvant radiotherapy. With a growing debate about overdiagnosis and overtreatment of low-risk DCIS, active surveillance is being explored in several ongoing trials. We conducted a systematic review and meta-analysis to evaluate the recurrence of low-risk DCIS under various treatment approaches., Methods: PubMed, Embase, Web of Science, and Cochrane were searched for studies reporting ipsilateral breast tumour event (IBTE), contralateral breast cancer (CBC), and breast cancer-specific survival (BCSS) rates at 5 and 10 years in low-risk DCIS. The primary outcome was invasive IBTE (iIBTE) defined as invasive progression in the ipsilateral breast., Results: Thirty three eligible studies were identified, involving 47,696 women with low-risk DCIS. The pooled 5-year and 10-year iIBTE rates were 3.3% (95% confidence interval [CI]: 1.3, 8.1) and 5.9% (95% CI: 3.8, 9.0), respectively. The iIBTE rates were significantly lower in patients who underwent surgery compared to those who did not, at 5 years (3.5% vs. 9.0%, P = 0.003) and 10 years (6.4% vs. 22.7%, P = 0.008). Similarly, the 10-year BCSS rate was higher in the surgery group (96.0% vs. 99.6%, P = 0.010). In patients treated with breast-conserving surgery, additional radiotherapy significantly reduced IBTE risk, but not total-CBC risk., Conclusion: This review showed a lower risk of progression and better survival in women who received surgery and additional RT for low-risk DCIS. However, our findings were primarily based on observational studies, and should be confirmed with the results from the ongoing trials., (© 2024. The Author(s).)

Ductal carcinoma in situ (DCIS) is a pre-invasive tumor that can progress to invasive breast cancer, a leading cause of cancer death. We generate a large-scale tissue microarray dataset of chromatin images, from 560 samples from 122 female patients in 3 disease stages and 11 phenotypic categories. Using representation learning on chromatin images alone, without multiplexed staining or high-throughput sequencing, we identify eight morphological cell states and tissue features marking DCIS. All cell states are observed in all disease stages with different proportions, indicating that cell states enriched in invasive cancer exist in small fractions in normal breast tissue. Tissue-level analysis reveals significant changes in the spatial organization of cell states across disease stages, which is predictive of disease stage and phenotypic category. Taken together, we show that chromatin imaging represents a powerful measure of cell state and disease stage of DCIS, providing a simple and effective tumor biomarker., (© 2024. The Author(s).)

Aims: Cytokeratin 5 (CK5) is a surrogate maker of progenitor cells and early glandular and myoepithelial cells (MECs) in the breast, and CK5 expression in breast MECs varies from ducts to lobules, and from normal to diseased tissue. However, the mechanisms underlying immunophenotypic alterations of CK5 expression in MECs remain unclear., Methods: CK5 expression in MECs of 20 normal breast samples, 58 ductal carcinoma in situ (DCIS; including 21 DCIS with extensive lobular involvement), 11 atypical ductal hyperplasia (ADH), 18 non-invasive lobular neoplasia consisting of 11 atypical lobular hyperplasia (ALH) and 7 lobular carcinoma in situ (LCIS), 20 cystic lobules and 10 usual ductal hyperplasia (UDH) involving lobules were observed to evaluate the effects of contact with benign hyperplastic or cancerous luminal cells and pressure of dilated glands on CK5 expression., Results: CK5 expression in normal ductal MECs was exclusively positive, whereas most normal lobular MECs were negative. In DCIS, cancerous ducts were primarily surrounded by CK5-positive MECs (91.0%), as were lobular acini involved by DCIS (89.2%), while the remaining normal acini maintained CK5-negative. CK5-positive MECs were found in 57.5% of acini in ALH and were more prevalent in LCIS (70.7%). CK5 expression was occasionally positive in both cystic lobules (16.7%) and lobules involved by UDH (14.3%), while an increase of CK5-positive MECs was found in ADH (38.2%)., Conclusions: These results suggest that CK5 expression in lobular MECs may be altered by contact with cancerous luminal cells rather than benign hyperplastic luminal cells or pressure from dilated glands., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ductal carcinoma in situ (DCIS), characterized by a proliferation of neoplastic cells confined within the mammary ducts, is distinctly isolated from the surrounding stroma by an almost uninterrupted layer of myoepithelial cells (MECs) and by the basement membrane. Heightened interactions within the adipose microenvironment, particularly in obese patients, may play a key role in the transition from DCIS to invasive ductal carcinoma (IDC), which is attracting growing interest in scientific research. Adipose tissue undergoes metabolic changes in obesity, impacting adipokine secretion and promoting chronic inflammation. This study aimed to assess the interactions between DCIS, including in situ cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages)., Methods: To this end, a 3D co-culture model was developed using bicellular bi-fluorescent DCIS-like tumoroids, adipose cells, and macrophages to investigate the influence of the inflammatory adipose microenvironment on DCIS progression., Results: The 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis ( BAX, BAG1, BCL2, CASP3, CASP8 , and CASP9 ), and an increase in genes related to cell survival ( TP53 , JUN , and TGFB1 ), inflammation ( TNF-α, PTGS2, IL-6R ), invasion and metastasis (TIMP1 and MMP-9) in cancer cells of the tumoroids under inflammatory conditions versus a non-inflammatory microenvironment. On the contrary, it confirmed the compromised functionality of MECs, resulting in the loss of their protective effects against cancer cells. Adipocytes from obese women showed a significant increase in the expression of all studied myofibroblast-associated genes (myoCAFs), such as FAP and α-SMA . In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of LIF and inflammatory cytokines such as TNF-α, IL-1β, IL-8 , and CXCL-10 . These changes also influenced macrophage polarization, leading to a pro-inflammatory M1 phenotype. In contrast, myoCAF-associated adipocytes, and the cancer-promoting microenvironment polarized macrophages towards an M2 phenotype, characterized by high CD163 receptor expression and IL-10 and TGF-β secretion., Discussion: Reciprocal interactions between the tumoroid and its microenvironment, particularly in obesity, led to transcriptomic changes in adipocytes and macrophages, may participate in breast cancer progression while disrupting the integrity of the MEC layer. These results underlined the importance of adipose tissue in cancer progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Habanjar, Nehme, Goncalves-Mendes, Cueff, Blavignac, Aoun, Decombat, Auxenfans, Diab-Assaf, Caldefie-Chézet and Delort.)

Mutations are abundantly present in tissues of healthy individuals, including the breast epithelium. Yet it remains unknown whether mutant cells directly induce lesion formation or first spread, leading to a field of mutant cells that is predisposed towards lesion formation. To study the clonal and spatial relationships between morphologically normal breast epithelium adjacent to pre-cancerous lesions, we developed a three-dimensional (3D) imaging pipeline combined with spatially resolved genomics on archival, formalin-fixed breast tissue with the non-obligate breast cancer precursor ductal carcinoma in situ (DCIS). Using this 3D image-guided characterization method, we built high-resolution spatial maps of DNA copy number aberration (CNA) profiles within the DCIS lesion and the surrounding normal mammary ducts. We show that the local heterogeneity within a DCIS lesion is limited. However, by mapping the CNA profiles back onto the 3D reconstructed ductal subtree, we find that in eight out of 16 cases the healthy epithelium adjacent to the DCIS lesions has overlapping structural variations with the CNA profile of the DCIS. Together, our study indicates that pre-malignant breast transformations frequently develop within mutant clonal fields of morphologically normal-looking ducts. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS., Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts., Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. AKT activation correlated with chromatin accessibility and EZH2 enrichment upregulating SOX11 expression. AKT and HER2 inhibitors decreased SOX11 expression along with diminished mammosphere formation. SOX11 was upregulated in HER2+ and basal-like subtypes (P < 0.001). Longitudinal DCIS cohort (n = 194) revealed shorter recurrence-free survival in SOX11+ than SOX11- patients (P = 0.0056 in all DCIS; P < 0.0001 in HER2+ subtype) associated with increased risk of ipsilateral breast event/IBE (HR = 1.9, 95%CI = 1.2-2.9; P = 0.003)., Discussion: Epigenetic activation of SOX11 drives recurrence of DCIS and progression to invasive cancer, suggesting SOX11 as a predictive biomarker of IBE., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Young patients with breast ductal carcinoma in situ (DCIS) often face a poorer prognosis. The genomic intricacies in young-onset DCIS, however, remain underexplored., Methods: To address this gap, we undertook a comprehensive study encompassing exome, transcriptome, and vmethylome analyses. Our investigation included 20 DCIS samples (including 15 young-onset DCIS) and paired samples of normal breast tissue and blood., Results: Through RNA sequencing, we identified two distinct DCIS subgroups: "immune hot" and "immune cold". The "immune hot" subgroup was characterized by increased infiltration of lymphocytes and macrophages, elevated expression of PDCD1 and CTLA4, and reduced GATA3 expression. This group also exhibited active immunerelated transcriptional regulators. Mutational analysis revealed alterations in TP53 (38%), GATA3 (25%), and TTN (19%), with two cases showing mutations in APC, ERBB2, and SMARCC1. Common genomic alterations, irrespective of immune status, included gains in copy numbers at 1q, 8q, 17q, and 20q, and losses at 11q, 17p, and 22q. Signature analysis highlighted the predominance of signatures 2 and 1, with "immune cold" samples showing a significant presence of signature 8. Our methylome study on 13 DCIS samples identified 328 hyperdifferentially methylated regions (DMRs) and 521 hypo-DMRs, with "immune cold" cases generally showing lower levels of methylation., Conclusion: In summary, the molecular characteristics of young-onset DCIS share similarities with invasive breast cancer (IBC), potentially indicating a poor prognosis. Understanding these characteristics, especially the immune microenvironment of DCIS, could be pivotal in identifying new therapeutic targets and preventive strategies for breast cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ductal carcinoma in situ (DCIS) accounts for 15-25% of all breast cancer diagnoses. Its prognosis is excellent overall, the main risk being the occurrence of local breast events, as most cases of DCIS do not progress to invasive cancer. Systematic screening has greatly increased the incidence of this non-obligate precursor of invasion, lending urgency to the need to identify DCIS that is prone to invasive progression and distinguish it from non-invasion-prone DCIS, as the latter can be overdiagnosed and therefore overtreated. Treatment strategies, including surgery, radiotherapy, and optional endocrine therapy, decrease the risk of local events, but have no effect on survival outcomes. Active surveillance is being evaluated as a possible new option for low-risk DCIS. Considerable efforts to decipher the biology of DCIS have led to a better understanding of the factors that determine its variable natural history. Given this variability, shared decision making regarding optimal, personalised treatment strategies is the most appropriate course of action. Well designed, risk-based de-escalation studies remain a major need in this field., Competing Interests: Declaration of interests SD reports institutional grants and non-financial support from Pfizer, Novartis, AstraZeneca, Seagen, and Roche Genentech; grants from Eli Lilly, Amgen, Sanofi, MSD, BMS, Exact Sciences, Rappta, the European Commission, the French National Cancer Institute, Fondation ARC, Banque des Territoires France 2023 (public entity), Besins, and Gilead outside the submitted work. SAK declares research funding from the National Cancer Institute (NCI) and from the Breast Cancer Research Foundation to her institution; personal honoraria from the University of Toronto, Japan Clinical Oncology Group, San Antonio Breast Cancer conference, and the Dana Farber Cancer Center for conferences; a patent for endoxifen transdermal therapy; travel funding from the NCI for the TMIST trial; and institutional drug supplies for a clinical trial from BHR Pharma. JW reports institutional research grants from Cancer Research UK, KWF Dutch Cancer Society, Antoni van Leeuwenhoek Investment Fund, ZonMW Healthcare innovation, and support for travel for international speaking from ESMO, UCSF, the National Physics Laboratory, Oslo University Hospital, and Maastricht University. JW is a member of the scientific advisory board of the KWF Dutch Cancer Society; is a review panel member for Cancer Research UK on an ad hoc basis; is a member of the scientific advisory board of the National Reference Center for Breast Cancer Screening; and is a member of the advisory board of the National Institute for Public Health and the Environment regarding population-based breast cancer screening. TW declares institutional research funding from Exact Sciences/Genomic Health and non-direct financial support for biomarker testing from Exact Sciences/Genomic Health for ongoing studies., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC ( n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.

Objective: To address the question of axillary lymph node staging in ductal carcinoma in situ with microinvasion (DCIS-MI), we retrospectively evaluated axillary lymph nodes metastasis (ALNM) rate in a cohort of postsurgical DCIS-MI patients. By analyzing these data, we aimed to generate clinically relevant insights to inform treatment decision-making for this patient population., Methods: A systematic search was conducted on PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang Database, Wipe, and China Biomedical Literature Database to identify relevant publications in any language. All the analyses were performed using Stata 16.0 software., Results: Among the 28 studies involving 8279 patients, the pooled analysis revealed an ALNM rate of 8% (95% CI, 7% to 10%) in patients with DCIS-MI. Furthermore, the rates of axillary lymph node macrometastasis, micrometastasis, and ITC in patients with DCIS-MI were 2% (95% CI, 2% to 3%), 3% (95% CI, 2% to 4%), and 2% (95% CI, 1% to 3%), respectively. Moreover, 13 studies investigated the non-sentinel lymph node (Non-SLN) metastasis rate, encompassing a total of 1236 DCIS-MI cases. The pooled analysis identified a Non-SLN metastasis rate of 33% (95% CI, 14% to 55%) in patients with DCIS-MI., Conclusion: The SLNB for patients with DCIS-MI is justifiable and could provide a novel therapeutic basis for systemic treatment decisions., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Superparamagnetic iron oxide (SPIO) (Magtrace®) is a non-radioactive liquid tracer that can stay in the sentinel lymph nodes for 30 days. Injection of SPIO at time of primary breast surgery where upfront sentinel lymph node biopsy (SLNB) is not immediately indicated allows for a return to theatre if pathology then identifies invasive disease. SLNB is associated with paraesthesia, pain, seroma formation and lymphoedema risk. Hence, our study aims to assess the use of SPIO to avoid upfront SLNB in breast surgery for ductal carcinoma in situ (DCIS) and prophylaxis., Methods: Retrospective single-centre study of consecutive patients who underwent injection of SPIO tracer at time of primary breast surgery to avoid upfront SLNB at Chris O'Brien Lifehouse, Sydney, NSW, Australia over a 10-month period., Results: SPIO was injected 38 times, with 34 at time of mastectomy and four cases at time of wide local excision. The indication for surgery was DCIS in 18 cases, risk reduction in 17 cases and other indications in three patients. Six cases (15.8%) required delayed SLNB (D-SLNB) due to the finding of invasive disease on post-operative histopathology. All patients who underwent D-SLNB had nodes successfully localized with SPIO., Conclusion: In our cohort, 84.2% of cases were able to avoid upfront SLNB, and hence avoid the associated complications of SLNB. SPIO injection was successful in localizing the SLN in all cases at time of surgery for D-SLNB. This technique was safe with few associated complications., (© 2024 Royal Australasian College of Surgeons.)

Objective: To investigate the independent risk variables associated with the potential invasiveness of ductal carcinoma in situ (DCIS) on multi-parametric ultrasonography, and further construct a nomogram for risk assessment., Methods: Consecutive patients from January 2017 to December 2022 who were suspected of having ductal carcinoma in situ (DCIS) based on magnetic resonance imaging or mammography were prospectively enrolled. Histopathological findings after surgical resection served as the gold standard. Grayscale ultrasound, Doppler ultrasound, shear wave elastography (SWE), and contrast-enhanced ultrasound (CEUS) examinations were preoperative performed. Binary logistic regression was used for multifactorial analysis to identify independent risk factors from multi-parametric ultrasonography. The correlation between independent risk factors and pathological prognostic markers was analyzed. The predictive efficacy of DCIS associated with invasiveness was assessed by logistic analysis, and a nomogram was established., Results: A total of 250 DCIS lesions were enrolled from 249 patients, comprising 85 pure DCIS and 165 DCIS with invasion (DCIS-IDC), of which 41 exhibited micro-invasion. The multivariate analysis identified independent risk factors for DCIS with invasion on multi-parametric ultrasonography, including image size (>2cm), Doppler ultrasound RI (≥0.72), SWE's Emax (≥66.4 kPa), hyper-enhancement, centripetal enhancement, increased surrounding vessel, and no contrast agent retention on CEUS. These factors correlated with histological grade, Ki-67, and human epidermal growth factor receptor 2 (HER2) (P < 0.1). The multi-parametric ultrasound approach demonstrated good predictive performance (sensitivity 89.7 %, specificity 73.8 %, AUC 0.903), surpassing single US modality or combinations with SWE or CEUS modalities. Utilizing these factors, a predictive nomogram achieved a respectable performance (AUC of 0.889) for predicting DCIS with invasion. Additionally, a separate nomogram for predicting DCIS with micro-invasion, incorporating independent risk factors such as RI (≥0.72), SWE's Emax (≥65.2 kPa), and centripetal enhancement, demonstrated an AUC of 0.867., Conclusion: Multi-parametric ultrasonography demonstrates good discriminatory ability in predicting both DCIS with invasion and micro-invasion through the analysis of lesion morphology, stiffness, neovascular architecture, and perfusion. The use of a nomogram based on ultrasonographic images offers an intuitive and effective method for assessing the risk of invasion in DCIS. Although the nomogram is not currently considered a clinically applicable diagnostic tool due to its AUC being below the threshold of 0.9, further research and development are anticipated to yield positive outcomes and enhance its viability for clinical utilization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)