Low-grade Ductal Carcinoma In Situ Research Articles

Abstract PO5-13-11: Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast

Abstract HER2 (ERBB2) is an established prognostic and predictive marker for patients with invasive breast cancer and used in HER2-targeted therapy. The clinical and biological significance of expression of HER2 protein in patients with intraductal neoplasms of the breast is not well characterized. In this study, we used our HS-HER2 (High Sensitivity-HER2) which is a CAP/CLIA certified laboratory derived test (LDT) using quantitative immunofluorescence (QIF). We evaluated HER2 expression in DCIS (ductal carcinoma in situ), LCIS (lobular carcinoma in situ) and benign lesions to correlate with their clinicopathologic characteristics. Thirty- eight cases of DCIS, and fourteen cases of LCIS and thirty benign cases were selected from the Yale Pathology department archives and 252 ROIs (regions of interest) were annotated by a board-certified pathologist. DCIS is classified according to the three-tier nuclear grading system: low, intermediate, and high-nuclear grade. LCIS is classified as PLCIS (pleomorphic variant) and CLCIS (classic LCIS) according to the WHO classification of breast tumors. Serial sections of FFPE tumor specimens were used to accurately quantify the HER2 expression by the HS-HER2 assay and the acquisition by QuPath v.04 with Qymia extension. According to the LOD (limit of detection,3 amol/mm2), LOQ (limit of quantification, 9 amol/mm2) and LOL (limit of linearity, 23 amol/mm2) of the optimized HS-HER2 assay as performed in our CLIA lab shows a broad range of HER2 expression in both DCIS and LCIS lesions, ranging from 0.7 amol/mm2 to 111.4 amol/mm2 in DCIS and 3.6 amol/mm2 to 49.9 amol/mm2 in LCIS. High grade DCIS lesions express higher average HER2 levels (111.4 + 0.7 amol/mm2) than combined low and intermediate grade DCIS (77.9 +1.9 amol/mm2) with no significant difference between low/intermediate and high-grade DCIS. CLCIS lesions express higher average HER2 level (49.9 + 3.6 amol/mm2) than PLCIS (35.1 + 5.4amol/mm2) but again this is not statistically significant. HER protein expression is relatively low in benign lesions ranging from 0.8 to 8.4 amol/mm2. Using the HS-HER2 assay, our results show quantitative level HER2 levels in DCIS and LCIS breast lesions. These findings may be important as HER2 targeted therapies that work in gene-unamplified cancer (HER2 conjugated ADCs) gain broader usage in the clinic. Citation Format: Nay Nwe Nyein Chan, Haiying Zhan, Revekka Khaimova, Thazin Aung, Charles Robbins, Patricia Gaule, David Rimm. Quantitative Assessment of HER2 Expression in Intraductal Neoplasms of the Breast [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-11.

Atypia Involving Fibroadenomas: Outcomes and Upgrade Rates.

Fibroadenomas (FAs) involved by atypia are rare. Consensus guidelines for management of FAs involved by atypia when diagnosed on image-guided biopsy do not exist because of limited data reporting surgical upgrade rates to ductal carcinoma in situ (DCIS) or invasive malignancy. Therefore, these lesions commonly undergo surgical excision. This single-institution retrospective study identified cases of FAs involved by atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and/or lobular carcinoma in situ (LCIS) diagnosed on image-guided biopsy between January 2014 and April 2023 to determine upgrade rates. Cases with incidental atypia adjacent to but not involving FAs were excluded. Among 1736 FAs diagnosed on image-guided biopsy, 32 cases (1.8%) were FAs involved by atypia including 43.8% (14/32) ALH, 28.1% (9/32) ADH, 18.8% (6/32) LCIS, 6.3% (2/32) LCIS + ALH, and 3.1% (1/32) unspecified atypia. The most common imaging finding was a mass. Most cases, 81.3% (26/32), underwent subsequent surgical excisional biopsy. A single case of ADH involving and adjacent to an FA was upgraded to FA involved by low-grade DCIS on excision for an overall surgical upgrade rate of 3.8%. There were no cases upgraded to invasive malignancy. For those omitting surgical excision, there was no subsequent malignancy diagnosis at the FA biopsy site over a mean follow-up of 73 months. Cases of radiologic-pathologic concordant FAs involved by atypia have a low upgrade rate of 3.8% and should undergo multidisciplinary review. Larger multi-institutional analysis is needed to determine whether guidelines for excision of atypia should apply to atypia involving FAs.

Sonography-based multimodal information platform for identifying the surgical pathology of ductal carcinoma in situ

BackgroundThe risk of ductal carcinoma in situ (DCIS) identified by biopsy often increases during surgery. Therefore, confirming the DCIS grade preoperatively is necessary for clinical decision-making. PurposeTo train a three-classification deep learning (DL) model based on ultrasound (US), combining clinical data, mammography (MG), US, and core needle biopsy (CNB) pathology to predict low-grade DCIS, intermediate-to-high-grade DCIS, and upstaged DCIS. Materials and MethodsData of 733 patients with 754 DCIS cases confirmed by biopsy were retrospectively collected from May 2013 to June 2022 (N1), and other data (N2) were confirmed by biopsy as low-grade DCIS. The lesions were randomly divided into training (n=471), validation (n=142), and test (n = 141) sets to establish the DCIS-Net. Information on the DCIS-Net, clinical (age and sign), US (size, calcifications, type, breast imaging reporting and data system [BI-RADS]), MG (microcalcifications, BI-RADS), and CNB pathology (nuclear grade, architectural features, and immunohistochemistry) were collected. Logistic regression and random forest analyses were conducted to develop Multimodal DCIS-Net to calculate the specificity, sensitivity, accuracy, receiver operating characteristic curve, and area under the curve (AUC). ResultsIn the test set of N1, the accuracy and AUC of the multimodal DCIS-Net were 0.752–0.766 and 0.859–0.907 in the three-classification task, respectively. The accuracy and AUC for discriminating DCIS from upstaged DCIS were 0.751–0.780 and 0.829–0.861, respectively. In the test set of N2, the accuracy and AUC of discriminating low-grade DCIS from upstaged low-grade DCIS were 0.769–0.987 and 0.818–0.939, respectively. DL was ranked from one to five in the importance of features in the multimodal-DCIS-Net. ConclusionBy developing the DCIS-Net and integrating it with multimodal information, diagnosing low-grade DCIS, intermediate-to high-grade DCIS, and upstaged DCIS is possible. It can also be used to distinguish DCIS from upstaged DCIS and low-grade DCIS from upstaged low-grade DCIS, which could pave the way for the DCIS clinical workflow.

Nonclinical factors associated with the treatment of older women with newly diagnosed low-grade ductal carcinoma insitu.

Ductal carcinoma in situ (DCIS) is the most common form of noninvasive breast cancer and is associated with an excellent prognosis. As a result, there is concern about overdiagnosis and overtreatment of DCIS because most patients with DCIS are treated as though they have invasive breast cancer and undergo either breast-conserving surgery (BCS)-most commonly followed by radiation therapy (RT)-or mastectomy. Little research to date has focused on nonclinical factors influencing treatments for DCIS. Population-based data were analyzed from five state cancer registries (California, Florida, New Jersey, New York, and Texas) on women aged 65 years and older newly diagnosed with DCIS during the years 2003 to 2014 using a retrospective cohort design and multinominal logistic modeling. The registry records with Medicare enrollment data and fee-for-service claims to obtain treatments (BCS alone, BCS with RT, or mastectomy) were merged. Surgeon practice structure was identified through physician surveys and internet searches. Patients of surgeons employed by cancer centers or health systems were less likely to receive BCS with RT or mastectomy than patients of surgeons in single specialty or multispecialty practices. There also was substantial geographic variation in treatments, with patients in New York, New Jersey, and California being less likely to receive BCS with RT or mastectomy than patients in Texas or Florida. These findings suggest nonclinical factors including the culture of the practice and/or financial incentives are significantly associated with the types of treatment received for DCIS. Increasing awareness and targeted efforts to educate physicians about DCIS management among older women with low-grade DCIS could reduce patient harm and yield substantial cost savings.

Proliferative epithelial changes in tumour adjacent tissue in Sri Lankan women with breast carcinoma: do morphological changes support molecular models of breast carcinogenesis?

BackgroundThe multistep molecular model of breast carcinogenesis is based on the oestrogen receptor(ER) status of the tumour. Its two main arms comprise ER-positive and ER-negative breast carcinomas(BCa), which are associated with Nottingham grade(NG) of the tumour and different proliferative epithelial changes. According to the model, columnar cell lesions(CCL), lobular carcinoma in-situ(LCIS) and atypical ductal hyperplasia(ADH), low-grade ductal carcinoma in-situ (LG-DCIS) are associated with low grade ER-positive tumours and microglandular adenosis (MGA), pleomorphic LCIS(PLCIS), high-grade DCIS(HG-DCIS) are associated with ER-negative high grade tumours. This study aims to describe the association between proliferative epithelial changes in breast tissue adjacent to tumour, in relation to the ER status and NG of the tumour.MethodsThis descriptive cross-sectional study included 420, wide local excision and mastectomy specimens of BCa from National Hospital of Sri Lanka, between 2017–2019. The histopathological features of the tumour and proliferative epithelial changes in tumour adjacent tissue within 10 mm distance from the tumour-host interface were evaluated independently by two pathologists. The ER, PR(Progesterone receptor) and HER2 status assessed by immunohistochemistry(IHC) was reviewed. The associations between above epithelial lesions and ER status and NG{categorised as low grade (NG1 and NG2) and high grade (NG3)} of the tumour were analyzed.ResultsER positive BCa showed significant associations with CCH (p = 0.04), FEA (p = 0.035) and LGDCIS (p < 0.001). Although PLCIS was more frequent in ER positive tumours, the association did not attain statistical significance. ER negative BCa showed a significant association with HGDCIS (p = 0.016). CCLs as a whole (p = 0.005) and also CCC (p = 0.006) and FEA (p = 0.048) and LGDCIS (p < 0.001) showed significant associations with low NG tumours. High NG tumours showed a significant association with HGDCIS (p < 0.001). Microglandular adenosis was not identified in our study population.ConclusionThese morphological findings support the multistep molecular based pathogenetic pathways of breast carcinoma in the studied setting in South Asia. Identification of these proliferative epithelial components in a core biopsy that is negative for BCa, should prompt for close clinicoradiological correlation, and if necessary re-biopsy of women suspected of harbouring a BCa.

87 (PB-087) Poster - The role of axillary staging in patients with Ductal Carcinoma In Situ (DCIS) on diagnostic tissue biopsy

Background: There is an inherent risk of overestimating the risk of coexisting invasive disease in patients with DCIS on a diagnostic core needle biopsy. This results in a potential escalation of surgical intervention with the introduction of a diagnostic SLNB for the synchronous staging of the axilla which may result in additional morbidity. Patients with pure low-grade DCIS (LG DCIS) do not benefit from SLNB at the time of their primary surgery as the incidence of upgrade to microinvasion/ invasion is very low.

The value of immunohistochemical expression of Ki-67 and CD34 in differentiating ductal carcinoma in situ from ductal carcinoma in situ-like invasive breast cancer

Objective: To investigate the expression of Ki-67 and CD34 in the differential diagnosis of ductal carcinoma in situ (DCIS) and DCIS-like invasive breast cancer (DLIBC). Methods: A total of 100 cases of DCIS and 150 cases of DLIBC diagnosed pathologically in Yantai Yuhuangding Hospital from January 2019 to March 2022 were collected. The expression of p63, CK5/6, Ki-67 and CD34 in both groups were detected by immunohistochemical (IHC) staining and evaluated. Results: The 100 cases of DCIS included 11 cases of low-grade DCIS, 28 cases of intermediate-grade DCIS and 61 cases of high-grade DCIS. IHC staining of p63 and CK5/6 showed the myoepithelial cells around cancerous duct were complete or partial absence. Ki-67 expression showed two patterns: high expression in the basal layers and scattered expression within the tumor. Most cases showed mainly high basal expression (77/100, 77%), and the proportion of this pattern was significantly different between low grade and high grade DCIS (P<0.05). All cases showed complete CD34 expression surrounding the cancerous duct with different proportion (vascular necklace) suggested small vessels proliferation. The 150 cases of DLIBC included 142 cases of invasive ductal carcinoma (IDC) (three cases of basal-like breast cancer was included), two cases of secretory carcinoma, three cases of solid papillary carcinoma, two cases of adenoid cystic carcinoma and one case of acinar cell carcinoma. Among 142 cases of IDC, 13 cases were grade Ⅰ, 77 were grade Ⅱ and 52 were grade Ⅲ. IHC staining of p63 showed complete absence of myoepithelium. CK5/6 was negative in most cases and only positively expressed within the tumor in 3 cases of basal-like breast cancer. Ki-67 indicated a scattered expression pattern within the tumor. In most cases, CD34 immunostaining showed scattered positive blood vessels within the tumor while only two cases showed incomplete expression of CD34 around the tumor (2/150, 1.3%). The different expression patterns of Ki-67 and CD34 in DCIS and DLIBC was statistically significant (P<0.05). Conclusions: The different expression patterns of Ki-67 and CD34 are helpful to distinguish DLIBC from DCIS. The appearance of "vascular necklace" with CD34 and the high expression of Ki-67 around the cancerous duct highly support the diagnosis of DCIS, and the scattered expression pattern of CD34 supports DLIBC.

US, Mammography, and Histopathologic Evaluation to Identify Low Nuclear Grade Ductal Carcinoma in Situ.

Background Low nuclear grade ductal carcinoma in situ (DCIS) identified at biopsy can be upgraded to intermediate to high nuclear grade DCIS at surgery. Methods that confirm low nuclear grade are needed to consider nonsurgical approaches for these patients. Purpose To develop a preoperative model to identify low nuclear grade DCIS and to evaluate factors associated with low nuclear grade DCIS at biopsy that was not upgraded to intermediate to high nuclear grade DCIS at surgery. Materials and Methods In this retrospective study, 470 women (median age, 50 years; interquartile range, 44-58 years) with 477 pure DCIS lesions at surgical histopathologic evaluation were included (January 2010 to December 2015). Patients were divided into the training set (n = 330) or validation set (n = 147) to develop a preoperative model to identify low nuclear grade DCIS. Features at US (mass, nonmass) and at mammography (morphologic characteristics, distribution of microcalcification) were reviewed. The upgrade rate of low nuclear grade DCIS was calculated, and multivariable regression was used to evaluate factors for associations with low nuclear grade DCIS that was not upgraded later. Results A preoperative model that included lesions manifesting as a mass at US without microcalcification and no comedonecrosis at biopsy was used to identify low nuclear grade DCIS, with a high area under the receiver operating characteristic curve of 0.97 (95% CI: 0.94, 1.00) in the validation set. The upgrade rate of low nuclear grade DCIS at biopsy was 38.8% (50 of 129). Ki-67 positivity (odds ratio, 0.04; 95% CI: 0.0003, 0.43; P = .005) was inversely associated with constant low nuclear grade DCIS. Conclusion The upgrade rate of low nuclear grade ductal carcinoma in situ (DCIS) at biopsy to intermediate to high nuclear grade DCIS at surgery occurred in more than a third of patients; low nuclear grade DCIS at final histopathologic evaluation could be identified if the mass was viewed at US without microcalcifications and had no comedonecrosis at histopathologic evaluation of biopsy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Rahbar in this issue. An earlier incorrect version appeared online. This article was corrected on April 14, 2022.

Abstract P1-22-06: A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme

Abstract Background The variable natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this retrospective cohort study was to determine the outcomes of women who were diagnosed through the English National Health Service Breast Screening Programme (NHS BSP) and had no surgery for screen-detected DCIS. Method English NHS BSP databases were searched for women diagnosed with DCIS without invasive cancer on needle biopsy between 1 April 2001 and 31 March 2018 inclusive, who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data for further treatment, event information and mortality records. Details of potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment, subsequent clinical course and outcomes. Results Data for 311 eligible women (median age 62 years) were included, with median follow-up (primary DCIS diagnosis to either surgery, development of invasive disease, death or last known to be alive) of 4.1 years (range 0.5 to 17.4 years). The median age at diagnosis was 64 years (range 47 to 90 years). Sixty (19%) women developed invasive breast cancer, 56 ipsilateral and 4 contralateral. Twenty-two women (7%) underwent surgery for DCIS (&amp;gt;6 months after diagnosis) and 86 (28%) died of other causes. Women with high or intermediate grade DCIS were significantly more likely to develop ipsilateral invasive breast cancer (iIBC) than those with low grade DCIS. 28/123 (23%) with high grade DCIS, 21/105 (20%) with intermediate grade DCIS, 5/76 (7%) with low grade DCIS and 2/7 (29%) with an unknown grade of DCIS developed iIBC. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. Women who developed iIBC were significantly younger than those who did not. This was driven primarily by a strong association among those with high grade DCIS. There was no significant difference in age between those with intermediate and low grade DCIS respectively who did or did not develop iIBC. The median baseline size of DCIS in women who developed iIBC was higher than in women who did not develop iIBC, both overall and in each of the three grade categories (median sizes - high grade 38 mm vs 29 mm, p=0.19; intermediate grade 35 mm vs 18 mm, p=0.31; low grade 18 mm vs 15 mm, p=0.38). This reached statistical significance for all grades combined: 37 mm (range 3-95) v 20 mm (range 3-200), p=0.02. Of the 262 women with a known microinvasion status, 8/25 (32%) with definite or possible microinvasion were subsequently diagnosed with ipsilateral invasive cancer compared to 38/237 (16%) without microinvasion (p=0.027). There was no significant association on univariable analysis between risk of iIBC and microcalcification as the predominant radiological feature (iIBC and microcalcification 47/258 vs iIBC and other radiological feature 7/46; p=0.83), the presence of histological necrosis (iIBC and necrosis, 14/89 vs iIBC and no necrosis, 31/157; p=0.49) or the use of ET (iIBC and ET 11/67 vs iIBC and no ET 45/244; p=0.86). Of the 51 invasive cancers that developed with a known grade, 46 (90%) were grade 2 or 3. Conclusion The findings suggest that women diagnosed with high or intermediate grade DCIS and those with microinvasion should continue to be offered surgery. For those with low grade DCIS there is a need for shared decision-making in the choice of surgery or active surveillance based on a discussion of the risks and benefits of the options as currently understood, and in the light of the low reproducibility of DCIS grading. Citation Format: Karen Clements, Anthony Maxwell, Bridget Hilton, Matthew Wallis, Cliona Kirwan, Hilary Stobart, Elena Provenzano, Nisha Sharma, Janet Litherland, Abeer Shaaban, David Dodwell, Joanne Dulson-Cox, Elinor Sawyer, Senthurun Mylvaganam, Olive Kearins, Samantha Brace-McDonnell, Sarah Pinder, Alastair Thompson. A longitudinal cohort study of outcomes in 311 women with unresected ductal carcinoma in situ detected through the English breast screening programme [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-06.

Abstract P5-01-01: Intraductal patient-derived xenograft models of ductal carcinoma in situ (DCIS) to distinguish indolent DCIS from aggressive DCIS

Abstract Ductal Carcinoma in Situ (DCIS) is a starting lesion in the milk duct of the breast, which accounts for 25% of all ‘breast cancers’ detected. DCIS is usually treated by surgery combined with radiotherapy, which can have a large impact on the life of patients. However, there is little to no evidence that treatment of low and intermediate grade DCIS reduces mortality, while women diagnosed with DCIS do perceive their risk of dying the same as patients with invasive disease. To reduce the negative perception and the overtreatment of DCIS, but assure proper treatment for high risk DCIS, it is crucial to understand the biology underlying DCIS. In order to study the biology of DCIS we established patient-derived xenograft (PDX) models by intraductally injecting fresh patient DCIS material into the mammary ducts of female immunocompromised mice (Mouse Mammary Intraductal(MIND)). To date, 150 primary DCIS patient samples were engrafted and &amp;gt;100 have been incubated in vivo for a period of 12 months. Using this method we obtain a take rate of 89% with 36% of our models showing progression. Histology and molecular subtyping by PAM50 classification are well preserved in the outgrown PDX lesions compared to the original human counterpart, ensuring that our models are a good representation of the patient disease. For &amp;gt;80 primary samples we obtained RNAseq as well as &amp;gt;50 matched PDX profiles. In addition WES or WGS data is generated from the same primary DCIS samples together with 10 matched PDX WES profiles as well as &amp;gt;40 matched CNV PDX profiles. On top of this we used whole mount imaging, in order to create 3D sections of the injected mammary glands extracted from our PDX models, showing two distinct growth patterns correlated with invasion. And as this is all done in the context of the PRECISION consortium this allows us to confirm and validate our findings in larger sequencing and imaging efforts of human samples. Besides collecting large amounts of data which we can now link to DCIS progression we have successfully sequentially transplanted &amp;gt;25 of our PDX models in order to create models that can be shared with the scientific community and can be manipulated to validate the role of genes in DCIS progression. As an example we took HER2 overexpression, which in our models was found to be associated to progressive disease. On the one hand we treated three progressive HER2 overexpressing DCIS PDX models with a HER2-antibody Herceptin showing a massive decline in growth, while on the other hand we infected two indolent HER2 negative DCIS PDX models with a HER2-GFP lentivirus showing a transformation to HER2 positive progressive growth. In conclusion all this data together enables us to create a well-characterized biobank of DCIS models of which we can follow the progression, sequentially transplant &amp;gt;25 models, find mutational and expression profiles related to high risk DCIS and manipulate gene expression to validate the role of genes in DCIS progression. Citation Format: Jelle Wesseling, Stefan Hutten, Catrin Lutz, Colinda Scheele, Madelon Badoux, Timo Eijkman, Roebi de Bruijn, Mathilde Almekinders, Joyce Sanders, Esther Lips, Jacco van Rheenen, Jos Jonkers, Grand challenge PRECISION consortium. Intraductal patient-derived xenograft models of ductal carcinoma in situ (DCIS) to distinguish indolent DCIS from aggressive DCIS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-01.

Abstract P3-12-36: The diagnosis and prognosis of ductal carcinoma in situ (DCIS) with microinvasion - Results from the United Kingdom Sloane project

Abstract Background/objectives The natural history of microinvasive carcinoma of the breast (one or more foci of invasion of 1mm or less) and its optimal management remain controversial. We analysed the frequency and outcome of patients with DCIS plus microinvasion within a large prospective cohort of screen-detected DCIS. Methods Patients with screen-detected DCIS diagnosed between 2003 and 2012 with or without microinvasion in the final surgical specimen were identified from the UK Sloane Project database. Comprehensive imaging, surgical, pathology, oncology and subsequent outcome data were collected with a median follow-up of 9 years. Results Among 11285 DCIS patients diagnosed in the UK, microinvasion was reported in 521 (4.6%). The frequency of reported microinvasion varied considerably among screening units (0-25%) but overall decreased from 7% in 2003/04 to 3% in 2011/12.As reported elsewhere, microinvasion was significantly associated with high grade DCIS (5.9% of 7182 cases) compared to 2.9% of intermediate grade and &amp;lt;1% of low grade DCIS (p&amp;lt;0.001, Chi square test). Microinvasion was associated with larger DCIS size (p&amp;lt;0.001) 2.2% of DCIS &amp;lt;10mm, 3.9% of DCIS 10-20mm, 5.8% of DCIS 20-30mm, 5.2% of DCIS 30-40mm and 8.0% of DCIS &amp;gt;40mm had microinvasive foci reported. Microinvasion was also associated with the presence of comedo necrosis (p&amp;lt;0.001), and solid (p&amp;lt;0.001), cribriform (p&amp;lt;0.001) or flat (p=0.03) DCIS architecture.Microinvasion was identified more frequently in patients who underwent mastectomy (6.9%) than in those who had breast conserving surgery (BCS) (3.6%; p&amp;lt;0.001). Axillary nodal surgery was more commonly performed for microinvasion (60.4% compared to 30.3%) including for patients undergoing BCS (43.4% vs 8.5% of all patients with BCS; p&amp;lt;0.001). The rate of nodal metastasis was, however, low and not statistically significantly different between those with and without microinvasion (0.4% and 0.1% respectively, p=0.27).Patients with microinvasion who underwent BCS were also more likely to receive radiotherapy (p&amp;lt;0.001). There was no significant association between the presence or absence of microinvasion with margin status or width. Subsequent events data for England showed that microinvasion was associated with a low rate of ipsilateral subsequent events, with 2.3% of patients having recurrent DCIS and 4.2% developing invasive carcinoma. This was not statistically significantly different from DCIS without microinvasion. All subsequent ipsilateral DCIS events in patients with microinvasion were of high grade. The majority (71.4%) of subsequent ipsilateral invasive carcinomas were of grade 3 compared with only 30.4% of grade 3 carcinomas in patients with DCIS without microinvasion (p=0.02). Breast cancer mortality was significantly higher in women whose tumours showed microinvasion (2.1%) compared with those without it (0.8%; p=0.005). Conclusions Microinvasion was most commonly identified within high-grade DCIS and in larger DCIS lesions, and was associated with comedo necrosis. Its pathological reporting decreased over a 10-year period, but there was significant variation between departments, which requires further evaluation. Patients with DCIS plus microinvasion were more likely to have undergone mastectomy, axillary node surgery and to receive radiotherapy after BCS. Microinvasive breast carcinoma was associated with a low rate of subsequent in situ/invasive events and had a good prognosis but, nevertheless, a higher breast cancer mortality than DCIS without microinvasion. Citation Format: Abeer M Shaaban, Bridget Hilton, Karen Clements, David Dodwell, Nisha Sharma, Cliona Kirwan, Elinor Sawyer, Anthony Maxwell, Matthew Wallis, Hilary Stobart, Senthurun Mylvaganam, Janet.Litherland Litherland, Samantha Brace-Mcdonnell, Joanne Dulson-Cox, Olive Kearins, Elena Provenzano, Sarah Pinder, Alastair Thompson. The diagnosis and prognosis of ductal carcinoma in situ (DCIS) with microinvasion - Results from the United Kingdom Sloane project [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-36.

A Model to Predict Upstaging to Invasive Carcinoma in Patients Preoperatively Diagnosed with Low-Grade Ductal Carcinoma In Situ of the Breast.

We aimed to create a model of radiological and pathological criteria able to predict the upgrade rate of low-grade ductal carcinoma in situ (DCIS) to invasive carcinoma, in patients undergoing vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. A total of 3100 VABBs were retrospectively reviewed, among which we reported 295 low-grade DCIS who subsequently underwent surgery. The association between patients' features and the upgrade rate to invasive breast cancer (IBC) was evaluated by univariate and multivariate analysis. Finally, we developed a nomogram for predicting the upstage at surgery, according to the multivariate logistic regression model. The overall upgrade rate to invasive carcinoma was 10.8%. At univariate analysis, the risk of upgrade was significantly lower in patients with greater age (p = 0.018), without post-biopsy residual lesion (p < 0.001), with a smaller post-biopsy residual lesion size (p < 0.001), and in the presence of low-grade DCIS only in specimens with microcalcifications (p = 0.002). According to the final multivariable model, the predicted probability of upstage at surgery was lower than 2% in 58 patients; among these 58 patients, only one (1.7%) upstage was observed, showing a good calibration of the model. An easy-to-use nomogram for predicting the upstage at surgery based on radiological and pathological criteria is able to identify patients with low-grade carcinoma in situ with low risk of upstaging to infiltrating carcinomas.

Unresected screen-detected ductal carcinoma in situ: Outcomes of 311 women in the Forget-Me-Not 2 study

Background and aimThe natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. MethodsEnglish breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. ResultsData for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4–21%), 39% (24–58%) and 36% (24–50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. ConclusionThe findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment.

Nuclear morphology in breast lesions: refining its assessment to improve diagnostic concordance.

Although evaluation of nuclear morphology is important for the diagnosis and categorisation of breast lesions, the criteria used to assess nuclear atypia rely upon the subjective evaluation of several features that may result in inter- and intraobserver variation. This study aims to refine the definitions of cytonuclear features in various breast lesions. ImageJ was used to assess the nuclear morphological features including nuclear diameter, axis length, perimeter, area, circularity and roundness in 160 breast lesions comprising ductal carcinoma in situ (DCIS), invasive breast carcinoma of no special type (IBC-NST), tubular carcinoma, usual ductal hyperplasia (UDH), columnar cell change (CCC) and flat epithelial atypia (FEA). Reference cells included normal epithelial cells, red blood cells (RBCs) and lymphocytes. Reference cells showed size differences not only between normal epithelial cells and RBCs but also between RBCs in varied-sized blood vessels. Nottingham grade nuclear pleomorphism scores 1 and 3 cut-offs in IBC-NST, compared to normal epithelial cells, were < ×1.2 and > ×1.4 that of mean maximum Feret's diameter and < ×1.6 and > ×2.4 that of mean nuclear area, respectively. Nuclear morphometrics were significantly different in low-grade IBC-NST versus tubular carcinoma, low-grade DCIS versus UDH and CCC versus FEA. No differences in the nuclear features between grade-matched DCIS and IBC-NST were identified. This study provides a guide for the assessment of nuclear atypia in breast lesions, refines the comparison with reference cells and highlights the potential diagnostic value of image analysis tools in the era of digital pathology.

Ductal Carcinoma In Situ - Quo Vadis?

The introduction of mammographic screening in the early 1980's was associated, in the three following decades, with a dramatic increase in the detection of ductal carcinoma in situ (DCIS), pathology rarely detected before, on surgical specimen, at the periphery of an invasive cancer (1,2,3). It is estimated that in the United States the incidence of DCIS, each year, varies between 18 to 25% of the total number of newly diagnosed breast cancers (4,5). Ductal carcinoma in situ belongs, genetically and pathomorphologically, to a heterogenous group of preinvasive neoplastic lesions characterized by clonal proliferation of malignant cells limited to the lumen of breast ducts. It has not a known natural history and its phenotypical spectrum is wide, varying from a slowly evolving disease to a fast growing one, invading the surrounding stroma and even metastasizing to distant sites (6). In the absence of reliable prognostic markers, most of patients are submitted to invasive treatments consisting mainly in surgery, alone or associated with radiation and endocrine therapy (7). Molecular subtyping has improved the understanding of breast cancer biology and its possibilities for evolution and have provided the tools to design a more personalized treatment (8). In the absence of reliable molecular markers clinical management of patients with DCIS is based on patient's option and tumor characteristics. Based on the knowledge of today, DCIS could be used to exemplify the notions of overdiagnosis and overtreatment. The final goal of the treatment of DCIS is to prevent invasive breast cancer recurrence. Mortality rate associated with DCIS is very low, being estimated at 1-2 % at 10 years, while patients with DCIS treated by wide local excision with or without radiation may have a local recurrence rate of 5 to 30% and half of these present as an invasive cancer. Today's clinicians are not able to predict the risk of progression for a DCIS diagnosed by biopsy, but neither the risk of local recurrence, as an invasive cancer, of DCIS treated by conservative surgery with or without radiation (9). Progression to invasive cancer is difficult to be predicted as the disease is highly heterogenous. Because of these uncertainties, it is highly important to carefully inform the patient and engage her in the treatment decision process (10). There is a trend for de-escalation of treatment for DCIS. A study comparing two groups of patients with pure DCIS was conducted: one with standard care and the other under active surveillance (11). The main outcome was the probability to die from breast cancer at 10 years after the diagnosis. The mortality risk from breast cancer is higher for younger women, than the older ones, under active surveillance. Women over the age of 70 years, have many comorbidities that could induce the risk of dying, regardless of DCIS treatment decision. This study suggested that active surveillance could be a reasonable option for certain category of patients. This attitude is not without risks. A patient with DCIS on core needle biopsy could hide an invasive cancer in 25% of cases (12). Today, there are four randomized control trials of active surveillance offered to patients with low-grade DCIS: LORD (LOw Risk DCIS), COMET (Comparison of Operative to Monitoring and Endocrine Therapy), LORIS (LOw RISk DCIS) and LORETTA (10,13-16). Non-surgical approaches are of two types: active surveillance alone or associated with hormone therapy. There are some differences between the trials. While in LORD and LORIS trials the study arms are represented by active surveillance only, hormone therapy is an option in COMET trial and mandatory in the single arm trial LORETTA. The aim of these studies is to examine the safety and the effectiveness of active surveillance compared with surgical management for low-risk DCIS. The results of these trials are awaited with great interest. Patients with ductal carcinoma in situ need special counseling. To talk about "a good" cancer or even no cancer and to recommend as treatment a mastectomy is highly confusing. The language used by all members of the team must be unitary, removing the anxiety and helping patients to make the best decision. This special issue is a great opportunity to have the opinions of highly respected international specialists in the field for a comprehensive review of DCIS of the breast.

EP.TH.3Male Breast Cancer: A Series of Three Extremely Rare Cases

Abstract Aims Male breast cancer (MBC) is rare and accounts for 1% of all breast cancers. We present a case series of three very rare histological subtype MBC within one year in a UK hospital. Methods We retrospectively identified all MBCs from the local breast cancer database. Their presentations, radiology and histopathology were analysed. Results Three MBCs were identified from 2019 to 2020. A healthy 28-year-old presented with a right breast lump. Ultrasound (USS) revealed a partially cystic 15mm U3 lesion. Mammography (MMG) was suggestive of gynaecomastia (M2). Biopsy was inconclusive. Diagnostic excision revealed Papillary Ductal Carcinoma in Situ (DCIS) with involved margin. Mastectomy and Sentinel Node Biopsy (SNB) confirmed low-grade Papillary DCIS. A 48-year-old with background of hyperlipidaemia presented with a 2-year history of left axillary lump. PET CT demonstrated an FDG-avid lesion. USS showed a superficial U3 28mm lesion. MMG showed a 34mm density (M4). Biopsy identified Mucinous Carcinoma. Wide Local Excision and SNB confirmed grade 2 Mucinous Carcinoma. A 75-year-old with history of cardiac disease, COPD and Type 2 Diabetes, presented with a right retro-areolar lump. MMG identified a 47mm mass (M4). USS showed a 41mm cystic lesion with wall thickening (U4). Cytology was inconclusive. Biopsy identified intra-cystic papillary carcinoma. Mastectomy and SNB confirmed intra-cystic papillary carcinoma. All three histological subtypes are extremely rare and account for less than 4% of all MBCs. Conclusions MBC is rare but increasing in incidence. More research and awareness are needed to minimise delays in diagnosis and treatment even in young men.

Touching tumour-infiltrating lymphocytes in low-risk ductal carcinoma in situ (DCIS) correlate with upgrading to high-grade DCIS.

To examine our hypothesis that a higher number of touching tumour-infiltrating lymphocytes (TILs) in low-risk ductal carcinoma in situ (DCIS) detected in a setting such as an active surveillance clinical trial correlates with upgrading to high-grade DCIS (HG-DCIS) in the subsequent excisional biopsy. The clinical inclusion criteria of the Comparison of Operative versus Monitoring and Endocrine Therapy (COMET) trial were applied to women who were mammographically screened between 2007 and 2017. In the core needle biopsy, touching TILs were assessed by counting the number of TILs touching the ductal basement membrane or away from it by one lymphocyte thickness. The highest number of TILs around a single involved duct and the average number among involved ducts were recorded. DCIS was graded as low or intermediate. Twenty-six of 129 (20.2%) cases had upgrading [14 (10.9%) to pure HG-DCIS, and 12 (9.3%) to invasive carcinoma, two of them with concurrent HG-DCIS]. An increased average number of touching TILs and intermediate-grade DCIS correlated with upgrading to HG-DCIS in 11 of 16 (68.8%) cases, and a decreased average number of touching TILs and low-grade DCIS correlated with no upgrading in 89 of 113 (78.8%) cases [accuracy of 0.775; area under the curve (AUC) of 0.746]. An increased highest number of touching TILs and intermediate-grade DCIS correlated with upgrading to HG-DCIS in 12 of 16 (75%) cases, and a decreased highest number of touching TILs and low-grade DCIS correlated with no upgrading in 82 of 113 (72.6%) cases (accuracy of 0.7287; AUC of 0.734). A highest number of touching TILs of ≥10 correlated with upgrading to invasive carcinoma and/or HG-DCIS (P = 0.018). Intermediate-grade and touching TILs may be good variables to examine in the COMET trial and to correlate with the risk of upgrading.

Discriminating low-grade ductal carcinoma in situ (DCIS) from non-low-grade DCIS or DCIS upgraded to invasive carcinoma: effective texture features on ultrafast dynamic contrast-enhanced magnetic resonance imaging.

To investigate effective model composed of features from ultrafast dynamic contrast-enhanced magnetic resonance imaging (UF-MRI) for distinguishing low- from non-low-grade ductal carcinoma in situ (DCIS) lesions or DCIS lesions upgraded to invasive carcinoma (upgrade DCIS lesions) among lesions diagnosed as DCIS on pre-operative biopsy. Eighty-six consecutive women with 86 DCIS lesions diagnosed by biopsy underwent UF-MRI including pre- and 18 post-contrast ultrafast scans (temporal resolution of 3s/phase). The last phase of UF-MRI was used to perform 3D segmentation. The time point at 6s after the aorta started to enhance was used to obtain subtracted images. From the 3D segmentation and subtracted images, enhancement, shape, and texture features were calculated and compared between low- and non-low-grade or upgrade DCIS lesions using univariate analysis. Feature selection by least absolute shrinkage and selection operator (LASSO) algorithm and k-fold cross-validation were performed to evaluate the diagnostic performance. Surgical specimens revealed 16 low-grade DCIS lesions, 37 non-low-grade lesions and 33 upgrade DCIS lesions. In univariate analysis, five shape and seven texture features were significantly different between low- and non-low-grade lesions or upgrade DCIS lesions, whereas enhancement features were not. The six features including surface/volume ratio, irregularity, diff variance, uniformity, sum average, and variance were selected using LASSO algorism and the mean area under the receiver operating characteristic curve for training and validation folds were 0.88 and 0.88, respectively. The model with shape and texture features of UF-MRI could effectively distinguish low- from non-low-grade or upgrade DCIS lesions.

Is Carboxypeptidase B1 a Prognostic Marker for Ductal Carcinoma In Situ?

Simple SummaryDuctal carcinoma in situ (DCIS) is an early-stage breast cancer (BC), in which tumor cells are growing in a localized duct of the mammary gland. DCIS is considered a precursor disease for invasive BC and, therefore, treated as soon as it is identified. However, low-grade DCIS can be confused with atypical ductal hyperplasia, which is not a malignant lesion, leading to unnecessary surgery in around 70% of women with suspected DCIS. On the other hand, if left untreated, a DCIS has the potential to progress to IDC. In this retrospective study, we identified a gene signature, carboxypeptidase B1 (CPB1), the expression of which could help differentiate DCIS from an ADH lesion and DCIS that may progress to an invasive BC.Ductal carcinoma in situ (DCIS) is considered a non-obligatory precursor for invasive ductal carcinoma (IDC). Around 70% of women with atypical ductal hyperplasia (ADH) undergo unnecessary surgery due to the difficulty in differentiating ADH from low-grade DCIS. If untreated, 14–60% of DCIS progress to IDC, highlighting the importance of identifying a DCIS gene signature. Human transcriptome data of breast tissue samples representing each step of BC progression were analyzed and high expression of carboxypeptidase B1 (CPB1) expression strongly correlated with DCIS. This was confirmed by quantitative PCR in breast tissue samples and cell lines model. High CPB1 expression correlated with better survival outcome, and mRNA level was highest in DCIS than DCIS adjacent to IDC and IDC. Moreover, loss of CPB1 in a DCIS cell line led to invasive properties associated with activation of HIF1α, FN1, STAT3 and SPP1 and downregulation of SFRP1 and OS9. The expression of CPB1 could predict 90.1% of DCIS in a cohort consisting of DCIS and IDC. We identified CPB1, a biomarker that helps differentiate DCIS from ADH or IDC and in predicting if a DCIS is likely to progress to IDC, thereby helping clinicians in their decisions.

Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project

BackgroundThe Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes.MethodsThis was a national, prospective cohort study of DCIS diagnosed during 2003–2012.ResultsAmong 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years.ConclusionDCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.