Intermediate-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.

Surgical outcomes of total duct excision in the diagnosis and management of nipple discharge.

Total duct excision (TDE) is performed for the diagnosis and management of nipple discharge. The Association of Breast Surgery's recent guidelines recommend considering diagnostic surgery for single-duct, blood-stained or clear nipple discharge, and for symptomatic management. We retrospectively reviewed the diagnostic and surgical outcomes of all cases of TDE between January 2013 and November 2019. In total, 259 TDEs were carried out: 219 for nipple discharge, 29 for recurrent mastitis, 3 for screening abnormalities and 8 for breast lumps. Of the nipple discharge group, 121 had blood-stained discharge. Mean patient age was 52 years (range 19-81). Median follow-up time was 45 months (interquartile range 24-63). The following cases were identified on histopathology: 236 benign breast changes, 10 atypical ductal hyperplasia, 4 lobular carcinoma in situ, 2 low-grade ductal carcinoma in situ (DCIS), 3 intermediate-grade DCIS, 2 high-grade DCIS and 2 invasive ductal carcinomas. In total, 3.5% of patients who underwent TDE had a diagnosis of DCIS or invasive carcinoma. Blood-stained discharge was associated with a significant increase in risk of DCIS or carcinoma compared with other nipple discharge colours (p = 0.043). The most common complications of TDE were infection, poor wound healing and haematoma. Nipple discharge recurred in 14.2% of cases. TDE can be considered for the diagnostics and management of nipple discharge. Blood-stained nipple discharge increases the risk of DCIS or malignancy, but the majority of the time TDE reveals benign breast pathology.

Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan–Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

Preoperative diagnosis of ductal carcinoma in situ of the breast over a 24-year period.

The method of diagnosis of ductal carcinoma in situ (DCIS) has changed since the 1980s. The aim of this audit was to assess changes in the preoperative diagnosis of DCIS since the introduction of needle core biopsy, particularly the proportion with a preoperative biopsy diagnosis of DCIS. The preoperative diagnoses of patients with a final diagnosis of DCIS in the surgical specimen were reviewed (i) in 809 patients who presented through breast screening from 1997 to 2021, and (ii) in all patients in 5 individual years at 5-year intervals from 2000 to 2020 (254 in total). For screening-detected DCIS the proportion with a preoperative diagnosis of DCIS increased from 75% to 98% over the study period. In a detailed analysis of all cases of DCIS in 5 separate years the proportion with a preoperative diagnosis of DCIS increased from 68% in 2000 to 96% in 2020. For high-grade DCIS the proportion increased from 87% to 97%, and for low- or intermediate-grade DCIS from 48% to 93%. The proportion of women who had vacuum-assisted biopsy increased from 7% in 2000 to 58% in 2015. There was a small increase in the number of biopsies that had basal cytokeratin and oestrogen receptor immunohistochemistry to aid diagnosis. There has been an increase in the preoperative diagnosis of DCIS, particularly of low- or intermediate-grade, over the last two decades. The increasing use of vacuum-assisted biopsy is likely to be a major contributory factor to this increase.

Upgrade Rate of Ductal Carcinoma In Situ to Invasive Carcinoma and the Clinicopathological Factors Predicting the Upgrade Following a Mastectomy: A Retrospective Study.

Background The rate of upgrading ductal carcinoma in situ (DCIS) to invasive cancer varies widely in the literature with no consensus regarding sentinel lymph node biopsy (SLNB) for DCIS; however, some guidelines do recommend it in the event of a mastectomy. The primary aim of this study was to determine the upgrade rate of DCIS to invasive carcinoma (IC) in patients undergoing mastectomy for DCIS and identify the clinicopathological predicting factors for the upgrade. The secondary aim was to determine the SLNB positivity rate. Methodology We retrospectively analysed consecutive patients with DCIS diagnosed through a biopsy who then underwent mastectomy over a 10-year period (2010 to 2020). Clinical, radiological, and histological variables were collected from medical records. Results We studied 143 women (mean age = 57.4 years, range = 26-85 years) who underwent mastectomy for DCIS identified on biopsy.Almost two-thirds (62.9%, 90/143) of the patients were detected on screening mammography, while 35.6% (51/143) were diagnosed following presentation with either an area of palpable concern or nipple discharge.The most common mammographic presentation of DCIS was calcification (83.9%, 120/143), and, in 85.9% of the patients, the mammographic lesion was more than 20 mm. High-grade DCIS was noted in 76.9% of preoperative biopsy results, while the rest was either low or intermediate-grade DCIS. Overall, 24.5% (35/143) were upgraded to IC (upgraded group) on postoperative histology, whereas 108/143 remained DCIS postoperatively (pure DCIS group).The positivity rate of SLNB was 4.8%. Multifocality was the only significant predictor of IC on multivariate analyses of clinicopathological predictors (odds ratio = 3.0, 95% confidence interval = 1.0-8.7). The presence of comedonecrosis was higher in the upgraded group compared to the pure DCIS group (42.9% vs. 27.8%), but this was not statistically significant. Conclusions In our study cohort, nearly one in four (24.5%) patients were upgraded from DCIS to IC on postoperative histology, with an SLNB positivity rate of 4.8%. This is important when counselling patients regarding the risk of coincident occult IC and the importance of SLNB at the time of mastectomy. Multifocality on preoperative imaging was the only significant predictive factor. Based on this result, we recommend that SLNB should also be considered if patients have multifocal DCIS and planned for oncoplastic breast-conserving surgery. However, further studies are required to investigate the association between multifocal DCIS and the risk of upgrading to IC.

Predicting Lymph Node Metastases in Patients with Biopsy-Proven Ductal Carcinoma In Situ of the Breast: Development and Validation of the DCIS-met Model

PurposeIn patients with a biopsy-proven ductal carcinoma in situ (DCIS), axillary staging is frequently performed, but in hindsight often turns out to be superfluous. The aim of this observational study was to develop a prediction model for risk of lymph node metastasis in patients with a biopsy-proven DCIS.MethodsData were received from the Dutch Pathology Databank and the Netherlands Cancer Registry. The population-based cohort consisted of all biopsy-proven DCIS patients diagnosed in the Netherlands in 2011 and 2012. The prediction model was evaluated with the area under the curve (AUC) of the receiver operating characteristic, and a calibration plot and a decision curve analysis and was validated in a Dutch cohort of patients diagnosed in the period 2016–2019.ResultsOf 2892 biopsy-proven DCIS patients, 127 had metastasis (4.4%). Risk factors were younger age (OR = 0.97, 95% CI 0.95–0.99), DCIS not detected by screening (OR = 1.55, 95% CI 1.01–2.38), suspected invasive component at biopsy (OR = 1.86, 95% CI 1.01–3.41), palpable tumour (OR = 2.06, 95% CI 1.34–3.18), BI-RADS score 5 (OR = 2.41, 95% CI 1.53–3.78), intermediate-grade DCIS (OR = 3.01, 95% CI 1.27–7.15) and high-grade DCIS (OR = 3.20, 95% CI 1.36–7.54). For 24% (n = 708) of the patients, the predicted risk of lymph node metastasis was above 5%. Based on the decision curve analysis, the model had a net benefit for a predicted risk below 25%. The AUC was 0.745. Of the 2269 patients in the validation cohort, 53 (2.2%) had metastasis and the AUC was 0.741.ConclusionsThis DCIS-met model can support clinical decisions on axillary staging in patients with biopsy-proven DCIS.

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.

Additional Excision Biopsy in Patients With Atypical Ductal Hyperplasia at Ultrasound-guided Vacuum-assisted Breast Biopsy.

We conducted this single-center, retrospective study to identify predictors of upgrading to malignancy and to discuss the necessity of additional excision biopsy in patients who were diagnosed with atypical ductal hyperplasia (ADH) at ultrasound (US)-guided vacuum-assisted breast biopsy (VABB) based on our 18-year, single-center experience. The current study was conducted in a total of 12,160 patients who were evaluated at our medical institution during an 18-year period between January of 2003 and December of 2020. We included the patients who were diagnosed with ADH at US-guided VABB using the Mammotome® (Devicor Medical Products, Inc., Cincinnati, OH, USA). We therefore included a total of 114 patients (n=114) with ADH in the current study. Of 114 eligible patients, 36 underwent additional excision biopsy and the remaining 78 did not. Of these 36 patients, 15 were found to have an upgrading to malignancy at a rate of upgrading of 41.7%. These include 7 cases (46.6%) of low-grade ductal carcinoma in situ (DCIS), 3 cases (20.0%) of intermediate grade DCIS, 1 case (6.7%) of microinvasive DCIS, 3 cases (20.0%) of multifocal lobular carcinoma in situ, and 1 case (6.7%) of mucinous carcinoma. Finally, only suspicious microcalcification on mammography was a significant predictor of upgrading to malignancy (p=0.023). An additional excision biopsy is recommended to reduce the rate of upgrading to malignancy in patients who were diagnosed with ADH through a US-guided VABB.

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.

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.

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.

Atypical Ductal Hyperplasia and Those Bordering on Ductal Carcinoma In Situ Should Be Included in the Active Surveillance Clinical Trials.

Women with atypical ductal hyperplasia (ADH), unlike those with ductal carcinoma in situ (DCIS), are denied eligibility for active surveillance clinical trials. We applied the inclusion criteria of the Comparison of Operative to Monitoring and Endocrine Therapy (COMET) trial to the cases of women (n = 165) at the Roswell Park Cancer Institute who had a diagnosis of ADH, ADH bordering on DCIS, or low- to intermediate-grade DCIS on core biopsy taken during screening mammography. Upgrade of lesions to high risk was based on invasive carcinoma, high-grade DCIS, or DCIS with comedo necrosis. In total, nine (5.5%) lesions were upgraded: two (1.7%) reported ADH, one (5.9%) reported ADH bordering on DCIS, and six (19.4%) reported DCIS (P = .002); and two (1.6%) reclassified ADH vs seven (17.1%) reclassified DCIS (P < .001). In multivariate analysis, only increased number of foci had the potential to predict high risk (odds ratio: 1.39; P = .06). We conclude that ADH and ADH bordering on DCIS have lower upgrade rates than DCIS. We recommend opening an active surveillance clinical trial for women with these diagnoses.

Population-based study of the effect of preoperative breast MRI on the surgical management of ductal carcinoma in situ.

BackgroundDeterminants of the use of breast MRI in patients with ductal carcinoma in situ (DCIS) in the Netherlands were studied, and whether using MRI influenced the rates of positive resection margins and mastectomies.MethodsAll women aged less than 75 years, and diagnosed with DCIS between 2011 and 2015, were identified from the Netherlands Cancer Registry. Multivariable logistic regression analyses were performed, adjusting for incidence year, age, hospital type, DCIS grade and multifocality.ResultsBreast MRI was performed in 2382 of 10 415 DCIS cases (22·9 per cent). In multivariable analysis, patients aged less than 50 years, those with high‐ or intermediate‐grade DCIS and patients with multifocal disease were significantly more likely to have preoperative MRI. Patients undergoing MRI were more likely to have a mastectomy, either as first surgical treatment or following breast‐conserving surgery (BCS) in the event of positive margins (odds ratio (OR) 2·11, 95 per cent c.i. 1·91 to 2·33). The risk of positive surgical margins after BCS was similar for those with versus without MRI. The secondary mastectomy rate after BCS was higher in patients who had MRI, especially in women aged less than 50 years (OR 1·94, 1·31 to 2·89). All findings were similar for low‐ and intermediate/high‐grade DCIS.ConclusionAdding MRI to conventional breast imaging did not improve surgical outcome in patients diagnosed with primary DCIS. The likelihood of undergoing a mastectomy was twice as high in the MRI group, and no reduction in the risk of margin involvement was observed after BCS.

Abstract P5-18-03: A predictive model for local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS)

Abstract Background: Ductal carcinoma in situ (DCIS) is a heterogeneous precursor, non-invasive breast lesion. There is a lack of specific DCIS molecular predictors of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC) after breast conserving surgery (BCS) +/- radiotherapy (RT). The aim of this was to identify novel biomarkers and combine these with clinical parameters to develop a new model to predict IBTR in patients treated by BCS for DCIS. Methods: A single institution DCIS biomarker discovery study included a case-control matched series of 180 patients (median age 61, range 35-94) treated at the Edinburgh Breast Unit between 2000 and 2010: · 88 patients with low/intermediate grade DCIS treated with BCS alone; 18 recurred within 10 years. · 92 patients with high grade DCIS treated by BCS and RT; 22 recurred within 10 years. Median follow-up was 7.4 years. RNA was extracted from DCIS lesions and whole-genome transcriptomics analysis was performed using Lexogen QuantSeq. Predictive models were generated based upon the most informative genes. Independent validation cohorts are also available and are currently being used for validation. Results: The models developed predict risk of IBTR in patients with low or intermediate grade DCIS treated with BCS alone and high grade DCIS treated with DCIS plus RT. The models were found to be independent of grade and stratify patients into binary groups of high and low risk of recurrence. A promising model was developed based on the expression of 5 genes combined with tumour diameter ≤15mm or &amp;gt;15mm. • In low/intermediate grade DCIS expression levels of a solute carrier family gene, kinetochore associated gene and an immunomodulatory gene are predictive of recurrence. • In high grade DCIS an additional solute carrier and a glutathione S-transferase related gene are predictive of recurrence. • In the training sets the models have 96% (high-grade) and 92% (low/intermediate grade) accuracy of prediction of subsequent recurrence and estimates of IBTR-free survival were highly significant in both groups (&amp;lt;0.0001). Validation of the model by RT-PCR and immunohistochemistry is underway in both the training cohort and an independent validation cohort. Conclusions: · Promising models to predict risk of IBTR in patients treated for DCIS have been developed. · Novel biomarkers that predict recurrence have been identified using new technologies that may have clinical potential. · Independent validation is currently underway. Citation Format: Martinez-Perez C, Turnbull AK, Fernando A, Ekatah GE, Arthur LM, Cartlidge CW, Johns N, Sims AH, Thomas JS, Dixon JM. A predictive model for local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-03.

Accuracy of Breast Magnetic Resonance Imaging Compared to Mammography in the Preoperative Detection and Measurement of Pure Ductal Carcinoma In Situ: A Retrospective Analysis

Ductal carcinoma in situ (DCIS) hinders imaging detection due to multifocal appearance and discontinuous growth. Preoperative determination of its extent is therefore challenging. Aim of this study was to investigate the additional benefit of breast magnetic resonance imaging (MRI) to mammography (MG) in the diagnosis of DCIS according to size and grading. Retrospective analysis of 295 patients with biopsy-proven, pure DCIS. Mean patient age was 57.0 years (27-87 years). All patients obtained MG. Additional MRI was performed in 41.7% (123/295). Mammographic breast density, background parenchymal enhancement (BPE), tumor size and grading were analysed. Tumor size on MG and MRI were compared to histopathological size of the surgical specimen. Mean tumor size was 39.6 mm. DCIS was occult on MG in 24.4% (30/123) and on MRI in 1.6% (2/123). Size was underestimated by 4.6 mm (mean) mammographically. DCIS was high grade in 54.5% (67/123), intermediate grade in 40.7% (50/123) and low grade in 4.9% (6/123). MG was exact regarding tumor size in low grade DCIS, underestimated intermediate grade DCIS by 1 mm (median) and high grade DCIS by 10.5 mm. MRI overestimated low grade DCIS by 1 mm (median), was exact regarding intermediate grade DCIS and underestimated high grade DCIS by 1 mm. BPE did not influence tumor detection and measurement. MRI outperforms MG in the detection and size estimation of DCIS and can reduce positive margin rates.

Not All Ductal Carcinomas In Situ Are Created IDLE (Indolent Lesions of Epithelial Origin).

Mammographic screening has increased the incidence of ductal carcinoma in situ (DCIS), but this has not been accompanied by a decline in the incidence of invasive carcinoma (IC). Consequently, the surgical treatment of DCIS has recently been questioned, with some advocating only surveillance (with or without neoadjuvant endocrine therapy) after a core biopsy diagnosis of DCIS. To examine the predictive value of a core biopsy diagnosis of DCIS, particularly the upgrade rate to IC, and to identify associated factors. Using the pathology database, we identified 2943 cases of DCIS diagnosed on core biopsy from 2000 to 2015, of which 229 cases (8%) later had the stage upgraded to IC. Ages ranged from 25 to 90 years (mean, 59 years). The DCIS presented with calcifications in 151 of 229 cases (65.9%), was widespread in 26 of 151 cases (17%), had a mass or density present in 70 of 229 cases (31%), with heterogeneous echogenic features in 44 of those 70 cases (63%), and an enhancement upon magnetic resonance imaging in 8 of 229 cases (3.5%). Of the 229 cases, the DCIS grades were as follows: low in 29 cases (13%), intermediate in 79 cases (36%), and high in 121 cases (53%). Of the 229 cases, necrosis was present in 152 (66.4%) and was comedo necrosis in 99 cases (43%). Of the 229 cases of IC, the tumor stage was as follows: microIC in 36 (16%), T1a in 119 (52%), T1b in 35 (15%), T1c in 28 (12%), T2 in 8 (3%), and T3 in 3 cases (1%). Axillary lymph nodes were staged in 167 patients as follows: N0, 141 cases (84%); N0(i+), 14 cases (8%); and N1, 12 cases (7%). The 12 N1 cases were subclassified by T stage as follows: T1a, 1 case (8%); T1b, 4 cases (33%); T1c, 2 cases (17%); T2, 4 cases (33%); and T3, 1 case (8%). The IC cases of stage upgrading were predominantly smaller than 2 cm (218 of 229; 95%), and more than two-thirds were smaller than 0.5 cm (155 of 229; 95%), most of which were accompanied by extensive DCIS. Approximately one-half of the upgrades were associated with high-grade DCIS, especially with comedo necrosis; nevertheless, the other one-half of the upgrades were due to low- and intermediate-grade DCIS and should not be underestimated. There were few positive results from axillary lymph node biopsies, but they occurred in 3% (7 of 218) of the carcinomas smaller than 2 cm. Our findings indicate that caution is needed when DCIS cases diagnosed by core biopsy are treated nonsurgically with surveillance (with or without neoadjuvant endocrine therapy), given the number of cases (229 of 2943; 8%) that are upgraded to IC and those with axillary lymph node metastases (12 of 167; 7%).

Detection Rates of Ductal Carcinoma in Situ with Biennial Digital Mammography Screening: Radiologic Findings Support Pathologic Model of Tumor Progression.

Purpose To compare detection rates of ductal carcinoma in situ (DCIS), classified according to nuclear grade, between the prevalence round (baseline screening) and two subsequent screening rounds of a population-based digital mammography screening program, to assess differences over time. Materials and Methods The cancer registry provided data for 1970 graded pure DCIS cases from 16 screening regions of the prevalence round (baseline screening, from 2005 to 2008), first subsequent round, and second subsequent round; the interval between all screening rounds was 22-30 months. Age-adjusted logistic regression analysis was performed to compare the grade-specific detection rates between the prevalence round (reference) and subsequent screening rounds. Results Over all screening rounds, cancer detection rates were lowest for low-grade DCIS (range, 0.11 [58 of 508 817 patients] to 0.25 [178 of 713 867 patients] per 1000 women screened) and highest for high-grade DCIS (range, 0.53[271 of 508 817 patients] to 0.59 [237 of 398 944 patients] per 1000 women screened). Detection rates for low-grade DCIS were significantly lower in the first (odds ratio [OR] = 0.45, P < .001) and second (OR = 0.57, P < .001) subsequent screening rounds compared with that in the prevalence round; the relative reduction of detection rates of intermediate-grade DCIS was less pronounced (OR = 0.79, P = .006 and OR = 0.76, P = .003, respectively). Conversely, the detection rate of high-grade DCIS remained at the high level found in the prevalence screening (OR = 0.89, P = .143 and OR = 0.97, P = .700, respectively). Conclusion The findings demonstrate persistently high detection rates of high-grade DCIS in two consecutive subsequent screening rounds compared with the prevalence round; conversely, rates of low-grade DCIS and, less markedly, intermediate-grade DCIS decreased in subsequent rounds. Grade-related changes of DCIS detection are suggestive of distinct dynamics of lesion progression. © RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on November 10, 2017.

Abstract P1-11-03: Rates of ipsilateral breast tumor recurrence (IBTR) following breast concerving surgery (BCS) and hypofractionated radiotherapy for ductal carcinoma in situ (DCIS)

Abstract P1-11-03: Rates of ipsilateral breast tumor recurrence (IBTR) following breast concerving surgery (BCS) and hypofractionated radiotherapy for ductal carcinoma in situ (DCIS)

Abstract P3-17-06: LORIS trial of active monitoring for DCIS: How does the online pathology eligibility review process work?

Abstract Introduction The LORIS Trial is a UK randomized clinical trial comparing active monitoring with surgery for low risk ductal carcinoma in situ (DCIS), defined as low or low-intermediate grade DCIS without comedo necrosis, as diagnosed on vacuum-assisted (wide bore) core needle samples. Because of the inconsistency of grading DCIS, we have underpinned this trial with a Central Histopathology Review (CHR) before randomisation. The process of the CHR for the first 22 months of a two year pilot study between July 2014 and May 2016 is reported here. Patients and methods Patients were eligible for CHR if they satisfied all of the eligibility criteria and had locally reported low or intermediate grade DCIS. Patients were identified at 28 pilot sites and were registered for potential trial entry following written informed consent before being subjected to CHR. CHR comprised online examination of digitally scanned histology slides of all material from all diagnostic biopsies and was performed by at least two of the three LORIS specialist breast pathologists. Histology slides were submitted using Royal Mail Safebox® to the University of Birmingham where they were digitally scanned and made available for review via the Leica digital image hub. The outcome of the review was reported in a separate secure online database by completion of a Central Pathology Review Form. Access to both online systems is password protected. Eligibility was confirmed if two pathologists agreed that there was low or low to intermediate grade DCIS and no comedo necrosis. A maximum of 7 calendar days from receipt of the diagnostic material was allowed for the central review process. The digital images of the histology slides are stored by the Leica system for future reference. Results 100 patients were registered and their slides reviewed. 55 of these were deemed eligible by CHR; of these 38 have been randomised. 45 patients were deemed ineligible, most commonly due to grade being in the upper half of the intermediate category and/or comedo necrosis. In addition, 9 patients were deemed not to have DCIS and 1 patient had invasive disease. Grouping the grade categories as low and low to intermediate grade (low risk and eligible for randomisation) Vs intermediate to high and high cytonuclear grade (ineligible for randomisation) showed 91% agreement on grade category amongst the reviewing pathologists. Results of the central review were made available to sites within 7 days for 97% of cases submitted. On average, central review was completed within 4 days. Average time between registration and randomisation was 3 weeks. The LORIS central review pathologists found online viewing and reporting of sections acceptable. Conclusions Central Histopathology Review using online viewing of digital slides provides timely and efficient pathology Quality Assurance in this clinical trial setting, with acceptable turnaround times and good agreement between reviewing specialist breast pathologists. This process will be continued in the main phase of the trial. Citation Format: Thomas J, Hanby A, Pinder S, Pirrie S, Rea D, Gaunt C, Young J, Francis A. LORIS trial of active monitoring for DCIS: How does the online pathology eligibility review process work? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-06.