Low-grade Ductal Carcinoma In Situ Research Articles

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.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ

BackgroundOestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision.MethodsIn total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate.ResultsER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence).ConclusionThe strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Ductal Carcinoma In Situ Biology, Language, and Active Surveillance: A Survey of Breast Radiologists' Knowledge and Opinions.

To understand how breast radiologists perceive ductal carcinoma in situ (DCIS). A 19-item survey was developed by the Society of Breast Imaging Patient Care and Delivery Committee and distributed to all Society of Breast Imaging members. The survey queried respondents' demographics, knowledge of DCIS biology, language used to discuss a new diagnosis of DCIS, and perspectives on active surveillance for DCIS. Five-point Likert scales (1= strongly disagree, 3= neutral, 5= strongly agree) were used. There were 536 responses for a response rate of 41%. There was agreement that DCIS is the primary driver of overdiagnosis in breast cancer screening (median 4), and respondents provided mean and median overdiagnosis estimates of 29.7% and 25% for low-grade DCIS as well as 4.2% and 0% for high-grade DCIS, respectively. Responses varied in how to describe DCIS but most often used the word "cancer" with a qualifier such as "early" (32%) or "pre-invasive" (25%). Respondents disagreed (median 2) with removing the word "carcinoma" from DCIS. Finally, there was agreement that current standard of care therapy for some forms of DCIS is overtreatment (median 4) and that active surveillance as an alternative management strategy should be studied (mean 4), but felt that ultrasound (median 4) and MRI (median 4) should be used to exclude women with occult invasive disease before active surveillance. Breast radiologists' opinions about DCIS biology, language, and active surveillance are not homogenous, but general trends exist that can be used to guide research, education, and advocacy efforts.

Atypical ductal hyperplasia: breast DCE-MRI can be used to reduce unnecessary open surgical excision.

To evaluate the diagnostic performance of dynamic contrast-enhanced (DCE)-MRI in predicting malignancy after percutaneous biopsy diagnosis of atypical ductal hyperplasia (ADH). In this retrospective study, 68 lesions (66 women) with percutaneous biopsy diagnosis of ADH and pre-operative breast DCE-MRI performed between January 2016 and December 2017 were included. Two radiologists reviewed in consensus mammography, ultrasound, and MR images. The final diagnosis after surgical excision was used as standard of reference. Clinical and imaging features were compared in patients with and without upgrade to malignancy after surgery. The diagnostic performance of DCE-MRI in predicting malignant upgrade was evaluated. A 9-gauge vacuum-assisted biopsy was performed in 40 (58.8%) cases and a 14-gauge core needle biopsy in 28 (41.2%) cases. Upgrade to malignancy was observed in 17/68 (25%) lesions, including 4/17 (23.5%) cases of invasive cancer and 13/17 (76.5%) cases of ductal carcinoma in situ (DCIS). In 16/17 (94.1%) malignant and 20/51 (39.2%) benign lesions, a suspicious enhancement could be recognized in DCE-MRI. The malignant lesion without suspicious enhancement was a low-grade DCIS (4mm size). Sensitivity, specificity, positive predictive value, and negative predictive value of DCE-MRI on predicting malignancy were respectively 94.1%, 60.7%, 44.4%, and 96.8%. No other clinical or imaging features were significantly different in patients with and without upgrade to malignancy. After a percutaneous biopsy diagnosis of ADH, malignancy can be ruled out in most of the cases, if no suspicious enhancement is present in the biopsy area at DCE-MRI. Breast DCE-MRI may be used to avoid surgery in more than half of the patients with final benign diagnosis. • Breast DCE-MRI can safely rule out malignancy if no suspicious enhancement is present in the biopsy area after a percutaneous biopsy diagnosis of ADH. • All cases of upgrade to high-grade DCIS and invasive cancers can be identified at breast DCE-MRI after a percutaneous biopsy diagnosis of ADH. • Breast DCE-MRI may be used to avoid surgery in more than half of the patients with final benign diagnosis.

Breast magnetic resonance imaging for estimation of the tumour extent in patients with pure ductal carcinoma in situ: Comparison between full diagnostic and abbreviated protocols

PurposeTo evaluate the rate of concordance between pathology and preoperative breast MRI performed with an abbreviated protocol (AP) or a full diagnostic protocol (FDP) for estimation of the tumour extent in patients with pure ductal carcinoma in situ (DCIS). MethodsThis retrospective study included 164 patients with pathologically proven DCIS who underwent preoperative breast MRI. Two radiologists independently evaluated the tumour extent on MRI with (FDP) and without the delayed phase (AP) and compared the readings with the pathological tumour extent. The background parenchymal enhancement (BPE) and morphology were also evaluated. Furthermore, the influence of the degree of BPE, presence or absence of B2 and B3 lesions, and pathological DCIS grade on the accuracy of MRI findings was assessed. Concordance between MRI and pathology was evaluated using correlation analysis. ResultsSpearman’s rank correlation coefficients for the concordance between MRI and pathology were 0.63 (reader 1) and 0.69 (reader 2) with AP and 0.65 and 0.73 (readers 1 and 2, respectively) with FDP. For both readers, the difference in the measured value between FDP and pathology was significantly smaller than that between AP and pathology (p < 0.001). The inter-reader variation in the measured tumour extent was larger with FDP than with AP. The presence of B3 lesions, low-grade DCIS, and moderate/marked BPE lowered the rate of concordance between MRI and pathology. ConclusionsOur findings suggest that preoperative MRI with FDP is more accurate than that with AP alone for estimation of the tumour extent in patients with pure DCIS.

Epidemiologic risk factors for in situ and invasive ductal breast cancer among regularly screened postmenopausal women by grade in the Cancer Prevention Study-II Nutrition Cohort.

Histopathologic grade provides an integrated measure of biologic features which affects cancer prognosis. In invasive ductal breast cancer (IDBC), the grade of the ductal carcinoma in situ (DCIS) and invasive components are usually concordant, suggesting grade is established early in tumorigenesis and may be linked to etiologic factors. In this study, we used prospectively collected data from postmenopausal women in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort to compare risk factor associations among low-grade and high-grade DCIS, as well as low-grade and high-grade IDBC. Among 73,825 cancer-free women at enrollment in the CPS-II Nutrition Cohort in 1992-1993 (mean age: 62.1years), we verified 802 diagnosed with DCIS (C50 8500/2; n = 430 low-grade and 372 high-grade) and 3,125 with IDBC (C50 8500/3; n = 2,221 low-grade and 904 high-grade) through June 2013. Person-time contribution was conditional on screening mammograms self-reported on biennial surveys. Multivariable-adjusted joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). A personal history of benign breast disease was more strongly associated with higher risk of low-grade DCIS (HR = 2.20, 95% CI 1.81-2.67; p for heterogeneity = 0.0004) than high-grade DCIS. Consumption of two or more alcoholic drinks/day was only associated with a higher risk of low-grade IDBC (HR = 1.58, 95% CI 1.33-1.88; p for heterogeneity = 0.005). These results suggest heterogeneity by grade for breast cancer etiology. Identification of potential risk factor differences among low-grade and high-grade DCIS and IDBC may help to clarify associations, and ultimately, improve breast cancer risk prediction models.

Low-Grade Ductal Carcinoma In Situ.

We aimed to determine the interobserver reproducibility in diagnosing low-grade ductal carcinoma in situ (DCIS). We also aimed to compare the interobserver variability using a proposed two-tiered grading system as opposed to the current three-tiered system. Three expert breast pathologists and one junior pathologist identified low-grade DCIS from a set of 300 DCIS slides. Months later, participants were asked to grade the 300 cases using the standard three-tiered system. Using the two-tiered system, interobserver agreement among breast pathologists was considered moderate (κ = 0.575). The agreement was similar (κ = 0.532) with the junior pathologist included. Using the three-tiered system, pathologists' agreement was poor (κ = 0.235). Pathologists' reproducibility on diagnosing low-grade DCIS showed moderate agreement. Experience does not seem to influence reproducibility. Our proposed two-tiered system of low vs nonlow grade, where the intermediate grade is grouped in the nonlow category has shown improved concordance.

7P - Current diagnostic strategy for mammographic microcalcification without specific ultrasound abnormality

BackgroundStereotactic vacuum-assisted breast biopsy (SVAB) is widely used to evaluate predominantly mammograhic microcalcifications without specific ultrasound abnormalities. Recently however, there raise the problem that screening mammography detect the indolent low grade ductal carcinoma in situ (DCIS), and such diseases don’t necessarily have to be diagnosed by invasive SVAB examination. Moreover, breast magnetic resonance imaging (MRI) has increasingly been performed over the past 10 years and reveals high sensitivity for detecting breast cancer, especially tumor undetectable by ultrasound. The purpose of this study was to assess the optimal indications for SVAB. MethodsFive hundred and eighty-one patients with mammographic microcalcifications underwent SVAB between 2008 and 2014 in our hospital. All calcification lesions were classified into several groups according to the calcification categories (CC) and the presence of suspicions MRI abnormalities. We examined the rate of malignant disease in the subgroups. BI-RADS 4 and 5 MRI lesions were defined as suspicious MRI abnormality (SMA). We considered high grade DCIS and invasive ductal carcinoma (IDC) as worrisome disease ought to be diagnosed. ResultsThe rate of malignancy was 6.3 % in CC2, 14.3% in CC3, 30.3% in CC4, and 80.0% in CC5 altogether. Of 581 patients, two hundred and thirty-three patients were underwent contrast enhanced MRI. Among category 3 or 4 microcalcifications without SMA (134 lesions), results of SVAB revealed 22 malignant lesions (16.4%), including 21 low grade DCIS and only one high grade DCIS and no IDC. If the lesions were accompanied by SMA, the rate of malignancy in these categories was increased to 66.2% (51/77), including 8 high grade DCIS and 14 IDC. If the regions were classified to category 5, about three forth cases were accompanied by SMA (17/23). Half of the category 5 lesions without SMA was malignant (3/6), including one high grade DCIS. ConclusionsMammographic microcalcification classified as 3 or 4 without suspicious MRI abnormal lesion were not be recommended for stereotactic vacuum-assisted biopsies. Legal entity responsible for the studyNaoki Sato. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.Table7PTableMRI (-)MRI (-)MRI (-)MRI (+)MRI (+)MRI (+)category 3category 4category 5category 3category 4category 5Benign753331760ADH400120Low grade DCIS138211186High grade DCIS101355IDC000688

Stereotactic Vacuum-Assisted Breast Biopsy in Ductal Carcinoma in situ: Residual Microcalcifications and Intraoperative Findings

Purpose: The question of overtreatment of ductal carcinoma in situ (DCIS) was raised because a significant proportion of especially low-grade DCIS lesions never progress to invasive cancer. The rationale for the present study was to analyze the value of stereotactic vacuum-assisted biopsy (VAB) for complete removal of DCIS, focusing on the relationship between the absence of residual microcalcifications after stereotactic VAB and the histopathological diagnosis of the definitive surgical specimen. Patients and Methods: Data of 58 consecutive patients diagnosed with DCIS by stereotactic VAB in a single breast center between 2012 and 2017 were analyzed. Patient records from the hospital information system were retrieved, and mammogram reports and images as well as histopathology reports were evaluated. The extent of microcalcifications before and after biopsy as well as the occurrence of DCIS in biopsy and definitive surgical specimens were analyzed and correlated. Results: There was no correlation between the absence of residual microcalcifications in the post-biopsy mammogram and the absence of residual DCIS in the final surgical specimen (p = 0.085). Upstaging to invasive cancer was recorded in 4 cases (13%) but occurred only in the group that had high-grade DCIS on biopsy. Low-grade DCIS was never upgraded to high-grade DCIS in the definitive specimen. Conclusions: The radiological absence of microcalcifications after stereotactic biopsy does not rule out residual DCIS in the final surgical specimen. Since upstaging to invasive cancer is seen in a substantial proportion of high-grade DCIS, the surgical excision of high-grade DCIS should remain the treatment of choice.

Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study

PurposeThe future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen.MethodsWe studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000–2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded.ResultsAmong 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3–18.1) were upstaged to IBC and a further 14.6% (11.3–18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference < 0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity = 0.01) and upstaging (pheterogeneity = 0.004).ConclusionsThe risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

Can dedicated breast PET help to reduce overdiagnosis and overtreatment by differentiating between indolent and potentially aggressive ductal carcinoma in situ?

To analyze the utility of metabolic imaging, and specifically of dedicated breast positron emission tomography (dbPET) to differentiate between indolent and potentially aggressive ductal carcinoma in situ (DCIS). After institutional review board approval, we retrospectively reviewed the cases of pure DCIS who underwent dbPET before biopsy and surgery in Lucus Augusti Universitary Hospital (Lugo, Spain) and in Fudan Cancer Institute (Shanghai, China) between January 2016 and May 2018. Grade 1 and "non-comedo" grade 2 DCIS were considered low-risk disease, while intermediate-grade with necrosis or grade 3 cases were included in the high-risk group. DbPET sensitivity and specificity to differentiate between indolent and potentially aggressive DCIS were determined along with their respective 95% confidence intervals. We enrolled 139 surgery-confirmed pure DCIS cases. Fifty were high-risk neoplasms and 89 low-risk DCIS. Only seven low-risk lesions were positive at dbPET and five of potentially aggressive neoplasms did not show FDG uptake, all included into the field of view (FOV). Sensitivity and specificity of dbPET to differentiate between indolent and potentially aggressive DCIS were 90% (95% CI, 77-96%) and 92% (95% CI, 84-97%), respectively. Metabolic imaging could help to identify the subgroup of indolent lesions from those potentially aggressive ones that may be managed by active surveillance. • Low- and high-grade DCIS likely arise from two distinct evolutionary paths and when low-grade lesions progress to invasive cancer, the tumor is frequently low grade and well differentiated. • Ongoing clinical trials evaluate whether patients with low-risk DCIS could be safely managed by an active surveillance approach, with avoidance of unnecessary treatments and without impact on ipsilateral invasive breast cancer free survival time. • Dedicated breast PET may differentiate harmless from potentially hazardous DCIS, supporting active surveillance for the management of those women with low-grade DCIS, decreasing the rate of the upgrade to invasive carcinoma at surgical excision.

Low-grade screen-detected ductal carcinoma in situ progresses more slowly than high-grade lesions: evidence from an international multi-centre study.

Nuclear grade is an important indicator of the biological behaviour of ductal carcinoma in situ (DCIS). De-escalation of treatment has been suggested for low-grade DCIS. Our aim is to estimate the relative rate of progression of DCIS by nuclear grade by analysing the distribution of nuclear grade by detection at initial or subsequent screening. We asked International Cancer Screening Network sites to complete, based on their screening and clinical databases, an aggregated data file on DCIS detection, diagnosis and treatment. Eleven screening programs reported 5068 screen-detected pure DCIS in nearly 7 million screening tests in women 50-69years of age. For all programs combined, low-grade DCIS were 20.1% (range 11.4-31.8%) of graded DCIS, intermediate grade 31.0% and high grade 48.9%. Detection rates decreased more steeply from initial to subsequent screening in low compared to high-grade DCIS: the ratios of subsequent to initial detection rates were 0.39 for low grade, 0.51 for intermediate grade, and 0.75 for high grade (p < 0.001). These results suggest that the duration of the preclinical detectable phase is longer for low than for high-grade DCIS. The findings from this large multi-centre, international study emphasize that the management of low-grade DCIS should be carefully scrutinized in order to minimize overtreatment of screen-detected slow-growing or indolent lesions. The high variation by site in the proportion of low grade suggests that further pathology standardization and training would be beneficial.

Combined application of pharamcokinetic DCE-MRI and IVIM-DWI could improve detection efficiency in early diagnosis of ductal carcinoma in situ.

PurposeDuctal carcinoma in situ (DCIS) is a precursor of invasive ductal breast carcinoma (IDC). This study aimed to use pharamcokinetic dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) for the early diagnosis of DCIS.MethodsForty‐seven patients, including 25 with DCIS (age: 28–70 yr, mean age: 48.7 yr) and 22 with benign disease (age: 25–67 yr, mean age: 43.1 yr) confirmed by pathology, underwent pharamcokinetic DCE‐MRI and IVIM‐DWI in this study. The quantitative parameters Ktrans, Kep, Ve, Vp, and D, f, D* were obtained by processing of DCE‐MRI and IVIM‐DWI images with Omni‐Kinetics and MITK‐Diffusion softwares, respectively. Parameters were analyzed statistically using GraphPad Prism and MedCalc softwares.ResultsAll low‐grade DCIS lesions demonstrated mass enhancement with clear boundaries, while most middle‐grade and high‐grade DCIS lesions showed non‐mass‐like enhancement (NMLE). DCIS lesions were significantly different from benign lesions in terms of Ktrans, Kep, and D (t = 5.959, P < 0.0001; t = 5.679, P < 0.0001; and t = 5.629, P < 0.0001, respectively). The AUC of Ktrans, Kep, D and the combined indicator of Ktrans, Kep, and D were 0.936, 0.902, 0.860, and 0.976, respectively. There was a significant difference in diagnostic efficacy only between D and the combined indicator (Z = 2.408, P = 0.016).ConclusionDCE‐MRI and IVIM‐DWI could make for the early diagnosis of DCIS, and reduce the misdiagnosis of DCIS and over‐treatment of benign lesions.

Expression of PD-L1 and IDO in hormone receptor negative DCIS.

e14116 Background: Although outcomes from ductal carcinoma in situ (DCIS) are generally excellent, hormone receptor (HR) negative DCIS is associated with a higher rate of recurrence. There is no chemopreventative agent that has been effective in this subgroup. The aim of our study was to evaluate expression of PD-L1 and IDO (Indoleamine 2,3-Dioxygenase) in HR negative DCIS, in an effort to identify a possible target for prevention using immunotherapy. Methods: Using pathology databases at the University of Iowa, we identified 60 cases of HR negative DCIS from 1995-2017, and 41 of these cases had adequate DCIS tissue for immunostaining. Immunohistochemical staining with antibodies against PD-L1 and IDO was performed on slides prepared from formalin-fixed paraffin-embedded tissue blocks retrieved from pathology archives. IDO was assessed by IHC using the mouse monoclonal antibody clone 10.1 (Millipore Sigma). An initial assessment for PD-L1 (M3653 mouse monoclonal antibody clone 22C3, DAKO) was negative. A repeat assessment for PD-L1 on a smaller sample in a different laboratory was also negative. Clinical data was abstracted from the medical record of each patient. Results: Of the 41 subjects with enough tissue for staining, the median age at diagnosis was 56.76 years, and median BMI was 26.59 kg/m2. Most common method of DCIS detection was screening mammogram (80.5%) versus a patient detected breast finding (19.5%). Most subjects had high grade DCIS (92.7%) and none had low grade DCIS. Six subjects (16.7%) had an ipsilateral in situ recurrence while another 6 subjects developed ipsilateral invasive cancer. Most of the subjects had HER2+ DCIS (63.9%). None of the 41 cases stained positive for IDO or PD-L1, thus no statistical analysis was done to analyze associations with clinicopathologic characteristics. Conclusions: Our sample of HR negative DCIS tumors did not express PD-L1 or IDO, making these receptors unlikely targets for immunopreventative efforts. It is still possible that tumor mutation burden, expression of PD-L2, PD-L1 or IDO expression on TILs, or expression of CTLA-4 may be future considerations for work in the DCIS microenvironment.

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma.

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Behaviour and characteristics of low‐grade ductal carcinoma in situ of the breast: literature review and single‐centre retrospective series

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease that has risen to prominence and more recently controversy, with the advent of screening mammography. Debate concerning the true biological potential of low nuclear grade DCIS continues to challenge therapeutic considerations. In this study, we carried out a comprehensive literature review of the behaviour, outcomes and current management trials of low-grade DCIS, as well as a retrospective study of a large single institutional series of low-grade DCIS diagnosed at our hospital. The study cohort comprised 195 cases of low-grade DCIS diagnosed at the Singapore General Hospital from 1994 to 2010. Clinicopathological parameters and follow-up data were retrieved and compared between screen-detected and symptomatic low-grade DCIS. Immunohistochemistry was performed for ER, PR and HER2. Among 195 cases, 123 (63.1%) were screen-detected, while 72 (36.9%) were symptomatic. Screen-detected cases had frequent calcifications (P < 0.001) and were smaller (P = 0.018) than symptomatic cases. All cases were ER-positive and rate of PR expression was high. No HER2 overexpression was observed. Mean and median follow-up periods were 107.8 and 109.6 months, respectively. Six patients recurred ipsilaterally, and one patient developed direct distant metastasis. One breast cancer-related death was recorded. Positive surgical margins (P = 0.023) were significantly associated with a higher risk of ipsilateral recurrences, as well as poorer disease-free survivals (P = 0.010). Our data indicate that low-grade DCIS may be followed by invasive recurrences and even metastatic disease, requiring more study before being regarded as innocuous and indolent.

Abstract P1-08-07: Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort

Abstract Background: Nuclear grade, believed to be established early in carcinogenesis, is an indicator of ductal carcinoma in situ (DCIS) prognosis. Women with high-grade DCIS have a higher risk of local recurrence compared to women with low-grade DCIS. Risk factors for DCIS overall are well-characterized but risk factors by grade are not. Given the prognostic capabilities of grade for DCIS, it is of interest to identify whether risk factors by DCIS grade differ. Methods: Among 75,630 women enrolled in the Cancer Prevention Study-II Nutrition Cohort in 1992-1993, we identified 422 who were diagnosed with low-moderate grade DCIS (i.e. grades 1 or 2) and 355 who were diagnosed with high-grade DCIS (i.e. grade 3) during follow-up through 2013. Beginning in 1997, biennial questionnaires were administered to update exposure status, including screening mammography in the previous two years. For this analysis, these questionnaires were used to partition follow-up time into approximately two-year intervals. Because screening is strongly linked to diagnosis of DCIS, contribution of person-time within a specific interval was conditional on reporting a screening mammogram in the interval prior. Multivariate joint Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the associations of known breast cancer risk factors with DCIS overall, and with high-grade and low-grade DCIS individually. Results: Parity (HR=0.70; 95% CI: 0.63-0.78, parous vs. nulliparous), smoking status (HR=0.69; 95% CI: 0.58-0.82, current vs. never smoking) and menopausal status (HR=0.79; 95% CI: 0.73-0.87, natural menopause &amp;lt;50 years vs. natural menopause ≥ 50 years) were inversely associated with risk of DCIS overall. Whereas, positive family history of breast cancer (HR=1.46; 95% CI: 1.36-1.57), personal history of benign breast disease (BBD) (HR=1.73; 95% CI: 1.62-1.85), and current use of combination estrogen and progestin hormone replacement therapy (HR=1.15; 95% CI: 1.04-1.28) were associated with higher risk of DCIS. In analyses stratified on DCIS grade, history of BBD was more strongly associated with higher risk of low-grade (HR=2.21; 95% CI: 1.81-2.70) than with high-grade DCIS (HR=1.29; 95% CI:1.04-1.60) (p for heterogeneity=0.001). Current combination estrogen and progestin hormone replacement therapy use was associated with a higher risk of high-grade DCIS (HR=1.40; 95% CI:1.03-1.90) but not low-grade DCIS (HR=1.02; 95% CI: 0.75-1.40), but the difference by grade was not statistically significant (p=0.5). Conclusions: In this study, which is the first to comprehensively assess risk factors by DCIS grade, the association between personal history of BBD and risk of DCIS appeared to differ by grade. Due to limited power for some risk factor analyses, future studies using larger prospective cohorts or pooled data should be conducted to better identify these associations. Citation Format: Puvanesarajah S, Gapstur SM, Gansler T, Patel AV, Gaudet MM. Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort [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 P1-08-07.

Abstract P1-08-09: Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012

Abstract Background The incidence of ductal carcinoma in situ (DCIS) has drastically increased over the past decades. Since DCIS is resected after diagnosis similarly to invasive breast cancer, the natural cause and behaviour of DCIS is not well known. We aimed to determine breast cancer-specific (BCSS) and overall survival (OS) according to grade in DCIS patients after surgical treatment in the Netherlands. Patients and methods All DCIS patients diagnosed between 1999-2012 were selected from the Netherlands Cancer Registry. Cause of death was obtained from 'Statistics Netherlands'. BCSS and OS were estimated using multivariable Cox regression in the entire cohort and stratified for grade. Results In total, 12,256 patients were included, of whom 1,509 (12.3%) presented with grade I, 3,675 (30.0%) with grade II, 6,064 (49.5%) with grade III and 1,008 (8.2%) with an unknown grade. During a median follow-up of 7.8 years, 1,138 (9.3%) deaths were observed, and 179 (1.5%) were breast cancer-related. Of these, 10 patients had grade I, 46 grade II, 95 grade III and 28 an unknown grade. After adjustment for confounding, grade II and III were related to worse BCSS compared to grade I with HRs of 1.92 (95% CI:0.97-3.81) and 2.14 (95% CI:1.11-4.12), respectively. No association between grade and OS was observed. Conclusion BCSS and OS rates in DCIS patients are excellent. Since superior rates were observed for low-grade DCIS, and earlier studies have shown that low-grade DCIS have a very low chance on recurrence or upstage to invasive cancer, it seems justified to investigate whether active surveillance may be a balanced alternative for conventional surgical treatment. Citation Format: van Maaren MC, Lagendijk M, Tilanus-Linthorst MM, de Munck L, Pijnappel RM, Schmidt MK, Wesseling J, Koppert LB, Siesling S. Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012 [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 P1-08-09.

Abstract P4-02-06: Inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: A nationwide study in the Netherlands

Abstract Background: A considerable part of ductal carcinoma in situ (DCIS) lesions may never progress into invasive breast cancer. Yet, standard treatment consists of surgical excision. Trials aim to identify a subgroup of low-risk DCIS that, under active surveillance, can safely forgo surgical treatment. These low-risk subgroups are in all trials solely based on histologic grade, which highlights the importance of accurate, consistent, and reproducible grading by pathologists. To improve standardization, we aimed to gain insight into laboratory-specific variation of DCIS grading in daily clinical practice. Materials and methods: All synoptic pathology reports of pure DCIS resection specimens between 2013-2016 were retrieved from PALGA, the nationwide Dutch Pathology Registry. Absolute differences in proportions of grade I-III between laboratories (inter-laboratory) were visualized using funnel plots, in which the proportions per laboratory are plotted against the number of DCIS per laboratory, with the national proportions per grade as target. Multivariable analysis to correct for case mix was performed by logistic regression, providing odds ratios (ORs) and 95% confidence intervals (CI) for high-grade (III) versus low-grade (I-II) DCIS per laboratory. Absolute differences of proportions of grade I-III between pathologists within laboratories (intra-laboratory) were also analyzed. Lastly, an online questionnaire was send to all pathology laboratories in the Netherlands to identify how pathologists determine histologic grade in daily clinical practice. Results: In total 4,952 DCIS cases from 36 laboratories were included, of which 12.5% were reported as grade I (range 6.1-24.4%), 39.5% as grade II (18.2-57.6%), and 48.0% as grade III (30.2-72.7%). After correction for case mix, 14 laboratories (38.9%) reported a significantly lower (n=4) or higher (n=10) proportion of high-grade DCIS than the reference laboratory. Adjusted ORs (95% CI) ranged from 0.52 (0.31-0.87) to 3.83 (1.42-10.39). Intra-laboratory analysis also showed significant differences between pathologists within 25% of the laboratories. The results of our questionnaire showed that pathologists mentioned numerous different guidelines as a reference for the histologic grading of DCIS, while 20.3% of them even stated that they grade DCIS (partially) based on intuition. Conclusion: We observed substantial inter- and intra-laboratory variation in the histologic grading of DCIS, which was not explained by differences in case mix. Therefore, there is an urgent need for nationwide standardization of grading practices, especially since the future management of DCIS may alter significantly depending on histologic grade. Citation Format: van Dooijeweert C, van Diest PJ, Willems SM, Kuijpers CC, Overbeek LI, Deckers IA. Inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: A nationwide study in the Netherlands [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 P4-02-06.

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.