Ductal Carcinoma In Situ Trial Research Articles

A prognostic and predictive computational pathology immune signature for ductal carcinoma in situ: retrospective results from a cohort within the UK/ANZ DCIS trial

The density of tumour-infiltrating lymphocytes (TILs) could be prognostic in ductal carcinoma in situ (DCIS). However, manual TIL quantification is time-consuming and suffers from interobserver and intraobserver variability. In this study, we developed a TIL-based computational pathology biomarker and evaluated its association with the risk of recurrence and benefit of adjuvant treatment in a clinical trial cohort. In this retrospective cohort study, a computational pathology pipeline was developed to generate a TIL-based biomarker (CPath TIL categories). Subsequently, the signature underwent a masked independent validation on H&E-stained whole-section images of 755 patients with DCIS from the UK/ANZ DCIS randomised controlled trial. Specifically, continuous biomarker CPath TIL score was calculated as the average TIL density in the DCIS microenvironment and dichotomised into binary biomarker CPath TIL categories (CPath TIL-high vs CPath TIL-low) using the median value as a cutoff. The primary outcome was ipsilateral breast event (IBE; either recurrence of DCIS [DCIS-IBE] or invasive progression [I-IBE]). The Cox proportional hazards model was used to estimate the hazard ratio (HR). CPath TIL-score was evaluable in 718 (95%) of 755 patients (151 IBEs). Patients with CPath TIL-high DCIS had a greater risk of IBE than those with CPath TIL-low DCIS (HR 2·10 [95% CI 1·39-3·18]; p=0·0004). The risk of I-IBE was greater in patients with CPath TIL-high DCIS than those with CPath TIL-low DCIS (3·09 [1·56-6·14]; p=0·0013), and the risk of DCIS-IBE was non-significantly higher in those with CPath TIL-high DCIS (1·61 [0·95-2·72]; p=0·077). A significant interaction (pinteraction=0·025) between CPath TIL categories and radiotherapy was observed with a greater magnitude of radiotherapy benefit in preventing IBE in CPath TIL-high DCIS (0·32 [0·19-0·54]) than CPath TIL-low DCIS (0·40 [0·20-0·81]). High TIL density is associated with higher recurrence risk-particularly of invasive recurrence-and greater radiotherapy benefit in patients with DCIS. Our TIL-based computational pathology signature has a prognostic and predictive role in DCIS. National Cancer Institute under award number U01CA269181, Cancer Research UK (C569/A12061; C569/A16891), and the Breast Cancer Research Foundation, New York (NY, USA).

A prognostic and predictive computational pathology immune signature for ductal carcinoma in situ: retrospective results from a cohort within the UK/ANZ DCIS trial

The density of tumour-infiltrating lymphocytes (TILs) could be prognostic in ductal carcinoma in situ (DCIS). However, manual TIL quantification is time-consuming and suffers from interobserver and intraobserver variability. In this study, we developed a TIL-based computational pathology biomarker and evaluated its association with the risk of recurrence and benefit of adjuvant treatment in a clinical trial cohort. In this retrospective cohort study, a computational pathology pipeline was developed to generate a TIL-based biomarker (CPath TIL categories). Subsequently, the signature underwent a masked independent validation on H&E-stained whole-section images of 755 patients with DCIS from the UK/ANZ DCIS randomised controlled trial. Specifically, continuous biomarker CPath TIL score was calculated as the average TIL density in the DCIS microenvironment and dichotomised into binary biomarker CPath TIL categories (CPath TIL-high vs CPath TIL-low) using the median value as a cutoff. The primary outcome was ipsilateral breast event (IBE; either recurrence of DCIS [DCIS-IBE] or invasive progression [I-IBE]). The Cox proportional hazards model was used to estimate the hazard ratio (HR). CPath TIL-score was evaluable in 718 (95%) of 755 patients (151 IBEs). Patients with CPath TIL-high DCIS had a greater risk of IBE than those with CPath TIL-low DCIS (HR 2·10 [95% CI 1·39-3·18]; p=0·0004). The risk of I-IBE was greater in patients with CPath TIL-high DCIS than those with CPath TIL-low DCIS (3·09 [1·56-6·14]; p=0·0013), and the risk of DCIS-IBE was non-significantly higher in those with CPath TIL-high DCIS (1·61 [0·95-2·72]; p=0·077). A significant interaction (pinteraction=0·025) between CPath TIL categories and radiotherapy was observed with a greater magnitude of radiotherapy benefit in preventing IBE in CPath TIL-high DCIS (0·32 [0·19-0·54]) than CPath TIL-low DCIS (0·40 [0·20-0·81]). High TIL density is associated with higher recurrence risk-particularly of invasive recurrence-and greater radiotherapy benefit in patients with DCIS. Our TIL-based computational pathology signature has a prognostic and predictive role in DCIS. National Cancer Institute under award number U01CA269181, Cancer Research UK (C569/A12061; C569/A16891), and the Breast Cancer Research Foundation, New York (NY, USA).

Radiotherapy versus low-dose tamoxifen following breast-conserving surgery for low-risk and estrogen receptor-positive breast ductal carcinoma in situ: an international open-label randomized non-inferiority trial (TBCC-ARO DCIS Trial)

BackgroundRadiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS.Methods/designThis is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% β-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial.DiscussionThis is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT.Trial registrationClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019.

Subtype-Specific Tumour Immune Microenvironment in Risk of Recurrence of Ductal Carcinoma In Situ: Prognostic Value of HER2.

Increasing evidence suggests that the significance of the tumour immune microenvironment (TIME) for disease prognostication in invasive breast carcinoma is subtype-specific but equivalent studies in ductal carcinoma in situ (DCIS) are limited. The purpose of this paper is to review the existing data on immune cell composition in DCIS in relation to the clinicopathological features and molecular subtype of the lesion. We discuss the value of infiltration by various types of immune cells and the PD-1/PD-L1 axis as potential markers of the risk of recurrence. Analysis of the literature available in PubMed and Medline databases overwhelmingly supports an association between densities of infiltrating immune cells, traits of immune exhaustion, the foci of microinvasion, and overexpression of HER2. Moreover, in several studies, the density of immune infiltration was found to be predictive of local recurrence as either in situ or invasive cancer in HER2-positive or ER-negative DCIS. In light of the recently reported first randomized DCIS trial, relating recurrence risk with overexpression of HER2, we also include a closing paragraph compiling the latest mechanistic data on a functional link between HER2 and the density/composition of TIME in relation to its potential value in the prognostication of the risk of recurrence.

Abstract OT1-09-01: A randomized study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS)

Abstract Lumpectomy and breast radiotherapy (RT) achieve good longterm control of disease in patients diagnosed with ductal carcinoma in situ (DCIS). In the combined analysis of NSABP B-17/B-24 DCIS trials, these treatments were shown to reduce invasive ipsilateral breast tumor recurrences by 52% compared to lumpectomy alone. RT has been consistently used as an adjuvant to surgery and therefore, little is known of its activity on intact/untreated DCIS. Elucidating the effectiveness of radiation therapy may help optimize the treatment of DCIS and avoid over-treatment.Trial Design The objective of the ongoing phase 2 pilot trial is to evaluate the ablative and treatment effects of neoadjuvant RT (neoRT) on DCIS. Patients diagnosed with DCIS on core needle biopsy are randomized to upfront lumpectomy (Arm 1) followed by partial breast irradiation (PBI) or neoRT PBI followed by delayed surgical excision (Arm 2). Arm 1 serves as a reference group for pathological-radiological correlations as well as to ascertain the rate of upstaging to invasive cancer. The neoRT regimen consists of 6 Gy daily x 5 (consecutive or non-consecutive days) to the intact tumor with a 0.5 cm margin. Surgical excision is delayed 12-16 weeks, allowing for the ablative effects of neoRT to occur. Specific Aims •To determine if neoRT can completely ablate 30% of DCIS cases•To determine if DCIS subtypes exhibit differential sensitivity to neoRT•To evaluate microscopic treatment effects; wound complication rates; post-RT breast imaging changes; and invasive carcinoma rate.Eligibility Women 18 years of age or older diagnosed with DCIS by core needle biopsy and intending to receive breast conserving surgery are eligible. Tumors must be ≤4 cm, discovered as mammographic microcalcifications and/or MRI non-mass enhancement measuring with evidence of residual imaging abnormality after diagnostic needle biopsy. Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10%. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoadjuvant PBI. Accrual 10 (open 2019) Contact wapnir@stanford.edu. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027.McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Carol Marquez, Kimberly Stone, Kimberly Allison, Wendy DeMartini, Catherine Salem, Jacqueline Tsai, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [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 OT1-09-01.

Prognostic and Predictive Value of HER2 Expression in Ductal Carcinoma In Situ: Results from the UK/ANZ DCIS Randomized Trial.

HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. HER2 expression was evaluated by IHC using the HercepTest™ in samples from UK/ANZ DCIS trial participants (n = 755) with IHC 3+ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1+), equivocal (IHC 2+), and positive (IHC 3+) and analyses restricted to a nested case-control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR = 2.29; 95% confidence interval (95% CI), 1.64-3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR = 2.90; 95% CI, 1.91-4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR = 1.40; 95% CI, 0.81-2.42; P = 0.23; Pheterogeneity = 0.04). Inclusion of HER2 significantly improved [Δχ2 (1d.f.) 12.25; P = 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR = 1.91; 95% CI, 1.33-2.76; P = 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity = 0.04) in HER2-positive DCIS (HR = 0.16; 95% CI, 0.07-0.41) compared with HER2-negative DCIS (HR = 0.58; 95% CI, 0.28-1.19). HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.

High PDGFRb Expression Predicts Resistance to Radiotherapy in DCIS within the SweDCIS Randomized Trial.

This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma in situ (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency. Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed. PDGFRb score was predictive for RT benefit with regard to IBE (P interaction = 0.002 and P interaction = 0.008 adjusted multivariably). Patients of the PDGFRblow group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRbhigh group (HR, 0.83; 0.51-1.34; P = 0.444; cumulative risk 22% vs. 25%). The RT response-predictive effect of stromal PDGFRb was equally strong in analyses for in situ and invasive IBE when analyzed separately (in situ IBE: P = 0.029; invasive IBE: P = 0.044). Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.

Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial.

The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS. Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method-analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed. ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66-9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84-3.53; P = 0.14), P heterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53-4.61). PgR status did not add to the prognostic information provided by ER. ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.

Abstract P5-06-15: Computer extracted features of nuclear shape, orientation disorder and texture from H&amp;E Whole slide images are associated with disease-free survival in ductal carcinoma in situ (DCIS)

Abstract Background: Ductal Carcinoma in Situ (DCIS) of the breast comprises a diverse group of cancerous lesions confined to the breast ducts. About 25% of all breast cancers in the US are DCIS and women with DCIS have a 10 times higher lifetime risk of progressing to invasive breast cancer (IBC). While DCIS is treated routinely with breast conserving therapy which includes a lumpectomy followed by adjacent radiation therapy (RT). However, studies have shown that RT can be omitted in women with a lower risk of recurrence/progression. Gene expression methods like Oncotype Dx can be used to risk stratify patients but are expensive, tissue-destructive and time consuming. Recently, there has been substantial interest in developing computerized approaches to quantitatively extract tumor histomorphometric (QH) features from digitized images of tissue slides to predict cancer outcome. In this work, we evaluate the role of QH features related to the architecture, shape, orientation disorder and texture of cancer nuclei from lumpectomy specimens of DCIS to predict disease-free survival (DFS). Methods: H&amp;E whole slide images (WSI) and corresponding outcome information for 121 DCIS patients (61 with progression/recurrence and 60 without) from the no adjuvant treatment arm of the UK/ANZ DCIS trial were retrieved and collected from Queen Mary university of London. WSIs were scanned by 3DHistech scanner at 43x magnification. For each image, a deep learning based generative adversarial network model was employed to segment the cancer nuclei, following which 379 nuclear features from four feature families including architecture, shape, orientation disorder and Haralick texture features were extracted within each candidate breast duct in the WSI and averaged across the multiple cancerous breast ducts for each patient. The dataset was randomly split into training (D1, n=60) and a hold-out validation set (D2,n=61) with events split equally in the two sets. For each of the four feature families, a set of 6 top features was identified by an elastic Cox Model to predict DFS (time from diagnosis to recurrence/invasive breast cancer or death whichever is sooner) onD1. The feature sets giving significant prognostic value (assessed by log rank test between the feature derived risk groups) were combined, from which 6 top features were further identified by a Cox Model to predict DFS on D1. Results: The top ranked QH features included features from three feature families: 2 shape features, 1 orientation disorder feature and 3 texture features. The Elastic Cox model predicted DFS on D1 with hazard ratio (HR) of 7.29 (95% CI = 2.94 ~18.05, p=1.75e-05) and on D2 with HR of 2.07 (95% CI = 1.02 ~2.94, p=0.045). Conclusion: Computer extracted nuclear histomorphometric features pertaining to shape, orientation disorder and texture were associated with disease free survival for DCIS. Additional independent multi-site validation of the approach is planned to further confirm the preliminary findings presented here. Citation Format: Haojia Li, Kaustav Bera, Hannah Gilmore, Zelin Zhang, Jack Cuzick, Mangesh A Thorat, Anant Madabhushi. Computer extracted features of nuclear shape, orientation disorder and texture from H&amp;E Whole slide images are associated with disease-free survival in ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-15.

Abstract P5-02-05: Variability in ductal carcinoma in situ grading among an international group of pathologists

Abstract Introduction: Ductal Carcinoma In Situ (DCIS) is a proliferation of neoplastic cells confined to the ducto-lobular system. Due to uncertainty which DCIS lesions progress to invasive breast cancer women with DCIS receive surgery and radiotherapy. The PRECISION (PREvent ductal carcinoma In Situ Invasive Overtreatment Now) initiative intends to improve the management of DCIS including reduction of unnecessary treatment. Histological high grade is an unfavorable prognostic indicator used to guide treatment decisions, and used as an exclusion criterion for DCIS trials that randomize between active surveillance and standard treatment. Hence, accurate assessment of grade is important in current clinical practice. Pathologists within PRECISION setup this study to compare histological parameters of four retrospective DCIS cohorts from three different countries to investigate interobserver variability particularly in grading of DCIS. Method: Tissue slides from two population-based cohorts (UK Sloane cohort n=110; Dutch DCIS cohort n= 110) and two hospital based cohorts (Duke n=110; MDACC n=95) were included, leading to a total of 425 slides. All slides were reviewed by 9 breast pathologists originating from the UK, US and the Netherlands (NL) using the digital software platform Slidescore. The slides included were a representative selection of histological grades from all cases in these respective studies (see table 1 for distribution). Kappa (κ) values were calculated based on a generalized linear mixed model using the ordinal package in R. Results: The distribution of grade according to the majority opinion and originally assigned during diagnosis is shown in table 1. The cohort from NL demonstrated less grade 1 lesions according to the majority opinion compared to originally assigned grade. Table 2 shows the κ values of all evaluated histological variables. DCIS grade 1,2,3, grade 1/2 vs 3, necrosis and calcification show moderate agreement (κ between 0.4-0.6). Lymphocytic infiltrate, periductal fibrosis and mitoses demonstrate poor agreement (κ between 0.2-0.4). Conclusion: Histological factors including DCIS grade 1/2/3 and DCIS grade 1/2 versus 3 show only moderate agreement in this study using whole slide images. Preliminary analyses show no differences in κ values with the inclusion of country of the pathologist. However, the distribution of grade differs between the grading originally assigned and determined by majority opinion. Since clinical decisions are based on histological variables, it is important to realize that interobserver variability play a part in the diagnostic process. We are currently reviewing con- versus discordant cases and discussing how pathology guidelines can be improved. In addition, we are exploring whether artificial intelligence-based methods could be used to standardize grading of DCIS. Table 1. Distribution of grade of all slides and slides from participating centers. Slides were excluded if the majority opinion was equally divided between two grades or if originally grade 1-2/2-3 was assigned.Origin of tissue slidesGrade 1 (n)Grade 2 (n) Grade 3 (n)Excluded nAll tissue slides (n=425)Distribution according to majority opinion12% (49)40% (163)48% (197)16Distribution originally assigned12% (36)36% (111)53% (165)113Slides from Netherlands Cancer Institute (n=110)Distribution according to majority opinion6% (6)31% (33)64% (68)3Distribution originally assigned17% (19)33% (36)50% (55)0Slides from Sloane (n=110)Distribution according to majority opinion20% (20)51% (52)29% (30)8Distribution originally assigned11% (12)31% (34)58% (64)0Slides from Duke (n=110)Distribution according to majority opinion9% (10)44% (47)47% (50)3Distribution originally assigned5% (5)45% (41)50% (46)18Slides from MDAnderson (n=95)Distribution according to majority opinion14% (13)33% (31)53% (49)2Distribution originally assignedTo be collected Table 2. Kappa values of evaluated histological parametersVariableModel based weighted kappa (κma)95% confidence intervalDCIS grade 1/2/30.500.440.57DCIS grade 1/2 vs 30.520.440.60DCIS grade 1 vs 2/30.450.400.50DCIS grade low vs high0.520.440.59Necrosis absent vs present (manually dichotomized)0.550.510.59Calcification absent vs present0.510.480.55Lymphocytic infiltrate0.470.390.55Periductal fibrosis0.350.300.40Mitoses0.340.250.42 Citation Format: Maartje van Seijen, Katarzyna Jóźwiak, Sarah E Pinder, Allison Hall, Savitri Krishnamurthy, Jeremy SJ Thomas, Laura Collins, Jonathan Bijron, Joost Bart, Danielle Cohen, Wen Ng, Hilary Stobart, Jan Hudecek, Esther H Lips, Jelle Wesseling. Variability in ductal carcinoma in situ grading among an international group of pathologists [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-05.

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer

BackgroundAlthough treatment delays have been associated with survival impairment for invasive breast cancer, this has not been thoroughly investigated for ductal carcinoma in situ (DCIS). With trials underway to assess whether DCIS can remain unresected, this study was performed to determine whether longer times to surgery are associated with survival impairment or increased invasion.MethodsA population-based study of prospectively collected national data derived from women with a clinical diagnosis of DCIS between 2004 and 2014 was conducted using the National Cancer Database. Overall survival (OS) and presence of invasion were assessed as functions of time by evaluating five intervals (≤ 30, 31–60, 61–90, 91–120, 121–365 days) between diagnosis and surgery. Subset analyses assessed those having pathologic DCIS versus invasive cancer on final pathology.ResultsAmong 140,615 clinical DCIS patients, 123,947 had pathologic diagnosis of DCIS and 16,668 had invasive ductal carcinoma. For all patients, 5-year OS was 95.8% and unadjusted median delay from diagnosis to surgery was 38 days. With each delay interval increase, added relative risk of death was 7.4% (HR 1.07; 95% CI 1.05–1.10; P < 0.001). On final pathology, 5-year OS for noninvasive patients was 96.0% (95% CI 95.9–96.1%) versus 94.9% (95% CI 94.6–95.3%) for invasive patients. Increasing delay to surgery was an independent predictor of invasion (OR 1.13; 95% CI 1.11–1.15; P < 0.001).ConclusionsDespite excellent OS for invasive and noninvasive cohorts, invasion was seen more frequently as delay increased. This suggests that DCIS trials evaluating nonoperative management, which represents infinite delay, require long term follow up to ensure outcomes are not compromised.

The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA).

TPS603 Background: Retrospective data suggest breast cancer-specific survival rates with versus without surgery in patients with low-grade ductal carcinoma in situ (DCIS) are similar. Some DCIS patients have a low likelihood of progression to invasive cancer, but predicting who is at risk has not been established. Thus, treatment with a well-balanced risk / benefit ratio has not been achieved. Four active surveillance clinical trials for low risk DCIS have commenced in the United Kingdom (LORIS), Europe (LORD), United States (COMET), and Japan (LORETTA). We aim to examine the effectiveness &amp; safety of active surveillance compared with surgical based treatment approaches for low-risk DCIS patients. Methods: Non surgical approaches are of the two types; active surveillance (AS) alone and AS + endocrine therapy (ET). In the randomized trials LORIS and LORD, the study arms are AS only, but while ET is an option in COMET, ET is mandatory in the single arm trial LORETTA. COMET and LORETTA have broader inclusion criteria as compared to LORIS and LORD. In COMET, comedo necrosis is eligible. In LORETTA, findings other than calcification on mammography (MMG) are also eligible (e.g. low echo area on breast ultrasound). Leaders of the four trials hold regular meetings to foster international DCIS trials collaboration to share information. LORIS Clinical trial information: ISRCTN27544579, LORD Clinical trial information: NCT02492607, COMET Clinical trial information: NCT02926911, LORETTA Clinical trial information: UMIN000028298 [JCOG1505]. Clinical trial information: UMIN000028298, NCT02492607, NCT02926911, ISRCTN27544579. [Table: see text]

Abstract 3259: When is cancer not really cancer: The PREvent Ductal Carcinoma In Situ Invasive Overtreatment Now (PRECISION)* initiative

Abstract Background. Ductal carcinoma in situ (DCIS) represents 25% of all breast neoplasia due to population-based breast cancer screening. As a result, thousands of women are confronted with DCIS each year. Conventional management includes surgery, supplemented by radiotherapy and/or endocrine therapy, but overtreats the majority of DCIS. Uncertainty as to which DCIS lesions will progress to invasive cancer drives this overtreatment. This urges us to learn how to distinguish DCIS that may progress to invasive breast cancer from the majority of indolent DCIS. Such distinction is best achieved by synergistic collaboration between leading global experts from various disciplines, driven by the essential input from patient voices. Aim. PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) aims to save thousands of women with low risk DCIS the burden of intensive inappropriate treatment of DCIS (surgery, radiation therapy, hormonal therapies) through the discovery of new data and development of novel tests that promote informed and shared decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS management presently achieved. Methods. First, three large DCIS cohorts and supplementary resources will be collected enabling in depth molecular studies. Second, extensive genomic characterization, immune profiling and imaging analysis will be performed. In vivo and in vitro modeling will be performed to study the biology of DCIS in detail. Finally, all clinical, immune, and molecular data will be incorporated into a clinical risk prediction model. This risk prediction model will be validated in three prospective randomized DCIS trials in the US (COMET trial), UK (LORIS trial), and mainland Europe (LORD trial). How the results of this research will be used. The discoveries from our laboratory studies, including a risk stratification model, will be cross-validated in three prospective trials of DCIS active surveillance versus conventional treatment (the COMET, LORIS, and LORD trials). As such, the main result of this study will be that we can identify a group of women for which active surveillance for DCIS could be a safer alternative to intensive treatment. Ultimately, this may also contribute to a more reassuring perception of risk regarding non-life threatening precancerous lesions in general, reducing anxiety and preserving quality of life. * The PRECISION Team is a Cancer Research UK Grand Challenge Award 2017 winning team and will be jointly funded by Cancer Research UK and the Dutch Cancer Society Citation Format: Jelle Wesseling, Alastair M. Thompson, Serena Nik-Zainal, Andrew Futreal, Shelley Hwang, Jos Jonkers, Esther H. Lips, Daniel Rea. When is cancer not really cancer: The PREvent Ductal Carcinoma In Situ Invasive Overtreatment Now (PRECISION)* initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3259.

Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II

BackgroundAnastrozole reduces breast cancer risk in women at high risk, but implementing preventive therapy in clinical practice is difficult. Here, we evaluate adherence to anastrozole in the International Breast Cancer Intervention Study (IBIS)-II prevention and ductal carcinoma in situ (DCIS) trials, and its association with early symptoms.Patients and methodsIn the prevention trial, 3864 postmenopausal women were randomized to placebo versus anastrozole. A total of 2980 postmenopausal women with DCIS were randomized to tamoxifen versus anastrozole. Adherence to trial medication was calculated using the Kaplan–Meier method and all P-values were two-sided.ResultsIn the prevention trial, adherence was 65.8% [anastrozole (65.7%) versus placebo (65.9%); HR = 0.97 (0.87–1.09), P = 0.6]. Adherence was lower for those reporting arthralgia in the placebo group (P = 0.02) or gynecological symptoms in the anastrozole group (P = 0.003), compared with those not reporting these symptoms at 6 months. In the DCIS study, adherence was 66.7% [anastrozole (67.5%) versus tamoxifen (65.8%); HR = 1.06 (0.94–1.20), P = 0.4]. Hot flashes were associated with greater adherence in the anastrozole arm (P = 0.02). In both studies, symptoms were mostly mild or moderately severe, and adherence decreased with increasing severity for most symptoms. Drop-outs were highest in the first 1.5 years of therapy in both trials.ConclusionsIn the IBIS-II prevention and DCIS trials, over two-thirds of women were adherent to therapy, with no differences by treatment groups. Participants who reported specific symptoms in the IBIS-II prevention trial had a small but significant effect on adherence, which strengthened as severity increased. Strategies to promote adherence should target the first year of preventive therapy.

Postoperative radiotherapy after DCIS: Useful for whom?

The number of patients with ductal carcinoma in situ (DCIS) increases with more widely used screening mammography programs. DCIS accounts for approximately 20% of all new breast cancer diagnoses in these programs and the natural course of this heterogeneous group of pre-invasive lesions is not fully known. Better definition of subgroups benefitting from radiotherapy and knowledge on the natural course of DCIS are important issues for the future management of DCIS.Four large randomized trials have studied the effects of postoperative radiotherapy after breast conserving surgery in patients with wider spectrum of DCIS and all of them have shown radiotherapy to halve the risk of ipsilateral events, however, without any significant effect on breast cancer mortality.SweDCIS is one of these four randomized trials (n = 1046) and with 20 years follow-up the relative risk reduction for an ipsilateral event was 37.5% and the absolute reduction was 12%. For an in-situ ipsilateral event the absolute reduction was 10% and for an invasive ipsilateral event the reduction was 2%. The reduction of new events in the SweDCIS was most evident during the first decade after treatment.In RTOG 9804 patients in a good-risk subset of DCIS were randomized to radiotherapy or not and with seven years of follow-up the ipsilateral local failure rate was 0.9% and 6.7% in the two arms, respectively.Radiotherapy to the conserved breast may also give long-term side effects in a small proportion of the patients, in which experience of breast pain is the most common, reported in about 10% of the patients. With modern radiotherapy techniques the dose to the heart can be restricted to low levels and meta-analyses from the randomized DCIS trials showed no difference in non-breast cancer mortality.Several factors in different trials have shown to influence the risk for an ipsilateral event: age, size, grade, necrosis, clear margin, and detected on mammography or not. But identification of subgroups without relative efficacy of radiotherapy has been challenging to find. The Van Nuys prognostic index and the nomogram from the Memorial Sloan-Kettering take several of these factors into account. These and genomic assays may help to optimize the treatments of patients with DCIS. Still, radiotherapy after breast conserving surgery is the standard of care for a majority of DCIS patients. For some low risk DCIS patients accepting a slight increased risk of an ipsilateral event it is reasonable to omit radiotherapy after close communication with the patient about pros and cons of radiotherapy.

Abstract P1-09-06: Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: The prognostic abilities of most gene expression signatures in breast cancer are often due to detection of proliferative activity measured from expression of genes regulated as a function of cell cycle progression. Cell Cycle Progression (CCP) score is an important prognostic factor in prostate cancer, and has shown promising results for renal and lung cancer; its role in ductal carcinoma in situ (DCIS) has not been explored. We investigated the prognostic and predictive relevance of CCP Score in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy (RT) or both as adjuvant treatment in DCIS. mRNA expression of 25 S- and M-phase CCP genes was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. CCP score is an un-weighted average of the expression values of CCP genes after normalisation with 14 housekeeping genes. CCP score was analysed as a continuous variable and also as an ordinal variable using tertile-based cut-offs. Exploratory analyses with subgroups defined by HER2 status by immunohistochemistry were performed. Results: CCP scores were evaluable in 521 (134 recurrence events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Increase in CCP score (median 1.15; IQR 0.71-1.74) was associated with increased risk of ipsilateral breast event (IBE) [Hazard ratio (HR) = 1.28; 95% Confidence Interval (95%CI) 1.08-1.51; p = 0.0049]. CCP score however was not an independent predictor in multivariate analyses [HR = 1.16; 95%CI 0.95-1.42; p = 0.14]. CCP scores were categorised as CCP low (&amp;lt;0.87), CCP intermediate (&amp;gt;/= 0.87 to &amp;lt; 1.52) and CCP high (&amp;gt;/= 1.52) by tertiles. The benefit of RT in reducing IBE was significant when CCP score was low [HR = 0.35; 95%CI 0.14-0.87; p = 0.024] or intermediate [HR = 0.23; 95%CI 0.09-0.59; p = 0.0023], however, those with high CCP score did not derive significant RT benefit [HR = 0.59; 95%CI 0.31-1.13; p = 0.11]. In exploratory subgroup analyses, HER2 negative DCIS with high CCP score (20.9% of all DCIS cases) did not derive RT benefit and the largest RT benefit was seen for DCIS that expressed HER2 and did not have a high CCP score (23.2% of all DCIS cases). Benefit of RT and 10-year IBE rates by CCP score (categorised) and HER2 status subgroups.SubgroupneventsHR (95%CI)p10-year IBE rates (%) - No RT10-year IBE rates (%) - RTCCP-high &amp; HER2 neg106220.83 (0.35-1.97)0.6722.5 (14.0-35.0)20.0 (10.5-36.0)CCP-high &amp; HER2 pos67210.43 (0.16-1.17)0.09840.6 (27.1-57.6)20.4 (8.9-42.9)CCP-non-High &amp; HER2 neg217300.43 (0.18-0.99)0.04816.2 (10.7-24.0)8.1 (4.0-16.3)CCP- non-High &amp; HER2 pos118330.14 (0.04-0.46)0.001239.5 (29.3-51.6)7.1 (2.3-20.4)CCP-non-High = low or intermediate CCP score Conclusions: CCP score is not independently associated with the risk of IBE but appears to be a predictor of RT benefit. Exploratory analyses suggest that combined with HER2 status, it may help in identifying a large DCIS subgroup where RT is highly indicated and another large subgroup where mastectomy may be merited. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of cell cycle progression (CCP) score in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial [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 P1-09-06.

Do LORIS Trial Eligibility Criteria Identify a Ductal Carcinoma In Situ Patient Population at Low Risk of Upgrade to Invasive Carcinoma?

The Surgery Versus Active Monitoring for Low-Risk DCIS (LORIS) trial is studying the safety of monitoring core-biopsy diagnosed low-risk ductal carcinoma in situ (DCIS) without excision. We sought to determine the incidence and characteristics of synchronous invasive carcinoma found in LORIS-eligible women who underwent excision, as this knowledge is essential in assessing the safety of observation alone. Women meeting LORIS eligibility criteria (age ≥46 years, screen-detected calcifications, non-high-grade DCIS diagnosed by core biopsy, absence of nipple discharge, or strong family history of breast cancer) who underwent surgical excision from 2009 to 2012 were identified. Histologic findings of excision specimens were reviewed. Overall, 296 LORIS-eligible cases were identified; 58 (20%) had invasive carcinoma on final pathology (90% invasive ductal, 78% >1mm in size, 21% high grade, 3% triple negative, 9% HER2 amplified). Of these, 18 (31%) were pT1b or larger and 3 (5%) were pN1. Among eligible upgraded cases, 90% received radiation, 89% received endocrine therapy, and 18% were recommended chemotherapy. Women upgraded to invasive carcinoma were more likely to have intermediate-grade DCIS on core biopsy and to have undergone mastectomy. Among LORIS-eligible women, 20% had invasive carcinoma at surgical excision that was heterogeneous in grade, size, and receptor status. Information gained from surgical excision influenced receipt of adjuvant radiation and endocrine therapy in most patients, and indicated benefit from chemotherapy in 18% of patients. Surgical excision is warranted until additional risk stratification is available to identify a cohort of DCIS patients at lower risk for clinically significant synchronous invasive carcinoma.

Abstract P3-07-02: Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: As compared to invasive breast cancer (IBC), HER2 is much more frequently overexpressed in ductal carcinoma in situ (DCIS). Unlike IBC, the prognostic significance of HER2 overexpression remains to be established in DCIS and large studies to investigate its predictive role are lacking. We investigated the prognostic and predictive relevance of HER2 protein and ERBB2 mRNA expression in DCIS using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. ERBB2 mRNA expression was evaluated by reverse transcription followed by PCR on customized Taqman low-density arrays. ERBB2 mRNA expression was analysed as a continuous variable and also as a binary variable using a cut-off to reproduce HER2 expression distribution similar to that observed with immunohistochemistry (IHC). HER2 protein expression was evaluated by IHC using HercepTest™ and scored as per ASCO-CAP 2013 recommendations; HER2 equivocal (IHC2+) were grouped with HER2 negative (IHC 0 or 1+) for main analyses. Additional analyses using binary ERBB2 mRNA expression as a reflex test for HER2 IHC2+ were also performed. Results: HER2 protein expression was evaluable in 713 (181 events) of 755 available samples (DCIS absent or lost during assay in 42). ERBB2 mRNA expression was evaluable in 521 (134 events) of 704 available samples (DCIS absent or insufficient RNA in 51, assay failure in 132). Both results were available in 508 cases (130 events). Increase in ERBB2 mRNA expression (median 0.62; range 0.07-36.76) was associated with increased risk of in situ ipsilateral breast event (DCIS-IBE) [Hazard ratio (HR) = 1.07; 95% Confidence Interval (95%CI) 1.04-1.10; p &amp;lt; 0.0001] but not with increased risk of invasive ipsilateral breast event (I-IBE) [HR = 1.03; 95%CI 0.97-1.10; p = 0.3209]. HER2 positivity by IHC was similarly associated with increased risk of DCIS-IBE [HR = 2.90; 95%CI 1.91-4.40; p &amp;lt; 0.0001] but not with increased risk of I-IBE [HR = 1.40; 95%CI 0. 0.81-2.42; p = 0.2313]. Reclassification of HER2 IHC2+ cases using binary ERBB2 mRNA expression (46 as negative, 16 as positive; 18 expression data unavailable) further improved prognostic discrimination of HER2 IHC [ΔX2 (1d.f.) 5.51; p = 0.0189] for any recurrence. The effect of radiotherapy (RT) for reducing I-IBE was greater in HER2 positive (by ERBB2 mRNA expression) cases [HR = 0.24; 95%CI 0.07-0.83; p = 0.0237] as compared with HER2 negative cases [HR = 0.60; 95%CI 0.23-1.55; p = 0.2925]. Kaplan-Meier estimates of 10-year I-IBE rates with and without RT were 4.5% (2.5%-1.4%) and 15.8% (9.6%-25.3%) in HER2 positive DCIS; rates in HER negative DCIS were 5.2% (2.1%-2.4%) and 7.3% (4.3%-12.2%) respectively. The differential benefit of RT by HER2 status was also seen for reduction in DCIS-IBE. Conclusions: HER2 overexpression is associated with increased risk of DCIS-IBE but not of I-IBE. HER2 status is predictive of radiotherapy response with larger reductions in both I-IBE and DCIS-IBE seen in HER2 positive DCIS. Citation Format: Thorat MA, Wagner S, Jones LJ, Levey PM, Bulka K, Hoff R, Sangale Z, Flake II DD, Bundred NJ, Fentiman IS, Forbes JF, Lanchbury JS, Cuzick J. Prognostic and predictive relevance of HER2 status in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-02.

Abstract P3-07-01: Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial

Abstract Background: Majority of studies investigating prognostic role of ER and PgR expression in ductal carcinoma in situ (DCIS) have failed to show a significant relationship with recurrence. Branched evolutionary tumour growth and resulting intratumour heterogeneity is now increasingly acknowledged in a variety of cancers. DCIS offers the opportunity to investigate relevance of clonal populations in different ducts that may have evolved differently and may impact outcome differently. We investigated prognostic role of ER and PgR expression in DCIS and impact of clonal variation in ER/PgR expression using material from UK/ANZ DCIS trial. Methods: Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. A nested case-control design was used; cases (patients with recurrence) were matched by treatment arm and age to 2 controls each (no recurrence). ER and PgR expression was evaluated on whole sections by immunohistochemistry using 1D5, PGR636 antibodies and EnVisionTM FLEX + detection system (Dako). Assays were scored by Allred method (positive if expression &amp;gt;1%) and clonal method. Clonal method documented presence of ducts with complete lack of ER or PgR expression in otherwise ER or PgR positive (Allred method) DCIS. Analyses categorising such multi-clonal DCIS as ER or PgR positive as per current practice (standard) and categorising these as ER or PgR negative DCIS (clonal method) were performed. Results: Of 540 samples (180 cases, 360 controls), ER and PgR status was evaluable in 504 and 498 patients respectively. ER expression was absent (ER-) in 148 (29.4%), 356 (70.6%) were ER positive (ER+) with 39 (7.7%) of these displaying multi-clonal expression (ERmulti-clonal). PgR expression was absent in 163 (32.7%), 335 (67.3%) were PgR positive with 84 (16.9%) of these displaying multi-clonal expression. ER- DCIS showed increased risk (Table) of in situ ipsilateral breast event (DCIS-IBE) and invasive ipsilateral breast event (I-IBE) (borderline significance). Prognostic discrimination was higher when ER status was determined by clonal method (ΔX2 1.57 for I-IBE and 9.05 for DCIS-IBE). Increases in the risk of I-IBE and DCIS-IBE were similar for ER- and ERmulti-clonal DCIS. TableEndpointComparisonScoring MethodHazard Ratio (95%CI)pI-IBEER- vs. ER+Standard1.75 (0.99-3.09)0.0544 ER- vs. ER+Clonal1.90 (1.10-3.30)0.0224 ER- vs. ER+*Clonal1.89 (1.05-3.41)0.0337 ERmulti-clonal vs. ER+*Clonal1.93 (0.74-5.03)0.1759DCIS-IBEER- vs. ER+Standard2.58 (1.68-3.94)&amp;lt;0.0001 ER- vs. ER+Clonal3.13 (2.02-4.85)&amp;lt;0.0001 ER- vs. ER+*Clonal3.11 (1.97-4.93)&amp;lt;0.0001 ERmulti-clonal vs. ER+*Clonal3.20 (1.62-6.34)0.0008* ER+ DCIS not exhibiting multi-clonal expression Lack of PgR expression was only associated with increased risk of DCIS-IBE and PgR status did not add to the prognostic information provided by ER status. Conclusions: ER expression is prognostic for recurrence in DCIS. ER+ DCIS with distinct ER- clones has a recurrence risk similar to ER- DCIS. ER scoring should take clonality of expression into account. Citation Format: Thorat MA, Jones LJ, Levey PM, Elia G, Evagora CA, Bundred NJ, Fentiman IS, Forbes JF, Cuzick J. Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-01.

Abstract S6-03: Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ (IBIS-II DCIS)

Abstract Background: Third generation aromatase inhibitors are a more effective treatment option than tamoxifen for hormone receptor positive invasive breast cancer in postmenopausal women. However, it is not known whether anastrozole is more effective than tamoxifen in preventing the recurrence of breast cancer in women with hormone receptor (HR) positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole versus tamoxifen in postmenopausal women with HR positive DCIS. Methods: A multi-centre randomised placebo-controlled trial of 1mg/day anastrozole (oral) vs. 20mg/day tamoxifen (oral) for five years was conducted in 2980 postmenopausal women with locally excised HR positive DCIS. The primary endpoint was to determine if anastrozole is at least as effective as tamoxifen in loco-regional control and prevention of contralateral disease. Secondary endpoints included breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths. All analyses were done on an intention-to-treat basis and Cox proportional hazard were used to compute hazard ratios and corresponding confidence intervals for recurrence. Results: Between 2003 and 2012, a total of 2980 postmenopausal women were recruited into the IBIS-II DCIS trial. 1471 women were randomly assigned to receive anastrozole and 1509 women tamoxifen. Median follow-up for this first analysis is 6.8 years and 131 breast cancer recurrences have been recorded. Median age was 60.3 years (56.1-64.6), median BMI was 26.7 (23.6-30.7), and 45.6% of women had used hormone replacement therapy (HRT) before joining the trial. Of the 131 women with recurrent disease, 77 had a loco-regional recurrence and 51 reported contralateral disease. A total of 61 deaths were recorded. We will present a comprehensive analysis of the efficacy of anastrozole and tamoxifen for preventing loco-regional/contralateral breast cancer and major adverse events by intention to treat (ITT). Conclusions: To follow. Citation Format: Cuzick J, Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones LJ, Ellis I. Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ (IBIS-II DCIS). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-03.