Subsequent Breast Events Research Articles

Trajectory of Subsequent Breast Cancer Diagnoses in a Diverse Patient Cohort with Breast Atypia.

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

Abstract PO3-09-01: Integrating pathomic and radiomic images to classify risk of subsequent events among women with DCIS

Abstract Background Multiple sources of ~omic data can be generated from women at different stages of developing breast cancer, the leading cancer diagnosed in women worldwide. Traditionally interrogation of risk factors to study associations and develop prediction models for future breast events has been limited to one or few risk factors, or summary scores of clinical and tumor characteristics. Methods to bring mammography images and breast biopsies of precancer lesions together to summarize risk of cancer developing in the breast are urgently needed. Integration of these two sources has not been performed to date, but has potential to increase accuracy of risk prediction. Approach The Repository of Archival Human Breast Tissue (RAHBT) was established in 2007 at Washington University School of Medicine (WUSM) and maintains biospecimens and medical record data of women treated with breast-conserving surgery (BCS) or mastectomy for breast cancer at WUSM and six other St Louis metropolitan hospitals between 1981-2016. Prospective follow-up of cases is achieved through health records and Siteman tumor registry. Among 1831 patients with pathologically confirmed DCIS who had no prior cancer, 174 developed breast events at least six months after initial DCIS diagnosis. For each case diagnosed between January 1998 and March 2016 with subsequent breast events, two DCIS controls were matched on race, year of diagnosis (±5 years), age (±5 years), and type of surgery. Tissue micro arrays (TMAs) are constructed after breast pathology review and processed for H&E and imaged. Breast cancer risk factor data are uniformly retrieved form the medical records at time of processing cases of DCIS. Mammogram images are retrieved for all women. Full-field digital mammograms (FFDM) are all using the same technology (Hologic). Risk factors and outcome variables: ipsilateral breast events (IBE) was defined as the development of invasive cancer or DCIS in the treated breast at least 6 months post-diagnosis. Follow-up time was calculated from the date of DCIS diagnosis to the date of first IBE, death, or last follow-up, whichever occurred first. The predictors included commonly used clinicopathological factors: age, tumor grade (high vs. low/intermediate), comedonecrosis, surgical margins (close (≤2mm) vs. negative ( >2mm)), local treatment (BCS only and mastectomy vs. BCS+radiation), and endocrine therapy. BMI, menopausal status, and ER were also available for evaluation as predictors. We limited this analysis to women with digital mammograms immediately prior to diagnosis and include 128 cases and controls. Validation cohort As the RAHBT cohort continues to be followed additional second breast events have been documented after the cut off for events identified through March 2016, and the identical procedures used to review/confirm DCIS and subsequent breast events, construct TMAs, process H&E and images, and assemble risk factor data, and the associated digital mammograms. We have 13 additional ipsilateral breast events with complete data and their controls for independently testing the model performance. Statistical methods Propose novel supervised learning approach to integrate image data from mammograms and TMA slides that accommodates agreement between multi-omics. Results 128 (cases and controls, 21.9% ipsilateral subsequent events) identified for development and internal cross validation. Median age at diagnosis was 52 and median time to subsequent breast event was 63 mo. Controlling for the clinical/pathologic risk factors (age, BMI, BI-RADs density, treatment, tumor grade, parous, menopausal status, ER status, and race) and integrating the whole mammogram and TMA pathology images, we observe a 5-yr ipsilateral AUC = 0.74; 10-yr AUC 0.75. The independent validation is ongoing. Conclusions Integrating heterogeneous multiomic data sources can generate significant improvement in long term risk prediction after initial DCIS diagnosis. Citation Format: Shih-Ting Huang, Debbie Bennett, Robert West, Graham Colditz, Shu Jiang. Integrating pathomic and radiomic images to classify risk of subsequent events among women with DCIS [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-01.

Abstract 6255: Personalized medicine for DCIS

Abstract Background: In 2023, 55,720 women will be diagnosed with non-invasive ductal carcinoma in situ (DCIS) in the United States. We evaluated RNA sequencing (RNA-Seq), clinical and social factors that drive subsequent breast events in a DCIS study population enriched for Black women (30%). Methods: RNA was extracted from macrosections of archival formalin-fixed paraffin-embedded (FFPE) DCIS tissue from Resource Archival Human Breast Tissue (RAHBT) from the St. Louis Breast Tissue Registry at Washington University School of Medicine and the Dana Farber Cancer Institute patient cohorts. Tissues were prepared by microsection of 5 uM whole section from unstained slides (Fisher). RNA was extracted using Qiagen RNeasy FFPE Kits from macrosectioned DCIS specimens. Purified total RNA was evaluated for quality and quantity using the Agilent Fragment Analyzer RNA assay. Bulk RNA sequencing was piloted in DCIS case-control samples using the SMART-seq and Hybrid Capture platforms at the DFCI Molecular Biology Core Facilities. Raw reads were aligned to the GRCh38/hg38 reference genome using STAR. Preliminary quality control analysis of a curated gene list showed higher quality data using the Hybrid Capture technology. Libraries for Hybrid Capture were pooled in 8plex reactions and hybridized to Twist Exome 2.0 probes for target enrichment. The final library pools were sequenced on an Illumina NovaSeq. Cases were defined as women diagnosed with DCIS in 1999 or later with subsequent invasive breast cancer, local DCIS recurrence, or lobular CIS recurrence. Controls were defined as women diagnosed with DCIS in 1999 or later without subsequent breast events during a similar follow-up time. The R package DESeq2 was used for data analysis. Results: The mean age at DCIS diagnosis was 56.3 (Std Dev 10.23). The mean follow-up time was 147.8 months. Hybrid Capture RNA-Seq files are stored and analyzed from the Harvard Medical School O2 Cluster using R programming (version 4.2.2, DEGreport). Quality control analyses demonstrated that the majority of the samples sequenced by Hybrid Capture had over 20 million total reads. Principal Component Analyses (PCA) and hierarchical clustering analyses of 19,821 protein-coding genes were conducted on the 143 DCIS samples sequenced using Hybrid Capture. PC1 was race (9%). A significant association was observed for follow-up time (PC3, 4.03%). First, we explored the association of the candidate gene ERBB2. The mean transcript abundance for ERBB2 was 11784.37 (case-control p-value=0.08). Preliminary analysis of selected genes of interest did not show statistically significant differences between cases and controls after FDR p-value adjustment. Differential gene expression analyses are ongoing. Conclusion: This study demonstrates the feasibility of generating high-quality RNA-seq data from diverse, archival DCIS samples. Citation Format: Aditi Hazra. Personalized medicine for DCIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6255.

Abstract P1-07-02: Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS

Abstract PURPOSE To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a previously reported multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of any ipsilateral recurrence (IR) event within five years after DCIS diagnosis. METHODS A derivation cohort consisted of participants in the Translational Breast Cancer Research Consortium (TBCRC) 038, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016 (n=216). The validation cohort, the Repository of Archival Human Breast Tissue (RAHBT) at Washington University School of Medicine, provided cases meeting the same eligibility criteria as TBCRC038 (n=97). Participants in both cohorts had RNA-seq data and either developed IR 1-5y after initial DCIS diagnosis or were free from subsequent breast events for at least five years. The previously reported 812-gene classifier had been developed from a subset of the TBCRC038 samples using a negative-binomial regression model to identify differentially expressed genes in the primary tumor associated with subsequent recurrence events. This classifier has been shown to be highly correlated with 5-year invasive, DCIS, and all breast cancer events, and validated in the RAHBT cohort. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of IR in the TBCRC038 cohort (76 with IR). The clinical score was developed using clinical predictors (aforementioned clinical factors and ER) and their regression coefficients from the model with the maximum predictive accuracy (e.g. c-index) and the minimum number of predictors; the summary score integrated the clinical score and multi-gene classifier. Predictive performance of both clinical and summary scores was validated in the RAHBT cohort (20 with IR). RESULTS In the TBCRC cohort derivation set, we used a multivariable model based on clinical factors alone (clinical score) and found that ER status, but not BMI or menopausal status, was independently associated with a higher IR risk (HR=2.06, 95% CI 1.18-3.58). Adding the multi-gene classifier to the clinical factors-based model (summary score) in the TBCRC038 test set increased predictive accuracy (c-index 0.68 to 0.70), with the genomic classifier-adjusted HR of 14.96 (95% CI 8.64-25.91). The summary score had higher predictive performance for IR risk than clinical score alone (c-index 0.82 vs. 0.70). In the RAHBT validation samples, model performance was similarly improved using summary scores clinical factors-based model plus multigene classifier as compared to clinical scores along (c-index 0.74 vs. 0.58). CONCLUSION Combining clinical factors and a multigene classifier provided more accurate risk estimates of IR within five years after excision of DCIS than clinical factors alone. Figure 1. Observed and predicted recurrence-free survival in the first five years after initial DCIS diagnosis in the RAHBT validation cohort, by risk groups defined by clinical scores (left) and clinical score plus multigene classifier (right). Citation Format: Ying Liu, Siri H. Strand, Lorraine King, Bryan Harmon, Fergus J. Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F. McAuliffe, Jeffrey Marks, Carlo Maley, Robert West, E Shelley Hwang, Graham A. Colditz. Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-02.

Abstract A012: Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS

Abstract Purpose: To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of ipsilateral recurrence (IR) within five years after DCIS diagnosis. Methods: A derivation cohort consisted of participants in the discovery cohort, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016. The validation cohort provided cases meeting the same eligibility criteria as the discovery cohort. This analysis includes 313 participants with RNA-seq data who either developed IR 1-5 years after initial DCIS diagnosis or were free from subsequent breast events at least five years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of IR in 216 TBCRC participants (76 with IR). We developed the clinical score using clinical predictors (aforementioned clinical factors and ER) and their regression coefficients from the model with the maximum predictive accuracy (e.g. c-index) and the minimum number of predictors, and the summary score integrating the clinical score and multi-gene classifier. Predictive performance of clinical and summary scores was validated in 97 RAHBT patients (20 with IR). Results: In the discovery cohort, ER negativity, but not BMI or menopausal status, was independently associated with a higher IR risk (HR=2.06, 95% CI 1.18-3.58), and adding ER to the clinical factors-based model increased predictive accuracy (c-index 0.68 to 0.70). The clinical score-adjusted HR was 14.96 (95% CI 8.64-25.91) for multi-gene classifier. Summary scores were better in predicting IR risk than clinical scores (c-index 0.82 vs. 0.70). Compared with their low-risk counterparts, the HR was 4.79 (95% CI 2.55-8.98) in the clinical score-defined high-risk group and 29.02 (95% CI 14.23-59.15) in the summary score-defined high-risk group. In the validation cohort, model performance was improved using summary scores as compared to clinical scores (c-index 0.74 vs. 0.58). Conclusion: Combination of clinical factors and multigene classifier provided more accurate risk estimates of IR within five years after excision of DCIS than clinical factors alone. Citation Format: Graham A. Colditz, Ying Liu, Siri H. Strand, Lorraine King, Jeff Marks, Carlo Maley, Robert B. West, E. Shelley Hwang. Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A012.

Abstract PD5-03: Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment

Abstract Background. Ongoing clinical trials are evaluating active surveillance as a potential alternative to immediate surgery in patients diagnosed with low-risk ductal carcinoma in situ (DCIS). Among women undergoing lumpectomy, the risk of ipsilateral invasive breast cancer (iIBC) after a diagnosis of DCIS can be reduced with adjuvant therapy, including endocrine therapy (ET) and radiation treatment (RT). Here we characterize the effects of ET and RT on iIBC risk after diagnosis with DCIS in a national cohort, in patients who received breast conserving surgery (BCS) within 6 months of diagnosis (BCS group) compared to patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods. A treatment-stratified random sample of patients diagnosed with biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Patients who received a mastectomy within 6 months of diagnosis were excluded. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcomes were the population-averaged 8-year absolute risks of iIBC for the following five treatment modalities: BCS alone, SV alone, BCS + ET, SV+ET, BCS+RT, and BCS+ET+RT (where ET was defined as ≥5 years of continuous treatment). Secondary outcomes were the average treatment effects (ATE) of SV+ET vs SV, BCS+RT vs SV+ET, and BCS+RT+ET vs SV+ET. A propensity score (PS) model for treatment choice BCS vs SV was fitted with sampling design (SD) weighting and random effects for patients within facilities. Relative treatment effects (hazard ratios [HR]) for the five treatment groups were obtained using multivariable Cox proportional hazards models adjusted for tumor and patient characteristics. The models were weighted by SD and PS and included a robust sandwich covariance estimator to account for clustering of patients within facilities. Population-averaged risks and ATEs were derived from the marginal outcome probabilities: assuming that the entire population received the treatment of interest, each patient’s counterfactual probability of an iIBC event by 8 years was predicted, and then averaged across the weighted population. 95% confidence intervals (CI) were obtained by bootstrapping. Results. The final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with hormone receptor-positive (79.9%), and nuclear grade I/II (54.5%) DCIS. Uptake of any ET was 48.5% and 23.7% in BCS and SV patients, respectively. The relative treatment effects (HR) for the receipt of BCS, RT and ≥5 years of ET were 1.65 (95% CI: 1.14-2.39), 0.40 (95% CI: 0.27-0.61) and 0.55 (95% CI: 0.17-1.72) respectively. The 8-year population-averaged iIBC risks and corresponding ATEs are shown Table 1. Conclusion. The 8-year risk of iIBC was below 7% for all six management options. Relative and absolute treatment effects of ET and RT were comparable to previously reported estimates. In SV patients, receipt of ≥5 years of ET nearly halved the 8-year risk, indicating a substantial risk reduction potential for ET in patients who do not receive immediate surgery after diagnosis. Table 1: Population-averaged 8-year iIBC risk and ATEs.TreatmentiIBC risk (%)95% CISurveillance6.906.79-7.01Surveillance + ET3.903.83-3.96BCS4.264.21-4.31BCS + RT1.761.73-1.79BCS + ET2.392.35-2.43BCS + ET + RT0.980.96-0.99Treatment comparisonATE (%)95% CISV+ET vs SV3.02.95-3.04BCS+RT vs SV+ET2.142.11-2.17BCS+RT+ET vs SV+ET2.922.78-2.97 Citation Format: Marc D Ryser, Christel N Rushing, Samantha M Thomas, Thomas Lynch, Anne McCarthy, Zahed A Mohammed, Amanda B Francescatti, Elizabeth S Frank, Anne H Partridge, Alastair M Thompson, Terry Hyslop, E. Shelley Hwang. Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-03.

Treating (low-risk) DCIS patients: What can we learn from real-world cancer registry evidence?

PurposeResults from active surveillance trials for ductal carcinoma in situ (DCIS) will not be available for > 10 years. A model based on real-world data (RWD) can demonstrate the comparative impact of non-intervention for women with low-risk features.MethodsMulti-state models were developed using Surveillance, Epidemiology, and End Results Program (SEER) data for three treatment strategies (no local treatment, breast conserving surgery [BCS], BCS + radiotherapy [RT]), and for women with DCIS low-risk features. Eligible cases included women aged ≥ 40 years, diagnosed with primary DCIS between 1992 and 2016. Five mutually exclusive health states were modelled: DCIS, ipsilateral invasive breast cancer (iIBC) ≤ 5 years and > 5 years post-DCIS diagnosis, contralateral IBC, death preceded by and death not preceded by IBC. Propensity score-weighted Cox models assessed effects of treatment, age, diagnosis year, grade, ER status, and race.ResultsData on n = 85,982 women were used. Increased risk of iIBC ≤ 5 years post-DCIS was demonstrated for ages 40–49 (Hazard ratio (HR) 1.86, 95% Confidence Interval (CI) 1.34–2.57 compared to age 50–69), grade 3 lesions (HR 1.42, 95%CI 1.05-1.91) compared to grade 2, lesion size ≥ 2 cm (HR 1.66, 95%CI 1.23–2.25), and Black race (HR 2.52, 95%CI 1.83–3.48 compared to White). According to the multi-state model, propensity score-matched women with low-risk features who had not died or experienced any subsequent breast event by 10 years, had a predicted probability of iIBC as first event of 3.02% for no local treatment, 1.66% for BCS, and 0.42% for BCS+RT.ConclusionRWD from the SEER registry showed that women with primary DCIS and low-risk features demonstrate minimal differences by treatment strategy in experiencing subsequent breast events. There may be opportunity to de-escalate treatment for certain women with low-risk features: Hispanic and non-Hispanic white women aged 50–69 at diagnosis, with ER+, grade 1 + 2, < 2 cm DCIS lesions.

Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ (DCIS): Comparison of patients with and without index surgery.

519 Background: Most women diagnosed with ductal carcinoma in situ (DCIS) undergo surgical resection, potentially leading to overtreatment of patients who would not develop clinically significant breast cancer in the absence of locoregional treatment. We compared the risk of ipsilateral invasive breast cancer (iIBC) between DCIS patients who received breast conserving surgery (BCS) for their index diagnosis of DCIS (BCS group) and patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods: A treatment-stratified random sample of patients diagnosed with screen-detected and biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Excluding patients who received a mastectomy ≤6 months, the final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcome was the 8-year absolute difference in iIBC risk between BCS and SV; a subgroup analysis was performed for grade I/II patients. A propensity score (PS) model for treatment was fitted with sampling design (SD) weighting and random effects for patients within facilities. Absolute risk differences were estimated using PS-SD-weighted Kaplan Meier estimators. Results: Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with estrogen receptor-positive (80.6%), and nuclear grade I/II (54.5%) DCIS. The fraction of patients with a Charlson comorbidity score of ≥2 was higher in SV (14.2%) compared to BCS (6.4%, p &lt; 0.001). The 8-year risk of iIBC was 3.0% (95% CI: 2.4%-3.6%) for BCS and 7.7% (95% CI: 4.9%-10.5%) for SV, with an absolute risk difference of 4.7% (95% CI: 4.5%-4.9%; log-rank p &lt; 0.001). Among patients with grade I/II tumors, the 8-year risk of iIBC was 3.1% (95% CI: 2.3%-4.0%) for BCS and 6.1% (95% CI: 2.5%-9.8%) for SV; difference: 3.0% (95% CI: 2.7%-3.2%; p = 0.005). Conclusions: Despite an increased risk of iIBC in SV patients compared to BCS patients, the 8-year risk did not exceed 10% in either group. The risk of recurrence in BCS patients was comparable to previously reported estimates. These data demonstrate a considerable degree of overtreatment among patients with non-high grade DCIS. Prospective clinical trials will help determine the tradeoffs between universally directed as opposed to selectively applied surgery for low risk DCIS.

Abstract P5-08-05: Risk of subsequent events after initial diagnosis of ductal carcinoma in situ - A large multi-center registry study

Abstract Introduction: Ductal carcinoma in situ (DCIS) is a pre-malignant lesion but 14-53% will not progress to an invasive cancer. Large, well characterized DCIS datasets with long term follow up are sparse, and there is uncertainty regarding the long term effects of various treatment modalities on subsequent breast events (SBE). Here, we analyze trends identified in the SBE rates from patients treated at two large academic breast care centers in California, UCSF and UCSD. Methods: Institutional Cancer Registries were used to collect demographic, clinical, imaging and pathologic data. Patients aged 18 years and older without any prior history of breast disease whose first diagnosed breast neoplasm was DCIS and who had at least 6 months of follow up were included. Only SBE beyond 6 months after initial diagnosis were included. All mastectomy types and associated adjuvant treatment were grouped. All patients not undergoing surgery were grouped. Differences between patients in the various treatment groups were assessed using χ2, Student’s t-test, and one-way ANOVA. Poisson regression was used to compare differences in SBE rates between treatment groups. For analysis, follow up times were divided into three 5 years periods (0-5, 6-10, 11-15 years) after initial DCIS diagnosis. Results: 2730 patients - 1575 (57.7%) at UCSF and 1155 (42.3%) at UCSD - were diagnosed between 1985 and 2017 and included in the study. 1910 (70.0%) underwent breast conserving surgery (BCS), 672 (24.6 %) had mastectomy, 144 (5.3%) did not have surgery, and 4 (0.1%) had missing surgery status. 623 (22.8%) received adjuvant endocrine therapy (ET), 2081 (76.2%) did not and 26 (1.0%) had missing adjuvant endocrine therapy status. 1092 (40.0%) received adjuvant radiation therapy (RT), 1619 (59.3%) did not and 19 (0.7%) had unknown radiation therapy status. Median follow up time for all patients was 7.9 years. 305 patients were diagnosed with SBE. Of these, 144 (47.2%) were in situ and 147 (48.2%) were invasive including 16 (5.2%) metastatic lesions, and 14 (4.6%) had missing invasiveness. Of the 289 patients who did not have a metastatic second lesion, 176 (60.9%) SBE were ipsilateral, 88 (30.4%) were contralateral, and 25 (8.7%) had missing SBE laterality. The overall incidence (i) for any SBE over the entire study period was 1.4%/yr. Compared to women who were treated with BCS alone (N=642, i=2.14%/yr, 95% CI 1.76-2.51), SBE rates were lower in women undergoing BCS with RT (N=719, i=1.13%/yr, 95% CI 0.87-1.40, p&amp;lt;0.001), BCS with RT and ET (N=356, i=0.63%/yr, 95% CI 0.30-0.97, P&amp;lt;0.001), and mastectomy (N=672, i=1.00%/yr, 95% CI 0.75-1.25, p&amp;lt;0.001) but were not significantly different for patients undergoing BCS with ET (N=159, i=2.25%/yr, 95% CI 1.35-3.15, p=0.813). Within the first 5 years of diagnosis, mastectomy, BCS with RT, and BCS with RT and ET all lowered the SBE rate of ipsilateral in situ and invasive SBE (p&amp;lt;0.05, in each case). In contrast, no treatment modalities impacted the rate of contralateral SBE rate during any of the time periods. Importantly, the majority of patients, even with BCS alone never had a subsequent event and only 147 had an invasive event overall. Conclusion: This large two-center registry study reveals that the rate of invasive and in situ SBE after an initial DCIS diagnosis are comparable. The effect of each treatment modality on SBE incidence rates are consistent with other published studies, with the notable exception of BCS and ET which requires deeper investigation. As expected, local treatment affects mostly ipsilateral events within the first 5 years after initial diagnosis, without impacting the rate of contralateral SBE. Complementary molecular and cellular profiling of selected specimens are underway to help build a more precise BSE risk model and prevent overtreatment. Citation Format: Thomas O'Keefe, Christina Yau, Eliza Jeong, Emma Iaconetti, Paul Kim, Ann Griffin, Joseph McGuire, Rita Mukhtar, Laura Esserman, Olivier Harismendy, Gillian L. Hirst. Risk of subsequent events after initial diagnosis of ductal carcinoma in situ - A large multi-center registry study [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 P5-08-05.

Outcomes and risk of subsequent breast events in breast-conserving surgery patients with BRCA1 and BRCA2 mutation.

PurposePrevious studies provide inconsistent interpretations of the effect of inherited genetic factors on the survival and prognosis of patients with breast cancer. The aim of this study was to examine the effect of germline BRCA1 and BRCA2 mutation on survival and subsequent breast events in Chinese women who underwent breast‐conserving surgery.MethodsA retrospective review of the clinical and pathological records was performed in patients diagnosed with primary invasive breast cancer between 2005 and 2018 in the cancer registry database. Clinicopathological data and data regarding treatment and outcomes, including date and site of disease progression, were collected. The survival outcomes and independent risk factors were conducted using SPSS.ResultsOverall, a total of 501 patients who underwent breast‐conserving surgery were identified and subjected to analyses, of which 63 cases with BRCA1 or BRCA2 mutation. The median age at diagnosis was 41 (range, 24‐74) for carriers and 37 (range, 17‐84) for noncarriers. After a median follow‐up time of 61 months (range, 8‐161) and 70 months (range, 0‐153), respectively, in carriers and noncarriers, the overall survival (P = .173) and disease‐free survival (P = .424) were not significantly different. Analogously, there was no significant difference between the two groups about the outcomes of ipsilateral breast tumor recurrence (P = .348), yet the contralateral breast cancer (CBC) was overt worse than noncarriers (P < .001). When adjusted to confounding factors, BRCA mutation was the only independent risk factors to CBC (HR = 7.89, P = .01).ConclusionIn this study, BRCA mutation carriers have higher risk of CBC. And, BRCA mutation is the only independent risk factor to CBC. Therefore, intensive surveillance and follow‐up as well as more effective individual prevention are urgent. Decisions on alternatively effective prevention, especially the prevention of CBC, are urgent and should take into account patient prognosis and preferences.

Abstract P5-18-01: Risk of contralateral breast cancer (CBC) in women with ductal carcinoma in situ (DCIS) with and without and synchronous lobular carcinoma in situ (LCIS)

Abstract Background: LCIS is considered a risk factor for bilateral breast cancer, but the effect of LCIS diagnosed concurrently with DCIS is not known. We sought to compare CBC and ipsilateral breast tumor recurrence (IBTR) rates in women with DCIS with and without synchronous LCIS treated with breast conserving surgery (BCS). Methods: A prospectively maintained database of DCIS patients undergoing BCS from 2000-2011 was used to identify women with a contralateral breast at risk. Patients with synchronous ipsilateral LCIS found at core needle biopsy or surgical excision were included in the “DCIS + LCIS” group; those with contralateral or bilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated using logistic regression. Results: Of the 1888 patients identified, 1475 (78%) had DCIS only and 413 (22%) had DCIS with synchronous LCIS. Median follow-up was 7.5 years (range 0-17 years). 305 patients had a subsequent breast event; 216 IBTR and 89 CBC. The 5 and 10-year cumulative incidence of IBTR was similar in both groups: 6.3% and 14.4% for DCIS only, compared with 5.9% and 14.0% for DCIS + LCIS (p = 0.94), respectively. The 5 and 10-year cumulative incidence of CBC was significantly greater in the DCIS + LCIS group: 5.7% and 10.0%, compared with 2.4% and 5.0% for DCIS only (p &amp;lt; 0.001). Table 1 summarizes uni-and multi-variable analyses of risk factors associated with CBC and IBTR among women with DCIS treated with BCS. After adjustment for other factors, CBC risk was more than 2-fold higher in the DCIS + LCIS group compared with the DCIS only group (HR 2.37, 95% CI 1.54-3.65, p &amp;lt; 0.001). There was no difference in IBTR risk based on presence of synchronous LCIS. Younger age and receipt of endocrine therapy were significantly associated with decreased risk of CBC. Table 1:Risk factors associated with CBC and IBTR in patients with DCIS treated with BCS Univariate Analysis Multivariate Analysis Hazard Ratio (95% CI) Hazard Ratio (95% CI) CBC IBTR CBC IBTRAge (continuous)1.02 (1.01-1.04) *0.99 (0.98-1.0)1.02 (1.0-1.04) *0.99 (0.97-1.0) *Presentation Radiologic1111Clinical0.36 (0.11-1.14)1.56 (1.05-2.3) *0.41 (0.13-1.31)1.67 (1.12-2.47) *Family history Yes1.32 (0.87-2.01)1.0 (0.76-1.32)1.33 (0.87-2.03)1.03 (0.78-1.35)Grade Low1111Intermediate/high1.83 (1.0-3.37)1.32 (0.93-1.88)1.74 (0.92-3.29)1.62 (1.11-2.35) *Radiation Yes1.16 (0.75-1.8)0.7 (0.54-0.92) *1.14 (0.71-1.82)0.64 (0.48-0.86) *Endocrine Therapy Yes0.43 (0.23-0.81) *0.51 (0.35-0.74) *0.42 (0.22-0.8) *0.53 (0.36-0.77) *DCIS group DCIS only1111DCIS + LCIS2.28 (1.49-3.5) *0.99 (0.71-1.36)2.37 (1.54-3.65) *0.99 (0.71-1.37)* p &amp;lt; 0.05 Conclusions: LCIS diagnosed concurrently with DCIS is not associated with IBTR, but increases the risk of CBC two-fold. Endocrine therapy should be considered both for the index DCIS and for prevention of subsequent CBC. Citation Format: Miller ME, Muhsen S, Zabor EC, Flynn J, Olcese C, Giri D, Van Zee KJ, Pilewskie M. Risk of contralateral breast cancer (CBC) in women with ductal carcinoma in situ (DCIS) with and without and synchronous lobular carcinoma in situ (LCIS) [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 P5-18-01.

Abstract 2576: Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma in situ

Abstract Objectives: To examine the relationship between radiation therapy delay and risk of subsequent breast events in the ipsilateral breast and to identify factors that are associated with delay in women with ductal carcinoma in situ (DCIS). Methods: From the Missouri Cancer Registry, we identified the women who were diagnosed with first primary DCIS between 1996 and 2011 and treated with breast conserving surgery (BCS). Radiation therapy delay was defined as the first radiation therapy that was delivered greater than eight weeks after BCS. Propensity scores were calculated for radiation therapy delay and no radiation therapy during the first course of treatment. A propensity score-adjusted Cox proportional hazards regression analysis was conducted to estimate the hazard ratio (HR) of ipsilateral breast tumors. Logistic regression analysis was conducted to identify factors associated with delay. Results: Among 5,916 patients, 1,053 (17.8%) received radiation therapy greater than eight weeks after BCS and 1,702 (28.8%) did not receive radiation therapy during the first course of treatment. During the 72- month follow-up, 182 (3.1%) developed ipsilateral breast tumors. After adjustment for propensity scores, the HR of ipsilateral breast tumors was 1.26 (95% CI, 1.00-1.59; p = 0.049) for radiation therapy delay and 1.35 (95% CI, 1.03-1.76; p = 0.03) for no radiation therapy compared with timely radiation therapy. Radiation therapy delay was associated with black race, being non-married and on Medicaid, later years of diagnosis, larger tumor size micropapillary architecture, and positive surgical margin. Conclusions: Receipt of radiation therapy greater than eight weeks after BCS was associated with a significantly increased risk of ipsilateral breast tumors in women with DCIS. Timeliness of radiation therapy should be improved, particularly for black and Medicaid patients. Citation Format: Ying Liu, Shumei Yun, Min Lian, Graham Colditz. Radiation therapy delay and risk of ipsilateral breast tumors in women with ductal carcinoma in situ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2576.

Abstract P3-07-03: The impact of Carcinoma in situ of the breast and family history on risk of subsequent breast cancer events and mortality - a population based study from Sweden

Abstract Purpose: To evaluate the long-term risk of subsequent breast cancer and mortality among women diagnosed with carcinoma in situ of the breast. Patients and Methods: Using the population-based Swedish Multi-Generation and Cancer Registers we selected 8,111 women diagnosed with in situ breast cancer between 1980 and 2004. We estimated the relative risks of subsequent ipsi- and contralateral invasive breast cancer or a contalateral in situ expressed as standardized incidence ratios (SIRs), in relation to age, year, time since diagnosis and family history (1st degree relative) for breast cancer. The relative risk of death was expressed as standardized mortality ratio, (SMR). Results: Of 8,111 women identified with first in situ, 859 had a family history for breast cancer. The overall risk of a subsequent invasive breast cancer is over four fold and the risk for contralateral in situ breasts cancer was almost seven fold, compared with the risk in healthy women. Women with a family history had almost a 50% increased risk for a contralateral invasive breast cancer, IRR 1.49 (95% CI 1.06–2.09) compared to women without, but had no increased risk for a contralateral in situ cancer or ipsilateral invasive breast cancer. The risk for subsequent breast cancer decreased over time after diagnosis, but still 15 years after first in situ diagnosis the risk was over three times higher compared to the general population. Women below 40 years at diagnosis had the highest risk for a subsequent breast event, SIR 8.54 (95% CI 6.07–11.67). The overall mortality for women with no second invasive event was the same as for women in the general population, SIR 1.01 (95% CI 0.95–1.08). Women below 50 years at first in situ diagnosis, with a second invasive cancer, had a higher mortality compare to women above 50 years, SIR 8.3 (95% CI 5.38–11.54) and SIR 1.70 (95% CI 1.39–2.06) respectively. Conclusion: The risk for a subsequent invasive breast cancer, as well as mortality was substantially higher in younger women, which should be taken into account when planning their treatment and follow-up. Family history did not increase the risk for a subsequent ipsilateral invasive cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-03.

Structural Estimates of Treatment Effects on Outcomes Using Retrospective Data

Analysis of observational cohort data is subject to bias from unobservable risk selection. The authors compared econometric models and treatment effectiveness estimates using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data for women diagnosed with ductal carcinoma in situ. Treatment effectiveness estimates for mastectomy and breast-conserving surgery (BCS) with or without radiotherapy were compared using three different models: simultaneous-equations model, discrete-time survival model with unobserved heterogeneity (frailty), and proportional hazards model. Overall trends in disease-free survival (DFS), or time to first subsequent breast event, by treatment are similar regardless of the model, with mastectomy yielding the highest DFS over 8 years of follow-up, followed by BCS with radiotherapy, and then BCS alone. Absolute rates and direction of bias varied substantially by treatment strategy. DFS was underestimated by single-equation and frailty models compared with the simultaneous-equations model and randomized controlled trial results for BCS with radiotherapy and overestimated for BCS alone.

Correlates and effect of suboptimal radiotherapy in women with ductal carcinoma in situ or early invasive breast cancer

The study aimed to identify factors associated with less-than-optimal radiotherapy (RT) and its impact on disease-free survival in women aged 66+ years diagnosed with stage I breast cancer or ductal carcinoma in situ (DCIS). The subjects were women diagnosed from 1991 to 1999 in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database who underwent breast-conserving surgery and RT within 12 months postdiagnosis. The authors conducted descriptive and multivariate survival analyses, and considered age, race, poverty, marital status, comorbidity indices, rural/urban, radiation oncologist density, comedo necrosis histology (DCIS only), chemotherapy receipt (stage I only), and RT completion (3+ weeks of treatment) and delay (8+ weeks postsurgery without chemotherapy; 4+ weeks postchemotherapy). Of 7791 subjects, 16% experienced RT delay, and 3% had incomplete RT. Subjects with stage I disease who were more likely to delay RT were of black race (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.17-2.08), whereas women in areas of high radiation oncologist density were less likely to delay (OR, 0.73; 95% CI, 0.66-0.81). Those living in high poverty areas were less likely to complete RT (P < .03), as were those undergoing chemotherapy (OR, 1.82; 95% CI, 1.15-2.88). Stage I breast cancer patients with delayed RT were more likely to experience a subsequent breast event (OR, 1.14; 95% CI, 1.00-1.30), and those with incomplete RT had a higher rate of overall mortality (OR, 1.32; 95% CI, 1.06-1.63). Factors associated with lower subsequent breast events included older age, lower poverty, and being married. RT delays of 12+ weeks (or 8+ weeks postchemotherapy) had a strongly negative impact on subsequent events (OR, 3.94; 95% CI, 2.51-6.17 for DCIS; OR, 2.77; 95% CI, 1.84-2.59 for stage I). RT should be facilitated to ensure completion and timeliness, especially for early invasive breast cancer patients.

Association between Breast Density and Subsequent Breast Cancer Following Treatment for Ductal Carcinoma In situ

Risk of invasive cancer following treatment for ductal carcinoma in situ (DCIS) is associated with both treatment- and tumor-related factors. However, it is unknown whether stromal factors such as breast density may also influence subsequent invasive breast events. We investigated whether breast density is an independent predictor of subsequent breast events among women treated for DCIS. A prospective cohort study of 3,274 women ages 30 to 93 in the Breast Cancer Surveillance Consortium treated with lumpectomy for DCIS between 1993 and 2005. All subjects had an American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) breast density measure recorded prior to diagnosis. Ipsilateral and contralateral breast cancer following lumpectomy for DCIS were ascertained through state tumor registries, regional Surveillance Epidemiology and End Results program or pathology databases. A Cox proportional hazard model was used to compare adjusted risk of breast cancer among women with high (BI-RADS 3 or 4) versus low (BI-RADS 1 or 2) breast density. During a median follow-up period of 39 months (0-132 months), 133 women developed invasive breast cancer. After adjusting for age and radiation treatment, high breast density was associated with increased hazard for contralateral (hazard ratio, 3.1; 95% confidence interval, 1.6-6.1) but not ipsilateral (hazard ratio, 1.0; 95% confidence interval, 0.6-1.6) invasive breast events. High breast density is associated with contralateral, but not ipsilateral, invasive breast cancer following lumpectomy for DCIS. Thus, women with DCIS and high breast density may especially benefit from antiestrogenic therapy to reduce the risk of contralateral invasive disease.