Subsequent Invasive Breast Cancer Research Articles

The Role of Residential Segregation in Treatment and Outcomes of Ductal Carcinoma in Situ of the Breast.

It remains unclear if residential segregation impacts on clinical treatment and outcomes for ductal carcinoma in situ (DCIS), a nonobligate precursor to invasive breast cancer (IBC). This population-based retrospective cohort study included adult non-Hispanic White (NHW) and Black (NHB) women diagnosed with unilateral DCIS between January 1990 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results dataset. County-level racialized economic segregation was measured using the Index of Concentration at the Extremes. Multilevel logistic regression and Cox proportional hazards regression accounting for county-level clustering were used to estimate the odds ratios (ORs) of local treatment, and hazard ratios (HRs) of subsequent IBC and mortality. Of 103,898 cases, mean age was 59.5 years, 12.5% were NHB, 87.5% were NHW, 97.5% underwent surgery, 64.5% received radiotherapy following breast-conserving surgery, 7.1% developed IBC, and 18.6% died from all causes. Among women living in the least vs most privileged counties, we observed higher odds of receiving mastectomy (vs breast-conserving surgery) (OR=1.51, 95% CI 1.35-1.69; Ptrend<0.001) and radiation therapy following breast-conserving surgery (OR=1.27, 95% CI 1.07-1.51; Ptrend<0.01); the risk was higher in subsequent ipsilateral IBC (HR=1.16, 95% CI 1.02-1.32; Ptrend=0.04), not in breast cancer-specific mortality (HR=1.04, 95% CI 0.88-1.23; Ptrend=0.56). The results provide evidence for disparities in clinical treatment for DCIS and prognostic outcomes among women in racially and economically segregated counties. Our findings may inform geographically targeted multilevel interventions to reduce breast cancer burden and improve breast cancer care and equity.

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.

Imaging Changes and Outcomes of Patients Undergoing Active Monitoring for Ductal Carcinoma In Situ: Seven-Year Follow-up Study

Rationale and ObjectiveTo determine the imaging changes and their associated positive predictive value (PPV) for invasive breast cancer in women undergoing active monitoring for DCIS. Materials and MethodsIn this seven-year follow-up retrospective IRB-exempted cohort study, we reviewed patients diagnosed with DCIS who elected active monitoring between 2003 to 2022 at a single academic institution. Imaging characteristics, histopathology at initial diagnosis, and subsequent follow-up were recorded. Low-risk DCIS was defined as low or intermediate grade and hormone receptor (HR) positive (estrogen and/or progesterone receptor positive) disease diagnosed in women at least 40 years of age. Progression was defined as subsequent ipsilateral invasive breast cancer diagnosis. ResultsThere were 39 patients with a median age of 58.4 years (IQR: 51.1 – 69.6 years) and a median follow-up of 4.3 years (range: 0.6-16.4 years). Nearly two thirds of patients (64%, 25/39) had stable imaging (range: 0.6-16.4 years) and remained progression-free during active monitoring. Among the remaining 14 patients (36%) there were 24 imaging findings which prompted 22 subsequent core needle biopsies (range: 1-3 biopsies per patient) and two surgical biopsies. The positive predictive value (PPV) of invasive cancer was 29% (7/24) overall and 38% (3/8) for masses, 33% (3/9) for calcifications, 17% (1/6) for non-mass enhancement, and 0% (0/1) for architectural distortion. ConclusionsOf the radiographic changes prompting an additional biopsy, development of a new mass (38%) and new calcifications (33%) had the highest PPV for invasive progression. Close imaging follow-up should be a critical component for patients undergoing monitoring for DCIS.

Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

Abstract 3126: Multimodal genome-wide survey of progressing and non-progressing DCIS

Abstract Introduction: Our current understanding of the molecular changes predisposing Ductal carcinoma in situ (DCIS) to progress to invasive breast cancer (IBC) is limited. The aim of this study is to characterize the molecular changes of DCIS to improve DCIS risk assessment. Methods: We obtained paraffin-embedded tissue of 210 DCIS samples with no concurrent or antecedent IBC from 5 cancer institutions, and extracted DNA and RNA. Transcriptome analysis: Illumina’s TruSeq RNA Exome kit was used for library construction, followed by sequencing. Methylome analysis: Bisulfite treated genomic DNA was restored and arrayed using the Illumina 450K methylation chips. DNA Copy number (CNV) analysis: CNV was estimated from the methylation data set using the EpiCopy R package. Results: Samples passing Q/C metrics: Transcriptome: 59 cases, 63 controls. Methylome &amp; CNV: 93 cases, 98 controls. We classified samples into their intrinsic PAM50 subsets. Cases showed an increase in the Her2 subtype, and the controls were enriched in LuminalA (LumA) samples, while Basal and LuminalB (LumB) subtypes were evenly distributed. Compared to the TCGA IBC dataset, proportions of Her2 and LumB subtypes in DCIS were increased while the LumA cohort was decreased. Unsupervised clustering of the transcriptome data resulted in 3 clusters with key differences between PAM50 subtypes: one cluster predominated in Basal and Her2 subtypes, and a second was enriched in hormone-positive samples (LumA and LumB). For the methylome data, the optimal number of clusters was 6. Again, several clusters showed correlation with PAM50 subtype, e.g., one was enriched for hormone-negative subtypes (Basal and Her2), while another was enriched for hormone-positive subtypes (LumA and LumB). For the CNV data, the optimal number of clusters was 4. Here, one CNV cluster appeared predominantly in the Basal subtype, and there were multiple regions showing significant subtype-specific differences with the TCGA IBC data set. While the well-known heterogeneity of DCIS prevents the above broad molecular categories from strongly stratifying DCIS by outcome, we are continuing to analyze our data sets for predictive molecular signatures. Since the long-term outcome of all DCIS in this cohort is known, we are in the unique position to pursue additional questions such as PAM50 subtype differences in times-to-events or lineage fidelity (i.e., whether the subtype of the subsequent IBC matches the preceding DCIS), and it appears that the time to IBC diagnosis is shortest in Basal DCIS, while at the same time, lineage fidelity is lowest in Basal DCIS, as has been previously reported. Conclusions: Our subtype-stratified analyses identified multiple molecular differences both between intrinsic subtypes as well as between DCIS and IBC that suggest subtype-specific characteristics that may be exploitable for risk stratification of DCIS. Citation Format: Marija Debeljak, Soonweng Cho, Bradley Downs, Michael Considine, Brittany Avin-McKelvey, Yongchun Wang, William Grizzle, Katherine Hoadley, Charles Lynch, Brenda Hernandez, Paul van Diest, Wendy Cozen, Ann Hamilton, Debra Hawes, Edward Gabrielson, Ashley Cimino-Mathews, Liliana Florea, Leslie Cope, Christopher B. Umbricht. Multimodal genome-wide survey of progressing and non-progressing DCIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3126.

Abstract F1-2: Clonal evolution of DCIS to invasion

Abstract F1-2: Clonal evolution of DCIS to invasion

Abstract B014: Improving prediction of second events after DCIS using whole breast mammogram images

Abstract Purpose: We aim to improve prediction of subsequent events after DCIS. Current models show relatively poor performance predicting subsequent events and often are limited to ipsilateral events. National population-based SEER data including over160,000 cases of DCIS and followed an average of 90 months indicate that second events (including risk of invasive breast cancer – IBC) are equality likely in the ipsilateral and contralateral breast. Thus, additional information on risk may be obtained by more complete modeling of risk estimating recurrence. Mammographic images have been largely ignored despite evidence that even breast density improves prediction of breast cancer in the general population. Furthermore, we have shown whole breast mammogram images (WBI) included in Cox models significantly improves prediction of breast cancer risk over using mammographic breast density alone and breast cancer risk factors. Population: We retrieved digital mammograms for women diagnosed with DCIS at Washington University School of Medicine from 2008 onwards and followed for subsequent diagnosis of pathology confirmed breast lesions. Using more than 100 cases and controls matched on year of mammogram and age we fit Cox models to evaluate risk of ipsilateral invasive breast cancer. To compare and accommodate laterality of subsequent breast lesions, we fit competing risk models using baseline covariates that are available on the women-level as well as WBI that are side-specific. Results: Preliminary analysis shows WBI predicts subsequent invasive breast cancer. Further, we will demonstrate appropriate models adjusting for competing risk gives unbiased estimates of invasive breast cancer. Conclusion: WBI and competing risk analysis improves our understanding of associations for side of occurrence of subsequent breast lesions after an initial diagnosis of DCIS. Citation Format: Shu (Joy) Jiang, Graham A. Colditz. Improving prediction of second events after DCIS using whole breast mammogram images [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 B014.

Comprehensive multiplexed immune profiling of the ductal carcinoma in situ immune microenvironment regarding subsequent ipsilateral invasive breast cancer risk

BackgroundDuctal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.MethodsPatients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8− T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with multiplex immunofluorescence (mIF) with digital whole-slide analysis and compared between primary DCIS lesions of 77 women with subsequent iIBC (cases) and 64 without (controls).ResultsHigher stromal density of analysed immune cell subsets was significantly associated with higher grade, ER negativity, HER-2 positivity, Ki67 ≥ 14%, periductal fibrosis and comedonecrosis (P < 0.05). Density, composition and proximity to the closest DCIS cell of all analysed immune cell subsets did not differ between cases and controls.ConclusionIME features analysed by mIF in 141 patients from a well-annotated cohort of pure DCIS with long-term follow-up are no predictors of subsequent iIBC, but do correlate with other factors (grade, ER, HER2 status, Ki-67) known to be associated with invasive recurrences.

Abstract 686: Subsequent invasive breast cancer risk after DCIS treatment in multinational PRECISION consortium cohorts comprising 48,576 patients

Abstract Background: Although DCIS is a precursor of invasive breast cancer (IBC), most DCIS lesions never will progress. As we cannot distinguish reliably progressive from harmless DCIS yet, almost all women with DCIS are treated extensively with surgery and often adjuvant radiotherapy or endocrine treatment, implying overtreatment of many thousands of women with harmless DCIS. PRECISION aims to reduce such overtreatment by identifying factors associated with subsequent ipsilateral IBC. Many factors have been implicated in subsequent DCIS and IBC risk, but most studies relied on small series with limited prognostic power. To overcome this, we conducted pooled analyses of four large cohorts with DCIS from three different countries. Methods: Cohorts were pooled with data of 48,804 women with DCIS: a population-based cohort (NL, n=18,996), prospective, a population-based, screening cohort (Sloane, UK, n=8,462), a single center cohort (MDACC, USA, n=2,363), and a representative DCIS patient series from the National Cancer Database Special Study (USA, n=18,983). Patients with missing data on treatment and follow-up or follow-up shorter than six months were excluded from analyses. Risk of a subsequent ipsilateral invasive breast cancer (iIBC) was assessed in three DCIS lesion size groups (&amp;lt;20mm, 20-50mm and ≥50mm) and in patients who had clear surgical margins (&amp;lt;2mm) after final breast conserving surgery (BCS) versus patients who did not. Cox proportional hazards models were used to assess differences in risk of IBC, with a focus on DCIS size and margin status. Results: In final analyses, 48,576 patients, diagnosed between 1999 and 2017, were included. Median follow-up was 7.6 years (range 0.5-21.1). In multivariable analyses, patients with smaller size of DCIS (&amp;lt;20mm) had a decreased risk of iIBC compared with women with larger lesion size (HR 0.81; 95% CI 0.68-0.97). In 33,091 BCS treated patients, patients with clear surgical margins had a decreased risk of iIBC (HR 0.68; 95% CI 0.52-0.90). Conclusion: In our quest to reduce overtreatment for women with DCIS, we have identified free surgical margins and smaller lesion size as independent factors reducing the risk of subsequent ipsilateral invasive breast cancer, irrespective of the treatment received. Knowledge of these, and additional, factors could aid in selecting patients suitable for less invasive management strategies such as active surveillance or omitting radiotherapy. This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043); Web site: https://cancergrandchallenges.org/teams/precision Citation Format: Renee S. Schmitz, Alexandra W. van den Belt-Dusebout, Karen Clements, Yi Ren, Chiara Cresta, Jasmine Timbres, Yat-Hee Liu, Danalyn Byng, Thomas Lynch, Brian Menegaz, Deborah Collyar, Terry Hyslop, Michael Schaapveld, Elinor Sawyer, Shelley E. Hwang, Alastair Thompson, Marc D. Ryser, Jelle Wesseling, Esther H. Lips, Marjanka K. Schmidt, Grand Challenge PRECISION Consortium. Subsequent invasive breast cancer risk after DCIS treatment in multinational PRECISION consortium cohorts comprising 48,576 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 686.

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Abstract SY25-02: Double-edged “soil”: Stromal microenvironment in breast cancer development

Alcohol consumption, smoking, and invasive breast cancer risk after ductal carcinoma in situ.

Alcohol is an established risk factor for invasive breast cancer, and women with a prior ductal carcinoma in situ diagnosis are at higher risk of invasive breast cancer than the general population. However, for women with a prior ductal carcinoma in situ diagnosis, few studies have evaluated the association between alcohol and smoking and risk of subsequent invasive breast cancer. Utilizing a population-based case-control design nested among women diagnosed with a ductal carcinoma in situ between 1995 and 2013, we compared 243 cases diagnosed with a subsequent invasive breast cancer and 423 individually matched controls never diagnosed with a subsequent breast cancer. Compared with never to occasional drinkers, drinkers consuming at least 7 alcoholic drinks per week on average at ductal carcinoma in situ diagnosis had a higher risk of invasive breast cancer that was borderline significant (OR 1.79, 95% CI 1.01-3.17, P value = 0.04). Smoking was not significantly associated with risk of developing an invasive breast cancer after adjustment for alcohol consumption. These findings suggest that consuming at least one alcoholic drink per day on average is positively associated with invasive breast cancer for women with a prior ductal carcinoma in situ diagnosis. If confirmed, modulating alcohol consumption could be one strategy for women with a history of ductal carcinoma in situ to impact their risk of invasive breast cancer.

Abstract P1-22-05: Identifying predictors of invasive recurrence based on molecular profiles of DCIS lesions

Abstract Introduction Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Patients with DCIS are routinely treated by breast-conserving surgery often supplemented by radiotherapy, although many will never develop invasive disease. To date, no robust predictors of invasive breast cancer recurrence following DCIS have been identified. In our efforts to find such predictors, we performed gene expression, copy number and mutation analysis on two large DCIS cohorts with long-term follow-up. Methods Two nested case control series were analyzed, where cases are defined as DCIS with a subsequent invasive breast cancer and controls remained disease free during follow up. Cases and controls were matched on age and on follow up duration and were derived from two nation-wide cohort studies. The Sloane cohort is a prospective breast screening cohort from the UK, median follow up is 6 years (range 1-10). The Dutch cohort is population-based and had a median follow up of 13 years (range 2-23). We performed copy number analysis using CytoSNP array or low pass whole genome sequencing (lpWGS) on 310 controls and 196 cases, and RNA-seq on 295 controls and 206 cases. Results First analyses on the copy number data suggest that cases are genetically more aberrant with multiple regions of amplification compared to controls (p &amp;lt; 0.05). RNA-seq was used to classify DCIS into the PAM50 subtypes which did not appear to be predictive of recurrence. Initial RNA-seq analysis did not show consistent gene expression differences between cases and controls in the Sloane or Dutch cohorts, possibly explained by differences in clinical characteristics of the cohorts. A new computational method has been developed accounting for the differences in follow-up times, results will be presented at SABCS. Targeted sequencing revealed that the most common mutations were in PIK3CA and TP53, but there was no association with recurrence. Conclusion Only small molecular differences were identified between DCIS that recurs as invasive breast cancer and DCIS that remains disease-free. Currently, we are seeking to identify reproducible differences by a combined analysis of two population-based cohorts in a time dependent fashion. These will be presented at the SABCS. This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043) Citation Format: Tycho Bismeijer, Ahmed A Ahmed, Michael Sheinman, Maria Roman-Escorza, Vandna Shah, Jeffrey R Marks, Lorraine M King, Anargyros Megalios, Lindy L Visser, Marlous Hoogstraat, Helen R Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Nicholas N Navin, Andrew Futreal, Serena Nik-Zainal, Shelley Hwang, Esther H Lips, Alastair Thompson, Lodewyk FA Wessels, Elinor J Sawyer, Jelle Wesseling, Grand Challenge PRECISION Consortium. Identifying predictors of invasive recurrence based on molecular profiles of DCIS lesions [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-05.

Abstract P1-22-02: Subsequent risk of ipsilateral breast events in a multinational DCIS cohort of 48.619 patients: A meta-analysis within the PRECISION consortium

Abstract Background: The PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) CRUK Grand Challenge project focusses on discriminating hazardous from indolent ductal carcinoma in situ (DCIS). Aim of these analyses is to identify factors associated with a lower or higher risk of developing invasive breast cancer after an initial DCIS diagnosis. Knowledge of these factors is crucial in our quest to reducing overtreatment for women with DCIS. Many clinicopathological features are hypothesized to be important factors affecting the risk of a subsequent breast lesion. Most studies performed so far are from trial or single country studies, we now present an integrated analysis of four different cohorts from three countries.Methods: Four cohorts from the three countries participating in PRECISION were identified. A population based cohort from the Netherlands cancer registry (Dutch cohort); a population based, prospective, screening cohort from the United Kingdom (Sloane cohort); a single center cohort from MD Anderson Cancer Center (MDACC) and a subset of DCIS patients abstracted from a population based National Cancer Database Special Study cohort (NCDB subset) in the United States. Patient-level data from these cohorts were combined for this analysis. Subsequent ipsilateral invasive breast cancer (iIBC) and subsequent ipsilateral DCIS (iDCIS) were assessed at five and ten years by Kaplan Meier analysis. The cumulative incidence of iIBC was assessed in three treatment groups: breast conserving surgery only (BCS), breast conserving surgery with radiotherapy (BCS+RT) and mastectomy (MST). Cumulative incidence of iDCIS was assessed in patients receiving BCS or BCS+RT. Additionally, cumulative incidences were calculated for iIBC and IDCIS in patients who received endocrine treatment (ET) after BCS or BCS+RT versus patients who did not receive ET. All cumulative incidences were calculated with death as competing risk. Results: The joint PRECISION cohort consisted of 48,619 patients, diagnosed between 1999 and 2017. Median follow-up was 7.4 years (0.6-17.9). In preliminary analyses, Kaplan Meier curves showed broadly similar risks in iIBC and iDCIS between the four different cohorts. The cumulative incidence of iIBC was 1.6% at five years and 3.5% at 10 years. Five-year cumulative incidence of iIBC was highest in patients receiving BCS (3.4%) compared with patients receiving BCS+RT or MST (1.3%). The cumulative incidence of iDCIS was 1.7% at 5 years and 2.4% at 10 years. Five-year cumulative incidence of iDCIS was higher in patients receiving BCS (3.5%) compared to patients receiving BCS+RT (1.9%). In univariate analyses, the effect of ET on cumulative incidence of both iIBC and iDCIS was modest, especially with respect to radiotherapy. Conclusion: Overall, 5- and 10-year incidence of an ipsilateral in situ or invasive breast lesion was low and similar between the four different cohorts. The incidence of iIBC and iDCIS was higher in patients receiving BCS, compared to women receiving BCS+RT or MST. Table 1.Cohort and patient characteristicsDutch Cohort Sloane MDACCNCDB subsetTotal CohortN=18,995N=8,425N=1,820N=19,379N=48,619Cohort descriptionProspectiveNoYesNoNoPopulation basedYesYesNo, single centerYesScreening and non-screeningYesScreening onlyYesYesMean (min - max)Mean (min - max)Mean (min - max)Mean (min-max)Mean (min-max)Age diagnosis DCIS58.3 (21-94)59.8 (46-88)55.6 (20-90)59.7 (20-98)59.0 (20-98)Year of diagnosis (range)1999-20152003-20121999-20172007-20151999-2017Follow-up in years10.4 (0.5-21.1)5.3 (0.5-9.7)8.7 (0.25-17.8)5.8 (0.5-10.7)7.6 (0.25-2.1)N (%)N (%)N (%)N (%)N (%)GradeGrade 12,844 (15.0)784 (9.3)141 (7.8)3,158 (16.3)6,927 (14.3)Grade 25,952 (31.3)2,328 (27.6)737 (40.5)6,844 (35.3)15,861 (32.6)Grade 38,944 (47.1)5,305 (62.9)933 (51.3)7,848 (40.5)23,030 (47.3)Unknown grade1,255 (6.6)8 (0.1)9 (0.5)1,529 (7.9)2,801 (5.8)Type of surgeryBreast conserving surgery (BCS)11,790 (62.1)5,830 (69.2)1,031 (56.7)14,504 (74.8)33,155 (68.2)Mastectomy (MST)7,205 (37.9)2,595 (30.8)789 (43.4)4,875 (25.2)15,464 (31.8)Adjuvant treatmentRadiotherapy (RT)9,650 (50.8)3,418 (40.6)762 (41.9)10,620 (54.8)24,450 (50.3)Endocrine treatmentNA1,151 (13.6)999 (54.9)8,849 (45.7)10,999 (37.0)5 years Cumulative IncidencesiIBC1.4%2.3%1.6%1.7%1.6%iDCIS1.5%2.0%1.6%1.7%1.7%Vital statusAlive16,472 (86.7)8,147 (96.7)1,668 (91.7)18,161 (93.7)44,448 (91.4)Deceased2,523 (13.3)278 (3.3)152 (8.4)1,218 (6.3)4,171 (8.6)This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043) Citation Format: Renée SJM Schmitz, Sandra W van den Belt-Dusebout, Chiara Cresta, Yat-Hee Liu, Michael Schaapveld, Karen Clements, Jasmine Timbres, Danalyn T Byng, Marc D Ryser, Yi Ren, Thomas Lynch, Terry Hyslop, Brian Menegaz, Deborah Collyar, Shelley Hwang, Alastair Thompson, Elinor Sawyer, Jelle Wesseling, Esther H Lips, Marjanka K Schmidt, Grand Challenge PRECISION consortium. Subsequent risk of ipsilateral breast events in a multinational DCIS cohort of 48.619 patients: A meta-analysis within the PRECISION consortium [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-02.

Breast screening atypia and subsequent development of cancer: protocol for an observational analysis of the Sloane database in England (Sloane atypia cohort study)

IntroductionThe National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would...

Racial and Ethnic Disparities in Rates of Invasive Second Breast Cancer Among Women With Ductal Carcinoma In Situ in Hawaiʻi

Women with ductal carcinoma in situ (DCIS) may develop a subsequent invasive second breast cancer (SBC). Understanding the association of racial and ethnic factors with the development of invasive SBC may help reduce overtreatment and undertreatment of women from minority groups. To evaluate risk factors associated with developing invasive ipsilateral SBC (iiSBC) and invasive contralateral SBC (icSBC) among women with an initial diagnosis of DCIS who are from racial and ethnic minority populations. This retrospective cohort study used deidentified data from the Hawai'i Tumor Registry of 6221 female Hawai'i residents aged 20 years or older who received a diagnosis of DCIS between January 1, 1973, and December 31, 2017. The 5 most populous ethnic groups were compared (Chinese, Filipino, Japanese, Native Hawaiian, and White). Data analysis was performed from 2020 to 2021. Patient demographic and clinical characteristics and the first course of treatment. The a priori study outcome was the development of invasive SBC. Logistic regression was used to identify factors associated with invasive SBC. Factors that were significant on unadjusted analyses were included in the adjusted models (ie, age, race and ethnicity, diagnosis year, DCIS histologic characteristics, laterality, hormone status, and treatment). The racial and ethnic distribution of patients with DCIS across the state's most populous groups were 2270 Japanese women (37%), 1411 White women (23%), 840 Filipino women (14%), 821 Native Hawaiian women (13%), and 491 Chinese women (8%). Women of other minority race and ethnicity collectively comprised 6% of cases (n = 388). A total of 6221 women (age range, 20 to ≥80 years) were included in the study; 4817 (77%) were 50 years of age or older, 4452 (72%) received a diagnosis between 2000 and 2017, 2581 (42%) had well or moderately differentiated histologic characteristics, 2383 (38%) had noninfiltrating intraductal DCIS, and 2011 (32%) were treated with mastectomy only. Of these 6221 women, 444 (7%) developed invasive SBC; 190 developed iiSBC (median time to SBC diagnosis, 7.8 years [range, 0.5-30 years]) and 254 developed icSBC (median time to SBC diagnosis, 5.9 years [range, 0.5-28.8 years]). On adjusted analysis, women who developed iiSBC were more likely to be younger than 50 years (adjusted odds ratio [aOR], 1.49; 95% CI, 1.08-2.06), Native Hawaiian (aOR, 3.28; 95% CI, 2.01-5.35), Filipino (aOR, 1.94; 95% CI, 1.11-3.42), Japanese (aOR, 1.58; 95% CI, 1.01-2.48), and untreated (aOR, 2.29; 95% CI, 1.09-4.80). Compared with breast-conserving surgery (BCS) alone, there was a decreased likelihood of iiSBC among women receiving BCS and radiotherapy (aOR, 0.45; 95% CI, 0.27-0.75), BCS and systemic treatment with or without radiotherapy (aOR, 0.40; 95% CI, 0.23-0.69), mastectomy only (aOR, 0.23; 95% CI, 0.13-0.39), and mastectomy and systemic treatment (aOR, 0.57; 95% CI, 0.33-0.96). Women who developed an icSBC were more likely to be Native Hawaiian (aOR, 1.69; 95% CI, 1.10-2.61) or Filipino (aOR, 1.70; 95% CI, 1.10-2.63). Risk of both iiSBC and icSBC decreased in the later years of diagnosis (2000-2017) compared with the earlier years (1973-1999). This study suggests that Native Hawaiian and Filipino women who initially received a diagnosis of DCIS were more likely to subsequently develop both iiSBC and icSBC. Japanese women and younger women were more likely to develop iiSBC. Subpopulation disaggregation may help guide clinical treatment and screening decisions for at-risk subpopulations.

Patterns of aggressiveness: risk of progression to invasive breast cancer by mammographic features of calcifications in screen-detected ductal carcinoma in situ.

Mammographic features of calcifications on mammograms showing invasive breast cancer are associated with survival. Less is known about mammographic features and progression to invasive breast cancer among women treated for ductal carcinoma in situ (DCIS). To investigate mammographic features of calcifications in screen-detected DCIS in women who later did and did not get diagnosed with invasive breast cancer. This registry-based nested case-control study analyzed data from women with screen-detected DCIS in BreastScreen Norway, 1995-2016. Within this cohort of women with DCIS, those who were later diagnosed with invasive breast cancer (cases) were matched (1:2) to women who were not diagnosed with invasive breast cancer (controls) after their DCIS and by the end of 2016. Information on mammographic features were collected by a national radiological review, where screening mammograms were reviewed locally at each of the 16 breast centers in Norway. We used conditional logistic regression analysis to estimate associations between mammographic features of calcifications in the DCIS mammogram and the risk of subsequent invasive breast cancer. We found a higher risk of invasive breast cancer associated with fine linear branching (casting) morphology (odds ratio 20.0; 95% confidence interval [CI] 2.5-158.9) compared to fine linear or fine pleomorphic morphology. Regional or diffuse distribution showed an odds ratio of 2.8 (95% CI 1.0-8.2) compared to segmental or linear distribution. Mammographic features of calcifications in screen-detected DCIS were of influence on the risk of invasive breast cancer. Unfavorable characteristics of DCIS were fine linear branching morphology, and regional or diffuse distribution.

Bisphosphonate Use and Breast Cancer Risk among Women with Ductal Carcinoma In Situ

Women with a history of ductal carcinoma in situ (DCIS) have an elevated risk of a subsequent invasive breast cancer, but there are few established potentially modifiable factors known to lower this risk. Bisphosphonates are a commonly used treatment for patients with osteoporosis and have been shown to lower risks of recurrence and mortality in patients with invasive breast cancer; however, their use has not previously been investigated within the context of DCIS. Utilizing a population-based nested case-control design, we compared 301 cases of women diagnosed with DCIS and a subsequent breast cancer and 587 individually matched controls (on age, DCIS diagnosis year, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but never a subsequent breast cancer. Information on recency and duration of bisphosphonate use was ascertained from patient interviews and medical record reviews. Current users of bisphosphonates had a reduced risk of developing an invasive breast cancer compared with never users [OR = 0.50; 95% confidence interval (CI): 0.26-0.99]. Users of bisphosphonates for ≥48 months had a similar reduction in risk (OR = 0.45; 95% CI, 0.24-1.06). This is the first study to document that bisphosphonate use is associated with a lower risk of subsequent invasive breast cancer among women with a history of DCIS. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. If validated by others, bisphosphonates may be an effective risk-reducing approach with the potential added benefits of its positive impacts on bone health and fracture risk. SIGNIFICANCE: This study finds that bisphosphonate use among women with a history of DCIS is associated with lower risk of subsequent invasive breast cancer, providing a potential preventative approach for this high-risk population.

Risk for Invasive Cancers in Women With Breast Cancer In Situ: Results From a Population Not Covered by Organized Mammographic Screening

BackgroundEven though breast cancer in situ (BCIS) incidence has been increasing, the prognosis of BCIS patients has not been extensively investigated. According to the literature, women with BCIS have a higher risk of developing subsequent invasive breast cancer; conflicting information has been reported regarding their potential risk for a subsequent invasive non-breast cancer.MethodsData from 1,082 women, whose first-ever cancer diagnosis was primary BCIS between 2003 and 2015 and were living in the canton of Zurich, were used. Standardized incidence ratios (SIRs) were calculated to compare the risk of an invasive breast or non-breast cancer among women with a primary BCIS with the corresponding risk of the adult female population. SIRs were calculated overall and by patient and tumor characteristics. To investigate potential risk factors (e.g., age at diagnosis, treatment) for a subsequent invasive breast or non-breast cancer we used Cox proportional hazards regression models.ResultsBCIS patients had 6.85 times [95% confidence interval (CI): 5.52–8.41] higher risk of being diagnosed with invasive breast cancer compared to the general population. They additionally faced 1.57 times (95% CI: 1.12–2.12) higher risk of an invasive non-breast cancer. The SIRs were higher for women < 50-years old for both invasive breast and non-breast cancer at BCIS diagnosis. Age ≥ 70-years old at BCIS diagnosis was statistically significantly associated with a subsequent invasive non-breast cancer diagnosis.ConclusionsBCIS patients had a higher risk of being diagnosed with invasive breast and non-breast cancer compared to the general population. Age 70 years or older at BCIS diagnosis was the only risk factor statistically significantly associated with a subsequent invasive non-breast cancer. Our results support the increased risk for subsequent cancers in BCIS patients reported in the literature. Future studies should establish the risk factors for subsequent cancers, highlight the need for intensive monitoring in this population, and help distinguish BCIS patients who could benefit from systemic therapy to prevent distant cancers.

Abstract PD5-02: Dcis as a risk lesion for invasive breast cancer and death from other cancers

Abstract Introduction: Ductal carcinoma in situ (DCIS) is considered a non-obligatory precursor of invasive breast cancer. Using a prospective cohort study of screen detected non-invasive neoplasia from a national breast screening program, this analysis examined subsequent DCIS or invasive cancers and death due to other cancers or other causes. Methods: Prospective data on 9191 screen detected non-invasive breast neoplasia with a median 9.2 years follow up was matched to a subsequent diagnosis of invasive breast cancer or death from another primary, non-breast cancer at any site or other cause of death, cross validating data from the National Cancer Registry, Hospital Episode Statistics and mortality data. Results: Following a diagnosis of screen detected DCIS, in 9191 women, for those undergoing breast conservation surgery (BCS), 413 women developed ipsilateral invasive breast cancer, at a proportion of 5/1000 per annum consistent over a decade and more. By contrast DCIS re-occurances in the same, conserved, breast (in 222 women) occurred at a similar rate for the first 5 years then the rate halved beyond 5 years. Contralateral breast cancer (DCIS or invasive) occurred in 431 women over the same time period. Mortality occurred in 1062/9191 (11.6%) women, attributed to breast cancer in 130/1062 (12.2%) and due to cancer at other sites in 397/1062 (37.4%). Death from other, non-breast, cancers was predominantly from primaries of the lung (98 women), ovary (43), pancreas (37) and colon (23) and rarely associated with a confounding diagnosis of invasive breast cancer (present in only 8% of those patients). Non-cancer mortality was identified in 496/1062 (46.7%) women, most commonly attributed to cardiovascular disease (in 188 women) or disease of the respiratory system (in 93). Conclusion: Screen detected DCIS is a marker for subsequent invasive breast cancer, but mortality from other, non-breast, cancers following treatment for DCIS is three times more likely than death due to breast cancer, suggesting DCIS is a more general marker for subsequent cancers than hitherto recognized. Awareness of, and potentially screening for, other cancers should be considered in women treated for DCIS. Citation Format: Alastair Thompson, Bridget Hilton, Joanna Dulson-Cox, Karen Clements, Sloane Project NHS Breast Screening Group. Dcis as a risk lesion for invasive breast cancer and death from other cancers [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 PD5-02.

Infiltrating immune cells in benign breast disease and risk of subsequent invasive breast cancer

BackgroundIt is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer.MethodsUsing a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk.ResultsThere was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96–1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96–1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking.ConclusionThe results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.