Ductal Carcinoma In Situ Breast Cancer Research Articles

Association of residual ductal carcinoma in situ with breast cancer treatment outcomes after neoadjuvant chemotherapy according to hormone receptor status

PurposeThis research aimed to clarify the impact of residual ductal carcinoma in situ(DCIS) in surgical specimens obtained after neoadjuvant chemotherapy(NAC) for breast cancer on the associated prognosis outcomes.MethodsThis retrospective study was performed on a cohort of 1,009 patients who achieved pCR following NAC for breast cancer and underwent subsequent breast surgery at a single institution between January 2008 and December 2019. Overall survival, local recurrence-free survival, distant metastasis-free survival, and disease-free survival of the residual and non-residual DCIS groups were the outcomes compared, with further subgroup analysis performed according to hormone receptor status. Results260 individuals (25.8%) presented with residual DCIS. Based on a median follow-up of 54.0 months, no significant differences in outcomes were observed between the two groups. Patients with residual DCIS and hormone receptor-negative (HR-) breast cancer demonstrated a significant decrease in distant metastasis-free survival (p = 0.030) compared to those without residual DCIS. In the HR + cohort, no significant difference was observed between the two groups. Multivariate analysis of the HR- cohort demonstrated a significant association between residual DCIS and an elevated risk for distant recurrence (hazard ratio = 2.3, 95% confidence interval = 1.01–5.20, p = 0.047).ConclusionsResidual DCIS following NAC may impact breast cancer outcomes, particularly with respect to the occurrence of distant metastasis in HR- patients. Therefore, clinicians must vigilantly monitor patients with residual DCIS after NAC, and further research is needed to expand our understanding of the clinical implications of residual DCIS.

Endocrine therapy initiation among women diagnosed with ductal carcinoma in situ breast cancer from 2001-2016.

487 Background: Endocrine therapy (ET) initiation in people within 1 year of diagnosis of estrogen-receptor-positive (ER+) ductal carcinoma in situ (DCIS) has ranged from 21-45% in prior studies; however, these studies did not evaluate initiation post-2011 and may not reflect current patterns of use. ET use following ER+ DCIS diagnosis can reduce the relative risks of recurrence and contralateral breast cancer by 30-50%. We evaluated ET initiation over time and by demographic, tumor, and treatment characteristics in the Kaiser Permanente Breast Cancer Survivors Study between 2001-2016. Methods: We included people aged 20+ years diagnosed with unilateral DCIS with at least 1 year of cancer-free follow-up from three U.S. integrated health systems. We excluded people with ER-negative disease, no surgery, and those who received chemotherapy or unknown radiation therapy. ET dispensings (tamoxifen and aromatase inhibitors) were extracted from electronic pharmacy records within 1 year of a person’s initial DCIS breast cancer diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated relative rates (RRs) of ET use (vs none) over time and by demographic, tumor, and other treatment characteristics. Results: Among 1,782 pre- and postmenopausal people, 577 (32%) initiated ET within 1 year of diagnosis. From 2001-2016, ET use did not change over time (34% vs 36%), tamoxifen use declined slightly (34% vs 29%), and aromatase inhibitor use increased slightly (0% vs 7%). People were less likely to initiate ET if they were ≥65 years, Black, had borderline or unknown ER status, were not tested for ER, had breast conserving surgery (BCS) without radiation, or had a unilateral mastectomy. Conclusions: Only one-third of people with DCIS diagnosed in a community healthcare setting and potentially eligible for ET, initiated treatment within 1 year of their diagnosis. Previous studies have shown long-term benefits of ET use in people with DCIS; however, we saw no increase in use over time. Concerns about side-effects, overdiagnosis and overtreatment of DCIS, and confusion about treatment guidelines may explain relatively low ET initiation.[Table: see text]

Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events.

Evidence from randomized clinical trials (RCTs) shows that receipt of hormonal therapy after surgery for estrogen receptor-positive ductal carcinoma in situ (DCIS) reduces the risk of DCIS and contralateral invasive breast cancer (IBC) but not death from breast cancer. RCTs examined homogeneous samples, and therefore whether this evidence can be generalized to diverse populations is unclear. Population-based data from four state cancer registries (California, New Jersey, New York, and Texas) were analyzed on women aged 65 years and older newly diagnosed with DCIS who underwent surgery with or without radiation during the years 2006-2013. Registry records were merged with Medicare enrollment in Parts A and/or B and D (prescription drugs) and associated claims. Whether adherence to hormonal therapy was associated with adverse breast cancer-related health events was analyzed. Achieving excellent adherence did not affect death from breast cancer. In contrast, the risk of developing a subsequent breast tumor was 6.24 percentage points (breast-conserving surgery [BCS] with radiation therapy [RT]) and 10.54 percentage points (BCS alone) lower for women with excellent versus low adherence (p<.00001). For excellent versus good adherence, the reduced risk among women who had BCS with and without RT was approximately 3 and 5 percentage points, respectively. A similar pattern emerged for the risk of IBC among women who achieved excellent versus good or low adherence, whereas good versus low adherence comparisons were not significant. This analysis of a diverse population-based cohort of women with DCIS demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors. Our analysis of a diverse population-based cohort of women with ductal carcinoma in situ demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors.

An MRI-Based Radiomics Nomogram to Distinguish Ductal Carcinoma In Situ with Microinvasion From Ductal Carcinoma In Situ of Breast Cancer

Accurate preoperative differentiation between ductal carcinoma in situ with microinvasion (DCISM) and ductal carcinoma in situ (DCIS) could facilitate treatment optimization and individualized risk assessment. The present study aims to build and validate a radiomics nomogram based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) that could distinguish DCISM from pure DCIS breast cancer. MR images of 140 patients obtained between March 2019 and November 2022 at our institution were included. Patients were randomly divided into a training (n=97) and a test set (n=43). Patients in both sets were further split into DCIS and DCISM subgroups. The independent clinical risk factors were selected by multivariate logistic regression to establish the clinical model. The optimal radiomics features were chosen by the least absolute shrinkage and selection operator, and a radiomics signature was built. The nomogram model was constructed by integrating the radiomics signature and independent risk factors. The discrimination efficacy of our nomogram was assessed by using calibration and decision curves. Six features were selected to construct the radiomics signature for distinguishing DCISM from DCIS. The radiomics signature and nomogram model exhibited better calibration and validation performance in the training (AUC 0.815, 0.911, 95% confidence interval [CI], 0.703-0.926, 0.848-0.974) and test (AUC 0.830, 0.882, 95% CI, 0.672-0.989, 0.764-0.999) sets than in the clinical factor model (AUC 0.672, 0.717, 95% CI, 0.544-0.801, 0.527-0.907). The decision curve also demonstrated that the nomogram model exhibited good clinical utility. The proposed noninvasive MRI-based radiomics nomogram model showed good performance in distinguishing DCISM from DCIS.

Abstract A003: Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes

Abstract Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) &amp;gt;2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [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 A003.

Clinical value of contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: a population-based cohort study

ObjectivesFor patients with ductal carcinoma in situ (DCIS), data about the impact of breast MRI at primary diagnosis on the incidence and characteristics of contralateral breast cancers are scarce.MethodsWe selected all 8486 women diagnosed with primary DCIS in the Netherlands in 2011–2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS (cDCIS) and contralateral invasive breast cancer (cIBC) was assessed for patients who received an MRI upon diagnosis (MRI group) and for an age-matched control group without MRI.ResultsNineteen percent of patients received an MRI, of which 0.8% was diagnosed with synchronous cDCIS and 1.3% with synchronous cIBC not found by mammography. The 5-year cumulative incidence of synchronous plus metachronous cDCIS was higher for the MRI versus age-matched control group (2.0% versus 0.9%, p = 0.02) and similar for cIBC (3.5% versus 2.3%, p = 0.17). The increased incidence of cDCIS was observed in patients aged < 50 years (sHR = 4.22, 95% CI: 1.19–14.99), but not in patients aged 50–74 years (sHR = 0.89, 95% CI: 0.41–1.93).ConclusionsMRI at primary DCIS diagnosis detected additional synchronous cDCIS and cIBC, and was associated with a higher rate of metachronous cDCIS without decreasing the rate of metachronous cIBC. This finding was most evident in younger patients.Key Points• Magnetic resonance imaging at primary diagnosis of ductal carcinoma in situ detected an additional synchronous breast lesion in 2.1% of patients.• In patients aged younger than 50 years, the use of pre-operative MRI was associated with a fourfold increase in the incidence of a second contralateral DCIS without decreasing the incidence of metachronous invasive breast cancers up to 5 years after diagnosis.• In patients aged over 50 years, the use of pre-operative MRI did not result in a difference in the incidence of a second contralateral DCIS or metachronous invasive breast cancer.

Presence of Non-classic LCIS Is Not a Contraindication to Breast Conservation in Patients with Concomitant Invasive Breast Cancer or DCIS.

Non-classic lobular carcinoma in situ (NC-LCIS) represents a spectrum of lesions, histologically distinct from classic LCIS (C-LCIS) and ductal carcinoma in situ (DCIS). Several studies have reported on the safety of breast conservation (BCS) in patients with DCIS or invasive breast cancer and concomitant C-LCIS, yet there are no data addressing this question for patients with concomitant NC-LCIS. We evaluated local recurrence (LR) after BCS in patients with DCIS or invasive cancer and concomitant NC-LCIS. We searched institutional databases using natural language processing to identify patients with DCIS or invasive breast cancer and concomitant NC-LCIS treated with BCS between 2000 and 2015. Charts were reviewed to collect demographics, disease and treatment details, and recurrence events. All results represent descriptive analyses. We identified 71 patients with DCIS (n = 13) or invasive cancer (n = 58) and concomitant NC-LCIS treated with BCS. Median patient age was 59 years (33-77 years), and median invasive tumor size was 1.2 cm (0.1-6.9 cm); 62% of DCIS and 79% of invasive cancer patients had hormone receptor (HR)-positive disease. Among DCIS patients, seven (54%) received radiation and none hormonal therapy. Among those with invasive cancer, 52 (90%) received radiation, 17 (29%) received chemotherapy and 44 of 55 with HR-positive disease (78%) received hormonal therapy. At median follow-up of 79 months (1-265 months), the LR rate was 8% and 2% among patients with DCIS and invasive cancer, respectively. NC-LCIS is rarely present in association with DCIS or invasive cancer, and it does not appear to impact LR outcomes following BCS.

Abstract 3380: Seven autoantibody panel, validated in two independent patient serum collections, can detect women with DCIS and invasive breast cancer

Abstract Mammography is essential to identify early breast cancer but the sensitivity is dependent on breast characteristics. A serum-based biomarker used along with mammography to identify lesions that need to be biopsied may improve the sensitivity of mammography and reduce the number of biopsies needed. We have identified a panel of autoantibodies found in early breast cancer. An autoantibody biomarker is ideal because antibody immunity can be detected with very low levels of antigen with direct antigen recognition by B cells resulting in clonal amplification of antigen specific plasma cells. Work in our laboratory has identified tumor-associated proteins present in pre-malignant tumors that are necessary for survival of human breast cancer cells across breast cancer subtypes. Increased autoantibodies to seven of these early tumor-associated proteins (PDIA6, KRT8, SERBP1, ARPC2, RRM2, AURKA, and NDC80) were present in the sera of women with DCIS and invasive breast cancer in two independent serum collections but not in control women with no known breast lesions. The presence of autoantibodies in the discovery set was evaluated in 185 individuals: 42 control women, 12 women with hyperplasia, 36 patients with fibroadenoma, 59 patients with ductal carcinoma in situ (DCIS), and 36 patients with invasive breast cancer (IBC). The validation set was evaluated in 228 individuals: 50 control patients, 50 patients with fibroadenoma, 18 patients with hyperplasia, 50 patients with DCIS, and 60 patients with IBC, 20 with hormone receptor positive (HR+) HER2 negative, 20 with HER2+, and 20 triple negative (TN). We defined a positive autoantibody response as over 2 standard deviations above the mean found in control women. All seven autoantibodies could predict patients with hyperplasia, fibroadenoma, DCIS, and IBC in both the discovery and validation sets. For example, the seven-antibody panel could identify DCIS from control women with AUC of 0.95 (95% CI 0.912 to 0.995, p&amp;lt;0.0001) and validation set AUC 0.63 (95% CI 0.52 to 0.74, p=0.026). The seven-antibody panel could identify IBC from control women with AUC of 0.85 (95% CI 0.73 to 0.97, p&amp;lt;0.0001) and validation 0.70 (95% CI 0.60 to 0.79, p&amp;lt;0.0001). Furthermore, the seven-antibody panel could identify women with each of the breast cancer subtypes as compared to control women. Women with HR+HER2- breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83 p=0.014), women with HER2+ breast cancer could be detected with AUC 0.69 (95% CI 0.52 to 0.90, p=0.02), and women with triple negative breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83, p=0.002) in the validation set. Future studies will evaluate this panel in a prospective study at the time of mammography to identify a serum biomarker that will improve sensitivity of mammography. Citation Format: Sasha Elizabeth Stanton, Jason Schlumbohm, Erik Ramos, Charles Drescher, Jeffrey Marks, Mary L. Disis. Seven autoantibody panel, validated in two independent patient serum collections, can detect women with DCIS and invasive breast cancer [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 3380.

Abstract 2979: ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer

Abstract Background: Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives a subset of luminal DCIS to transition to basal invasive breast cancers is unclear. Basal-like invasive breast cancers are aggressive and associated with the shortest overall survival and time to distant metastasis. We have previously shown that N-Ras is highly expressed selectively in the basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers. Methods: Wilcoxon rank-sum test was conducted to assess the relative expression of NRAS in DCIS compared to invasive breast cancers in a patient cohort (GSE59248). NRAS levels were also determined by fluorescence in situ hybridization (FISH) in a collection of 21 patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and NRAS’s association with DCIS and invasive breast cancer was assessed by Wilcoxon signed rank test. How NRAS levels correlated with basal biomarkers in the TMAs, as well as in patient datasets GSE59248 and GSE3369 was determined by Pearson correlation. Gene expression changes in cell line were assessed by RNA-seq. Results: Invasive breast cancers showed higher NRAS mRNA levels, as compared to DCIS samples. These NRAShigh lesions were also enriched with basal-like features, such as basal gene expression signature, lower ER, higher p53 protein levels, and higher Ki67 levels. We have shown previously that N-Ras is a driver for tumor growth in SUM102 cells, which is a DCIS-like cell line model displaying basal-like features. Here we found that NRAS-silencing in these cells induced a shift to a luminal gene expression pattern as determined by PAM50. Conclusions: These data suggest that the rise of N-RAS levels in DCIS can not only mark but also control the emergence of basal-like features leading to more aggressive tumor activities. Targeting N-Ras and/or its downstream pathway may prevent the emergence of basal invasive breast cancers. Citation Format: Ze-yi Zheng, Hanan Elsarraj, Yang Hong, Jonathan T. Lei, Meenakshi Anurag, Yichao Shen, Flora Lo, Long Feng, Zifan Zhao, Xiang H. Zhang, Fariba Behbod, Eric C. Chang. ElevatedNRASexpression as a potential driver of DCIS progression to basal-like invasive breast cancer [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 2979.

Mode of detection of second breast cancers in patients undergoing surveillance after treatment of ductal carcinoma in situ.

571 Background: The incidence of ductal carcinoma in situ (DCIS) has increased, resulting in more women undergoing post-treatment surveillance for second breast cancers. National Comprehensive Cancer Network (NCCN) guidelines recommend annual breast imaging and physical exam every 6-12 months for five years, and then annually. We assessed mode of detection (imaging, patient-reported, or physical exam) of secondary DCIS and/or invasive breast cancer in a large cohort of DCIS patients undergoing surveillance after treatment of primary DCIS. Methods: We performed a retrospective cohort study of DCIS patients treated between 1/1/2008 and 1/1/2011 within a large integrated health care system. Patients had a minimum of 5 years of follow up. Patient demographics, treatment for primary DCIS, and tumor characteristics (of both primary DCIS and secondary cancer) were obtained from the electronic health record or from manual chart review. Chart review also included mode of detection of secondary breast cancers. Results: Our study cohort consisted of 1561 women with DCIS, with a median age of 59 years (range 32-92) at time of diagnosis. Among initial DCIS tumors, tumor grade was low/intermediate in 942 (60.3%) and high in 619 (39.7%); 1274 (81.6%) were estrogen receptor positive, and 988 (63.3%) progesterone receptor positive. Surgical treatment for the initial DCIS included lumpectomy (n=1134, 72.6%), unilateral mastectomy (n=320, 20.5%), or bilateral mastectomy (n=61, 3.9%), and included sentinel lymph node biopsy in 211 (14%) of patients. Additionally, 691 (44.3%) received radiation therapy and 440 (28.2%) received endocrine therapy. The cohort was followed for a median of 120 months, during which we identified 179 women (11.5%) with a secondary cancer detected at a median time of 57 months. Of the second breast cancers, 77 (43.0%) were ipsilateral, 98 (54.8%) contralateral, and 4 (2.2%) presented with distant metastases; 110 (61.5%) were invasive, 65 (36.3%) were DCIS, and 4 (2.2%) Paget’s disease. See table for mode of detection of second breast cancers. Conclusions: In our cohort of patients undergoing surveillance following initial diagnosis and treatment of DCIS, 2% of secondary breast cancers were detected by clinical breast exam, a rate similar to incidental detection at time of plastic surgery. These results can help inform future recommendations for surveillance of second breast cancers in DCIS patients. [Table: see text]

Clinicopathological characteristics and prognostic analysis of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) and DCIS with microinvasion (DCIS-Mi) of the breast

ObjectiveOur purpose is to evaluate the correlation of TILs with clinicopathological characteristics and disease free survival (DFS) in DCIS and DCIS-Mi breast cancer (BC) patients.MethodsWe retrospectively reviewed the data of 360 DCIS patients and 125 DCIS-Mi patients treated by a single institution from 2016 to 2019. TILs are regarded as continuous variables and are divided into low (≤ 5%), medium (5–40%) and high (≥ 40%) for statistical analysis.ResultsIn DCIS and DCIS-Mi patients, larger tumor size, higher nuclear grade, hormone receptor (HR) negativity and human epidermal growth factor receptor 2(HER2) overexpression are all related to high TILs (P < 0.05). In addition, compared with DCIS, DCIS-Mi patients were significantly associated with high TILs (P < 0.001). Based on the different results of the subtypes, we further studied the correlation between TILs and DFS in 279 cases of HER2+ patients (204 of DCIS; 75 of DCIS-Mi). In HER2+ group, DCIS-Mi was significantly associated with HR negativity (P = 0.015) and high TILs (P = 0.002) compared with DCIS patients. In the survival analysis, we found that TILs had no effect on the DFS of DCIS (P = 0.938), DCIS-Mi (P = 0.807), and HER2+ (P = 0.379) BC patients. In the univariate and multivariate cox regression analysis, the correlation between TILs and the prognosis of DFS has not been confirmed in the three BC groups (P > 0.05).ConclusionTILs have played an non-negligible role in the progress of DCIS to DCIS-Mi, especially in HER2+ BC. The predictive and prognostic value of TILs still needs further research to confirm.

Abstract P5-08-03: Intraductal administration of a Transferrin Receptor-directed immunotoxin eliminates ductal carcinoma in situ in preclinical mammary in-duct (MIND) models of breast cancer

Abstract Background: Increased detection of ductal carcinoma in situ (DCIS) has been a consequence of mammographic screening. Currently there is a reappraisal of the necessity of aggressive treatment, with their attendant toxicities for a preneoplastic lesion with 15-20% chance of recurrence or progression. The recombinant immunotoxin, TFR(fv)PE40, binds to the abundantly expressed transferrin receptors on cancer cells, is internalized, processed and trafficked to the cytosol. The released Pseudomonas exotoxin (PE) catalyzes the transfer of ADP-ribose from NAD to elongation factor 2 (EF2), inactivates EF2, and leads to an arrest in protein translation, and cell death by apoptosis. However, TFR(fv)PE40 is toxic to liver cells. We hypothesized that, when administered via the opening at the mammary teat, the immunotoxin will destroy preneoplasias in the entire ductal tree. Because of the closed nature of the ductal system, the toxic effects of the TFR(fv)PE40 will be confined to the tumor cells alone, and systemic effects will be minimal or absent. The intraductal approach, we proposed, will provide a direct, safe and effective treatment for DCIS. Methods: We tested this concept in two models of DCIS using two luc-tagged cell lines-SUM225-luc, derived from a human DCIS, and in MCF-7-luc. In both cell lines, the IC50 of the toxin was in the nM range. DCIS develop within one week in MIND models following intraductal (i.duc) injection of tumor cells (right and left 4th mammary gland) of ex-breeder NSG mice. DCIS progressed to invasive cancer in 2-3 weeks. At day 7, mice were administered vehicle, TFR mAb alone, or the HB21(fv)PE40 conjugate at two doses (0.15 or 1.5 ug per teat x 2) by the i.duc route, 3 times at weekly intervals, and observed for 1-3 months. Mice treated with the TFR-Ab showed no significant reduction in tumor size. Treated with HB21(fv)PE40 i.duc, by IVIS imaging, tumors were undetectable in both models (P&amp;lt;0.0001) within two weeks. No recurrence was observed during 3 months of followup. Mammary whole mount analysis and histopathology showed that i.duc toxin rendered more than 90% of the mice cancer-free. Immunohistochemical analysis of tumor sections for huTFR (CD71), Ki67, and CD31 supported the loss of TFR-expressing and proliferating cancer cells, and reduction of blood vessels. Pharmacokinetics studies showed that toxin was detectable by TFR-ELISA in blood 5, 30 and 60 min after i.p injection, but was undetectable in the blood of i.duc-treated mice. Conclusions: Overall, we have shown that i.duc HB21(fv)PE40 has remarkable antitumor activity in cell culture with an IC50 in the nM range, and in two MIND models of DCIS. Blood levels of the toxin after i.duc injection were undetectable, suggesting that the toxin remains inside the ductal system during its 30 min half-life, and its effect occurs during this time. This preclinical study provides a strong basis for conducting human trials. The toxicity of HB21(Fv)PE40 by the i. duc route of drug administration could be determined in dose escalation studies in patients with DCIS and early breast cancer who will undergo mastectomy as part of their treatment regimen, using a previously successful study design (PMID:2230751). This design will allow detailed examination of the local and systemic effects of HB21(fv)PE40 administered i.duc and reintroduce a very potent agent into DCIS treatment, and in the future, cancer prevention in women at high risk of developing breast cancer. Citation Format: Saraswati Sukumar, Guannan Wang, Alok Kumar, Wanjun Ding, Preethi Korangath, Priya Pai, Kathleen Gabrielson, Ira Pastan. Intraductal administration of a Transferrin Receptor-directed immunotoxin eliminates ductal carcinoma in situ in preclinical mammary in-duct (MIND) models of breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-03.

Abstract P3-03-21: Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean?

Abstract Background: For patients with ductal carcinoma in situ (DCIS), data about contralateral breast cancers detected by MRI at primary diagnosis and the impact of MRI use on the incidence and stage of contralateral breast cancers during follow-up are scarce. Methods: We selected all women diagnosed with a primary DCIS in the Netherlands in 2011-2015 from the Netherlands Cancer Registry. The synchronous and metachronous detection of contralateral DCIS and contralateral invasive breast cancer was assessed for patients who did receive an MRI upon primary diagnosis (MRI group) and for an age-matched control group without MRI. Incidence of contralateral disease during follow-up was calculated using competing risk methods.Results: Of the 8486 patients diagnosed with primary DCIS, 1571 (19%) received an MRI. In the MRI group, 0.8% of patients were diagnosed with a synchronous contralateral DCIS and 1.3% with synchronous contralateral invasive breast cancer. Median follow-up time was 6.4 years (IQR: 5.1-7.6). The estimated five-year cumulative incidence of synchronous plus metachronous contralateral DCIS was 2.0% (95% CI: 1.4%-2.8%)) for the MRI group and 0.9% (95% CI: 0.5%-1.5%) for the age-matched control group. The five-year cumulative incidence of contralateral invasive breast cancer was 3.5% (95% CI: 2.7%-4.5%) for the MRI group and 2.3% (95% CI: 1.6%-3.1%) for the age-matched control group. In patients aged &amp;lt;50 years, the cumulative incidence of metachronous contralateral DCIS was statistically significantly higher in the MRI group than in the age-matched controls (sHR= 4.22 (95%CI: 1.19-14.99), P=0.03). This was not the case in patients aged 50-74 years (sHR=0.89 (95%CI: 0.41-1.93), P=0.77). Conclusions: MRI led to more frequent detection of synchronous contralateral invasive breast cancers without lowering the number of metachronous contralateral invasive breast cancers. In patients aged below 50 years, MRI added to conventional imaging led to a persisting higher rate of DCIS diagnosed in the opposite breast, also without influencing the occurrence of invasive breast cancers being detected during the first five years of follow-up. Footnotes Citation Format: Kristien Keymeulen, Sandra Geurts, Loes Kooreman, Lucien Duijm, Sanne Engelen, Sigrid Vanwetswinkel, Ernest Luiten, Sabine Siesling, Adri Voogd, Vivianne Tjan-Heijnen. Contralateral breast cancers detected by pre-operative MRI in patients diagnosed with DCIS: Whart do they mean? [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 P3-03-21.

Abstract P2-08-07: Predicting DCIS prognosis using infrared and raman spectroscopy of breast calcifications and soft-tissue microstructure

Abstract Introduction: Ductal carcinoma in situ (DCIS) is a potential precursor of invasive breast cancer. The uncertain trajectory of DCIS, to progress to invasive disease or to remain in situ, currently drives treatment, despite lack of proven benefit. Therefore, understanding the molecular features of the DCIS trajectory may prevent overtreatment of this disease. Breast calcifications are a common feature in DCIS and are seen mammographically in over 80% of cases. Calcifications have been largely characterised based only on x-ray morphology; their chemical composition, their association with the surrounding soft tissue and role in DCIS and invasive breast cancer biology is largely unexplored. In this regard, a bio-photonic approach, based on infrared (IR) and Raman spectroscopy in combination with machine learning, was used to study DCIS by probing the chemical composition of calcifications and the surrounding soft tissue in breast lesions. The main aim of the work is to identify molecular compositional changes in calcifications and in soft tissue that potentially accompany or drive the progression of DCIS to invasive breast cancer, or indicates a stable DCIS phenotype. Methods: Serial tissue sections from 303 patients with (i) ‘pure DCIS’ (DCIS without recurrence) (n=158), (ii) ‘DCIS with invasive recurrence’ (DCIS from a patient who subsequently was known to develop invasive disease) (n=123) and (iii) ‘DCIS plus invasive cancer contemporaneously’ (n=22), were measured using mid-IR imaging and Raman mapping. The same calcifications and soft tissue regions from specific DCIS ducts were targeted across the techniques on the serial sections. Spectral images were analysed using cluster analysis followed by unsupervised and supervised machine learning classification models to identify spectral features associated with the progression of DCIS to invasive breast cancer. Results: Segmentation of IR and Raman spectral images based on cluster analysis identified important histopathological features including calcifications, epithelium, necrotic areas, connective tissue and stroma based on the spectral heterogeneity. Based on analysis of Raman calcification data from 145 patients with (i) ‘pure DCIS’ (n=90) and (ii) ‘DCIS with invasive recurrence’ (n=55), an area under the receiver operating characteristic (AUROC) mean value of 85% was obtained in distinguish pure DCIS from DCIS that later recurred as invasive cancer. The calcification features appeared to indicate pathology specific changes in phosphate and carbonate content and appearance of magnesium whitlockite. Similar analysis of the surrounding soft tissue spectral features showed an AUROC mean value of 76%, which showed changes in protein secondary structure and content, particularly in the necrotic regions surrounding calcifications. In addition, classification models are being developed and refined from the IR spectral data, the initial results of which have shown an AUROC value of only 54% from the same patients’ data. Perspectives: It is anticipated that the current novel approaches allowing label-free measurement of calcifications and soft tissue will provide important cues in understanding DCIS prognosis and could be a promising way forward in determining DCIS management. Current and future efforts include identification of specific discriminatory spectral features for molecular and pathological correlation. Acknowledgments: This work was supported by Cancer Research UK and by KWF Kankerbestrijding (ref. C38317/A24043). Citation Format: Jayakrupakar Nallala, Doriana Calabrese, Sarah Gosling, Allison Hall, Sarah Pinder, Ihssane Bouybayoune, Lorraine King, Jeffrey Marks, Esther Lips, Thomas Lynch, Donna Pinto, Jelle Wesseling, Shelley Hwang, Keith Rogers, Nick Stone, on behalf of the Grand Challenge PRECISION consortium. Predicting DCIS prognosis using infrared and raman spectroscopy of breast calcifications and soft-tissue microstructure [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 P2-08-07.

Long-term risk of subsequent ipsilateral lesions after surgery with or without radiotherapy for ductal carcinoma in situ of the breast

BackgroundRadiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort.MethodsThe cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models.ResultsThe 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)age < 50 3.2 (95% CI 1.6–6.6); HRage ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HRage<50 2.1 (95% CI 1.4–3.2); HRage ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HRage < 50 0.7 (95% CI 0.3–1.5); HRage ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HRage < 50 0.6 (95% CI 0.4–0.9); HRage ≥ 50 1.2 (95% CI 0.9–1.6)).ConclusionRT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

Abstract PD5-06: Impact of an online ductal carcinoma in situ (DCIS) decision support tool on awareness of treatment options and knowledge of breast cancer risks

Abstract Background An interactive decision support tool (DST) was adapted to support patients diagnosed with DCIS who are making treatment decisions. The DST provides the following risk estimates over 10 years: 1) future DCIS or invasive breast cancer in the same breast, 2) the risk of dying from causes other than breast cancer, and 3) the risk of dying from invasive breast cancer. Estimates are personalized based on patient age and DCIS grade (low/intermediate versus high grade or “don’t know”) and were based on a model incorporating data from clinical trials and life tables. Methods The DST was implemented in collaboration with the COMET study on the website DCISoptions.org (www.dcisoptions.org). On the DST, personalized results are displayed separately using a 100-woman icon array and percentages with each outcome (future DCIS/invasive breast cancer, death due to breast cancer, death due to other causes) in a different color for each treatment selected by the patient (lumpectomy only, lumpectomy + radiation therapy, lumpectomy + endocrine therapy, lumpectomy + radiation and endocrine therapy, mastectomy with or without reconstruction, bilateral mastectomy with or without reconstruction). In addition, information regarding active monitoring was provided in descriptive terms without icon array display of personalized outcomes. DST users were defined as those who navigated to the website and entered age and DCIS grade allowing them to access the information about expected outcomes. Users were asked to complete an optional survey both prior to use of the DST and after to assess the impact of the DST on: 1) their awareness of options for DCIS treatment, 2) their willingness to consider these options, 3) their knowledge of mortality risks associated with DCIS, and 4) how helpful the DST was to them (after use only). Results As of June 1, 2020, there were 420 users of the DST (total) with 362 completing the pre-tool survey and 58 of whom completed the post-tool survey. Among all DST users, mean age was 54.0 (9.6 years SD) and DCIS was low/intermediate for 72.0%, high for 18.5% and unknown for the remaining 9.5%. Among users who submitted both the pre- and post-tool survey, median time spent on the tool was 10.4 minutes. Awareness of each treatment option was high and did not change with the tool: 90% among both pre-survey and post-survey users except for bilateral mastectomy which remained at 82.9% among pre-survey and post-survey responders. Among those users who completed the pre- and post-tool surveys, the DST increased the percentage of patients who believed the chance of dying from DCIS is very low from 60.3% at baseline to 74.1% (p&amp;lt;0.0001) and reduced the median estimated numerical risk of dying from DCIS in 10 years from 9.0% at baseline to 3.0% (p&amp;lt;0.0001). A large majority of DST users found the tool very helpful or helpful (79.3% of those who responded) in making a treatment decision for DCIS. Discussion DCIS patients have been shown to greatly overestimate the risks of dying from breast cancer and this has been associated with increased anxiety and potential overtreatment. Our personalized online DST significantly improved knowledge about DCIS risks. Future studies of the DST should assess patient characteristics associated with knowledge gains and whether improved knowledge translates to improved patient outcomes including more patient preference and values-based treatment decisions. Citation Format: Rinaa Sujata Punglia, Ann Partridge, Shelley Hwang, Alastair Thompson, Elizabeth Frank, Donna Pinto, Deborah Collyar, Desiree Basila, Thomas Lynch, Terry Hyslop, Marc Ryser, Elissa Ozanne. Impact of an online ductal carcinoma in situ (DCIS) decision support tool on awareness of treatment options and knowledge of breast cancer risks [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 PD5-06.

Ductal Carcinoma In Situ in Pregnant Women.

Breast cancer is the second most common malignancy affecting pregnant women. Ductal carcinoma in situ (DCIS) during pregnancy has not been well described with limited literature addressing the optimal treatment options. This is important topic as the incidence of pregnancy-associated breast cancer (PABC) has been increasing. In the United States, 1 in 3000 pregnancies are complicated by breast cancer diagnosis. Most DCIS are screen detected as most patients are asymptomatic. Since routine screening mammogram is not recommended during pregnancy, diagnosis of DCIS without invasive disease is uncommon diagnosis. Although PABC is reported to account for 0.2-3.8% of all newly diagnosed breast cancer, it has not been defined between the diagnosis of DCIS or invasive breast cancer making true incidence of DCIS in pregnancy difficult to report. This review summarizes multidisciplinary recommendations for optimal treatment for DCIS diagnosed during pregnancy.

Essential role of STAT5a in DCIS formation and invasion following estrogen treatment.

Ductal carcinoma in situ (DCIS) is one of the earliest stages of breast cancer (BCa). The mechanisms by which DCIS lesions progress to an invasive state while others remain indolent are yet to be fully characterized and both diagnosis and treatment of this pre-invasive disease could benefit from better understanding the pathways involved. While a decreased expression of Caveolin-1 (Cav-1) in the tumor microenvironment of patients with DCIS breast cancer was linked to progression to invasive breast cancer (IBC), the downstream effector(s) contributing to this process remain elusive. The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions. In addition, STAT5a overexpression in a human DCIS cell line (MCF10DCIS.com) promoted their invasion, a process accelerated by estrogen treatment and associated with increased levels of the matrix metalloproteinase-9 (MMP-9) precursor. In sum, our results demonstrate a novel regulatory axis (Cav-1♦STAT5a♦MMP-9) in DCIS that is fully activated by the presence of estrogen. Our sudies suggest to further study phosphorylated STAT5a (Y694) as a potential biomarker to guide and predict outcome of DCIS patient population.

Contrasting DCIS and invasive breast cancer by subtype suggests basal-like DCIS as distinct lesions

Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer with highly variable potential of becoming invasive and affecting mortality. Currently, many patients with DCIS are overtreated due to the lack of specific biomarkers that distinguish low risk lesions from those with a higher risk of progression. In this study, we analyzed 57 pure DCIS and 313 invasive breast cancers (IBC) from different patients. Three levels of genomic data were obtained; gene expression, DNA methylation, and DNA copy number. We performed subtype stratified analyses and identified key differences between DCIS and IBC that suggest subtype specific progression. Prominent differences were found in tumors of the basal-like subtype: Basal-like DCIS were less proliferative and showed a higher degree of differentiation than basal-like IBC. Also, core basal tumors (characterized by high correlation to the basal-like centroid) were not identified amongst DCIS as opposed to IBC. At the copy number level, basal-like DCIS exhibited fewer copy number aberrations compared with basal-like IBC. An intriguing finding through analysis of the methylome was hypermethylation of multiple protocadherin genes in basal-like IBC compared with basal-like DCIS and normal tissue, possibly caused by long range epigenetic silencing. This points to silencing of cell adhesion-related genes specifically in IBC of the basal-like subtype. Our work confirms that subtype stratification is essential when studying progression from DCIS to IBC, and we provide evidence that basal-like DCIS show less aggressive characteristics and question the assumption that basal-like DCIS is a direct precursor of basal-like invasive breast cancer.

Abstract C108: Race and risk of subsequent aggressive breast cancer in women with ductal carcinoma in situ

Abstract Background: Ductal carcinoma in situ (DCIS) is a heterogeneous group of preinvasive neoplastic lesions in the breast. Black women with DCIS are more likely than White counterparts to subsequently develop invasive cancer in either breast. We examined the association between race and the risk of developing aggressive invasive breast cancer, characterized with hormone receptor (HR) negativity (both estrogen receptor and progesterone receptor negative) or intermediate-to-high risk Oncotype scores (≥18) in HR-positive subtypes, in women with DCIS. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) data, we identified 133,705 women with DCIS diagnosed between 1990 and 2015, and 12.9% were black. Cox proportional hazards regression was used to estimate relative risks (RRs) of subtypes of subsequent invasive breast cancer in either breast and metastatic breast cancer. Results: During a median follow-up of 90 months, 6889 women developed invasive breast cancer and 6384 had HR status available. The risks of HR-defined (Pheterogeneity=0.0004) and Oncotype score-defined (Pheterogeneity=0.046) invasive breast cancer subtypes after initial DCIS significantly varied by race. The RR of HR-negative invasive breast cancer was 1.86 (95% CI 1.57-2.20) and the RR of subsequent invasive subtypes with intermediate-to-high Oncotype scores was 1.29 (95% CI 1.00-1.67) in Black women with DCIS, which was independent of age, pathologic features and treatment. In women who had data on HR status in both primary DCIS and subsequent invasive breast cancer, the HR discordant rate was higher in Black patients than in White patients (21.2% versus 18.9%, P=0.003), which was largely driven by HR loss (15.4% versus 9.5%). Black race was more strongly associated with HR loss (RR=1.92, 95% CI 1.41-2.61, Pheterogeneity=0.03) than HR concordance (RR=1.24, 95% CI 1.09-1.41) and HR gain (RR=1.04, 95% CI 0.67-1.62). Conclusions: Black women with DCIS had higher risks of developing aggressive invasive breast cancer compared with White counterparts, which may contribute to their worse survival. Future studies examining biologic differences in the progression of DCIS for Black patients are warranted. Citation Format: Ying Liu, Graham Colditz. Race and risk of subsequent aggressive breast cancer in women with ductal carcinoma in situ [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C108.