Ductal Carcinoma In Situ Cohort Research Articles

Impact of surgical types on overall survival in patients with ductal carcinoma in situ: an analysis based on the SEER database.

Breast cancer, as one of the most common malignancies among women globally, presents a concerning incidence rate, underscoring the importance of addressing the treatment of its precursor lesion, ductal carcinoma in situ (DCIS). Treatment decisions for DCIS, involving the balance between breast-conserving surgery (BCS) and mastectomy, remain an area requiring further investigation. This study aimed to compare influence of different surgical types on overall survival (OS) of patients with DCIS and identify specific subgroups with improved OS to develop an effective survival nomogram for patients. Patient data from the Surveillance, Epidemiology, and End Results (SEER) database for DCIS cohort from 2010 to 2020 were retrieved. Kaplan-Meier (K-M) survival curves were utilized to compare prognostic OS of patients with different surgical methods. Cox regression analysis was employed to determine prognostic factors and establish a nomogram to predict 3-, 5-, and 10-year survival rates. The model was confirmed by Concordance Index (C-index), calibration curves, and receiver operating characteristic (ROC) curves. A total of 71,675 patients with DCIS were included. Patients who underwent subcutaneous mastectomy (SM) demonstrated the best OS compared to other surgical types. Additionally, adjuvant radiotherapy or chemotherapy in combination with surgery significantly improved OS compared to surgery alone. Among DCIS patients aged ≤74 years, those who underwent SM benefited the most in terms of OS, while in the age group of 63-74 years, patients who underwent BCS had significantly higher OS than those who underwent total (simple) mastectomy (TM)/modified radical mastectomy (MRM). Multiple factors were associated with improved OS in DCIS patients, and these factors were integrated into the nomogram to establish OS predictions. The C-index, calibration curves, and ROC curves indicated that the nomogram was suitable for assessing patient prognosis. This study demonstrated that SM treatment yielded the best survival rates for DCIS patients, providing important guidance for future surgical decision-making. Moreover, identifying multiple independent factors related to survival and establishing reliable survival nomograms can assist physicians in developing personalized treatment plans and prolonging patient survival.

Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging.

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer's ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. Although there has been extensive research on genetic and epigenetic causes of breast carcinogenesis, none of these studies have successfully identified a biomarker for the progression and/or upstaging of DCIS. In this study, we show that ecological habitat analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intra-ductal microenvironment based on oxygen diffusion distance in our DCIS cohort of 84 patients. Then, we identify cancer cells with metabolic phenotypes attributed to their habitat conditions, such as the expression of CA9 indicating hypoxia responding phenotype, and LAMP2b indicating a hypoxia-induced acid adaptation. Traditionally these markers have shown limited predictive capabilities for DCIS upstaging, if any. However, when analyzed from an ecological perspective, their power to differentiate between indolent and upstaged DCIS increased significantly. Second, using eco-evolutionary guided computational and digital pathology techniques, we discovered distinct spatial patterns of these biomarkers and used the distribution of such patterns to predict patient upstaging. The patterns were characterized by both cellular features and spatial features. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve(AUC) of 0.74. Our results affirm the importance of using eco-evolutionary-designed approaches in biomarkers discovery studies in the era of digital pathology by demonstrating the role of eco-evolution dynamics in predicting cancer progression.

Identification of patients with DCIS with low-risk clinicopathology who benefit from radiation therapy with and without endocrine therapy after breast-conserving surgery assessed with the 7-gene biosignature.

528 Background: Ductal carcinoma in situ (DCIS) accounts for 20% of breast cancers. For most patients with DCIS, the standard treatment involves breast-conserving surgery (BCS) followed by radiotherapy (RT). Adjuvant endocrine therapy (ET) is typically recommended for hormone receptor-positive disease. However, prospective trials have failed to identify a low-risk CP group not benefitting from RT with respect to ipsilateral breast recurrence (IBR), with no modern trials evaluating ET. We utilized the 7-gene predictive DCIS biosignature to assess the effects of RT and/or ET on 10yr IBR in women with low-risk CP DCIS. Methods: Women (n=926) from four DCIS cohorts treated with BCS had tissue samples analyzed at a CLIA lab (Laguna Hills, CA). Low-risk CP was defined with RTOG 9804-like criteria (margin negative by no-ink on tumor) or MSKCC-like criteria using nomogram-weighted factors (low-risk score<220, excluding number of re-excisions, using negative margin, and RT treatment). Women with either low-risk CP criteria were classified as molecular Low Risk (DS≤2.8, no Residual Risk subtype, RRt) or High Risk (DS>2.8 +/- RRt) using the 7-gene DCIS biosignature. Ten-year IBR Kaplan-Meier rates and Cox proportional hazard ratios (HR) were calculated for ET and RT. Results: Overall, 66% of 926 women were classified as low risk by one of the CP criteria. Patients with low-risk CP treated without ET (n=315) had 10yr IBR rates of 13% after BCS without RT and 7% with RT (HR=0.51, p=.10), while those treated with ET (n=291) had 10yr IBR rates of 9% after BCS without RT and 4% with RT (HR=0.39, p=.09). Overall, 37% of women were classified as low risk (n=338) by the biosignature and had a 10yr IBR rate of 5.6% after BCS with no significant ET (HR=0.66, p=.41) or RT benefit (HR=0.88, p=.78) in multivariable analysis. Of patients with low-risk CP, 48% of those treated without ET were classified as High Risk by the biosignature and had elevated 10yr IBR rates without RT (21%) and a substantial RT benefit (HR=0.31, p=.03, n=151), while 59% of those treated with ET after BCS were classified by the biosignature as High Risk and had elevated 10yr IBR rates without RT (14%) and a 9% absolute reduction from RT (HR=0.22, p=.02, n=173). Patients with concordant low-risk CP and biosignature Low Risk (n=269) had a 5.5% 10yr IBR rate after BCS and no significant RT (HR=1.10 95% CI 0.33 to 3.7, p=.87) or ET benefit (HR=0.44, 95%CI 0.1 to 1.6, p=.22) in multivariable analysis. Conclusions: The 7-gene biosignature provided better identification of patients with low 10yr IBR rates and no significant RT benefit compared to using CP low-risk criteria. Importantly, the biosignature classified over half of women with low-risk CP treated with ET as High Risk. This group received a substantial benefit from RT, while those with biosignature Low Risk did not.

Epigenetic activation of SOX11 is associated with recurrence and progression of ductal carcinoma in situ to invasive breast cancer.

Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS. Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts. RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. AKT activation correlated with chromatin accessibility and EZH2 enrichment upregulating SOX11 expression. AKT and HER2 inhibitors decreased SOX11 expression along with diminished mammosphere formation. SOX11 was upregulated in HER2+ and basal-like subtypes (P < 0.001). Longitudinal DCIS cohort (n = 194) revealed shorter recurrence-free survival in SOX11+ than SOX11- patients (P = 0.0056 in all DCIS; P < 0.0001 in HER2+ subtype) associated with increased risk of ipsilateral breast event/IBE (HR = 1.9, 95%CI = 1.2-2.9; P = 0.003). Epigenetic activation of SOX11 drives recurrence of DCIS and progression to invasive cancer, suggesting SOX11 as a predictive biomarker of IBE.

Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women with Low-Risk DCIS after Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-Year Ipsilateral Breast Recurrence (IBR) Rates

Most women diagnosed with ductal carcinoma in situ (DCIS) receive radiotherapy (RT) after breast conserving surgery (BCS); however, clinical trials show that over 70% of women with BCS alone will not have a recurrence and therefore not benefit from RT. Traditionally, clinicopathologic (CP) factors have been used to select for whom to de-escalate treatment, but prospective trials have failed to identify a low risk CP group that did not benefit from RT with respect to local control. This study assessed the re-classification of patients with low-risk CP into Risk groups defined by the 7-gene biosignature and compared to 10-yr IBR rates. Women (n = 926) from four international DCIS cohorts treated with BCS had formalin-fixed paraffin embedded tissue samples analyzed at a CLIA lab (Laguna Hills, CA). CP low-risk patients were identified using a) RTOG-9804-like criteria [Nuclear Grade 1 or 2 & Size ≤2.5 cm & non-Palpable & Screen Detected & margin negative (no-ink on tumor)] and b) MSKCC-like criteria [low-risk score<220, determined using nomogram weighted factors (excluding: number of re-excisions and RT treatment), and using no-ink-on-tumor instead of close margin]. The 7-gene DCIS biosignature combined biomarkers with CP factors (age, size, palpability, and margin status) using an algorithm reporting a Decision Score (DS) and Residual Risk subtype (RRt). Women with low-risk CP were classified into biosignature Low Risk (DS≤2.8, no RRt) or High Risk (DS>2.8 +/- RRt) groups. 10yr in-breast event (IBR) rates with and without RT were assessed by Kaplan-Meier rates and Cox proportional hazard analyses. Overall, 37% of all women were classified into the biosignature Low Risk group, while 51% and 34% were classified into CP low-risk groups (RTOG-9804-like, MSKCC-like, respectively). The biosignature Low Risk group (n = 338) had a 10-yr IBR risk of 5.6% after BCS and no significant RT benefit (absolute RT benefit = 0.8%, p = 0.70), 99% negative predictive value (NPV) for RT benefit. CP low-risk groups had 10-yr IBR rates of 12% and 8% after BCS without RT with absolute 6% (p = 0.04) and 4% (p = 0.1) IBR rate reductions with RT. The biosignature reclassified 51% and 63% of CP low-risk patients into the biosignature High Risk group. Importantly, these patients had higher IBR rates without RT (20% and 12%) and significant 13% (p = 0.005) and 8% (p = 0.01) absolute IBR rate reductions from RT. CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. The 7-gene predictive biosignature more reliably identified patients with low 10-yr IBR rates and no significant RT benefit than the traditional CP low-risk criteria (RTOG-9804-like, MSKCC-like). Importantly, those CP low-risk patients who were re-classified as biosignature High Risk had increased 10-year IBR rates and significant RT benefit.

Prognostic and Predictive Significance of Tumor Immune Microenvironment in Breast Ductal Carcinoma In Situ

This study aims to identify the role of different subtypes of tumor infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) in predicting risk of recurrence and benefit of whole breast irradiation (WBI). Immunohistochemical stain for CD3, CD4, CD8, FOXP3 and CD20 were carried in a well characterized DCIS cohort who received breast-conserving surgery (BCS) from Jan 2009 to Dec 2018. All the TILs subtypes were evaluated by the average numbers of touching-TILs which defined as TILs touching or within one lymphocyte cell thickness from the malignant ducts' basement membrane. The optimal cut-off values of TILs subtypes were selected by the X-tile. In total, 167 patients were enrolled in this analysis with 114 patients received WBI. After a median follow-up of 67 months, 15 IBTR events occurred with 6 invasive-IBTRs. Nine out of 15 IBTRs occurred outside of the original quadrant (elsewhere failure event, EFE). CD3+ lymphocytes were the predominant cell subtype while Treg showed the lowest levels. High abundance of TILs subtypes was associated with high tumor grade, presence of microinvasion, high Ki67 index, ER negativity and HER2 positivity. For various TILs subtypes, the multivariate analyses showed that dense CD4+ TILs (HR = 9.84, 95% CI 2.43-39.91, p<0.01) and dense Treg (HR = 4.22, 95% CI 1.24-14.36, p = 0.02) were independent prognostic factors for higher IBTR. As the infiltration of TIL subsets was correlated with one another, we also analyzed the relationship between IBTR and the ratios of different TILs subtypes. By adjusted by clinicopathological parameters, high ratios of CD4+/CD8+, Treg/CD4+ and Treg/CD8+ were found to be independent prognostic factors for higher IBTR (HR = 11.31, 95% CI 3.14-40.76, p<0.01; HR = 3.09, 95% CI 1.05-9.11, p = 0.04; HR = 7.14, 95% CI 1.98-25.73, p<0.01). Consistent with the results of IBTR, the 5-y rate of invasive-IBTR and EFE was both significantly associated with the high CD4+/CD8+, Treg/CD4+ and Treg/CD8+ TILs ratios (all p<0.01). WBI reduced the rate of 5y-IBTR risk from 8.4% to 1.3% (p = 0.02) in the low Treg/CD8+ group, but there was no benefit of WBI in the high group. With respect to EFE, WBI significantly reduced the rate from 2.8% to 0.0% (p = 0.03) in the low Treg/CD8+ group while not in the high group. The benefits of WBI in reducing IBTR and EFE were not significant difference between different CD4+/CD8+ and Treg/CD4+ groups. Assessment of overall TILs provides a tool for comprehensive evaluation of the DCIS immune microenvironment. Patients with pro-tumoral immune infiltrate (high Treg, high ratios of CD4+/CD8+, Treg/CD4+ and Treg/CD8+) in tumor microenvironment show an increased risk of IBTR and less benefit from breast radiotherapy.

Estrogen Receptor-negative Ductal Carcinoma In Situ (DCIS) of the Breast - an Institutional Review of Outcomes.

Estrogen receptor (ER)-negative [ER(-)] invasive breast cancers (IBCs) are known to be more aggressive than their ER(+) counterparts. This is less well defined for ductal carcinoma in situ (DCIS). This study investigated the outcomes following the treatment of ER(-) DCIS. A total of 103 ER(-) DCIS patients diagnosed between 2004-2018 were retrospectively analyzed. Median follow-up was 63.9 months. Statistical analysis included descriptive statistics, non-parametric tests, T-test, logistic regression. The outcomes were compared to a group of 102 ER(+) DCIS patients from our institution. Any breast event (BE) occurred in 10 (9.7%) patients at a median of 3.2 (1.7-7.2) years. The incidence of ipsilateral breast events (IBEs) was 5.8% (6/103). All IBE cases were ER(-) DCIS. All (n=4) contralateral breast events (CBEs) were ER(+) including 3 IBCs. Cumulative incidence of any BEs at 1, 2, and 5 years was 0%, 1.1%, and 9.1%, respectively. Among patients with ER(-) DCIS who developed BE, breast conserving surgery (BCS) had been performed for the initial DCIS in 90% of cases. In those without any BE, the BCS rate (vs. mastectomy) was 58.1% (p=0.08). Adjuvant radiotherapy after BCS was used less often among patients with vs. without subsequent BE (55.5% vs. 77.4%) (p=0.22). Predictors for BE occurrence were not identified. The incidence of any BE among patients with ER(+) DCIS was 6.9% and was not significantly different compared to ER(-) DCIS group (p=0.46). ER(-) DCIS outcomes were similar to our institutional ER-positive DCIS group and the previously reported ones for predominantly ER-positive DCIS cohorts.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Abstract A017: Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer

Abstract Background: Screening mammography has dramatically increased incidental detection of Ductal Carcinoma in situ (DCIS), a non-obligate precursor of breast cancer. Approximately 10-50% of DCIS progress to the invasive disease and the risk of developing recurrence or progression after surgery is still not well defined based on clinical and pathological characteristics. Our study investigated the genetic and epigenetic mechanisms associated with recurrence and progression of DCIS to invasive cancer. Methods: To identify genes associated with recurrence and progression of DCIS to invasive cancer, we performed Nanostring nCounter analysis (MDACC, n = 40) and RNA-sequencing (Sloane study, n = 183) in two independent prospective primary DCIS cohorts. Mammary epithelial-specific Pten knockout mouse model developed in our lab was used to interrogate the genetic pathway deregulated during development of mammary intraepithelial neoplasia to adenocarcinoma. ATAC-seq and ChIP-qPCR were performed to assess chromatin accessibility in the genome and validate binding of histone-modifying enzymes on target promoters. Histopathological analyses were performed to determine DCIS grades, subtypes, and protein expression profiles. Results: RNA expression profiles of normal mammary and primary DCIS tissues (n = 40) identified 10 gene transcripts that were significantly and differentially expressed between normal and high-grade DCIS. Only SOX11 expression was significantly and progressively correlated with KI67 and the DCIS recurrence score as described by Solin (JNCI 2013). Mammary intraepithelial neoplasia in Pten knockout mice and 21T DCIS to IDC progression cell line model also revealed SOX11 upregulation compared to controls. Since PTEN/PI3K/AKT pathway is known to regulate global active histone marks and open accessible chromatin, we investigated the role of AKT on SOX11 expression. Results demonstrated that inhibition of AKT altered enrichment of histone-modifying enzymes KDM5A and EZH2 on the promoter accompanying downregulated SOX11 expression in DCIS cell lines. SOX11 and EZH2 expression profiles revealed significant correlation in DCIS tissue samples. In two independent DCIS cohorts, SOX11 was found significantly upregulated in HER2+ and basal-like DCIS subtypes (P &amp;lt; 0.001). RNA sequencing in 183 longitudinal DCIS cases of the Sloane study (median follow-up of 96 months) revealed significantly shorter recurrence-free survival in SOX11+ than SOX11- patients (P &amp;lt; 0.02 in all subtypes; P = 0.002 in HER2+ subtype). Based on COX proportional hazards model, SOX11 alone was significantly associated with the risk of developing recurrence and invasive breast cancer (HR = 1.7, 95% CI = 1.1 to 2.6; P &amp;lt; 0.02). Conclusions: Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer. SOX11 and its epigenetic regulators can be developed as prognostic markers for DCIS patients with recurrence risk independent of traditional clinical and pathologic characteristics. Citation Format: Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin W. Wong, Farah A Ladha, Brian Menegaz, Sarah E. Pinder, Wei Lu, Fei Yang, Ximing Tang, Savitri Krishnamurthy, Ignacio I. Wistuba, Elinor J. Sawyer, Alastair M. Thompson, Subrata Sen. Epigenetic activation of SOX11 is associated with recurrence and progression of DCIS to invasive breast cancer [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 A017.

Abstract PR002: Genomic predictor can discriminate between high- and low-risk DCIS

Abstract Introduction: Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor of invasive ductal carcinoma. With the aim of preventing a subsequent invasive cancer, all DCIS lesions are currently treated with surgical excision often supplemented with radiotherapy (RT). To prevent DCIS over- or undertreatment, a reliable marker of DCIS invasiveness risk is urgently needed. Methods: We studied two large DCIS cohorts: the Sloane cohort, a prospective breast screening cohort from the UK (median follow-up of 11 years), and a Dutch population-based cohort (NKI, median follow-up of 13 years). FFPE tissue specimens from patients with pure primary DCIS after breast-conserving surgery (BCS) +/- RT that did develop a subsequent ipsilateral event (DCIS or invasive) were considered as cases, whereas patients that did not develop any form of recurrence up to the last follow-up or death were considered as controls. We performed copy number analysis (CNA) and RNAseq analysis on 229 cases (80 DCIS only recurrences) and 344 controls. Results: DCIS was classified into the PAM50 subtypes using RNAseq data which revealed an enrichment of luminal A phenotype in DCIS that did not recur (P = 0.01, Fisher Exact test). No single copy number aberration was more common in cases compared to controls. RNAseq data did not reveal any genes significantly over/under-expressed in cases versus controls after FDR correction. However, by limiting the analysis to samples that had not had RT and excluding pure DCIS recurrences, we could develop a penalized Cox model from RNAseq data. The model was trained on weighted samples (to correct for the biased sampling of the case-control dataset) from the NKI series with double loop cross-validation. The genes were selected using the Elastic net framework of penalization. Using this predicted hazard ratio, the samples were split into high, medium, and low-risk quantiles, with a recurrence risk of 23%, 7% and 2%, respectively at 5 years (p = 10-10, Wald test). The NKI-trained predictor was independently validated in the Sloane No RT no DCIS recurrence cohort (p = 0.02, Wald test). GSEA analysis revealed proliferation hallmarks enriched in the recurrence predictor (FDR = 0.058). The RNAseq predictor was more predictive of recurrence than PAM50, clinical features (Grade, Her2 and ER) and the 12-gene Oncotype DCIS score (p &amp;lt; 0.001, permutation test using the Wald statistic) in both the NKI and Sloane series. Conclusion: Genomic profiling of two independent series of DCIS with outcome data did not reveal any clear associations with recurrence until analysis was limited to a set of samples who had not had radiotherapy and DCIS recurrences were excluded. We then identified an RNAseq-based classifier that could differentiate primary DCIS in low-, medium-, and high-risk groups, and validated it in an independent cohort. This classifier, if validated in other datasets, will allow us to identify women who do not need intensive treatment for their DCIS. Citation Format: Maria Roman Escorza, Michael Sheinman, Tycho Bismeijer, Ahmed A. Ahmed, Vandna Shah, Jeffrey R. Marks, Lorraine M. King, Anargyros Megalios, Lindy L. Visser, Marlous Hoogstrat, Helen R. Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Sarah Pinder, Nicholas N. Navin, Andrew Futreal, Serena Nik-Zainal, E. Shelley Hwang, Esther H. Lips, Alastair Thompson, Lodewyk F.A. Wessels, Jelle Wesseling, Elinor J. Sawyer. Genomic predictor can discriminate between high- and low-risk DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR002.

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.

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.

Breast adipocyte size associates with ipsilateral invasive breast cancer risk after ductal carcinoma in situ

Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case–control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO®, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25–6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59–8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10–46.3, P < 0.001) for subsequent iIBC compared with women with smaller adipocyte size and low COX-2 expression. Large breast adipocytes combined with high COX-2 expression in DCIS is associated with a high risk of subsequent iIBC. Besides COX-2, adipocyte size has the potential to improve clinical management in patients diagnosed with primary DCIS.

Collagen Organization in Relation to Ductal Carcinoma In Situ Pathology and Outcomes.

There is widespread interest in discriminating indolent from aggressive ductal carcinoma in situ (DCIS). We sought to evaluate collagen organization in the DCIS tumor microenvironment in relation to pathologic characteristics and patient outcomes. We retrieved fixed tissue specimens for 90 DCIS cases within the population-based Vermont DCIS Cohort. We imaged collagen fibers within 75 μm of the tumor/stromal boundary on hematoxylin and eosin-stained slides using multiphoton microscopy with second-harmonic generation. Automated software quantified collagen fiber length, width, straightness, density, alignment, and angle to the tumor/stroma boundary. Factor analysis identified linear combinations of collagen fiber features representing composite attributes of collagen organization. Multiple collagen features were associated with DCIS grade, necrosis pattern, or periductal fibrosis (P < 0.05). After adjusting for treatments and nuclear grade, risk of recurrence (defined as any second breast cancer diagnosis) was lower among cases with greater collagen fiber width [hazard ratio (HR), 0.57 per one standard deviation increase; 95% confidence interval (CI), 0.39-0.84] and fiber density (HR, 0.60; 95% CI, 0.42-0.85), whereas risk was elevated among DCIS cases with higher fiber straightness (HR, 1.47; 95% CI, 1.05-2.06) and distance to the nearest two fibers (HR, 1.47; 95% CI, 1.06-2.02). Fiber length, alignment, and fiber angle were not associated with recurrence (P > 0.05). Five composite factors were identified, accounting for 72.4% of the total variability among fibers; three were inversely associated with recurrence (HRs ranging from 0.60 to 0.67; P ≤ 0.01). Multiple aspects of collagen organization around DCIS lesions are associated with recurrence risk. Collagen organization should be considered in the development of prognostic DCIS biomarker signatures.

Contralateral breast cancer risk and endocrine therapy use in patients with ductal carcinoma in situ treated with unilateral mastectomy in the modern era

BackgroundIn patients with ductal carcinoma in situ (DCIS), the risk of developing contralateral breast cancer (CBC) and the role of adjuvant endocrine therapy (ET) in decreasing CBC risk is not well understood. MethodsA retrospective review was performed on patients with DCIS who underwent a unilateral mastectomy (UM) from 2000 to 2010. CBC incidence, time to CBC and disease free survival were evaluated for women who took ET versus those who did not. Results176 patients underwent a UM for DCIS, 72% were ER positive and 16% of patients took ET. At a median of 12 year follow up, 15 patients experienced CBC. Women over 63 years had highest incidence of CBC. CBC risk was not different between those who took ET versus those who did not. ConclusionThe overall incidence of CBC was 9% in our DCIS cohort and was not significantly different among patients who took ET versus those who did not.

Long-term Survival Outcomes of ‘Low Risk’ Ductal Carcinoma in situ from a Territory-wide Cancer Registry

AimsThe LORIS trial is an ongoing phase III clinical trial on low risk ductal carcinoma in situ (DCIS). DCIS patients aged ≥46 years with screen-detected low/intermediate nuclear grade were considered low risk and were randomised into surveillance or standard surgery. Here we review the 10-year territory-wide breast cancer registry database and evaluate the clinical outcomes of low versus high risk DCIS patients. Materials and methodsThis was a retrospective study of a prospectively maintained territory-wide breast cancer registry in Hong Kong. ResultsBetween 1997 and 2006, 1391 DCIS patients were identified from the Hong Kong cancer registry breast cancer database. The mean age at diagnosis was 49.2 years (range 30–70). In total, 372 patients were classified as ‘low risk’, whereas the remaining 777 patients were classified as ‘high risk’. After a median follow-up of 11.6 years, the 10-year overall breast cancer-specific survival of the entire DCIS cohort was 1136/1149 (98.9%). Overall breast cancer-specific survival of low risk DCIS was 99.5%, whereas that in high risk DCIS was 98.6% (Log-rank test, P = 0.208).Forty-six (12.4%) patients in the LORIS low risk group did not receive surgery, whereas 93 (12%) patients in the LORIS high risk group did not receive surgery. The 10-year breast cancer-specific survival in the non-operated low risk DCIS group was 97.8%; that in the non-operated high risk DCIS group was 96.7% (P = 1). ConclusionLong-term survival of DCIS was excellent, especially in low risk DCIS, regardless of surgical treatment.

The prognostic significance of immune microenvironment in breast ductal carcinoma in situ

BackgroundThe role of different subtypes of tumour infiltrating lymphocytes (TILs) in breast ductal carcinoma in situ (DCIS) is still poorly defined. This study aimed to assess the prognostic significance of B and T lymphocytes and immune checkpoint proteins expression in DCIS.MethodsA well characterised DCIS cohort (n = 700) with long-term follow-up comprising pure DCIS (n = 508) and DCIS mixed with invasive carcinoma (IBC; n = 192) were stained immunohistochemically for CD20, CD3, CD4, CD8, FOXP3, PD1 and PDL1. Copy number variation and TP53 mutation status were assessed in a subset of cases (n = 58).ResultsCD3+ lymphocytes were the predominant cell subtype in the pure DCIS cohort, while FOXP3 showed the lowest levels. PDL1 expression was mainly seen in the stromal TILs. Higher abundance of TILs subtypes was associated with higher tumour grade, hormone receptor negativity and HER2 positivity. Mutant TP53 variants were associated with higher levels of stromal CD3+, CD4+ and FOXP3+ cells. DCIS coexisting with invasive carcinoma harboured denser stromal infiltrates of all immune cells and checkpoint proteins apart from CD4+ cells. Stromal PD1 was the most differentially expressed protein between DCIS and invasive carcinoma (Z = 5.8, p < 0.0001). Dense TILs, stromal FOXP3 and PDL1 were poor prognostic factors for DCIS recurrence, while dense TILs were independently associated with poor outcome for all recurrences (HR = 7.0; p = 0.024), and invasive recurrence (HR = 2.1; p = 0.029).ConclusionsImmunosuppressive proteins are potential markers for high risk DCIS and disease progression. Different stromal and intratumoural lymphocyte composition between pure DCIS, DCIS associated with IBC and invasive carcinoma play a potential role in their prognostic significance and related to the underlying genomic instability. Assessment of overall TILs provides a promising tool for evaluation of the DCIS immune microenvironment.

Abstract P1-16-04: How patient advocates and researchers work together in PRECISION* to identify low-risk ductal carcinoma in situ (DCIS) that may not need aggressive treatment

Abstract BACKGROUND: Ductal carcinoma in situ (DCIS) was virtually unknown before breast screening and now accounts for up to 25% of all ‘breast cancers’ detected. Over 50,000 women are diagnosed annually with DCIS in the US alone; most receive treatments intended for women with invasive breast cancer which may offer no benefit and are associated with physical and psychological complications, and financial burdens. Observational studies show a majority of DCIS never becomes invasive, even if left untreated. Lack of prospective data and concerns about “overtreatment” are now being addressed by PRECISION - an international consortium of clinicians, scientists and patient advocates - collaborating to understand the biological nature of DCIS and how it evolves. Our goal is to develop tests that distinguish between women with DCIS who will likely develop breast cancer and should be treated, and those who can safely avoid treatment. Patient advocates are fully integrated into PRECISION as well as 3 prospective randomized clinical trials - LORD (EU), LORIS (UK) and COMET (US) – aiming to produce evidence to show whether or not Active Surveillance has equivalent outcomes to surgery for low-risk DCIS. These trials are critical because PRECISION uses biospecimens from each trial, in addition to other DCIS cohorts around the world. PATIENT ADVOCATE AIMS: • Help foster teams that contribute to better outcomes for women with DCIS. • Assist in designing effective informational tools for providers, organizations, and the public. • Understand international differences in health services, medical culture, and patient expectations, and recommend improvements. • Measure the value of patient involvement in PRECISION research. • Raise awareness and communicate about ongoing research and (over)treatment of DCIS. METHODS: The PRECISION Patient Advocate Involvement Panel (PAIP) includes representatives from each country: NL, UK, and US. PAIP members provide encouragement that helps to shape ongoing projects into a cohesive team, while encouraging new synergistic projects that can potentially improve clinical practice. The PAIP actively participates in the Steering Group, all Work Packages (WPs), and a variety of internal and external communications. This includes making posters and presentations at international conferences, preparing for PRECISION reviews, creating website and newsletter content, giving interviews, co-authoring publications, and developing social media campaigns to raise awareness. RESULTS: The PAIP has: a) helped build collaborations between institutions; b) developed public-facing information about PRECISION and the 3 clinical trials; c) offered patient-oriented ideas and feedback to all WPs; d) helped resolve international contract barriers; e) helped identify additional DCIS cohorts; f) suggested ideas to improve recruitment for the clinical trials; g) given feedback on surveys and co-authored publications; h) built relationships with postdocs and PhD students; and i) engaged public and clinician audiences on DCIS dilemmas in each country. Additional ongoing PAIP work includes engaging in research to reduce pathology report DCIS grade discordance within and between countries (a critical issue for women diagnosed with DCIS). CONCLUSIONS: There is a need to better understand DCIS subtypes, stratify associated risks for invasive cancer, synergize accurate communication about DCIS, and improve pathology standards within and between countries. The PAIP will continue to work closely with researchers and communicate evidence that answers important questions related to risk factors for women who may or may not need treatment for DCIS. *PRECISION is sponsored by a Cancer Research UK Grand Challenge Award, which is also funded by the Dutch Cancer Society. Citation Format: Deborah Collyar, Donna Pinto, Hilary Stobart, Ellen Verschuur, Marja van Oirsouw, on behalf of the PRECISION Project. How patient advocates and researchers work together in PRECISION* to identify low-risk ductal carcinoma in situ (DCIS) that may not need aggressive treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-16-04.

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

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

Abstract OT3-09-01: Use of Oncotype DX DCIS for disease management in a prospective DCIS registry

Abstract Background: Ductal carcinoma in situ (DCIS) now represents nearly a quarter of newly diagnosed breast cancers in the United States. Standard-of-care treatment for DCIS is aggressive local therapy consisting of either mastectomy or breast conserving surgery with radiation. However, DCIS mortality is low regardless of initial treatment, suggesting opportunities to explore a spectrum of treatment options. With these treatment options, there is the potential to create risk-adapted treatment plans, but the question of how to assess risk remains. Molecular tests can help to personalize treatment by stratifying disease sub-types and providing prognosis. One such tool is the Oncotype DX® Breast DCIS Score, a risk measure which was validated in a meta-analysis of 773 patients from the E5194 and Ontario DCIS Cohort studies. Along with calculating a Breast DCIS Score™ from the expression levels of 12 genes, the test provides a predicted 10-year risk of local recurrence from the score result, age, and tumor size for patients who receive breast conserving surgery alone. Understanding how such a tool might impact decision-making will inform its implementation. Eligibility &amp; trial design: The ATHENA Breast Health Network is a consortium of the five University of California Medical centers. Through ATHENA, patients with histologically confirmed DCIS and no concurrent invasive cancer are approached to participate in the Athena DCIS Registry. Patients in the registry facing an active management decision are eligible to participate in the Oncotype DX® DCIS prospective study. Specific aims: The primary aim of the study is to determine whether the additional diagnostic information (i.e. the DCIS Score™) impacts patient treatment decisions and physician recommendation. Additional goals are to correlate the DCIS Score™ with mammographic findings, pathological variables, and treatment recommendations, and to estimate risk within each DCIS Score™ group. Participants and their physicians answer survey questions both before and after receiving the score to evaluate the impact of the DCIS Score™ on treatment recommendations and decisions. Statistical methods: The study will assess the percentage of patients who thought the DCIS risk score influenced their treatment decision. The study will also assess whether a significant proportion of physicians changed their recommendations after considering the DCIS Score™ using the chi-square test. Similarly, the patients’ preferred treatment option pre- and post- test surveys will be evaluated. In addition, the concordance between physicians’ and patients’ choices will be assessed by the Kappa statistic before and after the score. The patients’ and physicians’ confidence levels in their treatment recommendation and decision pre- and post- test will be compared using a Wilcoxon signed-rank test, as well as the percentage of patients and physicians who are glad they used the test. In addition, the study will assess whether the DCIS test influences a patient’s perception of their recurrence risk by comparing the self-reported 10-year breast cancer recurrence risk in their pre- and post- test questionnaires using a Wilcoxon signed-rank test. Current and target accrual: The current accrual across all sites in the Oncotype study is 94 patients. The target accrual for the initial pilot phase data is defined as the first 100 patients accrued. If interested in learning more about the study, please contact Rita Mukhtar, MD (Rita.Mukhtar@ucsf.edu). Citation Format: Jane M Wei, Paul Kim, Cheryl Ewing, Jasmine Wong, Laura J Esserman, Michael D Alvarado, Abimbola O Olusanya, Skye Stewart, Ashley Tydon, Parima Daroui, Jeffrey V Kuo, Hannah L Park, Karen T Lane, Eliza Jeong, Kelsey Brown, Ava Hosseini, Barbara A Parker, Sarah L Blair, Athena Breast Health Network Investigators, Frederick Baehner, Olivier Harismendy, Antonia Petruse, Carlie K Thompson, Helena R Chang, Alexander D Borowsky, Christina Yau, Gillian L Hirst, Richard J Bold, Rita A Mukhtar. Use of Oncotype DX DCIS for disease management in a prospective DCIS registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-01.