Low-risk Ductal Carcinoma In Situ Research Articles

Abstract PO4-13-04: Added Value from Patient Advocates in a Translational Working Group: the COMET Study

Abstract Introduction: A phase III multicenter prospective randomized clinical trial called “Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET)” (NCT02926911) assesses the risks/benefits of active monitoring (AM) versus surgery for women with low-risk ductal carcinoma in situ (DCIS). It is funded by the Patient-Centered Outcomes Research Institute and enrolled 997 women between 06/30/17 and 01/13/23. Research Patient Advocates (PAs) have been embedded from the study design stage and continue to provide guidance as part of the COMET leadership team. The COMET biobank is funded by independent foundations and is managed through monthly Translational Working Group (TWG) meetings. The TWG includes PAs, clinicians, pathologists, radiologists, and researchers from multiple institutions who discuss topics like categorization of biospecimens into discovery/validation sets; development of a pathology workflow/sample tracking process; use of small samples; and potential areas of future research/technologies that may improve DCIS diagnostics, prognostics, and care management. Methods: The TWG leveraged the existing Alliance Foundation Trials, LLC biobank infrastructure and facilitates the collection, submission, storage and analysis/use of blood, tissue, and breast images collected at specified timepoints and stored in central tissue/image repositories. PAs are active and integral in the TWG, assisting with logistical issues (contracts, transfer agreements, resource requests); communicating with sites; identifying study topics and biomarkers relevant to diverse patients; providing guidance on commercial predictive/prognostic tests; promoting effective stewardship of samples; ensuring overall focus remains on advancing clinical utility; and reporting translational study results to trial participants who agreed to donate samples/images. Results: Over 90% of requested samples/images have been submitted by ˃85 sites. Each patient’s biospecimens and pathology images are linked and de-identified for research. Use of artificial intelligence (AI) is being considered to assist in sample review. TWG members have complementary areas of expertise/experience and promote active stewardship for effective management of these scarce resources. PAs have played key roles concerning equitable data-sharing and acceleration of data and material transfer agreements. They have also been active in development of standards for discovery/training sets, validation test sets; communication procedures for patient cases that progress to future breast events; ways to catalog technologies (e.g., multi-omics, AI); and in research proposal review. Consensus has been achieved regarding major issues such as authorship, biospecimen custodianship, intellectual property, and criteria relevant to patient needs. Logistical barriers, including data sharing and technicalities of biospecimen release, have been resolved. The TWG also played an integral role in resolving recruitment challenges to COMET by creating standard pathology eligibility criteria, resulting in evidence-based protocol amendments that increased accrual. A retrospective review of biospecimens has been performed to determine adequacy for ensuing correlative molecular and spatial profiling studies. Conclusion: PAs help the COMET TWG set policy, and oversee biospecimen/image collection, and biobank use and sharing. PA input also facilitates equitable, transparent research studies and technology development that can improve personalized decisions for surgery versus AM in women with low-risk DCIS. PAs in the TWG aim to integrate the diagnostic and prognostic tools developed as part of the COMET study into future patient care. Citation Format: Deborah Collyar, Desiree Basila, Thomas Lynch, Stuart Schnitt, Jeffrey Marks, Siri Strand, Terry Hyslop, Sunil Badve, Mark Watson, H. T. Carisa Le-Petross, Lars Grimm, Robert West, Anna Weiss, Anna Rapperport, Lorraine King, Rachel Factor, Marc Ryser, Ann Partridge, E Shelley Hwang, Alastair Thompson. Added Value from Patient Advocates in a Translational Working Group: the COMET Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-04.

Application of deep learning on mammographies to discriminate between low and high-risk DCIS for patient participation in active surveillance trials

BackgroundDuctal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296–2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA), L. E. Elshof et al., Eur J Cancer, 51, 1497–510, 2015). Low-risk is defined as grade I or II DCIS. Because DCIS grade is a major eligibility criteria in these trials, it would be very helpful to assess DCIS grade on mammography, informed by grade assessed on DCIS histopathology in pre-surgery biopsies, since surgery will not be performed on a significant number of patients participating in these trials.ObjectiveTo assess the performance and clinical utility of a convolutional neural network (CNN) in discriminating high-risk (grade III) DCIS and/or Invasive Breast Cancer (IBC) from low-risk (grade I/II) DCIS based on mammographic features. We explored whether the CNN could be used as a decision support tool, from excluding high-risk patients for active surveillance.MethodsIn this single centre retrospective study, 464 patients diagnosed with DCIS based on pre-surgery biopsy between 2000 and 2014 were included. The collection of mammography images was partitioned on a patient-level into two subsets, one for training containing 80% of cases (371 cases, 681 images) and 20% (93 cases, 173 images) for testing. A deep learning model based on the U-Net CNN was trained and validated on 681 two-dimensional mammograms. Classification performance was assessed with the Area Under the Curve (AUC) receiver operating characteristic and predictive values on the test set for predicting high risk DCIS-and high-risk DCIS and/ or IBC from low-risk DCIS.ResultsWhen classifying DCIS as high-risk, the deep learning network achieved a Positive Predictive Value (PPV) of 0.40, Negative Predictive Value (NPV) of 0.91 and an AUC of 0.72 on the test dataset. For distinguishing high-risk and/or upstaged DCIS (occult invasive breast cancer) from low-risk DCIS a PPV of 0.80, a NPV of 0.84 and an AUC of 0.76 were achieved.ConclusionFor both scenarios (DCIS grade I/II vs. III, DCIS grade I/II vs. III and/or IBC) AUCs were high, 0.72 and 0.76, respectively, concluding that our convolutional neural network can discriminate low-grade from high-grade DCIS.

Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

184 (PB-091) Poster - Validation Study on the OSCAR score for Treatment Decision Planning for Low-risk DCIS patients

184 (PB-091) Poster - Validation Study on the OSCAR score for Treatment Decision Planning for Low-risk DCIS patients

Personalizing the Treatment of Women with Ductal Carcinoma In Situ (DCIS) Using the DCIS Score: A Qualitative Study on Score Use.

A twelve-gene molecular expression assay (DCIS score) may help guide radiation oncology treatment under specific circumstances. We undertook a study to examine radiation oncologist (RO), surgeon, and decision maker views on implementing the DCIS score in practice for women with low-risk DCIS. We conducted a qualitative study involving telephone interviews that were audio-recorded and transcribed. Two researchers conducted a thematic analysis of transcripts. Twenty-eight individuals (ROs, breast cancer surgeons, and cancer policy decision makers) were invited to participate; 22 out of the 28 people (79%) agreed. The final sample included 20 participants: 11 of 13 (85%) ROs, 5 of 7 (71%) surgeons, and 4 of 8 (50%) decision makers. Most ROs expressed concerns about overtreatment but could not predict with certainty which low-risk patients could safely avoid radiation. The DCIS score was viewed as contributing valuable personalized risk information as part of treatment decision making that included clinicopathological factors and women's preferences. Future implementation would require guidelines with input from the oncology team. ROs had concerns about the overtreatment of women with DCIS, but lacked the tools to reliably predict which women could safely avoid radiation. By providing oncologists and women with personalized tumor information, the DCIS score was an important component of treatment decision making.

Imaging changes and outcomes of patients undergoing active monitoring for ductal carcinoma in situ: Seven-year follow-up study

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

Association of DCIS size and margin status with risk of developing breast cancer post-treatment: multinational, pooled cohort study

ObjectiveTo examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage...

Recruiting women with ductal carcinoma in situ to a randomised controlled trial: lessons from the LORIS study

BackgroundThe LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented.MethodsWomen aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews.ResultsEighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference.ConclusionsRecruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials.Trial registrationISRCTN27544579, prospectively registered on 22 May 2014

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.

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

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

Active surveillance versus treatment in low-risk DCIS: Women’s preferences in the LORD-trial

BackgroundDuctal carcinoma in situ (DCIS) can progress to invasive breast cancer (IBC), but most DCIS lesions remain indolent. However, guidelines recommend surgery, often supplemented by radiotherapy. This implies overtreatment of indolent DCIS. The non-randomised patient preference LORD-trial tests whether active surveillance (AS) for low-risk DCIS is safe, by giving women with low-risk DCIS a choice between AS and conventional treatment (CT). Here, we aim to describe how participants are distributed among both trial arms, identify their motives for their preference, and assess factors associated with their choice. MethodsData were extracted from baseline questionnaires. Descriptive statistics were used to assess the distribution and characteristics of participants; thematic analyses to extract self-reported reasons for the choice of trial arm, and multivariable logistic regression analyses to investigate associations between patient characteristics and chosen trial arm. ResultsOf 377 women included, 76% chose AS and 24% CT. Most frequently cited reasons for AS were “treatment is not (yet) necessary” (59%) and trust in the AS-plan (39%). Reasons for CT were cancer worry (51%) and perceived certainty (29%). Women opting for AS more often had lower educational levels (OR 0.45; 95% confidence interval [CI], 0.22–0.93) and more often reported experiencing shared decision making (OR 2.71; 95% CI, 1.37–5.37) than women choosing CT. ConclusionThe LORD-trial is the first to offer women with low-risk DCIS a choice between CT and AS. Most women opted for AS and reported high levels of trust in the safety of AS. Their preferences highlight the necessity to establish the safety of AS for low-risk DCIS.

Women's views about current and future management of Ductal Carcinoma in Situ (DCIS): A mixed-methods study.

Management of low-risk ductal carcinoma in situ (DCIS) is controversial, with clinical trials currently assessing the safety of active monitoring amidst concern about overtreatment. Little is known about general community views regarding DCIS and its management. We aimed to explore women's understanding and views about low-risk DCIS and current and potential future management options. This mixed-method study involved qualitative focus groups and brief quantitative questionnaires. Participants were screening-aged (50-74 years) women, with diverse socioeconomic backgrounds and no personal history of breast cancer/DCIS, recruited from across metropolitan Sydney, Australia. Sessions incorporated an informative presentation interspersed with group discussions which were audio-recorded, transcribed and analysed thematically. Fifty-six women took part in six age-stratified focus groups. Prior awareness of DCIS was limited, however women developed reasonable understanding of DCIS and the relevant issues. Overall, women expressed substantial support for active monitoring being offered as a management approach for low-risk DCIS, and many were interested in participating in a hypothetical clinical trial. Although some women expressed concern that current management may sometimes represent overtreatment, there were mixed views about personally accepting monitoring. Women noted a number of important questions and considerations that would factor into their decision making. Our findings about women's perceptions of active monitoring for DCIS are timely while results of ongoing clinical trials of monitoring are awaited, and may inform clinicians and investigators designing future, similar trials. Exploration of offering well-informed patients the choice of non-surgical management of low-risk DCIS, even outside a clinical trial setting, may be warranted.

Can Molecular Biomarkers Help Reduce the Overtreatment of DCIS?

Ductal carcinoma in situ (DCIS), especially in the era of mammographic screening, is a commonly diagnosed breast tumor. Despite the low breast cancer mortality risk, management with breast conserving surgery (BCS) and radiotherapy (RT) is the prevailing treatment approach in order to reduce the risk of local recurrence (LR), including invasive LR, which carries a subsequent risk of breast cancer mortality. However, reliable and accurate individual risk prediction remains elusive and RT continues to be standardly recommended for most women with DCIS. Three molecular biomarkers have been studied to better estimate LR risk after BCS-Oncotype DX DCIS score, DCISionRT Decision Score and its associated Residual Risk subtypes, and Oncotype 21-gene Recurrence Score. All these molecular biomarkers represent important efforts towards improving predicted risk of LR after BCS. To prove clinical utility, these biomarkers require careful predictive modeling with calibration and external validation, and evidence of benefit to patients; on this front, further research is needed. Most trials do not incorporate molecular biomarkers in evaluating de-escalation of therapy for DCIS; however, one-the Prospective Evaluation of Breast-Conserving Surgery Alone in Low-Risk DCIS (ELISA) trial-incorporates the Oncotype DX DCIS score in defining a low-risk population and is an important next step in this line of research.

Comparison of conventional clinical models and a multigene assay to assess DCIS risk in a prospective single center study.

e12578 Background: Ductal carcinoma in situ (DCIS) is a preinvasive breast cancer typically excised and treated with adjuvant therapy. While there is consensus that this results in overtreatment, there is little agreement on who may avoid radiation or endocrine therapy. Two freely available prediction models, Van Nuys Prognostic Index (VNPI) and Memorial Sloan Kettering Nomogram (MSK-N), are commonly used to identify low-risk DCIS based on standard clinicopathological features. Oncotype DCIS is a newer commercially available tissue-based multigene assay also used to assess risk, but its use is limited due to cost and unclear value over VNPI and MSK-N. We sought to compare these tests’ agreement in determining DCIS ipsilateral breast recurrence (IBR) risk and potential to de-escalate therapy. Methods: In this subanalysis from a prospective single center clinical trial, we analyzed 38 patients with newly diagnosed pure DCIS confirmed at excision. Each risk assessment tool presents risk in a different manner. Oncotype DCIS provides multiple assessments: a raw score (0-100), a DCIS Score Category (low, intermediate, high), and a Refined Score incorporating clinical features (10-year IBR risk). The VNPI calculates a raw score (4-12) and assigns a risk category (low, intermediate, high). MSK-N calculates a 10-year IBR risk. The tests were dichotomized as low vs. not-low risk categories using these thresholds: DCIS Score Category = low, DCIS Refined Score ≤ 10% IBR risk, VNPI risk category = low, MSK-N ≤ 10% IBR risk. Agreement of the 4 models (DCIS Score Category, DCIS Refined Score, VNPI, MSK-N) were compared using Spearman’s rank correlation for continuous data; percent agreement and Cohen’s kappa (k) were used to compare categorized data. Results: There was poor agreement of continuous risk assessments across the 4 models, with only VNPI and DCIS Refined Score showing significant but moderate correlation (r = 0.53, p = 0.001; others ranged r = 0-0.27, p &gt; 0.1). The number of cases identified as low-risk for each assay was DCIS Score Category = 14 (37%), DCIS Refined Score = 3 (8%), VNPI = 1 (3%), and MSK-N = 0. Percent agreement of low vs. not-low risk categorizations between DCIS Refined Score, VNPI, and MSK-N was 92-97%, but each assay classified 3 or fewer cases as low-risk and kappa was not significant (k = 0-0.48, p &gt; .1). DCIS Score Category demonstrated 63-71% agreement with the other 3 assays (k = 0-0.26). Only 1 case was classified as low-risk DCIS on multiple tests. Conclusions: DCIS risk models have poor agreement for determining IBR risk. DCIS Score Category initially identified many low-risk lesions; however, inclusion of clinical features to create a Refined Score decreased this substantially, providing very few additional low-risk cases for de-escalation over VNPI or MSK-N. Additional studies are needed to determine precise IBR rates when these models are used for adjuvant therapy decision-making. Clinical trial information: NCT03495011 .

From the lab to the clinic: Lessons learned from a translational working group.

e12576 Background: Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET), is a phase III multicenter prospective randomized clinical trial comparing the risks/benefits of active monitoring (AM) versus surgery for women with low-risk DCIS. Funded by the Patient-Centered Outcomes Research Institute, accrual opened 06/30/17 and closed 01/13/23 with 995 women enrolled. Biospecimens (blood/tissue) and breast images were collected at specified timepoints (funded by the Breast Cancer Research Foundation) and stored in central tissue/image repositories. To date, more than 90% of requested samples/images have been submitted. Methods: In 2017, the COMET Translational Working Group (TWG) was formed to facilitate the collection, submission, storage, and subsequent analysis of biospecimens/images. The TWG, consisting of clinicians, pathologists, radiologists, researchers, and patient advocates (PAs), discuss topics such as categorization of biospecimens into discovery/validation sets; development of a pathology workflow/sample tracking process; and potential areas of future research that may improve DCIS diagnostics, prognostics, and care management. Results: The TWG consists of multiple partner institutions, and team members have complementary areas of expertise/experience. While competing views may exist, consensus has been achieved in relation to major issues such as authorship, biospecimen ownership, intellectual property and criteria relevant to patient needs, through targeted discussion at monthly meetings. Logistical barriers, including data sharing and the technicalities of biospecimen release, have also been resolved through this process. The TWG has played an integral role in resolving recruitment challenges. In 2019, guidance from the TWG related to standardizing pathology eligibility criteria resulted in evidence-based protocol amendments that subsequently increased accrual. A retrospective review of biospecimens was performed to determine adequacy for ensuing correlative molecular and spatial profiling studies. PAs are integral to the TWG, assisting with logistical issues (resource requests); identifying study topics relevant to patients; providing guidance on existing (commercial) predictive/prognostic tests; promoting effective stewardship of a finite resource (tissue samples); and ensuring that the overall focus of the TWG remains firmly on advancing clinical utility. Conclusions: The COMET TWG serves the important role of overseeing biospecimen/image collection including its use and sharing. This facilitates development of research and technology that can impact the decision for surgery vs AM in women with low-risk DCIS, and ensure the translation of research findings into everyday clinical practice. Subsequent correlative science studies identified by the TWG stand to improve future DCIS pathology diagnostics, prognostics and care management.

Active Surveillance of Atypical Ductal Hyperplasia of the Breast

BackgroundWhen needle core biopsy (NCB) of the breast yields atypical ductal hyperplasia (ADH), excision is typically recommended. The natural history of ADH undergoing active surveillance (AS) is not well described. We investigate the rates of upgrade to malignancy of excised ADH and the rates of radiographic progression under AS. Materials and MethodsWe retrospectively reviewed records of 220 cases of ADH on NCB. Of patients who had surgery within 6 months of NCB, we examined the malignancy upgrade rate. In the AS cohort, we examined rates of radiographic progression on interval imaging. ResultsThe malignancy upgrade rate among patients who underwent immediate excision (n = 185) was 15.7%: 14.1% (n = 26) ductal carcinoma in situ (DCIS) and 1.6% (n = 3) invasive ductal carcinoma (IDC). Upgrade to malignancy was less common in lesions <4 mm in size (0%) or with focal ADH (5%), and more common among lesions presenting with a radiographic mass (26%). Among the 35 patients who underwent AS, median follow-up was 20 months. Two lesions progressed on imaging (incidence 3.8% at 2 years). One patient without radiographic progression was found to have IDC at delayed surgery. The remaining lesions remained stable (46%), decreased in size (11%), or resolved (37%). ConclusionsOur findings suggest that AS is a safe approach to managing ADH on NCB for most patients. This could spare many patients with ADH from unnecessary surgery. Given that AS is being investigated for low-risk DCIS in multiple international prospective trials, these results suggest that AS should also be investigated for ADH.

Abstract P6-05-11: Active surveillance versus conventional treatment in low-risk DCIS; women’s preferences in the LORD trial

Abstract Background: Ductal carcinoma in situ (DCIS) is a potential precursor to breast cancer. Its incidence has increased multifold with the introduction of breast cancer screening and makes for 20% of all malignant breast lesions in women. DCIS has the potential to progress into invasive breast cancer. However, the majority of DCIS lesions are indolent and will never progress during the patient’s lifetime. Consequently, there is a growing concern of overdiagnosis and overtreatment for women with DCIS. The LORD trial is a non-randomized, patient preference trial comparing active surveillance to conventional treatment (i.e., breast conserving surgery with or without radiotherapy or mastectomy). The primary outcome of this trial is the percentage of women without an occurrence of ipsilateral invasive breast cancer after 10 years of follow up. Within the patient preference design, women are free to opt for either treatment arm. In addition to active surveillance of the DCIS, quality of life (QOL) of women included in the LORD trial is also actively monitored. The aims of this study were to: a) describe the distribution of participants within the treatment arms, b) identify women’s motives to opt for their preferred treatment arm, and c) assess factors associated with a preference for either treatment arm. Methods: Data from the baseline patient QOL questionnaire was collected. This questionnaire was completed after the women’s diagnosis and first consultation with their physician. Descriptive statistics were used to assess the distribution in both treatment arms. Thematic analyses were used to describe self-reported reasons for treatment selection derived from the open-ended question about treatment preference. Multivariable logistic regression analyses were used to assess associations between the patient characteristics and their preferred treatment arm. Results: In total 384 women completed the baseline questionnaire, of which 376 entered their final treatment decision. Of these women, 287 (76%) opted for active surveillance and 89 (24%) for conventional treatment. Most frequently cited reason for opting for active surveillance was that treatment was not yet necessary (55%). Also, patients’ reasons for preferring active surveillance alluded to a high level of trust in the active surveillance plan (24%) and that disease progression could be picked up and treated in a timely manner (14%). Furthermore, 11% of patients cited the advice of their healthcare professional as a reason for opting for active surveillance and 8% cited reasons relating to altruism. Most reported reasons for opting for the conventional treatment arm were avoiding unnecessary risks (26%), avoiding cancer worry (18%), the notion that what doesn’t belong, should be removed from the body (18%) and a need for closure (13%). In multivariable logistic regression analyses, high level of education (OR 2.17; 95%CI 1.09-4.38) and higher knowledge score (OR 1.8; 95%CI 1.07-3.02) were associated with a preference for conventional treatment. Furthermore, women opting for active surveillance more often reported the decision to be a shared decision between them and their healthcare professional (OR 2.30; 95%CI 1.18-4.47) compared to women who chose conventional treatment, who more often reported decision-making to be patient-driven. Age and tolerance of uncertainty were not significantly associated with treatment preference. Conclusion: The LORD trial is the first to actively offer women with low-risk DCIS a choice between conventional treatment and active surveillance. Within this trial, most women opt for active surveillance, even though clinical guidelines still recommend treatment for all women with DCIS. Women with low-risk DCIS report high levels of trust in their physicians and the safety of active surveillance. Their preferences also highlight the necessity to proof that de-escalating treatment of low-risk DCIS is safe. Citation Format: Renée S. Schmitz, Ellen G. Engelhardt, Miranda A. Gerritsma, Carine M. Sondermeijer, Sena Alaeikhanehshir, Ellen Verschuur, Marja van Oirsouw, Julia Houtzager, Rosalie Griffioen, Nina Bijker, Ritse M. Mann, Frederieke van Duijnhoven, Jelle Wesseling, Eveline Bleiker. Active surveillance versus conventional treatment in low-risk DCIS; women’s preferences in the LORD trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-11.

Abstract F1-2: Clonal evolution of DCIS to invasion

Abstract F1-2: Clonal evolution of DCIS to invasion

Clinical Outcomes of Conservative Treatment for Low-Risk Ductal Carcinoma in Situ: A Systematic Review and Pooled Analysis

AimsThe current gold standard of treatment for ductal carcinoma in situ (DCIS) is surgical resection with or without adjuvant radiotherapy. However, the increased detection and radical treatment of DCIS did not result in a declined incidence of invasive breast cancers, leading to the debate if DCIS has been overtreated. While ongoing randomised controlled trials on active surveillance of DCIS are still in progress, this systematic review aims to evaluate the best evidence on conservative treatment for DCIS from the literature. Materials and methodsThis systematic review was conducted in line with the PRISMA statement. We included all relevant studies published up to June 2022 for analysis. The primary outcomes were overall survival and breast cancer-specific survival (BCSS) of conservative treatment for DCIS. ResultsThree studies, with a total of 34 007 women with low-risk DCIS, were included in the analysis. Active and conservative treatments both resulted in excellent 10-year BCSS, with no statistically insignificant difference (98.6% versus 96.0%, 31 478 women). One study comparing 5-year BCSS of active and conservative treatments only in subjects aged over 80 years also reported [AQ1]an insignificant difference (98.2% versus 96.0%, 2529 women). One study measuring 5- and 10-year overall survival between the treatment groups also reported [AQ1]an insignificant difference (5-year: 96.2% versus 92.4%; 10-year: 85.6% versus 86.7%, 31 106 women). ConclusionBCSS between active and conservative treatment for women with low-risk DCIS is both excellent and comparable, suggesting that conservative treatment is a possible alternative without compromising survival.

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.