Chemoresistance is a major cause of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single-cell culture to identify and isolate patient-derived proliferating and quiescent ovarian cancer cells (qOvCa). RNA-seq analysis indicated that hundreds of genes that are differentially expressed in qOvCa cells are transcriptional targets of the Myocardin-Related Transcription Factor-A/Serum Response Factor (MRTFA/SRF) pathway, and both genetic disruption and pharmacologic inhibition of MRTFA/SRF interaction (with the inhibitor CCG257081) induced quiescence across multiple cancer types. MRTFA/SRF inhibition-mediated quiescence is p27/Kip1 dependent and associated with a downregulation of cell cycle regulators, NCL, MYH9, and alterations in the proteasome. We show that the MRTFA/SRF axis plays a dual role in chemotherapy resistance, with both pathway inhibition and activation contributing to chemotherapy resistance in vitro and in patient samples. CCG081 treatment results in a proteasome-dependent downregulation of the stem-cell marker CD133. Suggesting a critical role for the proteasome in quiescent cells, CCG081 therapy sensitized OvCa cells to proteasome inhibitors. In vivo, we found that CCG257081 therapy could be used to induce tumor growth-arrest and delay disease growth to improve overall survival. Moreover, we found that dual therapy with CCG081 and proteasome inhibition further improved outcomes, leading to undetectable tumors in ∼20% of mice. Together, these data suggest that the MRTFA/SRF pathway is a critical regulator of quiescence in cancer and a potential therapeutic target.

Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. How systemic and tumor microenvironment hormone signaling intersects with chronic inflammation and how this shapes aging-associated tumor biology remain incompletely understood. Here, using an aged rat model of ER+ tumors, we identify age-associated differences in tumor development and immune features. In parallel, analysis of samples from patients with ER+/HER2- breast cancer and age-matched controls demonstrated estrone-predominant systemic estrogen patterns and increased tumor HSD17B7 expression in older patients, consistent with enhanced local estrone-to-estradiol conversion. In patient-derived organoids from older women, pharmacologic inhibition of HSD17B7 reduced estrogen conversion and proliferation-associated transcriptional programs. Tumors from older patients also exhibited chemokine enrichment, including CCL2, associated with immunosuppressive macrophage features. Targeting both estrogen signaling and chemokine pathways attenuated macrophage polarization ex vivo. These findings support a model linking age-associated hormonal and inflammatory changes to features of a tumor-permissive microenvironment in ER+ breast cancer.

e12616 Background: The optimal extent of axillary management in patients with biologically low-risk, node-positive breast cancer remains uncertain. While OncotypeDX has refined systemic therapy decision-making in estrogen receptor(ER)–positive, HER2-negative disease, its role in guiding locoregional treatment de-escalation is less well-defined. The ongoing TAILOR-RT trial aims to clarify whether regional nodal irradiation (RT) can be safely omitted in select low-risk patients with limited nodal disease. Using a national database, we evaluated the extent of pathologic nodal burden and the association between regional radiotherapy and overall survival in this population with biologically favorable disease and limited nodal burden. Methods: Using the National Cancer Database (NCDB), women age≥40Y with ER+HER2− breast cancer with OncotypeDX Score<18 were identified. Consistent with TAILOR-RT eligibility, the cohort was defined by limited nodal disease (cN1). First, to assess the possibility of greater extent of pathologic nodal burden, we limited our population to only those patients who underwent upfront axillary lymph node dissection (ALND) or initial sentinel lymph node biopsy (SLNB) converted to ALND. Secondarily, we performed a Kaplan-Meier analysis of all patients meeting the above inclusion criteria, who underwent SLNB or ALND, to determine the impact of adjuvant radiotherapy on overall survival in this low-risk population. Results: In total, 3,646 patients met inclusion criteria who had ALND, with 2,745 (75%) having invasive ductal carcinoma and 788 (22%) lobular histology. Median age was 63 years (IQR 54–70). Median lymph nodes examined was 12 (IQR 8–17), with a median of 2 positive nodes (IQR 1–3). On final pathology, 814 patients (22%) had >3 positive nodes, suggesting higher nodal burden than previously estimated. Next, 5101 patients were identified who underwent SLNB or ALND, and had documented receipt (2574, 50.5%) or omission (2527, 49.5%) of regional nodal therapy. Following SLNB and ALND, respectively, 54% (1130/2090) and 48% (1444/3011) received regional radiation. Due to the possibility of selection bias prompting either SLNB or ALND, survival between these groups was analyzed separately to assess the impact of regional radiotherapy, which did not differ (ALND 5YS: NoRT 91.7% vs. RT 93.2% & SLNB 5YS: NoRT 94.7% vs RT 93.1%, p =0.12). Conclusions: While we acknowledge NCDB limitations, including inability to assess breast surgery type, receipt of endocrine therapy, or recurrence, we provide reassuring evidence that most patients meeting TAILOR-RT eligibility did not have markedly higher nodal burden on final pathology. Furthermore, this population may have been adequately treated with axillary surgery alone, without regional radiotherapy. Pending prospective findings, our report further supports axillary therapy de-escalation to reduce morbidity.

PURPOSE:For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible. EXPERIMENTAL DESIGN:In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET). RESULTS:ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pretreatment ctDNA positivity was associated with a significant risk of tumor progression (HR, 30; 95% confidence interval, 4.4-209; P = 0.0011). No patients with pretreatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation. CONCLUSIONS:These findings suggest that ctDNA may be a modality to identify older patients who can safely receive long-term pET, warranting future evaluation in a randomized setting.

BACKGROUND:Postoperative complications of mastectomy include seroma, hematoma, and infection. Hemostatic agents such as Arista AH absorbable hemostatic powder (AHP) is an FDA approved surgical adjunct to control intraoperative bleeding. This study evaluated the impact of AHP on postoperative outcomes in patients undergoing mastectomy. METHODS:Patients undergoing mastectomy between May 2022 and May 2024 were retrospectively identified from a prospectively maintained single-institution cancer registry. Inclusion criteria were patients undergoing therapeutic or prophylactic total mastectomy without immediate reconstruction. Statistical analysis included Chi-squared, Mann-Whitney U, and Student's t-tests. RESULTS:Of 644 mastectomies, 45% received AHP and 55% did not. Hematoma occurred in 3.8% of the AHP group versus 7.9% in the no AHP group (P-value = .03). Seroma occurred in 22.2% of the AHP group versus 25% in the no AHP group (P-value = .41). Among patients with seroma or hematoma, postoperative infection rates were not significantly different regardless of AHP usage (P-value = .90). In patients who received AHP, a history of ipsilateral breast surgery was significantly associated with seroma (P-value = .02). In patients who did not receive AHP, neoadjuvant therapy (P-value = .02) and previous ipsilateral chest wall irradiation (P-value = .04) were significantly associated with seroma, while anticoagulation medication use was significantly associated with hematoma (P-value = .01) and seroma (P-value = .03). CONCLUSIONS:In patients undergoing mastectomy without immediate reconstruction, AHP use was associated with decreased hematoma rate, with no differences in seroma, infection, or drain duration. Hematoma and seroma rates were increased in patients on peri‑operative anticoagulation who did not receive AHP, suggesting that AHP use may benefit select patient populations.

Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8+, TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to αOX40 and αPD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8+ effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.

TPS656 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for men. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across 9 sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for 3 weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) vs tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) vs anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is 4 months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha = 10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: change in estradiol and testosterone levels from baseline, preoperative endocrine prognostic index (PEPI) score at surgery, adverse events, and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened at Dana-Farber in October 2023, and is also open at Mayo Clinic, MD Anderson Cancer Center, Georgetown University, University of North Carolina, University of Pennsylvania, University of Pittsburgh, and Vanderbilt University. One more site will open in 2026. Clinical trial information: NCT05501704 .

Background: Over 50,000 women in the United States will be diagnosed with ductal carcinoma in situ (DCIS) this year alone. Almost all of these diagnoses will be made in completely asymptomatic individuals with a highly variable risk of progression to invasive cancer. In some low-risk malignancies, “watchful waiting,” is offered as a treatment option. Such an approach is likely reasonable for some DCIS and could reduce the harms of treatment while helping to identify those most likely to benefit from more aggressive therapy. To date, this approach has not been tested in a clinical trial setting. Methods: The COMET study (Comparing an Operation to Monitoring, with or without Endocrine Therapy for low risk DCIS; AFT-25) is a large pragmatic randomized non-inferiority trial that compares oncologic outcomes between patients randomized to guideline concordant care (GCC; surgery +/- radiation therapy) or active monitoring (AM). The study population were women seeking treatment for DCIS at one of the Alliance Clinical Trial sites. Eligible participants were age>40 with low-intermediate grade estrogen and/or progesterone receptor positive, HER2 receptor negative (if HER2 tested) DCIS on core biopsy without microinvasive or invasive cancer. The choice for endocrine therapy was offered in both groups. Participants in the AM group had surgical intervention only upon diagnosis of invasive progression. All study endpoints were collected prospectively. Results: This is the first planned interim Intention-to-Treat (ITT) analysis of the COMET trial primary endpoints at a median follow up of XX months. We will present patient characteristics for the 997 participants who enrolled in the study and were randomized to either GCC or AM. The primary endpoint to be presented is whether the ipsilateral invasive cancer rate for AM is non-inferior to that for GCC. Characteristics of invasive cancer events in the two groups will be compared. Secondary endpoints (rates of mastectomy, radiation, chemotherapy) and survival endpoints between groups will also be presented. Conclusion: These data will provide the first randomized trial evidence of whether an active monitoring strategy is a safe alternative for women with low-risk DCIS. Longer-term data could support practice changing guidance as to how DCIS is managed and treated and will have future implications for treatment guidelines for these excellent prognosis patients. Citation Format: Eun-Sil Hwang, Terry Hyslop, Thomas Lynch, Marc D Ryser, Anna Weiss, Anna Wolf, Kelsey Norris, Meredith Witten, Lars Grimm, Stuart Schnitt, Sunil Badve, Rachel Factor, Elizabeth Frank, Deborah Collyar, Desiree Basila, Donna Pinto, Mark A Watson, Robert West, Louise Davies, Jenny Donovan, Ayako Shimada, Yutong Li, Yan Li, Antonia V Bennett, Shoshana Rosenberg, Jeff Marks, Eric Winer, Marc Boisvert, Armando Giuliano, Kelsey Larson, Kathleen Yost, Priscilla McAuliffe, Lisa Carey, Alastair Thompson, Ann H Partridge. Early Oncologic Outcomes Following Active Monitoring or Surgery (+/- Radiation) for Low Risk DCIS: the Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET) Study (AFT-25) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-05.

Importance:Active monitoring (AM) for low-risk ductal carcinoma in situ (DCIS) has been considered as a potential alternative to guideline-concordant care (GCC; inclusive of surgery with or without radiation). Reported data comparing patient-reported outcomes (PROs) between GCC and AM for DCIS are lacking. Objective:To compare PROs at baseline and over time in patients with low-risk DCIS randomized to receive either AM or GCC. Design, Setting, and Participants:This prespecified secondary outcome analysis used prospectively collected validated questionnaires at baseline, 6 months, 1 year, and 2 years from participants enrolled from June 2017 to January 2023 in the Comparing an Operation to Monitoring, With or Without Endocrine Therapy (COMET) study for low-risk DCIS, which randomized participants to receive GCC or AM. Intervention:Randomization to GCC or AM. Main Outcomes and Measures:Context-relevant PROs, including health-related quality of life, anxiety, depression, and symptoms measured by validated survey instruments. Mixed models, including sensitivity analyses, with group, point, and group-by-point effects were used to compare PROs between groups. Results:Of the 957 participants in COMET, 225 (24%) were younger than 55 years at enrollment, 325 (34%) were aged 55 to 65 years, and 403 (42%) were older than 65 years, and 953 (99.5%) completed questionnaires at some point within the first 2 years, with a completion rate of more than 83% at all points. Quality of life, anxiety, depression, worries about DCIS, and symptom trajectories were comparable between groups, with modest fluctuations over time of limited clinical significance. Physical functioning was the only specific Medical Outcomes Study 36-item short-form health survey (SF-36) domain for which changes in the score trajectory differed by group over time, with mean scores ranging from 50 (baseline) to 48 (6, 12, and 24 months) in the GCC group and 50 (baseline) to 47 (12 months) and 48 (6 and 24 months) in the AM group (pooled SD, 9.9; P = .01), although these were also of limited clinical significance. Conclusions and Relevance:In this prespecified secondary analysis of the COMET prospective randomized trial, the overall lived experience of women randomized to undergo AM for low-risk DCIS was similar to that of women randomized to GCC during the 2 years following diagnosis. Trial Registration:ClinicalTrials.gov Identifier: NCT02926911.

INTRODUCTION:Oncoplastic breast conserving surgery (OBCS) can offer oncologically safe and cosmetically satisfying results for patients with breast cancer. However, the relative oncologic safety of high tumor-volume oncoplastic resections is largely unknown. This study investigated the association between tumor-to-breast volume ratio, recurrence, and surgical complications in OBCS. The relationship between tumor-to-breast ratio and quality of life was also assessed. METHODS:A retrospective review was performed for all women who underwent OBCS for breast cancer between 2010 and 2023 at a university-based tertiary referral center. The BREAST-Q questionnaire was utilized to assess quality of life outcomes. Tumor-to-breast ratio was calculated by dividing lumpectomy specimen volume by total breast volume. Surgical complications, reexcision, local recurrence, and revision procedures were noted. Multivariate logistic regression was performed to assess the association of tumor-to-breast ratio with outcomes. RESULTS:This study included 192 patients, of which 65 (34%) completed the BREAST-Q. Median tumor-to-breast volume ratio was 7.3% (IQR, 3.6%-12.5%). Quartiles of tumor-to-breast ratio were not associated with local cancer recurrence rate (P = 0.50), reexcision (P = 0.29), wound-related complications (P = 0.45), complications requiring reoperation (P = 0.34), and elective revision of reconstruction (P = 0.67). BREAST-Q scores for Psychosocial Well-being, Physical Well-being, and Overall Satisfaction were similar across tumor-to-breast ratio. Cancer worry was significantly higher in larger tumor-breast ratio quartiles (P = 0.03). CONCLUSIONS:These data suggest that OBCS is a reasonable approach for patients with higher tumor-to-breast ratio. Complications and quality of life metrics did not appear to vary significantly with increasing tumor size, except for "cancer worry," which was higher among patients with larger tumor-breast ratio patients.

Flat epithelial atypia (FEA), a rare breast proliferative lesion, is often diagnosed following core biopsy (CB) of mammographic microcalcifications. In the prospective multi-institution TBCRC 034 trial, we investigate the upgrade rate to ductal carcinoma in situ (DCIS) or invasive cancer following excision for patients diagnosed with FEA on CB. Patients with a breast imaging reporting and data system (BI-RADS) ≤ 4 imaging abnormality and a concordant CB diagnosis of FEA were identified for excision. Upgrade rates were determined on the basis of local and central pathology review. The prespecified threshold to omit excision of FEA on CB was an upgrade rate of ≤ 3

Women receiving aromatase inhibitors (AIs) for breast cancer frequently experience musculoskeletal symptoms (AIMS) including joint pain, stiffness, and muscle weakness. Aerobic exercise may reduce AIMS, but the evidence is inconclusive. This investigation examined whether aerobic exercise reduces pain in women with breast cancer. Pain was a secondary outcome of a randomized controlled trial where postmenopausal women with breast cancer receiving AIs (N = 136) with or without pain were randomized to 6 months of moderate-intensity aerobic exercise (n = 70) or usual care (n = 66). The primary (Brief Pain Inventory severity, interference and worst pain) and secondary (SF-36 Bodily Pain and Breast Cancer Prevention Trial Symptom Checklist Musculoskeletal Pain) pain outcomes were assessed at pre-randomization (T1) and post-intervention (T2). Linear mixed modeling with linear contrasts was used to examine the effect of group assignment on outcomes. Participants were a median = 4.7 months post-breast cancer diagnosis at T1. Group-by-time interactions were observed for pain severity ( x = 0.848, 95 x = 0.997, 95 x = 1.371, 95

Background: Data comparing patient-reported outcomes (PROs) comparing management strategies for low-risk ductal carcinoma in situ (DCIS) are lacking. Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET), for low-risk DCIS is a prospective randomized controlled trial that evaluated the effects of active monitoring (AM) compared to breast surgery (lumpectomy followed by radiation vs. unilateral mastectomy vs. bilateral mastectomy) on PROs including quality of life (QOL), anxiety, depression and specific symptoms. Methods: We compared PROs among patients who completed questionnaires at baseline prior to randomization, at 6 months and 1 year after randomization, then annually in years 2-5. Patients completed validated measures that assessed QOL, anxiety and depression and breast cancer treatment-related symptoms using the SF-36, EQ-5D-5L, a modified 19-item version of the Breast Cancer Prevention Trial (BCPT) Symptom Checklist, the Breast-Q, four items from the Quality of Life in Adult Cancer Survivors (QLACS), the State Trait Anxiety Inventory (STAI) scale and the Center for Epidemiologic Studies Depression Scale (CES-D-10), as well as the Breast Cancer Pain and Brief Pain Inventory. Results: We will present patient characteristics for the 997 patients who enrolled in the study and PRO questionnaire completion rates overall and within relevant subgroups to assess response bias. The analysis of differences by randomized group will include differences in the SF-36, STAI and CES-D, as well as the Breast Cancer Pain, Brief Pain Inventory and BCPT symptoms. We will also assess group differences over time and within specific subgroups (e.g., by age). Conclusion: In this analysis of PROs after active monitoring or surgical +/- radiation management for low-risk DCIS, quality of life, anxiety, depression and symptom patterns (severity, recovery, decline etc.) likely differed between the two groups; how they differed will be presented and whether these differences persisted over time. Citation Format: Ann Partridge, Terry Hyslop, Shoshana Rosenberg, Antonia Bennett, Sarah Drier, Mattias Jonsson, Ayako Shimada, Yutong Li, Yan Li, Thomas Lynch, Elizabeth Frank, Deborah Collyar, Desiree Basila, Donna Pinto, Anna Weiss, Anna Wolf, Kelsey Norris, Meredith Witten, Marc Boisvert, Armando Giuliano, Kelsey Larson, Kathleen Yost, Priscilla McAuliffe, Amy Krie, Nina Tamirisa, Sonja Darai, Lisa Carey, Alastair Thompson, Shelley Hwang. Patient Reported Outcomes Following Active Monitoring or Surgery (+/- Radiation) for Low Risk DCIS in the Comparing an Operation to Monitoring, with or without Endocrine Therapy (COMET) Study (AFT-25) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-06.

1533 Background: In women newly diagnosed with unilateral breast cancer (BC), contralateral risk-reducing mastectomy (CRRM) to decrease risk for additional primary BC is an appropriate option for some individuals, such as those with significantly increased risk due to a pathogenic variant (PV) in a breast cancer predisposition gene. Genetic testing at the time of BC diagnosis for young women has become more available and could aid in the decision-making process. We evaluated the trends for CRRM in a cohort of women diagnosed with BC at age ≤45 years who were seen in a multidisciplinary clinic where genetic counseling and testing is offered to each patient. Methods: A single institution, prospectively maintained database of patients seen in a BC multidisciplinary clinic between November 2014 and June 2019 was reviewed. Patients were included if they had non-metastatic, unilateral BC diagnosed ≤45 years of age, and underwent genetic testing at the time of BC diagnosis. Associations between surgical treatment (lumpectomy, mastectomy, or mastectomy with CRRM) and age at diagnosis, BC stage, family history, and genetic testing results were evaluated. Results: 184 patients were included in the analysis. The prevalence of a PV in a breast cancer predisposition gene was 15.8% (29/184; 1 in ATM, 12 in BRCA1, 8 in BRCA2, 5 in CH EK2, 2 in NBN, and 1 in NF1). 69% of the PV were in BRCA1 and BRCA2. 126 (68.4%) tested negative, and 29 (15.8%) had a variant of uncertain significance (VUS) in various genes. Overall, 63 patients (34.2%) elected to have CRRM. Of the 29 patients with a PV, 24 (82.8%) had CRRM. Women who chose CRRM were younger, more likely to test positive for a PV in a breast cancer predisposition gene, and more likely to have a significant family history of breast and/or ovarian cancer. Among the 155 patients who tested negative or had a VUS, there was no statistically significant association between CRRM and age (p = 0.58), test result (negative vs. VUS. p = 0.12), or family history (p = 0.32). Conclusions: For young women with BC seen in a multidisciplinary clinic, a younger age, significant family history, and positive genetic testing result were found to be associated with the decision to undergo CRRM. Among those without a genetic predisposition, having a VUS result was not associated with choosing CRRM. Incorporation of genetic services in the initial evaluation of young patients newly diagnosed with BC could add relevant information in surgical decision making and promote risk-appropriate management.

Many women ≥75 years of age continue to undergo screening for breast cancer despite a lack of evidence supporting this practice. Evidence from the past 5 years suggests rising rates of breast cancer diagnosis in this age group without a corresponding increase in survival — either because the tumour itself is biologically indolent or because life-limiting comorbidities render a biologically aggressive tumour unlikely to further reduce life expectancy. Here, we review what we know, and what we do not know, about screening and overdiagnosis of breast cancer in women ≥75 years of age and build a case for active monitoring for selected screen-detected breast cancers in this population.

Spatial transcriptomics provides insights into tissue architecture by linking gene expression with spatial localization. Current deconvolution methods rely heavily on single-cell RNA sequencing (scRNA-seq) references, which are costly and often unavailable, mainly if the tissue under evaluation is limited, such as in a core biopsy specimen. We present a novel tool, CITEgeist, that deconvolutes spatial transcriptomics data using antibody capture from the same slide as the reference, directly leveraging cell surface protein measurements from the same tissue section. This approach circumvents the limitations of scRNA-seq as a reference, offering a cost-effective and biologically grounded alternative. Our method employs mathematical optimization to estimate cell type proportions and gene expression profiles, incorporating sparsity constraints for robustness and interpretability. Benchmarks against state-of-the-art deconvolution methods show improved accuracy in cell type resolution, particularly in dense tumor microenvironments, while maintaining computational efficiency. This antibody-based tool advances spatial transcriptomics by providing a scalable, accurate, and reference-independent solution for deconvolution in complex tissues. We validate this tool by using a combined approach of simulated data and clinical samples by applying CITEgeist to translational pre-treatment and post-treatment ER+ breast tumors from an ongoing clinical trial, emphasizing the applicability and robustness of CITEgeist.

Abstract Background Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. Methods We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up. Results Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. Conclusions Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women.

Background: Adjuvant endocrine therapy (ET) recommendations for patients (pts) with invasive lobular carcinoma (ILC) are no different than for other breast cancer subtypes. However, due to unique differences in estrogen pathway signaling of ILC, identifying biological markers of ET sensitivity or resistance could have a major impact on its clinical management. Pre-clinical studies suggest that fulvestrant may be more effective than anastrozole or tamoxifen for ILC. Here we test reduction in the proliferation marker Ki67 as a surrogate for treatment response to ET. Methods: This open label, randomized, controlled, multicenter phase 0 window of opportunity trial (NCT02206984) was conducted at 12 TBCRC institutions between 10/8/15 and 7/28/23. Postmenopausal women with previously untreated hormone receptor-positive (HR+), HER2 negative ILC, centrally histologically confirmed on diagnostic core needle biopsy (CNB), measuring ≥ 1 cm, were eligible. Stage IV was excluded. Pts were randomized 1:1:1 to fulvestrant (500 mg IM on days 1 and 15), anastrozole (1mg/day) or tamoxifen (20 mg/day). After 21-27 days of treatment, pts underwent operation (from which a CNB of residual tumor bed was taken) or a post-treatment image-guided CNB. The primary endpoint was change in Ki67 immunohistochemistry at post-treatment compared to baseline. Given the log-normal distribution of Ki67 measurements generally observed in this population, values were log-transformed for statistical analysis [log (post/pre)]. Group medians were compared using a quantile regression linear model adjusting for institutional-level random effects. A linear mixed model (glmmTMB R package) was fit that allowed for treatment level error variance. Post-hoc pairwise comparison of log(post/pre) were performed using Tukey adjustment for multiple comparison. Results: 201 women were randomized, 172 completed the assigned treatment, and 138 (fulvestrant n=37; anastrozole n=49; tamoxifen n=52) had evaluable pre- and post-treatment tissue. No serious adverse events or deaths occurred. Pre-treatment demographic and tumor characteristics were well-balanced between the treatment groups. Median [range] age was 67 [48-86] years. Race was reported as Asian in 2 (1.5%), Black in 15 (10.9%), other in 4 (2.9%) and White in 117 (84.8%). Presenting clinical stage was IA in 54 (39.1%), IB in 4 (2.9%), IIA in 51 (37%), IIB in 19 (13.7%), IIIA in 4 (2.9%), IIIB in 5 (3.6%), and IIIC in 1 (0.7%). Median H-score [IQR] was ER 260 [50], PR 140 [215]. In the fulvestrant, anastrozole and tamoxifen groups respectively, pre-treatment Ki67 [IQR] was 13.8 [13.5], 13.6 [8.7], and 12.6 [11.9]; and post-treatment Ki67 [IQR] was 4.8 [5.4], 4.5 [5.6], and 5.7 [10]. A statistically significant reduction in Ki67 was found favoring fulvestrant vs tamoxifen (p=0.0419). No significant difference after adjustment was seen between anastrozole and tamoxifen (p = 0.2602) or between fulvestrant and anastrozole (p = 0.6643). Conclusions: A greater reduction in Ki67 was seen post-treatment in CNB of pts with ILC treated with fulvestrant vs tamoxifen. Interestingly, tamoxifen treatment resulted in a reduction in Ki67 of a similar magnitude to anastrozole, despite clinical concerns about its reduced efficacy in ILC. Planned correlative studies will determine whether Ki67 reduction is associated with alterations in expression of ER and ER-regulated genes and/or in other novel pathways, potentially opening avenues for improved treatment strategies in ILC. Citation Format: Priscilla McAuliffe, Clark BZ, Hieken TJ, Mukhtar RA, Linden H, Nangia J, Gallagher K, Stringer-Reasor E, Bedrosian I, Feldman S, Nanda R, Boisvert M, Rothman J, Sikora MJ, Atkinson JM, Thorpe H, Tatsuoka C, Lee AV, Thompson A, Davidson NE, Oesterreich S, Jankowitz RC; on behalf of the Translational Breast Cancer Research Consortium (TBCRC). Endocrine Response in Women with Invasive Lobular Carcinoma (TBCRC 037): A Multicenter Randomized Clinical Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS18-09.

Importance: Active monitoring for low-risk ductal carcinoma in situ (DCIS) of the breast has been proposed as an alternative to guideline-concordant care, but the safety of this approach is unknown. Objective: To compare rates of invasive cancer in patients with low-risk DCIS receiving active monitoring vs guideline-concordant care. Design, setting, and participants: Prospective, randomized noninferiority trial enrolling 995 women aged 40 years or older with a new diagnosis of hormone receptor-positive grade 1 or grade 2 DCIS without invasive cancer at 100 US Alliance Cancer Cooperative Group clinical trial sites from 2017 to 2023. Interventions: Participants were randomized to receive active monitoring (follow-up every 6 months with breast imaging and physical examination; n = 484) or guideline-concordant care (surgery with or without radiation therapy; n = 473). Main outcomes and measures: The primary outcome was 2-year cumulative risk of ipsilateral invasive cancer diagnosis, according to planned intention-to-treat and per-protocol analyses, with a noninferiority bound of 0.05%. Results: The median age of the 957 participants analyzed was 63.6 (95% CI, 55.5-70.5) years in the guideline-concordant care group and 63.7 (95% CI, 60.0-71.6) years in the active monitoring group. Overall, 15.7% of participants were Black and 75.0% were White. In this prespecified primary analysis, median follow-up was 36.9 months; 346 patients had surgery for DCIS, 264 in the guideline-concordant care group and 82 in the active monitoring group. Forty-six women were diagnosed with invasive cancer, 19 in the active monitoring group and 27 in the guideline-concordant care group. The 2-year Kaplan-Meier cumulative rate of ipsilateral invasive cancer was 4.2% in the active monitoring group vs 5.9% in the guideline-concordant care group, a difference of -1.7% (upper limit of the 95% CI, 0.95%), indicating that active monitoring is not inferior to guideline-concordant care. Invasive tumor characteristics did not differ significantly between groups. Conclusions and relevance: Women with low-risk DCIS randomized to active monitoring did not have a higher rate of invasive cancer in the same breast at 2 years compared with those randomized to guideline-concordant care.