639 Background: Large cohort studies have shown a survival benefit with the use of GLP1 receptor agonists (GLP1 RA) in cancer patients. The impact of GLP1 RA usage in breast cancer (BC) and the different subtypes is unknown. To investigate the potential influence of GLP1 RA usage on BC survival, a study was conducted on a large institutional database. Methods: A de-identified institutional database identified newly diagnosed Stage I, II, and III BC patients from 2005 to present and use of GLP1 RA. The study compared survival rates for BC patients with and without GLP1 RA and further stratified by BC subtype [ER+HER2-, HER2+, ER-PR-HER2-(triple negative BC (TNBC))], BMI, and age. Kaplan-Meier survival curves were used to estimate overall survival. This study analyzed de-identified data accessed through Mayo Clinic Platform Discover. Per 45 CFR 46.102, this activity did not require IRB review. Data was extracted using an established privacy-preserving protocol and de-identified via expert determination under the HIPAA Privacy Rule. Raw EHR data and other unreported data cannot be shared due to de-identification parameters. Results: 88015 BC patients were identified, of which 3919 (4.5%) received GLP1 RA. The 5-year survival rate was 98.5% with vs 85.5% without GLP1 RA (p-value <0.0001). The survival benefit persisted for different BMI’s and ages: BMI >30 (98.4% vs 85.1%), >25 (98.4% vs 85.4%), and age <50 (99.5% vs 89.3%) and >50 (98.1% vs 84.8%) [all p<0.0001]. 21770 patients with ER+ disease were identified, of which 1412 (6.5%) received GLP1 RA. The 5-year survival rate was 99.0% vs 87.7% (p-value <0.0001). The survival benefit persisted by BMI and age: BMI >30 (99.0% vs 86.2%), >25 (98.9% vs 87.1%) and age <50 (99.6% vs 90.5%) and >50 (98.7% vs 87.2%) [all p<0.0001]. 3599 patients with HER2+ disease were identified, of which 202 (5.6%) received GLP1 RA. The 5-year survival rate was 99.3% vs 80.1% (p-value <0.0001). The survival benefit persisted by stratification: BMI >30 (100.0% vs 80.0%, p-value <0.0004), and <25 (97.7% vs 76.2%, p-value <0.019), and age <50 (100% vs 87.0%, p-value <0.043) and > 50 (99.0% vs 77.2%, p-value <0.0002). 8389 patients with TNBC disease were identified, of which 360 (4.3%) received GLP1 RA. The 5-year survival rate was 91.0% vs 71.9% (p-value <0.0001). The survival benefit persisted by stratification: BMI >30 (96.4% vs 72.9%, p-value <0.0001), >25 (93.2% vs 71.8%, p-value <0.0001), and age <50 (96.0% vs 73.0%, p-value <0.0028) and >50 (88.9% vs 71.8%, p-value <0.0001). For those TNBC patients who received GLP1 RA, having a BMI >30 conferred a protective effect with a 5-year survival rate was 97.9 vs 89.8% (p-value <0.0014). Conclusions: The study suggests that GLP1-RA improves 5-year survival rates of patients with BC and this applies to all subtypes of BC. These results suggest that further study of the impact of GLP1-RA on BC patients is warranted.

e12749 Background: Breast cancer (BC) survivors are at higher risk for recurrence or new primary disease and often require complex surveillance imaging. Use of contrast enhanced surveillance imaging modalities with contrast-enhanced digital mammography (CEM) and magnetic resonance imaging (MRI) has increased in recent years. This study evaluates characteristics of those BC survivors who receive contrast enhanced imaging and whether the addition of contrast enhanced imaging affects biopsy outcomes in BC survivors. Methods: An IRB-approved retrospective chart review identified female BC survivors who underwent breast surgery and subsequent surveillance imaging at a single academic center between 2016 and 2025. Surveillance episodes were categorized as mammography alone versus mammography with addition of CEM and/or MRI. Multivariable generalized estimating equations were used to compare patient and tumor characteristics associated with enhanced imaging modality use. Similarly rates of biopsy and cancer were evaluated with enhanced imaging use. Results: A total of 4,050 surveillance imaging episodes in 861 patients were identified and 54 resulted in biopsy-proven malignancy. Mammography alone was performed in 3,459 episodes, while enhanced imaging with CEM or MRI was used in 591 (14.6%) episodes. Use of CEM or MRI for surveillance imaging increased over time. In 2016, surveillance imaging consisted predominantly of mammography alone (93.3%) with 6.6% incorporating MRI or CEM. By 2025, mammography only surveillance decreased to 78.4% while use of MRI or CEM increased to 21.6%. Use of contrast enhanced imaging was associated with higher incidence rate ratios (IRR) for dense breast tissue [IRR 2.33; 95% CI 1.92, 2.82), p < 0.001] and less frequently used among patients aged 65–79 years [IRR 0.60, 95% CI 0.49, 0.74; p < 0.0001] and > = 80 years of age [IRR 0.40; 95% CI 0.24, 0.66; p < 0.001]. Ductal carcinoma in situ (DCIS) (IRR 3.09, p = 0.0061), and immunotherapy use (IRR 2.56, p = 0.0006) also were associated with increased use of CEM/MRI enhanced imaging. Biopsies were performed in 146 (4.2%) mammography alone episodes and 55 (9.3%) enhanced imaging episodes [IRR 2.20; 95% CI 1.63, 2.96; p < 0.001]. Surveillance with mammography yielded malignant biopsy results in 39 (1.1%) episodes, compared with 15 (2.5%) episodes using enhanced imaging [IRR 2.25; 95% CI 1.25, 4.06; p = 0.007). Conclusions: In breast cancer surveillance at our institution, the addition of contrast enhanced imaging modalities were utilized in a minority of surveillance episodes but did increase over time and were higher in patients with dense breasts. CEM or MRI usage demonstrated higher biopsy rates and increased malignancy detection compared with mammography alone, but the incidence of a positive biopsy was low. These findings suggest and are in keeping with 2023 ACR guidelines that enhanced imaging may improve cancer detection in select breast cancer survivors.

9568 Background: Stage IIB/C cutaneous melanoma is associated with high recurrence risk, however stratification of risk in relation to time after surgery has not been comprehensively evaluated. We evaluated recurrence-free survival (RFS) at key time points, stratified by clinicopathologic factors, to identify patients (pts) at higher recurrence risk and personalize postoperative surveillance strategies. Methods: In this multi-institutional, international retrospective cohort study from the Sentinel Lymph Node Working Group database, we included pts with pathologic T3b/T4a/T4b and N0 disease who underwent surgical resection and sentinel node biopsy from 1994-2025. The type of first recurrence (local, regional, distant) was characterized based on time category (0-12, 12-24, 24-60, and 60+ months after surgery). Restricted mean survival time (RMST) analysis was used to measure the average survival time up to a specified time point (6-, 12-, 24-, and 60-months after surgery), and associations of clinicopathologic variables (age, sex, Breslow thickness, ulceration and lymphovascular invasion [LVI]) with RFS. Results: We included 2514 stage IIB/C pts from 19 sites in 4 countries, with a median follow-up of 53 (stage IIB) and 49 (stage IIC) months. 675 (27%) pts experienced a recurrence (92 [14%] local, 238 [35%] regional and 345 [51%] distant), and 400 (59%) recurrences occurred within 24 months. The proportion of distant recurrences as the first recurrence increased significantly with time, comprising 39%, 50%, 62%, and 59% of recurrences in the 0-12, 12-24, 24-60, and 60+ month time categories respectively (χ 2 p<0.001). No significant differences were observed for the included clinicopathologic variables for 6-month RMST estimates. At 12 months, RMST estimates for thickness ≥4 mm (11.2 vs 11.6 months for thickness 2-3.99 mm, p<0.001) and presence of LVI (10.7 vs 11.4 months, p=0.009) were significantly different. 24-month RMST estimates differed for male sex (20.7 vs 21.5 months vs females, p=0.002), thickness ≥4 mm (20.5 vs 21.9 months, p<0.001), and presence of LVI (19.0 vs 21.1 months, p<0.001). Lastly, 60-month RMST estimates differed for male sex (42.0 vs 45.2 months, p=0.001), thickness ≥4 mm (41.5 vs 46.2 months, p<0.001), LVI (36.0 vs 43.7 months, p<0.001), and age >65 years (41.5 vs 46.4 for age <42, p=0.022). Conclusions: In this real-world, multi-center analysis of pathologic stage IIB/C melanoma pts, recurrence patterns varied based on time after surgery. Breslow thickness, LVI, male sex, and age were significantly associated with earlier recurrence at different time intervals on RMST analysis. Additionally, given that >50% of first recurrences 12+ months after surgery were distant, active surveillance for distant relapses may be warranted.

Although most melanomas develop de novo, about 30

BACKGROUND:Recently, a model to predict 5-year recurrence-free survival (RFS) and melanoma-specific survival (MSS) after sentinel lymph node biopsy (SLNB) was published. The aim of this study was to validate that model in a large independent international cohort. METHODS:The database of the Sentinel Lymph Node Working Group (SLNWG) was analysed for patients with malignant melanoma who underwent SLNB. Patients with clinical stage III melanoma, a history of other malignancies, or receiving concomitant systemic therapies during follow-up were excluded. The model's predictive performance was evaluated using discrimination and calibration metrics in the eligible cohort. Decision curve analysis was performed to assess the clinical value of the model. RESULTS:The external validation cohort consisted of 6174 patients of the SLNWG from the USA, Europe, and Israel. A positive sentinel node was found in 788 patients (12.8%). The area under the time-dependent receiver operating characteristic (ROC) curve of the external validation was 0.76 (95% c.i. 0.74 to 0.77) for RFS and 0.79 (95% c.i. 0.76 to 0.81) for MSS. The model was well calibrated, as the observed 5-year survival rates aligned closely with the predicted survival rates (calibration slope of 0.98 for RFS and calibration slope of 0.99 for MSS). The model provided a net benefit versus the 'treat all' and 'treat none' strategies at the predetermined probability threshold for recurrence of 45%. CONCLUSION:The model demonstrated good performance in a large heterogeneous independent cohort, emphasizing its robustness. Decision curve analysis revealed a clear net benefit of the model over a treat all strategy, highlighting its potential for clinical use.

Background The relationship between tumor infiltrating lymphocytes (TIL) and survival in melanoma is poorly understood. We present a large multicenter study assessing the association between TIL and survival. Methods The Sentinel Lymph Node Working Group database was queried from 1993 to 2024 for cases with known TIL and survival data. TIL was analyzed dichotomously and stratified as non-brisk, brisk, and absent. Clinicopathologic factors were correlated with melanoma-specific survival (MSS), overall survival (OS), and recurrence-free survival (RFS). Results Among 4957 patients, TIL was present in 3980 (80.2%) of patients. TIL was prognostic of MSS (p=0.0033), OS (p=0.0053), and RFS (p=0.0011). In the stratified analysis, brisk TIL was more strongly associated with MSS, OS, and RFS than non-brisk TIL (all p<0.04). Among patients with a positive sentinel lymph node, TIL was prognostic of MSS, OS, and RFS (all p<0.03). Conclusions TIL is strongly predictive of survival in melanoma and may be useful in risk stratification when deciding whether risks of adjuvant therapy outweigh benefits for certain patients.

Purpose: To compare the diagnostic accuracy of post-treatment contrast-enhanced mammography (CEM) to MRI in the detection of residual tumor following neoadjuvant systemic therapies (NST). Methods: This retrospective study included women with newly diagnosed breast cancer who underwent post NST imaging with either MR and/or CEM imaging from September 2014 to December 2023. Imaging findings on post-NST was compared with surgical pathology. For this study, pathological complete response (pCR) was defined as the absence of invasive cancer and/or DCIS within the breast at surgery. Radiological complete response (rCR) was defined as no residual tumor seen on post-contrast post-treatment imaging. Accuracy was further stratified by various breast cancer tumor subtypes. Sensitivity, specificity, PPV and NPV values were calculated. Results: We identified 397 unique patients with pathologically confirmed invasive breast cancer who underwent either post-treatment contrast-enhanced imaging, 338 (85%) with CEM, 313 (79%) with MR imaging, and 254 (64%) patients who had both CEM and MR. Mean age was 54 (range 25–83) years. 57% of patients were post-menopausal, 82% were white, 69% of patients had dense breasts. NST consisted of chemotherapy in 76% and endocrine therapy in 24% of patients. Tumor subtype analyses included 29% Triple Negative disease ER-/HER2-, 38% Estrogen driven (ER+/HER2-), and 33% HER2 positive disease (HER2+/ER+ 24% and HER2+/ER- 9%), 90% of tumors were clinical T1 or T2, 66% had no axillary disease. 57% of patients ultimately underwent mastectomy and 43% underwent BCT. rCR was identified in 47% (159/338) of cases by CEM and 39% (121/313) by MR. Overall, 35% (160/452) achieved pCR. Comparing CEM versus MRI for assessment of residual disease, the sensitivity was 74% versus 81%, specificity 83% versus 71%, PPV 88% versus 82%, and NPV 65% versus 69% respectively. Specificity was higher for CEM as compared to MRI (p=0.02). NPV was lowest for ER+/HER2- subgroups for both CEM (39%) and MRI (44%). Conclusions: Diagnostic accuracy of post-treatment response on CEM imaging is comparable to that of MRI in assessing residual malignancy amongst various breast cancer tumor subtypes. Specificity (defined as the ability to correctly identify patients achieving pCR after preoperative therapy) was increased with CEM compared to MR imaging. Sensitivity (defined as ability to correctly identify residual disease (non-pCR) after preoperative therapy) is slightly better with MR than CEM. Citation Format: Whitney Harris, Bhavika Patel, Heidi Kosiorek, Richard Sharpe, Karen Anderson, Donald Northfelt, Lida Mina, Felipe Batalini, Brenda Ernst, Carlos Vargas, Imon Banerjee, Patricia Cronin, Julie Billar, Richard Bold, Barbara Pockaj. Diagnostic Accuracy assessing residual disease in breast cancer patients receiving neoadjuvant systemic therapies (NST) is comparable between contrast enhanced mammography(CEM)& breast magnetic resonance imaging(MRI)across various cancer subtypes [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 P2-09-14.

Solid tumors develop within a complex environment called the tumor microenvironment (TME), which is sculpted by the presence of other cells, such as cancer-associated fibroblasts (CAFs) and immune cells like macrophages (Mφs). Despite the presence of immune cells, tumor cells orchestrate a tumor-supportive environment through intricate interaction with the components of the TME. However, the specific mechanism by which this intercellular dialogue is regulated is not fully understood. To that end, the development of an organotypic 3D breast TME-on-a-chip (TMEC) model, integrated with single-cell RNA sequencing analysis, is reported to mechanistically evaluate the progression of triple-negative breast cancer (TNBC) cells in the presence of patient-derived CAFs and Mφs. Extensive functional assays, including invasion and morphometric characterization, reveal the synergistic influence of CAFs and Mφs on tumor cells. Furthermore, gene expression and pathway enrichment analyses identify the involvement of the KYNU gene, suggesting a potential immune evasion mechanism through the kynurenine pathway. Lastly, the pharmacological targeting of the identified pathway is investigated.

Background:Metastatic breast cancer (MBC) is an incurable disease, affecting 10-15% of breast cancer (BC) patients, with a 5-year overall survival of less than 25%. MBC arises when small populations of disseminated BC cells remain in the body after primary therapy, otherwise known as minimal residual disease (MRD). MRD is currently difficult to detect following primary therapy. Despite, improvements, there remains a need for more effective and sensitive clinical tools to identify patients with MRD following primary treatment who may benefit from additional treatment or increased surveillance. In the current study, we aimed to develop a plasma only MRD test, based on cfDNA methylation markers specifically associated with developing breast cancer metastasis, rather than markers that may prioritize markers of tumor burden, making this approach a partially-informed MRD assay. Methods: Blood was collected under informed consent from multiple commercial and academic sources. We constructed 6 pools of cfDNA comprising a total 43 samples from MBC patients, and 3 pools comprised of cfDNA from 39 healthy individuals. In addition, we sequenced 21 cfDNA libraries from treatment-naïve patients with stage I-III breast cancer who either developed a future recurrence (REC, N = 12) or remained disease-free survivors (DFS, N = 9). The 6 MBC pools represented all major BC subtypes (ER+/HER2-, ER-/HER2+, ER+/HER2+, TNBC). To improve model performance and represent DNA methylation patterns associated with underrepresented populations, we also included 19 samples from African American patients with triple-negative breast cancer (TNBC) across varying stages. Whole genome bisulfite sequencing (WGBS) was performed on the 9 pools and 21 individual cfDNA samples. Differentially methylated regions (DMRs) were identified between MBC versus healthy pools and between REC versus DFS samples. A total of 5077 DMRs were then used to generate a targeted methylation assay using hybridization probe capture, which was used to analyze 72 individual cfDNA samples from patients with MBC (5 stage I-III), and 83 healthy cfDNA controls. Next, we developed a binary classification model called MammaTrace to distinguish between MBC and healthy samples. To evaluate the model for MRD, we subsequently applied the classifier to assess its accuracy in distinguishing REC from DFS in patients with early-stage breast cancer prior to recurrence. Specifically, cfDNA was sequenced using the MammaTrace targeted panel at multiple timepoints from 107 patients with early-stage breast cancer who underwent neoadjuvant chemotherapy. Of these patients, 51 had blood collected 9–27 months after definitive therapy and was determined as the most predictive time point and used for landmark analysis. At the time of writing, 11 patients developed metastasis, while 40 remained disease-free. Blood samples were collected prior to recurrence for all patients. Results: The classifier model, constructed primarily using samples from MBC patients and healthy individuals, demonstrated excellent performance in distinguishing MBC from healthy samples, achieving a ROC AUC of 0.96. For assessing MRD detection in early-stage breast cancer samples collected at least 9 months after the completion of therapy, MammaTrace achieved an ROC AUC of 0.88, correctly classifying 10 of 11 REC patients as MRD positive and 33 of 40 DFS patients as MRD negative (sensitivity = 0.91, specificity = 0.83). The 10 positive REC landmark samples were collected an average of 457 days prior to clinical recurrence. Conclusion: MammaTrace, a plasma-only cfDNA methylation-based classifier, effectively distinguishes MBC patients from healthy individuals, and can detect MRD before clinical recurrence, identifying high-risk patients in need of additional therapy. Prospective studies are ongoing to validate MammaTrace. Citation Format: David N Buckley, Gerald Gooden, Alex Kalfa, Barbara Pockaj, Bodour Salhia. MamaTrace - A cell-free DNA methylation plasma only assay for minimal residual disease detection in breast cancer [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 P4-05-26.

Purpose: To develop a retrieval-augmented generation (RAG) system powered by LLaMA-4 109B for automated, protocol-aware, and interpretable evaluation of radiotherapy treatment plans. Methods and Materials: We curated a multi-protocol dataset of 614 radiotherapy plans across four disease sites and constructed a knowledge base containing normalized dose metrics and protocol-defined constraints. The RAG system integrates three core modules: a retrieval engine optimized across five SentenceTransformer backbones, a percentile prediction component based on cohort similarity, and a clinical constraint checker. These tools are directed by a large language model (LLM) using a multi-step prompt-driven reasoning pipeline to produce concise, grounded evaluations. Results: Retrieval hyperparameters were optimized using Gaussian Process on a scalarized loss function combining root mean squared error (RMSE), mean absolute error (MAE), and clinically motivated accuracy thresholds. The best configuration, based on all-MiniLM-L6-v2, achieved perfect nearest-neighbor accuracy within a 5-percentile-point margin and a sub-2pt MAE. When tested end-to-end, the RAG system achieved 100 Conclusion: Our findings highlight the feasibility of combining structured population-based scoring with modular tool-augmented reasoning for transparent, scalable plan evaluation in radiation therapy. The system offers traceable outputs, minimizes hallucination, and demonstrates robustness across protocols. Future directions include clinician-led validation, and improved domain-adapted retrieval models to enhance real-world integration.

Objective: This study investigates Enhanced Recovery After Surgery (ERAS®) protocols’ impact on long-term opioid and sedative use following mastectomy with or without implant-based breast reconstruction (IBBR). Summary Background Data: ERAS® protocols for patients undergoing mastectomy with or without IBBR are associated with decreased length of stay, increased rate of same-day discharge, decreased postoperative pain, and decreased postoperative opioid requirements. However, less is known about their effect on opioid and sedative use beyond 90 days after surgery. Methods: A retrospective review of all patients undergoing mastectomy with or without IBBR at a single institution between January 2013 and December 2019. Mastectomy ERAS® protocols were implemented in February 2017, creating two groups: pre-ERAS® and ERAS®. Baseline characteristics and prevalence of chronic opioid and sedative use were compared. Univariable and multivariable logistic regression predicted factors associated with increased odds of chronic opioid and sedative use. Results: 756 patients were evaluated: 405 pre-ERAS® and 351 ERAS®. Post-ERAS®, chronic opioid use decreased in opioid-naïve (40% vs. 30%, P =0.024) and opioid-tolerant patients (58% vs. 37%, P =0.002), with no increase in chronic sedative use. There were decreased odds of chronic opioid use for all ERAS® patients (OR=0.57, 95% CI: 0.42-0.76)), and of IBBR patients, those receiving subcutaneous implants (OR=0.31, 95% CI: 0.20-0.48). There was increased chronic opioid-use odds if undergoing bilateral surgery (OR=1.54, 95% CI: 1.14-2.08), two-stage reconstruction (OR=9.78, 95% CI: 5.94-16.09), and for patients with higher PACU pain scores (OR=1.09, 95% CI: 1.03-1.14) or >150 discharge OMEs (OR=2.63, 95% CI: 1.48-4.68). Conclusion: ERAS® protocols for mastectomy patients with or without IBR are associated with decreases in chronic opioid use, without concomitant increases in chronic sedative use.

Abstract We demonstrate development and technical validation of a novel approach for analysis of plasma circulating-tumor DNA (ctDNA) for residual disease detection and monitoring that offers improvements over existing technologies. ctDNA in blood can be leveraged to monitor treatment response, detect cancer recurrence, and inform treatment decisions for cancer patients. However, accurate detection and quantification of ctDNA is technically challenging due to low concentration of plasma DNA, especially in the adjuvant setting. Most current assays rely on interrogating multiple patient-specific point mutations to achieve exquisite limits of detection but struggle with polymerase errors, sequencing artifacts and limited conversion of input DNA. To overcome these challenges, we developed an approach called Structural Variant Enrichment and Normalization (SVEN) that targets patient-specific genomic rearrangements to achieve sensitive detection and quantification of plasma ctDNA. This method leverages intrinsic features of tumor-derived structural variants (SVs) to improve enrichment and confidence of detection at low tumor fraction through multiplexed PCR and amplicon-based next generation sequencing. To evaluate the assay, we performed whole genome sequencing of DNA from two breast cancer cell lines, as well as matched FFPE tumor and buffy coat samples from 21 early-stage breast cancer patients. We identified consensus SVs, and designed multiplexed SV-specific primers for each subject. We then conducted PCR amplification of cell-free DNA followed by sequencing, amplicon identification, and quantification. Analytical validation was conducted using 284 replicates of cell line dilutions from 1% to 0.003%, and 5 to 40 ng of input. We developed multiplexed assays targeting 25 and 32 SVs across two cell lines, and 3 - 43 SVs across breast cancer patients (median 23 per patient). 91% and 42% of PCR targets were successfully validated for cell lines and FFPE samples respectively. Cell line dilutions demonstrated a sensitivity of 89% at 0.003% tumor fraction with 10 ng input or more. Tumor fractions measured using SVEN agreed with known values (R2 = 0.989). Application of validated panels to patient plasma samples and tumor/germline dilutions is ongoing. SVEN is a novel approach for tumor-guided ctDNA detection and quantification with potential relevance for residual disease detection. On-going studies are investigating the performance of this approach for ctDNA detection in patients with early and locally advanced breast cancer treated with neoadjuvant therapy. Citation Format: Bradon R. McDonald, Kirsten L. Dennison, Amanda L. Schussman, Stephanie M. McGregor, Barbara A. Pockaj, Muhammed Murtaza. Personalized minimal residual disease detection using tumor-derived structural variants in cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2416.

PURPOSE:Contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) have shown similar diagnostic performance in detection of breast cancer. Limited CEM data are available for high-risk breast cancer screening. The purpose of the study was to prospectively investigate the efficacy of supplemental screening CEM in elevated risk patients. MATERIALS AND METHODS:A prospective, single-institution, institutional review board-approved observational study was conducted in asymptomatic elevated risk women age 35 years or older who had a negative conventional two-dimensional digital breast tomosynthesis screening mammography (MG) and no additional supplemental screening within the prior 12 months. RESULTS:Four hundred sixty women were enrolled from February 2019 to April 2021. The median age was 56.8 (range, 35.0-79.2) years; 408 of 460 (88.7%) were mammographically dense. Biopsy revealed benign changes in 22 women (22/37, 59%), high-risk lesions in four women (4/37, 11%), and breast cancer in 11 women (11/37, 30%). Fourteen cancers (10 invasive, tumor size range 4-15 mm, median 9 mm) were diagnosed in 11 women. The overall supplemental cancer detection rate was 23.9 per 1,000 patients, 95% CI (12.0 to 42.4). All cancers were grade 1 or 2, ER+ ERBB2-, and node negative. CEM imaging screening offered high specificity (0.875 [95% CI, 0.844 to 0.906]), high NPV (0.998 [95% CI, 0.993 to 1.000), moderate PPV1 (0.164 [95% CI, 0.076 to 0.253), moderate PPV3 (0.275 [95% CI, 0.137 to 0.413]), and high sensitivity (0.917 [95% CI, 0.760 to 1.000]). At least 1 year of imaging follow-up was available on all patients, and one interval cancer was detected on breast MRI 4 months after negative screening CEM. CONCLUSION:A pilot trial demonstrates a supplemental cancer detection rate of 23.9 per 1,000 in women at an elevated risk for breast cancer. Larger, multi-institutional, multiyear CEM trials in patients at elevated risk are needed for validation.

Cancer thrives in a complex environment where interactions between cellular and acellular components, surrounding the tumor, play a crucial role in disease development and progression. Despite significant progress in cancer research, the mechanism driving tumor growth and therapeutic outcomes remains elusive. Two-dimensional (2D) cell culture assays and in vivo animal models are commonly used in cancer research and therapeutic testing. However, these models suffer from numerous shortcomings including lack of key features of the tumor microenvironment (TME) & cellular composition, cost, and ethical clearance. To that end, there is an increased interest in incorporating and elucidating the influence of TME on cancer progression. Advancements in 3D-engineered ex vivo models, leveraging biomaterials and microengineering technologies, have provided an unprecedented ability to reconstruct native-like bioengineered cancer models to study the heterotypic interactions of TME with a spatiotemporal organization. These bioengineered cancer models have shown excellent capabilities to bridge the gap between oversimplified 2D systems and animal models. In this review article, we primarily provide an overview of the immune and stromal cellular components of the TME and then discuss the latest state-of-the-art 3D-engineered ex vivo platforms aiming to recapitulate the complex TME features. The engineered TME model, discussed herein, are categorized into three main sections according to the cellular interactions within TME: (i) Tumor-Stromal interactions, (ii) Tumor-Immune interactions, and (iii) Complex TME interactions. Finally, we will conclude the article with a perspective on how these models can be instrumental for cancer translational studies and therapeutic testing.

Abstract BACKGROUND: The amplification of genes PDL-1, PDL-2, and JAK2 on chromosome 9p24, known as the PDJ amplicon, has been identified in 15% of triple negative breast cancer (TNBC) and is associated with tumor infiltrating lymphocytes and elevated JAK2 mRNA, suggesting a coordinated inflammatory response in TNBC. Adding pembrolizumab to chemotherapy in KEYNOTE trials 355 and 522 has validated the use of PD-1 blockade in TNBC and redefined the standard of care. Despite preclinical data suggesting a role for targeting the IL- 6/JAK2/STAT3 pathway, the JAK1/JAK2 inhibitor ruxolitinib has not shown efficacy as a single Agent in breast cancer. This is the first phase I clinical trial evaluating the combination of pembrolizumab and ruxolitinib in the treatment of metastatic TNBC. METHODS: We conducted a phase I clinical trial with accrual from 2018 to 2023 at Mayo Clinic Arizona. Patients (n=12) received 200 mg of IV pembrolizumab per cycle (every 3 weeks) with 3+3 dose escalation of oral ruxolitinib twice a day (dose level 0: 10 mg PO BID, level 1: 15 mg PO BID, level 2: 20 mg PO BID). The primary endpoint was to determine the maximum tolerated dose (MTD) of ruxolitinib and secondary endpoints were treatment safety and efficacy. Clinical response was assessed by computed tomography of the chest, abdomen, and pelvis every 3 cycles. PD-L1 expression in tumor was measured by immunohistochemistry (IHC). The effect of the combined therapies on T and B cell populations were assessed by flow cytometry and antibody profiling of 695 tumor antigens and 8 viral antigens by nucleic acid protein programmable array. RESULTS: Twelve female patients with chemotherapy refractory metastatic TNBC were treated on study. All received 200 mg IV pembrolizumab every cycle. Due to rapid disease progression of three patients early after treatment initiation, eligibility was restricted to prohibit patients with extensive pulmonary disease or elevated LDH. Those patients were excluded from efficacy or correlative analysis. The most common toxicities were transaminitis (n=12), anemia/leukopenia (n=12), and fatigue (n=9). The majority of adverse events were grade 1 and occurred at dose level 2. There were 5 adverse events grade 3 or higher: respiratory or thoracic complications (n=3), hypertension (n=1), and abdominal pain (n=1), but MTD was not established. The median number of cycles was 4 for each dose level (range n=2.0-9.0) and the median time to progression was 3 months (range n=1.4-6.3). No patient had tumor response by RECIST v1.1 criteria and there was no association of disease stability with PD-L1 tumor expression by IHC. Circulating antibodies to tumor antigens remained stable, and viral-specific antibodies mildly decreased by month 2 in all patients at dose levels 0 and 1. Of the 7 patients reactive to TRIM21 autoantibodies, 2 patients had a transient increase at 2 months. CONCLUSIONS: The combination of pembrolizumab with ruxolitinib was well tolerated at all dose levels, and the number but not the severity of adverse events increased with higher ruxolitinib dose. Two of six patients in dose level 0 and 1 had stable disease for six months on treatment, suggesting that the lower dose levels of ruxolitinib (i.e. 10 mg PO BID) may have more activity in combination with pembrolizumab. Citation Format: Anelia Kassi, Jacqueline Carmona, Sarah M. Green, Heidi Kosiorek, Michael T. Barrett, Barbara A. Pockaj, Donald Northfelt, Karen S. Anderson. Phase I trial of combination pembrolizumab and ruxolitinib in metastatic triple negative breast cancer [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 PO1-18-07.

Objective: This study investigates Enhanced Recovery After Surgery (ERAS) protocols' impact on long-term opioid and sedative use following mastectomy with or without implant-based breast reconstruction (IBBR). Background: ERAS protocols for patients undergoing mastectomy with or without IBBR are associated with decreased length of stay, increased rate of same-day discharge, decreased postoperative pain, and decreased postoperative opioid requirements. However, less is known about their effect on opioid and sedative use beyond 90 days after surgery. Methods: A retrospective review of all patients undergoing mastectomy with or without IBBR at a single institution between January 2013 and December 2019. Mastectomy ERAS protocols were implemented in February 2017, creating 2 groups: pre-ERAS and ERAS. Baseline characteristics and prevalence of chronic opioid and sedative use were compared. Univariable and multivariable logistic regression predicted factors associated with increased odds of chronic opioid and sedative use. Results: A total of 756 patients were evaluated: 405 pre-ERAS and 351 ERAS. Post-ERAS, chronic opioid use decreased in opioid-naive (40% vs 30%, P=0.024) and opioid-tolerant patients (58% vs 37%, P=0.002), with no increase in chronic sedative use. There were decreased odds of chronic opioid use for all ERAS patients (OR=0.57, 95% CI: 0.42-0.76), and of IBBR patients, those receiving subcutaneous implants (OR=0.31, 95% CI: 0.20-0.48). There was increased chronic opioid-use odds if undergoing bilateral surgery (OR=1.54, 95% CI: 1.14-2.08), 2-stage reconstruction (OR=9.78, 95% CI: 5.94-16.09), and for patients with higher PACU pain scores (OR=1.09, 95% CI: 1.03-1.14) or >150 discharge OMEs (OR=2.63, 95% CI: 1.48-4.68). Conclusion: ERAS protocols for mastectomy patients with or without IBR are associated with decreases in chronic opioid use, without concomitant increases in chronic sedative use.