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INTRODUCTION: There is an urgent need for effective and safe treatment of gastroparesis. Metopimazine, a selective, peripherally restricted dopamine D 2 receptor antagonist, is used in France for the symptomatic treatment of nausea and vomiting and chemotherapy-induced nausea and vomiting. The aim of this study is to assess the safety and efficacy of oral NG101, the mesylate salt of metopimazine, for the treatment of gastroparesis. METHODS: We conducted a 12-week phase 2 multicenter trial with NG101 5, 10, and 20 mg 4 times a day versus placebo. The primary end point was the change in mean nausea severity from the Diabetic and Idiopathic Gastroparesis Symptoms Daily Diary (DIGS-DD) during weeks 7–12 of the Treatment Period from baseline. The DIGS-DD measured nausea, abdominal pain, early satiety, postprandial fullness, and vomiting at their worst in the past 24 hours using a 0-10 point numeric rating scale. Patient Global Impression of Change questionnaires, including nausea, were assessed weekly using a 7-point balanced ordinal score. RESULTS: Of 161 randomized participants (45.3% diabetic and 54.7% idiopathic), mean DIGS-DD nausea severity scores decreased from baseline during weeks 7–12 in all treatment groups, but these improvements were not statistically significant compared with placebo. However, there were statistically significant improvements in nausea Patient Global Impression of Change during weeks 1–12 for all treatment groups compared with placebo. Trends in safety and efficacy favored patients with idiopathic gastroparesis compared with those with diabetic gastroparesis. DISCUSSION: While NG101 did not meet statistical significance in its primary end point for reducing nausea severity, it demonstrated a favorable safety profile and significant improvement in some secondary end points. Further study is needed to determine whether NG101 is an effective treatment for patients with idiopathic gastroparesis.

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Importance Use of modern neoadjuvant chemotherapy (NAC) regimens has markedly increased rates of pathologic complete response (pCR) in breast cancer, raising the question of whether surgical removal of the primary tumor is required for patients with pCR. For surgery to be omitted, one must be able to accurately predict pCR before surgery. Objective To investigate if adding post-NAC core needle biopsy of the tumor bed to trimodality imaging in patients who have clinical complete response (cCR) will predict pCR (resolution of both invasive disease and ductal carcinoma in situ) in 90% or more cases. Design, Setting, and Participants This was a phase 2, prospective, nonrandomized clinical trial. Patients were enrolled from August 2017 to June 2019. This is the final analysis, which was completed in December 2023. The setting included academic and community hospital center members of NRG (ie, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) in the US and Canada. Patients with operable (T1-T3, stage I-III) invasive ductal carcinoma who completed NAC and achieved cCR and radiological complete response (rCR) or near rCR by mammography (mass ≤1 cm and no malignant microcalcifications), ultrasound (mass ≤2 cm), and magnetic resonance imaging (no mass with rapid rise or washout kinetics). Interventions Patients underwent marker-directed stereotactic multiple-core needle biopsy of the tumor bed with marker placement before breast-conservation surgery. Main Outcomes and Measures End points were negative predictive value (NPV) and sensitivity of the biopsy. Results A total of 105 patients were enrolled with 101 evaluable (mean [SD] age, 52.8 [10.5] years); 77 patients (76.2%) were younger than 60 years, and all breast cancer subtypes were represented with 32 (31.7%) triple-negative breast cancer, 21 (20.8%) hormone receptor–positive/epidermal growth factor receptor 2 ( ERBB2 ; formerly HER2 )–negative ( ERBB2 −) breast cancer, and 46 (45.5%) ERBB2 -positive ( ERBB2 +) breast cancer. In 101 evaluable patients, 36 had residual disease at surgery (pCR = 64%). With imaging criteria, NPV of the biopsy was 78.3% (95% CI, 67.9%-86.6%), and the sensitivity of the biopsy was 50% (95% CI, 32.9%-67.1%). In an exploratory subset analysis, the NPV in patients with ERBB2 + breast cancer was 90% (95% CI, 76.3%-97.2%). On retrospective central review, 62 of 101 enrolled patients met imaging eligibility criteria. In this exploratory post hoc analysis, NPV in these patients was 86.8% (95% CI, 74.7%-94.5%). Conclusions and Relevance These findings do not support breast conservation treatment without surgery based on the study criteria for cCR and rCR/near rCR by trimodality imaging and negative tumor-bed biopsy. Strict adherence to imaging criteria may be required to achieve acceptable predictive values. TRIAL Registration ClinicalTrials.gov Identifier: NCT03188393

Abstract Background: Endocrine therapy (ET) with aromatase inhibitors (AI) plus ovarian function suppression (OFS) is standard for premenopausal women with ER+/HER2- breast cancer. However, many premenopausal women are intolerant of AI + OFS, leaving tamoxifen (with or without OFS) as their only option. Extensive studies have demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy (defined as endocrine sensitive disease (ESD)) achieve 5-year distant disease-free survival > 96%. Problematically, only 41% of patients reach this ESD threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator (SERM) that inhibits ERα at plasma concentrations of 3-5 ng/ml and dually targets PKCβ1, a suspected oncogene in breast tumors, at concentrations ≥ 500 ng/ml. We therefore developed the EVANGELINE study (NCT05607004) is an open label, randomized neoadjuvant phase II study that includes a pharmacokinetic (PK) Run-in, aiming to evaluate whether ENDX +/- goserelin is non-inferior to exemestane plus goserelin with respect to ESD rate. Following the completed PK run-in portion of the study, where 40mg/day or 80mg/day ENDX were assessed, the 40 mg/day dose was selected for further evaluation in the second part of the trial. The second part is comprised of a randomized treatment cohort, for patients with a Ki-67% >10% at preregistration randomized to either 40mg (Z)-endoxifen + goserelin or exemestane + goserelin neoadjuvant treatment and a Single Arm Treatment Cohort for patients who have a Ki-67 ≤ 10% at pre-registration assigned to 40mg/day (Z)-endoxifen monotherapy neoadjuvant treatment. Methods: To investigate ENDX further in premenopausal women, a multicenter study in the United States, was designed(EVANGELINE; NCT05607004). This phase 2, open-label, randomized, neoadjuvant trial includes a PK run-in phase designed to assess whether the 4-week ESD rate with (Z)-endoxifen + goserelin is non-inferior to that of exemestane + goserelin in premenopausal women with Stage IIA or IIB ER+/HER2- breast cancer with diagnostic Ki67 > 10%. Additionally, a single arm Phase 2, open-label neoadjuvant Cohort was designed to assess the 4-week ESD rate with ENDX monotherapy in premenopausal women with Stage IIA or IIB ER+/HER2- BC with diagnostic Ki67 ≤10%. Subjects will undergo neoadjuvant treatment for six months before receiving surgical treatment in the involved breast. This study will additionally assess safety, tolerability, response rates, surgical outcomes, and monitor disease progression. Comprehensive biomarker evaluations will be conducted using paired tumor biopsies and blood samples collected at baseline and week four, as well as 6 month surgical specimens. Enrollment in the PK run-in phase (n-22) was completed in Fall 2024 with the second portion of the trial slated to begin early in 2025. Citation Format: Matthew P. Goetz, Vera J. Suman, Claudia Lopez, Hayley Erickson, Lonnissa Nguyen, Sandra S. Hammer, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Daniel Flora, Jason M. Jones, Nusayba A. Bagegni, Katie N. Hunt, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah A. Buhrow, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven C. Quay. A randomized phase 2 non-inferiority trial of (Z)-endoxifen + goserelin and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT237.

Abstract Purpose: While an addition of immune checkpoint inhibitor (ICI), pembrolizumab, has improved outcomes of patients with TNBC, early-stage TNBC patients with residual cancer burden (RCB) II/III after neoadjuvant chemotherapy in combination with pembrolizumab (NAP) still have poor outcomes. Previously, we demonstrated that intratumoral HLA-DRA expression and interferon-alpha (IFNα) responses were associated with immune-inflamed phenotype and better outcomes in TNBC patients receiving chemotherapy. This study utilized the CosMx™ SMI to investigate in early-stage TNBC treated with NAP. Methods: Of 151 samples from TNBC patients treated with NAP at Mayo Clinic, 8 pre-treatment biopsy samples (5 pCR and 3 RCB II/III were analyzed using the CosMx™ SMI platform. Linear mixed models to assess differential expression (DE), adjusting for hierarchical data structures. DE analyses were expressed as log2-fold changes (logFC), with the Benjamini-Yekutieli method. GSEA and IPA for signaling pathway exploration. Results: 1.7 million cells were identified across 8 samples after stringent quality control. Immune cell profiling revealed higher B cells, plasma cells, plasmablasts, and T cells (CD4 and CD8) in responders, whereas fibroblasts and myeloid cells were enriched in non-responders. DE analysis showed significantly elevated expression of HLA-DRA (logFC 1.955, p<0.001), other MHC class I and II components, and IFNα in responders. Tumor cells in responders exhibited the highest IFNα expression across cell types. GSEA and IPA analysis revealed enrichment in interferon signaling, antigen presentation, and the cGAS-STING pathway, which drives IFNα production. Spatial analysis categorized cells by their proximity to tumor cells: within 50 µm, 50-100 µm, and over 100 µm. T cells, particularly CD8 T cells, showed a distance-dependent distribution, with a higher abundance near tumor cells in responders. CD8 T cell activation scores declined with increasing distance from IFNα-positive tumor cells but remained consistently low near IFNα-negative tumor cells. IFNγ-positive CD8 T cells exhibited higher activation compared to IFNγ-negative cells, with activation levels influenced by proximity to tumor cells. Lastly, MHC expression in tumor cells was examined relative to CD8 T cell proximity. HLA-DRA and CIITA expression decreased as tumor cells were farther from CD8 T cells. Conclusions: This spatially resolved single-cell analysis highlights the pivotal role of tumor-immune interactions in response to pembrolizumab in TNBC. Our data suggest that tumor cells secrete IFNα through the activation of the cGAS-STING pathway, which activates T cells within close proximity, highlighting the potential role of cGAS-STING agonist as well as IFNα signaling and antigen presentation in augmenting TNBC responses to ICIs. Citation Format: Yi Liu, Saranya Chumsri, Yaohua Ma, Jodi M. Carter, Aziza Nassar, Edith Perez, Roberto A. Leon-Ferre, David Zahrieh, David W. Hillman, Judy C. Boughey, James Ingle, Krishna R. Kalari, Fergus J. Couch, Matthew P. Goetz, Keith L. Knutson, E. Aubrey Thompson. Spatially resolved single-cell analysis reveals cGAS-STING-mediated tumor-immune interactions via IFNα as determinants of pembrolizumab sensitivity in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7130.

Abstract Deep learning has advanced digital pathology and multi-omics data analysis. However, there is still a critical need to integrate these modalities to better understand complex diseases. Deep learning models, such as Prov-Gigapath, a state-of-the-art pathology foundation model, have been developed for analyzing whole-slide images (WSI). Our previously published deep-learning framework, OmicsFootPrint (OFP), transforms high-dimensional multi-omics data into intuitive genomically-arranged circular images and utilizes transfer learning to overcome the challenges of high-dimensional, low-sample-size data. In this study, we aimed to combine WSI and multi-omics data to develop a framework capable of distinguishing between invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), which is clinically significant as it may help explain differential responses to therapies, such as tamoxifen versus letrozole. We enhanced the performance of our OFP model by dividing each multi-omics circular image (1024x1024x3 pixels) into 16 equal-sized patches (256x256x3 pixels). Each patch was trained using a separate EfficientNetV2 architecture with pre-trained ImageNet weights. The probability outcomes from these 16 models were subsequently combined through a meta-learner model using the AutoGluon framework. Concurrently, WSI images corresponding to the same patients were independently trained, maintaining consistent train/validation/test splits. The Prov-Gigapath model, which was trained using a dataset from the Providence Health System, was employed to extract patch-level embeddings from the WSI data. These embeddings were fine-tuned using a LongNet-based masked autoencoder to predict outcomes. Finally, predictions from the OFP model and the WSI-based Prov-Gigapath model were integrated through a meta-learner, preserving the original train/validation/test split. Model performances (AUC) were evaluated using the held-out test set. The gold standard used for the analysis was histological identification of IDC versus ILC, against which the performance of omics data alone, WSI data alone, and the multi-modal integration approach were compared. We evaluated our integrated model as a proof-of-concept using The Cancer Genome Atlas (TCGA) breast cancer cohort, comprising 92 ILC and 391 IDC samples. Multi-omics data, including gene expression, microRNA, copy number variation, and RPPA, were analyzed using the OFP framework, while WSI data were processed using the Prov-Gigapath method. The results demonstrated that the multi-modal integration approach significantly outperformed individual modalities, achieving an AUC of 0.98 compared to 0.87 for OFP (original), 0.95 for OFP (16-patches), and 0.92 for WSI. Integrating WSI and multi-omics data improves predictive accuracy, significantly improving the classification of breast cancer subtypes over histology alone. Citation Format: Naresh Prodduturi, Xiaojia Tang, Hamid R. Tizhoosh, Kevin J. Thompson, Richard Weinshilboum, Karthik V. Giridhar, Judy C. Boughey, Eric W. Klee, Liewei Wang, Matthew P. Goetz, Vera Suman, Krishna R. Kalari. A multi-modal learning framework to integrate digital pathology image and multi-omics data in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2429.

Background: Immediate lymphatic reconstruction (ILR) via lymphovenous anastomosis is performed in patients undergoing axillary lymph node dissection (ALND) to minimize the risk of lymphedema. Following ALND, drains are placed to prevent seromas, while prolonged drain days are associated with increased risk of infection. The study aim was to determine the impact of ILR on the number of drain days following ALND in patients with breast cancer. Methods: We report a post-hoc analysis of a prospective trial (April 2018-January 2023) comparing patients with breast cancer who underwent ALND with ILR (intervention arm) vs ALND without ILR (control arm). Wilcoxon rank sum test and chi-squared or Fisher’s exact tests compared continuous and categorical variables, respectively. Multivariable quantile regression models evaluated the difference in drain days and days until drain removal criteria were met with covariates adjusted. Results: Data from 214 patients were analyzed (n = 115 interventional arm, n = 99 control arm). The intervention arm had a median of 15 axillary drain days compared to 11 days in the control arm ( P = .001). There was no significant difference between groups when measuring drain days based on the date the drain met removal criteria, rather than actual drain removal date. Seroma incidence was lower in the intervention arm (3.5%) vs the control arm (12.1%) ( P = .017) without a statistical difference in incidence of infection. Conclusion: ALND with ILR does not decrease the number of drain days compared to ALND without ILR in patients with breast cancer, although we found the incidence of seromas to be lower without increase in incidence of infection.

PURPOSE Adjuvant endocrine therapy (ET) improves overall survival (OS) in estrogen receptor (ER)–positive early-stage breast cancer (BC). However, the benefit of ET for those with ER-low BC (ER 1%-10%) is unclear. METHODS Using the National Cancer Database, we studied patients with high-risk stage I to III, ER-low BC (defined as immunohistochemistry 1%-10%) who received (neo)adjuvant chemotherapy and did or did not initiate ET. OS was analyzed with ET initiation as a time-dependent covariate using Cox proportional hazards regression. RESULTS Of 10,362 patients with stage I to III ER-low BC, 7,018 received chemotherapy and met inclusion criteria. ET omission was 42% at 12 months and more common in patients with tumors that were progesterone receptor–negative, human epidermal growth factor receptor 2–negative, higher-grade (grade 2/3) and higher Ki-67 (≥20%; all P < .001) and those who received neoadjuvant chemotherapy (NAC; P < .001). With a median follow-up of 3 years, 586 deaths were observed. In a multivariable analysis, ET omission was associated with a higher risk of death (hazard ratio [HR], 1.23 [95% CI, 1.04 to 1.46]; P = .02), with a greater impact in those with higher ER levels: ER 1%-5% (HR, 1.15 [95% CI, 0.91 to 1.45]; P = .24) versus ER 6%-10% (HR, 1.42 [95% CI, 1.00 to 2.02]; P = .048). Among patients treated with NAC (n = 4,377, 62%), ET omission was associated with worse OS in those with residual disease (RD; HR, 1.26 [95% CI, 1.00 to 1.57]; P = .046) but not in those who achieved a pathologic complete response (HR, 1.06 [95% CI, 0.62 to 1.80]; P = .84). CONCLUSION In ER-low, early-stage BC, ET omission is associated with significantly worse OS, especially in patients with RD after NAC and those with higher (6%-10%) ER levels. Until prospective data are available, patients with ER-low BC should be counseled regarding the potential benefit of ET.