Citations

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged >70 and 11.7% were aged >80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (<5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-04.

ABSTRACT Tumorigenesis and metastasis are frequently attributed to the intricate interplay between cancer cells and the tumor microenvironment (TME). Comprehending the mechanisms and key regulators of cancer‐immune crosstalk in the TME is imperative for developing efficacious immunotherapy. Through a series of in vivo CRISPR screens, we identified tumor‐intrinsic ITGB1 as a critical regulator of triple‐negative breast cancer (TNBC) development and deciphered its underlying mechanisms. Tumoral ITGB1 facilitated the establishment of pro‐tumorigenic TME by orchestrating tumor‐associated myeloid populations. Suppressing ITGB1 favored the enrichment of anti‐tumorigenic myeloid cells and enhanced infiltration of CD4 and CD8 T cells, culminating in superior antitumor effects. CRISPR scanning pinpointed a previously unrecognized functional domain essential for ITGB1's pro‐tumorigenic activity. This domain is distinct from all known ligand‐binding sites in ITGB1. An antibody capable of sterically blocking this domain significantly impaired TNBC progression. These findings position tumoral ITGB1 as a promising therapeutic target for reprogramming the TME from a pro‐ to an anti‐tumorigenic state, thereby effectively inhibiting TNBC development. Our study uncovers a novel mechanism of TNBC development and provides a unique therapeutic strategy for targeting ITGB1 in TNBC treatment.

OBJECTIVE Early discharge following uncomplicated endonasal resection of pituitary adenoma has been described as safe and feasible. Discharge on postoperative day (POD) 1 is not a widely implemented practice in the United States. This study aimed to evaluate the safety of routine POD1 discharges by assessing postoperative unplanned medical care rates compared with those of patients discharged on POD 2 or later (POD2+). The secondary endpoint was to identify predictors of delayed discharge in the POD2+ cohort. METHODS A retrospective database review of the medical records of 534 patients who underwent endonasal resection of pituitary adenoma at the Mayo Clinic was performed. Relevant demographics, tumor characteristics, and perioperative metrics were abstracted from the medical record, including intraoperative CSF leakage, postoperative complications, emergency department visits, or inpatient readmissions within 30 days. Descriptive, univariate, and multivariate analyses were performed. RESULTS In comparison to 422 (79%) patients discharged on POD1, 112 (21%) patients discharged on POD2+ had a higher unplanned medical care rate (13% vs 5.5%, p = 0.019). There were significantly more men in the POD1 group (48%) than in the POD2+ group (37%) (p < 0.04). The most common reasons for POD1 unplanned care were endocrine dysfunction (2.4%), split evenly between syndrome of inappropriate antidiuretic hormone and adrenal insufficiency, whereas the most frequent reason in the POD2+ cohort was medical (0.06%). Univariate analyses indicated that female sex, higher BMI, intensive care unit (ICU) admission, obstructive sleep apnea, continuous positive airway pressure dependence, intraoperative CSF leakage, and diabetes insipidus (DI) increased the likelihood of POD2+ discharge. The reduced logistic regression model demonstrated a higher likelihood of POD2+ discharge with older age, ICU admission, intraoperative CSF leakage, and DI (p < 0.001). Common factors contributing to discharge after POD1 included endocrine (n = 66, 35%) and/or medical (n = 65, 34%) reasons. CONCLUSIONS Routine patient discharge on POD1 following uncomplicated endonasal resection of pituitary adenoma is a safe practice, as evidenced by the significantly lower rates of unplanned medical care and complications compared with those of patients discharged on POD2 or later. Delayed discharge was associated with older age, ICU admission, intraoperative CSF leakage, and DI. The most frequent reasons for POD1 readmission were endocrine versus medical reasons for POD2+. Preoperative identification of risk factors for delayed discharge and preemptive management of endocrine and medical complications may reduce the length of stay and return to medical care.

Abstract Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol—including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data—is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA—ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).

Abstract Background MR‐guided adaptive radiotherapy (ART) allows for daily plan optimization based on patient‐specific anatomy. Accumulated doses, driven by deformable image registration (DIR), of daily fractions can provide cumulative dose metrics and insights into toxicity and tumor control. In prostate ART, inter‐ and intra‐factional deformations, particularly due to bladder and rectum, pose a challenge to accurate DIR generation. Purpose To quantify geometric and dosimetric accuracy of a proposed prostate MR‐to‐MR DIR approach to support MR‐guided ART dose accumulation. Methods We evaluated DIR accuracy in 25 patients treated with 30 Gy in five fractions on a 1.5 T MR‐linac using an adaptive workflow. For all patients, a reference MR was used for planning, with three images collected at each fraction: adapt MR for adaptive planning, verify MR for pretreatment position verification and beam‐on for capturing anatomy during radiation delivery. We assessed three DIR approaches: intensity‐based, intensity‐based with controlling structures (CS), and intensity‐based with controlling structures and points of interest (CS + P). DIRs were performed between the reference and fraction images and within fractions (adapt‐to‐verify and adapt‐to‐beam‐on). For the evaluation, we propagated CTV, bladder, and rectum contours using the DIRs and compared each to manually delineated contours using Dice similarity coefficient, mean distance to agreement, and dose–volume metrics. Results CS and CS + P improved geometric agreement between manual and propagated contours over intensity‐only DIR. For example, mean distance to agreement (DTA mean ) for reference‐to‐beam‐on intensity‐only DIR was 0.131 ± 0.009 cm (CTV), 0.46 ± 0.08 cm (bladder), and 0.154 ± 0.013 cm (rectum). For the CS, the DTA mean values were 0.018 ± 0.002, 0.388 ± 0.14, and 0.036 ± 0.013 cm. Finally, for CS + P, these values were 0.015 ± 0.001, 0.025 ± 0.004, and 0.021 ± 0.002 cm. Dosimetrically, comparing CS and CS + P for reference to beam‐on DIRs resulted in a change of CTV D98% from [−29 cGy, 19 cGy] to [−18 cGy, 26 cGy], bladder D5cc from [−51 cGy, 544 cGy] to [−79 cGy, 36 cGy], and rectum D1cc from [−106 cGy, 72 cGy] to [−52 cGy, 74 cGy]. Conclusion CS improved geometric and dosimetric accuracy over intensity‐only DIR, with CS + P providing further performance improvement, particularly for bladder. However, session image segmentation remains a challenge, which may be addressed with automated contouring.