Citations

Abstract Background: In MBC, CTC enumeration is highly prognostic for both progression free survival (PFS) and overall survival (OS). Multiparametric technologies enable for expanded phenotypic profiling of CTCs, including ER and HER2 assessment. Limited information is available on the concordance of CTC ER and HER2 levels compared to synchronously obtained tissue. We assessed the prognostic performance of CTC enumeration and phenotypic profiling of ER and HER2 on CTCs. Methods: The prospective, multi-institutional Aurora study enrolled pts with MBC of any subtype either at diagnosis of metastatic disease or at time of progression on any line of systemic therapy. Pts underwent a metastatic site biopsy, consented to archival primary tissue collection and donated blood samples serially every 3-4 months until progression. CTCs, from blood collected at study entry, were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells using an automated imaging system (RareCyte, Seattle). ER and HER2 expression levels were measured by mean fluorescence intensity (MFI), with thresholds above 80 (ER) and 160 (HER2) considered positive. Comparisons were made to total RNAseq from paired metastatic tissue biopsies. PFS and OS were calculated from the time of study entry to last follow up or death. Results: Baseline CTC enumeration was performed in 154 pts. The most common clinical subtype was HR+/HER2- (59.7%), followed by HER2-positive (16.8%) and TNBC (15.5%). The median lines of prior therapy were 1 (range 0-10). At least 1 CTC was identified in 68/154 pts (44%), 30 (19%) had ≥ 5 CTCs, and 15 (9.7%) had CTC clusters. The median CTC value was 0 (0-877). The presence of CTCs (≥1 or ≥5) and CTC clusters was adversely associated with PFS and OS (Table 1 Table 1. CTC survival analyses Number Median PFS PFS HR (95% CI) Median OS OS HR (95% CI) Presence of CTC 0 CTC 86 7.37 (0.03 - 43.1) reference 20.72 (0.03 - 50.6) reference ≥ 1 CTC 68 4.7 (0.43 - 19.5) 1.65 (1.16-2.36) 12.04. (0.43-44.1) 2.13 (1.44-3.16) Presence of ≥ 5 CTC <5 CTC 124 7.7 (0.03 - 43.1) reference 19.31 (0.03 - 50.6) reference ≥ 5 CTC 30 2.88 (0.43 - 18.7) 1.77 (1.15 - 2.71) 5.74 (0.43 - 29.3) 3.59 (2.26-5.70) Presence of clusters 0 clusters 139 7.37 (0.03 - 43.1) reference 18.06 (0.03 - 50.6) reference ≥ 1 cluster 15 1.91 (0.43 - 18.7) 2.06 (1.16 - 3.68) 3.42 (0.43 - 18.7) 5.44 (2.94-10.09) ). Across all subtypes, the median CTC ER-MFI across was 36.2 (range 4.2-10,016.6) and the median HER2-MFI was 139.6 (range 4.2-2480.5). We observed high intra-patient heterogeneity of ER-MFI (CV: 0.65 [0.34-1.25]) and HER2-MFI (CV: 0.79 [0.42-1.54]). Clinical metastatic subtype from metastasis at study entry was available in 54/68 pts with CTCs. Pts with clinical ER+ MBC had a higher median ER-MFI compared to clinical TNBC (111.9 vs 68.6, p = 0.02). However, 11 pts (26.8%) with clinical ER+ MBC had all CTCs with an ER-MFI <80. Lower ER expression was observed in CTCs collected after prior exposure to a SERD (median ER-MFI: post-SERD [n=8] 27 vs post-aromatase inhibitor [n=4] 252, p<2.22e-16). No correlations were observed between the median CTC ER-MFI or HER2-MFI and paired tissue ESR1 or ERBB2 RNA expression (n=66). Conclusions: CTCs are strongly predictive of PFS and OS. CTC ER- and HER2-MFI were highly heterogeneous without clear correlation with bulk tissue RNA expression. The clinical impact of discordant clinical receptor status and CTC receptor status warrants further exploration. Citation Format: K. V. Giridhar, W. C. Nenad, H. Ye, G. L. Wheeler, T. Hinoue, A. R. Michmerhuizen, B. M. Felsheim, U. R. Chandran, B. J. Kelly, E. R. Mardis, P. W. Laird, J. M. Balko, A. C. Garrido-Castro, S. Coppens, J. Bowen, R. Nanda, N. U. Lin, C. K. Anders, C. Isaacs, J. J. Tao, J. D. Anampa, N. Jahan, L. Huppert, A. DeMichele, B. H. Park, S. Vinayak, A. L. Delson, M. M. Magbanua, M. Balic, H. A. Parsons, A. V. Lee, L. A. Carey, L. Norton, A. C. Wolff, N. E. Davidson, I. Krop, T. A. King, C. M. Perou, K. A. Hoadley, Aurora US Metastases Network. Characterizing circulating tumor cell (CTC) enumeration and phenotypic profiling in blood with synchronously obtained tissue in metastatic breast cancer (MBC) in TBCRC /AURORA US [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 PS2-07-17.

Abstract Introduction: Breast cancer most commonly metastasizes to the bones, with bone pain and other skeletal related events (SREs) having a limiting effect on quality of life. Bisphosphonates are widely used in breast cancer patients to reduce SREs and bone loss, particularly in those with bone metastases or receiving endocrine therapy. We aim to study the real world comparative data between two widely used bisphosphonates in clinical practice, zoledronic acid and pamidronate, along with evaluation of their toxicity profiles. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, and encompassing data from 105 global healthcare organizations. Female patients aged 18 and above with breast cancer metastatic to the bone were identified and then stratified into two groups based on treatment with zoledronic acid or pamidronate. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including mortality, osteoporotic fracture, hypercalcemia, pathological fracture, fall, and osteonecrosis. Results: We identified 7887 patients in the zoledronic acid cohort and 635 patients in the pamidronate cohort. After propensity matching, each cohort consisted of 625 patients with similar baseline characteristics. The average age was 66.4 years in zoledronic acid cohort and 69.1 in the pamidronate cohort. In the zoledronic acid cohort, the ethnicity distribution was 74.68 % White, 11.55% African American, and 6.36% Hispanic. In contrast, the pamidronate group had an ethnicity distribution of 63.04% White, 20.64% African American, and 8.16% Hispanic. Our analysis found that within 5 years, patients with breast cancer metastatic to the bone who received zoledronic acid had a significantly lower risk of mortality (Hazard Ratio [HR] 0.593, 95% CI: 0.509-0.691, p-value <0.001), osteoporotic fracture (Risk difference: -5.28%, 95% CI: -7.65 to -2.90), p-value < 0.001), hypercalcemia [HR: 0.262, 95% CI: 0.212 - 0.323, p-value = 0.001), pathological fracture (Risk difference: -6.88%, 95% CI: -10.69 to -3.07), p-value < 0.001). However, the zoledronic acid group had higher risk of falls [Risk difference: 3.52%, 95% CI: 0.518 to 6.522), p-value = 0.021). There was no statistically significant difference in the occurrence of osteonecrosis between the two cohorts. Conclusion: Our study revealed that patients with breast cancer with metastatic disease to the bone who received zoledronic acid had significantly lower rates of mortality, osteoporotic fracture, hypercalcemia, and pathological fracture compared to those receiving pamidronate. Additional longitudinal cohort studies are imperative to explore the outcomes between these agents and inform clinical practice guidelines. Citation Format: Y. Arya, A. Syal, C. Jones, H. Mahadevia, N. Batra, A. Uriepero-Palma. Real-world outcomes comparing zoledronic acid and pamidronate in patients with metastatic breast cancer with bone metastases: A propensity score matched analysis from a global federated health research network [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 PS2-06-02.

Abstract Background: Smoking, a known risk factor for numerous cancers, negatively impacts long-term survival in breast cancer (BC) survivors (Parada H Jr et al., 2017; Pierce et al., 2019). This study aims to characterize baseline smoking behaviors among breast cancer patients who self-reported smoking during an initial survey. Objectives: To assess attributes of patients self-reporting as current smokers near BC diagnosis, examining demographics, habits, quality of life, cancer treatments, comorbidities, and finances. Methods: Patients with newly diagnosed BC seen at Mayo Clinic Rochester between 2014-2024 were invited to enroll in the Mayo Clinic Breast Disease Registry. Consenting participants who completed self-reported questionnaires at baseline were included in this study. Smoking status and related variables at the time of survey completion were assessed via a baseline questionnaire, classifying participants as current, former, or never smokers. Of 3,959 participants completing baseline surveys, 3,729 were analyzed after excluding 103 with missing smoking data and 127 with their baseline survey returned >1-year post-diagnosis. Categorical variables were summarized with frequencies and percents, continuous variables with distributional statistics. Univariable associations with current smoking were assessed via two-sample t-tests (continuous) and chi-square or Fisher exact tests (categorical). Significant variables (p<0.05) were included in a multivariable logistic regression model. Results: Among 3,729 BC patients (mean age 58.3 years, SD 12.9), 99.1% were female, 97.1% White, and 98.7% non-Hispanic. Only 2.7% reported financial difficulty, 56.4% had a bachelor's degree or higher, 81.7% were married or equivalent, and 21.7% consumed ≥5 alcoholic drinks/week. Tumor stage distribution was as follows: Stage 0 (13.9%), Stage 1 (43.9%), Stage 2 (28.9%), Stage 3 (8.9%), and Stage 4 (4.5%); 33.8% received chemotherapy, 56.5% radiotherapy, 63.6% endocrine therapy, and 42.2% underwent mastectomy. Current smokers (2.6%, n = 95) had a median diagnosis age of 59.1 (IQR 31.8-87.1),with 32.6% consuming ≥5 drinks/week (vs. 21.5% in non-smokers, univariable p = 0.012), 69.5% with less than a Bachelor’s degree (vs. 42.9%, p<0.001), 9.6% facing financial difficulty (vs. 2.5%, p<0.001), and 10.5% diagnosed within 270-365 days after survey return (vs. 4.2%, p = 0.022). Tumor stage showed 47% with Stage 1 (vs. 43.7%, p = 0.245); 33.7% received chemotherapy, 60.0% radiotherapy, and 58.9% endocrine therapy. Current smokers had a mean smoking initiation age of 19.9 (SD 6.2), smoked 12.5 cigarettes/day (SD 7.9) for 32.8 years (SD 14.1), with mean 22.3 pack-years (SD 17.2).Univariable associations of demographic and clinical characteristics with current smoking showed Compared to never or former smokers, current smokers at the time of survey took a longer time to return their baseline survey (p = 0.022), were more likely to consume five or more alcoholic drinks per week (p = 0.012), were more likely to have difficulty paying their bills (p<0.001) and were less likely to obtain a Bachelor's degree or higher (p<0.001). These associations remained significant after multivariable adjustment. Conclusion: Current smoking (2.6%) soon after a BC diagnosis was independently associated with delayed survey return, higher alcohol use, financial difficulty, and lower education. Assessing smoking status and referring patients to smoking cessation programs are critical for addressing these risk factors and improving health outcomes. These findings highlight distinct socioeconomic and behavioral profiles among current smokers, suggesting potential targets for tailored interventions. Citation Format: S. Hirani, R. A. Vierkant, N. L. Larson, S. D. D’Andre, F. J. Couch, J. E. Olson, K. J. Ruddy. Identifying Smoking-Related Factors in Breast Cancer Patients: Mayo Clinic Registry Insight [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 PS1-04-18.

Abstract Background: Up to 68% of patients will experience CIPN. There are no FDA or ASCO recommended therapies. The pain (P), numbness (N), and tingling (T) can persist for month, years or even lifetime. Duloxetine reduces pain scores by 0.6-1.0 on the 0-10 scale but does not help N or T. Scrambler therapy (ST) is a novel form of neuromodulation that uses EKG electrodes on the dermatomes to capture the pain c-fiber receptors, and generate an action potential of “non-pain” information to replace the pain information. It appears to reset central sensitization by altering cerebral blood flow and re-establishing the balance of neuropeptides (e.g., NGF, GDNGF) in the blood (Smith et al NEJM 2023). Yet many professionals and patients are unaware of it. Methods: We reviewed all available studies. Results: Smith et al (2010, VCU) noted a 59% P reduction (5.8 to 2.4 at the end of 10 days (P<0.0001)) in 16 subjects, and 4 had 0 pain at day 10. Pachman et al (2015, Mayo) in 37 subjects showed a 53% P reduction by day 10; a 44% reduction in T; and a 37% reduction in N. In a randomized trial of 50 patients using ST versus TENS (transcutaneous electrical nerve stimulation), Loprinzi et al (2020, Mayo), in a randomized trial, showed more than twice as many ST patients reported a 50% improvement (36-56%) vs. TENS (16-28%). At 8 weeks the reductions were important: 33%P, 28%N, 41%T. In a subsequent crossover trial (Childs 2021) of the TENS patients to ST, 6 of 12 ST patients achieved a 50% reduction in P and T. Smith et al (2021 Hopkins) did a randomized sham-controlled trial with 35 patients but observed no lasting effect; in retrospect, the electrodes and electrode placement were incorrect in this trial. Abdi et al (2024, MDACC) did a Phase II trial of ST in 10 patients and found symptoms of N, T, trouble walking, and disturbed sleep had significant improvements at 6 months. Worst pain was reduced at 6 months by 3 points. Pain medication use decreased by 70% at the end of treatment and by 42% at 6 months. Patient satisfaction was high (82%) and no adverse events with ST treatment were reported. Wang Z. et al (Hopkins, unpublished data 2025) showed a 60% reduction in pain (6.2 to 2) in twelve subjects, with one achieving complete remission. Strouse et al (2025, UCLA) will soon report similar results in over 60 patients. Wang E. et al (2023, Hopkins) reviewed 1152 patients treated with ST and found just 3 adverse events: one hematoma and two red spots under the EKG electrodes. The only other therapy that reduces all the symptoms of CIPN is spinal cord stimulation (Gupta 2024) but that is invasive, expensive, and can cause a multitude of adverse events. Conclusions: Scrambler Therapy is a safe and effective treatment for the P, N, and T of CIPN with rare and minimal side effects in a syndrome with no other effective treatment. It is hindered by reimbursement ($32/30 minutes, the same as TENS even though the technology is completely different). Scrambler Therapy should become more available in the future. Citation Format: Z. Wang, C. L. Loprinzi, S. Abdi, T. B. Strouse, T. J. Smith. Scrambler Therapy: a safe and effective way to treat chemo-induced neuropathy [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 PS1-02-17.

Abstract Background Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. Methods A wide battery of complementary tests from RNA level to high-resolution respirometry on permeabilized muscle fibers was performed. The relationship between respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine the clinical significance of the findings. Results The study included a total of 67 patients with IBM and 45 controls. IBM muscle tissue exhibited reduced maximal respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, males had decreased State 3 intrinsic respiration, whereas females had greater intrinsic respiration in leak states. Complex II control ratio strongly correlated with disease duration and severity only in females. IBM was associated with decreased RNA and protein expression of OXPHOS complexes. Complex I activity was decreased mainly in females. IBM samples exhibited lower maximal H 2 O 2 emission, accompanied by a higher total antioxidant capacity that correlated with disease duration in females. In IBM, there was decreased mtDNA content, and impaired mitophagy, both of which strongly correlated with respirometry measures and markers of disease severity, indicating these pathways are likely interconnected and of clinical significance. Conclusion IBM is characterized by multilevel impairments in mitochondrial coupling efficiency, revealing several potential therapeutic targets to improve mitochondrial fitness, while accounting for sex-specific differences.

Background: This study aimed to determine whether trapezium morphology, specifically trapezial inclination, is a risk factor for the failure of primary conservative or minimally invasive treatment for acute traumatic thumb carpometacarpal (CMC) joint dislocations in the relatively early period. We hypothesized that an elevated trapezial inclination would be associated with a higher rate of treatment failure. Methods: We retrospectively reviewed patients treated for acute thumb CMC joint dislocations between 1976 and 2025 with closed reduction and subsequent immobilization or percutaneous pinning. Patients were classified into “failure” (recurrent dislocation or subsequent symptomatic subluxation) or “non-failure” groups. Trapezial inclination, measured on oblique hand radiographs, was compared between the groups using the Mann-Whitney U test. Results: Fourteen patients met the inclusion criteria (7 failure, 7 non-failure). While demographics were not significantly different, the failure group demonstrated a significantly higher mean trapezial inclination (19.1° vs 8.7°; P = .0012). This significant difference persisted in a subgroup analysis that excluded associated Gedda type 3 Bennett fracture ( P = .0318) Conclusions: Elevated trapezial inclination may predict the failure of primary conservative or minimally invasive treatment in the relatively early period for acute thumb CMC joint dislocation. Our findings suggest that patients with this steep trapezium may be poor candidates for conservative or minimally invasive management and should be considered for primary definitive surgery.

Abstract Background Despite the high precision of deep learning models on internal tests on CT, their effectiveness often drops on external validation due to artifacts caused by patient motion and implants like metal or silicone that were not accounted for in the carefully curated training data. Potential wide categories of “unknown” anomalies within a CT exam makes training a supervised model for out‐of‐distribution (OOD) identification impractical, especially when considering unseen external data. Purpose To develop an artificial intelligence (AI) model to detect and identify anomalies/OOD data in abdominal–pelvis CT exams for the purpose of improving the performance of downstream applications. Methods Our proposed 2D and 3D generative architecture receives the third lumbar vertebra (L3) slice (slice‐level model) or all the slices from the series (series‐level model), generates a reconstruction and the secondary part of our architecture—anomaly score computation block, computes the anomalies pixels/voxels (slice‐level/series‐level) to identify anomalous L3‐slices/volumes (slice‐level/series‐level). We trained on data from over 2850 abdominal–pelvis CT volumes from adults over age 50 years collected throughout multiple Mayo Clinic campuses (60% female; mean age: 66.9, 92.4% non‐Hispanic White) and tested on a prospective test set of 544 CTs from July 2024 (47.3% female; mean age: 70.9, 94% non‐Hispanic White) as well as an external test set. Results We found that while traditional methods show moderate success, our generative models—Vector Quantized Variational Autoencoder (VQVAE) and Vision Transformer‐Masked Autoencoder (VIT‐MAE)—deliver excellent results with negligible false positives (FPs) and are also superior in identifying varied types of OOD samples. Prospective analysis showed the model was able to handle the under‐documentation of anomaly in radiology reports with 86.11% true positive (TP) rate. We also performed external validation using the publicly available AbdominalCT‐1k dataset, which contains 1062 CT scans compiled from several existing benchmark datasets. The model achieved a 75.26% TP rate, while the 24.7% FP rate was primarily triggered by anomalies located outside the body. Conclusions The proposed method can be leveraged to detect both intra‐ and interclass OOD data from abdominal CT images and can assess the quality of CT datasets to provide actionable insights. This workflow is particularly valuable for nonshareable healthcare collaborations, where it can be deployed as a service within local firewalls for automated dataset curation without prior knowledge about the OOD types. The implementation of the algorithm is available in the GitHub: https://github.com/gokul‐ramasamy/implant_detection.git .

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14–28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.

Background: A summary of pharmacist-based practices and preferences regarding the prevention and management of high-dose methotrexate (HDMTX) toxicity in patients with lymphoma does not exist. The objective of the study was to describe current practices surrounding management of HDMTX therapy. This was done through a self-administered, web-based, cross-sectional survey of hematology/oncology pharmacists to ascertain practices and individual attitudes about HDMTX therapy management. Responses were summarized with descriptive statistics. Response comparisons were made using Chi-square or Fisher’s exact test for categorical data, and Kruskal-Wallis test for variables on the Likert scale. A total of 175 pharmacists provided 116 eligible surveys [68 (59%) complete responses and 48 (41%) partial responses] for analysis. The Cockcroft-Gault estimated creatinine clearance formula was the most preferred method (61%) to estimate kidney function and determine HDMTX dosing. Respondents would proceed with HDMTX therapy until the predicted risk of AKI, or AKI stage 2 or 3, exceeded 50% and 20%, respectively. Preferred treatment modifications for a high predicted AKI risk after HDMTX exposure included additional prehydration, HDMTX dose reduction, and increased kidney function monitoring, although levels and degrees of agreement varied. Respondents indicated that serum cystatin C-based GFR estimates lacked evidence, accuracy, and practicality in HDMTX therapy management. There was limited familiarity with cell cycle arrest biomarker use during HDMTX therapy. Glucarpidase was considered time-sensitive and highly effective; however, acquisition cost represented a barrier to use, and the optimal dose was felt to be unknown. In conclusion, there is significant heterogeneity in supportive practices and beliefs about the optimal management for patients with lymphoma receiving HDMTX therapy.