Citations

e12644 Background: Standard neoadjuvant therapy for HER2-positive early breast cancer combines multi-agent chemotherapy with HER2-targeted antibodies and is associated with substantial toxicity. HER2-directed antibody–drug conjugates (ADCs) may enable de-escalation. We compared efficacy and toxicity of neoadjuvant ADC-based regimens given without concurrent chemotherapy versus standard chemotherapy-based regimens, including by platinum use in the control arm. Methods: We searched PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science through December 18, 2024 for randomized controlled trials in early/locally advanced HER2-positive breast cancer. Eligible trials compared neoadjuvant ADC-based regimens without concurrent chemotherapy versus standard chemotherapy-based regimens. Outcomes were pathologic complete response (pCR; per trial definition), grade ≥3 adverse events (AEs), and treatment discontinuation. Odds ratios (ORs) were pooled and heterogeneity was summarized with I². Results: Nine randomized trials (n = 2,021; mean age 50.7±13.7) were included. There was no significant difference in pCR between groups (OR 0.93, 95% CI 0.62–1.40; I² = 59.8%). ADC-based regimens were associated with fewer grade ≥3 AEs (OR 0.30, 95% CI 0.11–0.84; I² = 91.5%). Treatment discontinuation did not differ (OR 1.10, 95% CI 0.39–3.12; I² = 85.8%). Findings were consistent when stratified by platinum use in the control regimen. Conclusions: In HER2-positive early breast cancer, neoadjuvant ADC-based regimens without concurrent chemotherapy achieve pCR comparable to standard chemotherapy while substantially reducing severe toxicity without increasing discontinuation, independent of platinum use. Confirmation in phase III trials with mature survival endpoints is needed.

1673 Background: Survivorship care plans (SCPs) summarize cancer treatments and provide evidence-based recommendations for surveillance, screening, and management of treatment-related complications. Despite the availability of guidelines and templates, SCPs remain underutilized in routine practice due to the time-intensive and error-prone nature of manual creation. Empowering cancer survivors to use publicly available large language models (LLM)–based chatbots, such as ChatGPT, may offer a feasible solution to this problem. Methods: Standardized patient profiles were developed for six common cancers: breast, colorectal, non–small cell lung, small cell lung, prostate cancer, and diffuse large B-cell lymphoma. Profiles were reviewed by a primary care physician and an oncologist to ensure clinical accuracy and representativeness of common survivorship scenarios. Using lay language to simulate real-world patient input, ChatGPT (version 5.2, publicly available at the time of the study) was prompted with each profile using the question, “What follow-up care do I need?” Common survivorship symptoms for each cancer were also tested. Responses were evaluated across five domains: medical accuracy (concordance with current ASCO or NCCN guidelines), thoroughness, patient safety and risk framing, clarity and patient comprehension, and actionability. Five-point Likert scales were used (1 = not at all; 5 = very much). Scores were averaged across two independent physician raters. Readability was assessed using the Flesch Reading Ease Score. Results: ChatGPT-generated SCPs demonstrated high medical accuracy (mean score 4.25/5), with no factual errors or hallucinations identified on manual review. Patient safety and risk framing scored 3.75/5; symptom red flags and care escalation guidance were appropriately stated in most scenarios. Thoroughness was moderate (3.50/5), with key survivorship elements, such as smoking cessation counseling or genetic risk considerations; sometimes omitted unless explicitly prompted. Readability was limited, with a mean Flesch Reading Ease Score of 40.5, corresponding to a college reading level and exceeding recommended readability standards for patient education materials. Clarity (3.38/5) and actionability (3.38/5) were similarly constrained due to dense medical language. Conclusions: ChatGPT demonstrated high medical accuracy in generating survivorship care plans across six common cancers, supporting the feasibility of using publicly available LLMs to guide survivorship care. However, improvements in comprehensiveness, readability, and patient-centered actionability are necessary before such tools can be safely integrated into clinical survivorship workflows.

1110 Background: CDK4/6 inhibitors with endocrine therapy are widely used for HR+/HER2– metastatic breast cancer (BC). While studies have shown similar progression-free outcomes across agents, overall survival (OS) data are limited. Since OS is a definitive endpoint and BMI may influence outcomes, this study examines BMI-dependent OS differences among CDK4/6 inhibitors. Methods: A retrospective cohort study was conducted using the Mayo Clinic Platform full AMC1 dataset. Postmenopausal women with BC receiving palbociclib/ribociclib/abemaciclib plus aromatase inhibitor (AI) were included. Patients with prior use of fulvestrant, anthracyclines, radiation therapy, GnRH agonists, or history of MACE, heart failure, myocardial infarction, or stroke before BC diagnosis were excluded. Patients were stratified by BMI and CDK4/6 inhibitor. The primary outcome was 5-year OS. Results: Among 1,989 patients (palbociclib: 868; ribociclib: 465; abemaciclib: 656), palbociclib was associated with significantly worse OS compared to ribociclib in BMI <25 (HR 2.91; 95% CI: 1.76–4.79; P < 0.01) and BMI ≥30 (HR 1.91; 95% CI: 1.21–3.01; P < 0.01). Compared to abemaciclib, palbociclib showed worse OS: BMI <25 (HR 1.73; P < 0.01), BMI 25–30 (HR 1.56; P < 0.01), and BMI ≥30 (HR 1.82; P < 0.01). No significant OS differences were observed between ribociclib and abemaciclib. Palbociclib patients were older, particularly in BMI <25 (Cohen's D = 0.39 vs. ribociclib; 0.27 vs. abemaciclib) and BMI ≥30 (0.28 vs. ribociclib; 0.23 vs. abemaciclib). In the BMI 25–30 group, palbociclib group was also older than ribociclib group (Cohen's D = 0.26). Conclusions: In postmenopausal BC patients on AIs and CDK4/6 inhibitors, palbociclib was associated with worse OS in BMI < 25 and BMI ≥ 30 groups, while ribociclib and abemaciclib showed similar outcomes across BMI groups. Palbociclib patients were older than those on other drugs, which may partially confound results; however, in the BMI 25–30 group, despite similar age differences, no survival difference was observed between palbociclib and ribociclib, suggesting age alone may have limited impact. These findings indicate a potential interaction between BMI and drug choice, and highlight the need for prospective studies to confirm and adjust for these variables. Limitations include the observational design and inability to perform multivariable regression analyses to adjust for confounders. Overall survival comparisons by CDK4/6 inhibitor and BMI subgroup. Comparison BMI Group Hazard Ratio (95% CI) P-value Palbociclib vs Ribociclib <25 2.91 (1.76 – 4.79) < 0.01 25 – 30 1.34 (0.87 – 2.071) 0.17 ≥30 1.91 (1.21 – 3.01) < 0.01 Palbociclib vs Abemaciclib <25 1.73 (1.29 – 2.32) < 0.01 25 – 30 1.56 (1.09 – 2.23) < 0.01 ≥30 1.82 (1.15 – 2.88) < 0.01 Ribociclib vs Abemaciclib <25 1.27 (0.81 – 1.99) 0.29 25 – 30 0.87 (0.54 – 1.43) 0.59 ≥30 1.05 (0.63 – 1.75) 0.85

10585 Background: Prior studies suggest that thyroid cancer (TC) survivors may have an elevated risk of secondary malignancies. However, whether this risk differs by TC histology, specifically with breast cancer (BC), remains unclear. We aimed to investigate the association between TC subtype—papillary thyroid carcinoma (PTC) versus medullary thyroid carcinoma (MTC)—and subsequent BC risk, adjusting for demographic factors. Methods: We conducted a retrospective cohort study using the SEER (2000–2022), including adults with a primary, microscopically confirmed PTC or MTC. Subsequent BC occurrence was defined as a binary outcome (yes/no). Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for MTC versus PTC, controlling for age (<50 vs ≥50 years), sex, and race. Stratified analyses by age and race were also performed. Stata 15 was used for statistical analyses. Results: 14,840 patients (14,563 PTC, 277 MTC) were included. MTC patients were older (mean 59.08±12.66 vs 56.16±12.98 years, p<0.001) and had a higher proportion of males (44.4% vs 29.4%, p<0.001). The overall incidence of secondary BC was lower in MTC patients (7.6% vs 22.5%, p<0.001). In unadjusted logistic regression, MTC was associated with significantly lower BC risk (OR=0.28, 95% CI: 0.18–0.44, p<0.001). After adjustment, MTC remained significantly protective (aOR=0.34, 95% CI: 0.22–0.55, p<0.001). Stratified analyses demonstrated consistent findings across age groups (<50: aOR=0.10, 95% CI: 0.03–0.42; ≥50: aOR=0.34, 95% CI: 0.21–0.54), , as well as white and Hispanic patients. Conclusions: Survivors of MTC have a substantially lower risk of developing secondary BC compared to PTC survivors. This association persists after adjustment for age, sex, and race, and is consistent across age and most racial subgroups. However, different BC types were not assessed due to limited number of BC patients among MTC survivors, and the small MTC sample size and potential survival differences between groups may affect the results. These findings highlight a possible effect of TC subtype on BC risk, suggesting the potential influence of underlying biological or genetic mechanisms. Baseline demographic characteristics of patients with papillary and medullary thyroid carcinoma. Characteristic Papillary Thyroid Carcinoma (PTC) (N=14,563) Medullary Thyroid Carcinoma (MTC) (N=277) P-value Age at Diagnosis 0.0002* Mean ± SD, years 56.16 ± 12.98 59.08 ± 12.66 Median, years 57 61 Sex, n (%) <0.001† Female 10,288 (70.6) 154 (55.6) Male 4,275 (29.4) 123 (44.4) Race, n (%) 0.015† White 10,263 (70.5) 197 (71.1) Black 921 (6.3) 15 (5.4) American Indian 77 (0.5) 1 (0.4) Asian 1,379 (9.5) 13 (4.7) Hispanic 1,903 (13.1) 50 (18.1) SD: Standard Deviation. *P-value from two-sample t-test (equal variances assumed). †P-value from chi-square test for the overall distribution across categories.

As an emerging tire wear-derived environmental contaminant, 6PPD-quinone (6PPDQ) has raised significant concerns regarding its neurotoxic potential, particularly for children exposed to recycled tire crumb rubber in playgrounds. However, the molecular mechanisms by which 6PPDQ influences neurological disorders such as epilepsy remain poorly understood. In this study, we employed an integrative framework combining network toxicology, bulk analysis of human epileptic brain tissues, Mendelian randomization, and molecular dynamics simulations to elucidate these mechanisms. Our findings, validated through CETSA-WB and SPR, identify 6PPDQ as a direct ligand that binds to and stabilizes neuronal TP53. Through a synergistic double-hit mechanism, 6PPDQ directly engages the TP53 pathway while simultaneously triggering microglial interleukin-6 secretion. These converging pathways lead to the suppression of the master antioxidant regulator Nrf2, resulting in glutathione depletion, excessive reactive oxygen species accumulation, and exacerbated neuronal damage under excitotoxic stress. Experimental validation using glutamate-induced HT22 cell models and microglia–neuron crosstalk systems confirmed that targeting the TP53/Nrf2 axis or scavenging ROS significantly attenuates 6PPDQ-induced neurotoxicity. Our findings highlight critical risks to pediatric neurological health posed by tire-derived contaminants and identify the TP53/Nrf2 axis as a promising therapeutic target. Furthermore, this work provides a robust scientific basis for refining risk assessment frameworks and developing regulatory strategies to mitigate environmental exposure to 6PPDQ.

Background Recent studies have disputed the association between bisphenol A (BPA) and endometriosis. This updated meta-analysis was conducted to investigate the impact of BPA exposure on endometriosis. Methods This study evaluated BPA exposure and endometriosis risk, analyzing studies from Web of Science, PubMed, Embase, Cochrane Library, and Chinese databases (CNKI, CBM, Wanfang, VIP) through August 2025. Methodological quality was assessed via the Newcastle-Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality Tool (AHRQ). Heterogeneity was quantified using I 2 statistics. Pooled odds ratios (ORs) and 95% CIs were calculated using fixed- or random-effects models according to heterogeneity. Subgroup analysis, sensitivity analysis, and publication bias assessment were supplemented to validate the overall finding. Results Seven studies comprising 2,488 participants were included in quantitative synthesis. The meta-analyses demonstrated that BPA exposure was associated with a statistically significant increase in endometriosis risk (OR = 1.36, 95% CI = 1.13–1.63, p = 0.008). Additionally, subgroup analysis indicated that BPA exposure may further elevate endometriosis risk in cases with different regions, populations, and measurement methods. Sensitivity analysis confirmed that the results of these meta-analyses were relatively robust. No publication bias was detected. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251019552 , identifier PROSPERO (CRD420251019552).

NF-κB activating protein (NKAP) plays important roles in various cancers, including breast cancer. However, its expression and prognosis value in breast cancer remains uncertain. Gene expression profiling interactive analysis, Human protein atlas database, and University of Alabama at Birmingham Cancer data analysis portal database were used to predict the expression and prognostic value of NKAP in breast cancer. Immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR) and western blot were performed to detect NKAP expression. The effects of NKAP on cell proliferation, migration and drug sensitivity were investigated in MDA-MB-231 and SK-BR-3 cells. NKAP protein expression differed in breast cancer tissues and paraneoplastic tissues based on the cancer genome atlas data. The high NKAP expression was significantly correlated with a poor prognosis in breast cancer patients. The results of immunohistochemistry, western blot assay, and qRT-PCR proved that NKAP was highly expressed in breast cancer tissues compared with paraneoplastic tissues. In addition, qRT-PCR results showed that high expression of NKAP was significantly correlated with the larger tumor size and higher TNM stage. Moreover, knockdown of NKAP significantly inhibited the proliferation, migration, and enhanced drug sensitivity of MDA-MB-231 and SK-BR-3 cells. NKAP is highly expressed in breast cancer tissues, and its high expression is closely associated with poor prognosis. NKAP also promotes proliferation, migration, and inhibits drug sensitivity of breast cancer cells.

851 Background: Diffuse idiopathic skeletal hyperostosis (DISH) has been associated with increased risk of vertebral fractures in elderly men with prostate cancer. However, its potential role in the development of malignancies is poorly defined. In particular, the relationship between DISH and gastrointestinal (GI) cancers—including esophageal, gastric, colorectal, liver, biliary system, and pancreatic cancers—has not been examined. This study aimed to explore the risk of GI cancers among patients with DISH compared to those without DISH. We also assessed survival and incidence of vertebral fractures in these groups. Methods: Using the Mayo Clinic Platform (Full AMC1 dataset), we identified patients with and without a documented history of DISH. Outcomes included (1) prevalence and risk of GI cancers, (2) survival among GI cancer patients, and (3) vertebral fracture incidence. Relative risks (RRs) and hazard ratios (HRs) were calculated using SPSS20.0 and platform-based statistical tools, respectively. Kaplan–Meier survival analyses were performed to evaluate cancer survival outcomes. Results: A total of 6,189,860 patients were included, of whom 2,802 (0.05%) had DISH and 6,187,058 (99.95%) did not. Patients with DISH had a significantly higher prevalence of GI cancers compared with those without (RR = 1.63, 95% CI: 1.377–1.930). Survival analysis suggested worse outcomes among GI cancer patients without DISH (HR = 1.72, 95% CI: 1.25–2.35). Vertebral fracture incidence appeared lower among DISH patients, although low event numbers limit the reliability of this observation. Conclusions: DISH is associated with increased risk of GI cancers, while GI cancer patients without DISH may experience poorer survival. The observed trend toward lower vertebral fracture incidence among DISH patients should be interpreted cautiously due to limited event numbers. These findings highlight the importance of integrating musculoskeletal and oncologic perspectives in patient management and warrant further mechanistic and interventional studies. Survival analysis. Statistic Without DISH With DISH Patient Count 214,180 109 1 Month Survival 95.3% 98.2% 5 Month Survival 82.2% 87.9% 10 Month Survival 72.4% 85.1% 30 Month Survival 54.3% 74.1% 60 Month Survival 44.9% 60.6% Log-Rank 11.90 P-Value 0.00056 Hazard Ratio 1.72 (95% CI: 1.25 - 2.35)

331 Background: The relationship between plant-based dietary patterns and upper gastrointestinal (GI) cancers remains unclear. The Healthful Plant-Based Diet Index (hPDI) is a tool that measures adherence to plant-based diet and generates “scores” for clinical comparison. We conducted a systematic review and meta-analysis to examine the association between hPDI and the risk of esophageal and gastric cancers. Methods: A PubMed search identified relevant studies reporting on the association between hPDI and upper GI cancers. Reference lists were manually searched for additional studies. Study selection followed PRISMA guidelines, and quality was assessed using the Newcastle–Ottawa Scale (NOS). Pooled risk estimates were calculated using inverse-variance fixed-effects models, with subgroup analyses by cancer type. Sensitivity analyses were conducted using leave-one-out approach and by switching between fixed- and random-effects models. Forest plots and funnel plots were generated with RevMan 5.4, while Begg’s and Egger’s tests for publication bias were performed using Stata 15. Results: A total of four studies were included, all with high NOS scores. Overall, higher hPDI scores were associated with a significantly lower risk of upper GI cancers (RR = 0.64, 95% CI: 0.56–0.75). In subgroup analyses, the inverse association was consistent for both esophageal cancer (RR = 0.66, 95% CI: 0.54–0.79) and gastric cancer (RR = 0.63, 95% CI: 0.50–0.79). Between-study heterogeneity was low (I² = 35%, P = 0.16). Publication bias assessment indicated no evidence of small-study effects, as Begg’s test was non-significant (P = 0.88) and Egger’s test showed no significant bias (P = 0.76). Sensitivity analyses confirmed the robustness of the findings, with consistent results after sequential exclusion of individual studies and when using random-effects models. Conclusions: Higher hPDI scores were associated with a significantly reduced risk of esophageal and gastric cancers, indicating that adherence to a healthy plant-based diet may reduce upper GI cancer risk. These findings highlight the potential role of dietary modification in upper GI cancer prevention.

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.