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The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Disclosure: R. Castaneda: None. D. Bechenati: None. R.D. Rivera Gutierrez: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. P. Bennett: None. A. Acosta: Novo Nordisk, Gila Therapeutics, Amgen Inc, Regeneron Pharmaceuticals, Boehringer Ingelheim, Rhythm Pharmaceuticals, General Mills, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, MedAll, AiCME, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix. Introduction: Tirzepatide, a dual GIP and GLP-1 receptor agonist, is an FDA-approved medication demonstrating the highest efficacy for weight loss among currently available treatments. However, the influence of sex and age on weight loss outcomes with tirzepatide remains unclear. Objective: To investigate the influence of sex and age on weight loss outcomes in patients treated with tirzepatide. Methods: This retrospective study evaluated weight loss outcomes associated with tirzepatide across sex and age groups. Patients with active malignancy, prior bariatric surgery, or concurrent anti-obesity medication were excluded. The primary endpoint was total body weight loss percentage (TBWL%) at 15 months by sex and age. The influence of age was analyzed as a categorical (≤45, 46-59, ≥60 years) and continuous variable. Secondary outcomes included TBWL% at 3, 6, 9, and 12 months by sex and age. Data were analyzed using independent t-tests, one-way ANOVA, and multivariate regression; results are reported as mean ± standard deviation. Results: The study included 1033 patients (57.1% female; mean age 56 ± 11 years; mean BMI, 37.7 ± 8 kg/m2). By age category, 18.8% (196) were ≤45 years (35.7% males, 64.3% females), 45.9% (473) were 46-59 years (42.7% males, 57.3% females), and 35.3% (364) were ≥60 years (54.7% males, 45.3% females). At all timepoints, TBWL was significantly greater in females compared to males at all timepoints. At 15 months females had a higher TBWL than males: 15.3% ± 10, n=340, vs. 10.2% ± 8, n=244, (p < 0.001). Among females, premenopausal women achieved a higher TBWL than postmenopausal women: 16.9% ± 10 vs 14.4% ± 9, p = 0.04. Analysis by age groups revealed a trend toward higher TBWL in younger patients that did not reach statistical significance (p = 0.152): ≤45 years (14.7% ± 10%), 46-59 years (12.9% ± 10%), and ≥60 years (12.7% ± 9%). After adjusting for baseline age, BMI, and diabetes status, sex remained a strong predictor for weight loss outcomes (PE= 4.5, 95% CI [2.96, 5.97], p < 0.001), following type 2 diabetes status (PE= 4.8, 95% CI [3.0, 6.7], p < 0.001). Conclusion: Sex but not age was a strong predictor of weight loss with tirzepatide. Female sex was associated with greater weight loss than male sex. These results emphasize the importance of considering sex-specific factors in weight loss strategies and warrant further investigation into the underlying biological mechanisms. Differential weight loss by menopause, underscores the role of sex hormones. Presentation: Monday, July 14, 2025

Abstract Disclosure: R.D. Rivera Gutierrez: None. D. Bechenati: None. R. Castaneda: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. T.M. Taaffe: None. P.K. Bennett: None. A.J. Acosta: Novo Nordisk, Gila Therapeutics, Rhythm Pharmaceuticals, Amgen Inc, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, AiCME, MedAll, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix Sciences. Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular (CV) benefits. Tirzepatide (TZP), a dual GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist approved for weight management and glycemic control, currently lacks evidence on CV outcomes. This study evaluates TZP’s impact on cardiometabolic parameters and atherosclerotic cardiovascular disease (ASCVD) risk scores. Methods: We conducted a multicenter retrospective study of adults prescribed TZP from June 1, 2022, to November 1, 2024. Inclusion criteria included 12 months of TZP use and age >18 years. Exclusion criteria were pregnancy, active malignancy, concurrent FDA-approved antiobesity medications, and prior bariatric surgery. Endpoints included changes in blood pressure, lipid profiles, liver enzymes, glucose control parameters, medication use (statins, aspirin, antihypertensives), and ASCVD risk scores from baseline to 12 months, stratified by sex. Data were obtained from electronic medical records. We present data as mean differences [95% CI]. We used T-tests and multivariate regression analyses for analyses. Results: Among 831 participants (59.4% female; 91.2% White; mean age: 58 ± 12 years), 12-month weight loss was -12% [-13, -11], p<0.001. We observed significant improvement in systolic blood pressure (SBP) (-4 [-5, -3] mmHg, p<0.001), triglycerides (TG) (-38 [-52, -23] mg/dL, p<0.001), total cholesterol (TC) (-7 [-10, -4] mg/dL, p<0.001), LDL cholesterol (LDL) (-6 [-9, -4] mg/dL, p<0.001), fasting glucose (FG) (-39 [-48, -29] mg/dL, p<0.001), ALT (-10 [-15, -5] U/L, p<0.001), HbA1c (-1.3% [-1.5, -1.2], p<0.001), and HDL cholesterol (HDL) (+4 [+3, +5] mg/dL, p<0.001). The Lifetime and 10-year ASCVD scores did not significantly change after 12 months (p>0.05), underscoring TZP’s potential in mitigating the aging-associated increase in CV risk. Considering sex, females had greater weight loss (-13% [-14, -12] vs. -10% [-11, -9], p<0.001), and greater improvements in TC (-5% [-8, -2] vs -3% [-6, 0.1], p<0.001) and LDL (-10% [-14, -6] vs -4% [-8, 1], p<0.001). Males had a greater reduction in DBP (-2% [-4, -1] vs (-1% [-6, 3], p=0.006). Both males and females demonstrated similar improvements in FG and HbA1c. Conclusion: TZP significantly improved CV and metabolic parameters after 12 months, with greater benefits observed in females. These improvements effectively mitigated the age-related rise in ASCVD risk scores. Larger, prospective studies are warranted to confirm these findings and further investigate TZP’s long-term CV effects. Presentation: Monday, July 14, 2025

ImportanceReceipt of anthracycline-based chemotherapy and statin therapy have been found to be associated with deterioration of cognitive function in patients with cancer.ObjectiveTo assess the association of statins with attention, verbal fluency, and executive function in patients receiving doxorubicin treatment for cancer.Design, Setting, and ParticipantsThis secondary analysis of the Preventing Anthracycline Cardiovascular Toxicity With Statins randomized clinical trial, conducted across 31 US community and academic sites from February 5, 2014, through September 24, 2020, involved participants with stage I to IV lymphoma or stage I to III breast cancer undergoing doxorubicin treatment. The data analysis was conducted between August 1, 2024, and April 4, 2025.InterventionsParticipants were randomized (1:1) to receive a daily 40-mg dose of atorvastatin or placebo before initiating doxorubicin treatment and then continued for 24 months.Main Outcomes and MeasuresAttention, executive function, and verbal fluency were assessed using the Trail Making Test part A (TMT-A) and part B (TMT-B) and the Controlled Oral Word Association test, respectively. Time to complete the assessments were modeled using a linear mixed model, while errors (counts) were modeled using a generalized linear mixed model assuming a Poisson distribution.ResultsA total of 238 participants (mean [SD] age, 49 [12] years; 217 female [91.2%]) were randomized to the statin (n = 118) or placebo (n = 120) groups. Values for TMT-A at 6 and 24 months were similar between the statin group (mean, 32.5 seconds [95% CI, 29.4-35.7 seconds] and 29.8 seconds [95% CI, 26.4-33.2 seconds], respectively) and the placebo group (mean, 28.4 seconds [95% CI, 25.2-31.5 seconds] and 27.8 seconds [95% CI, 24.5-31.0 seconds], respectively). From before treatment to 24 months after treatment, statin recipients had a significant mean improvement of 10.2 seconds for TMT-B (95% CI, 1.9-18.5 seconds), whereas placebo recipients had a nonsignificant improvement of only 0.2 seconds for TMT-B (95% CI, −8.5 to 8.1 seconds). Analysis of the time-by-treatment interaction showed no significant difference between groups. For Controlled Oral Word Association scores in the same period, both the placebo and statin groups showed a mean improvement of 3.62 points (95% CI, 1.71-5.54 points) and 4.74 points (95% CI, 2.69-6.79 points), respectively, with no difference between groups.Conclusions and RelevanceThis secondary analysis of a randomized clinical trial suggests that the receipt of statins during doxorubicin therapy for lymphoma or breast cancer was not associated with worsening cognitive functions over 24 months. Within-group analyses suggested that statins may have contributed to better executive function on the TMT-B.Trial RegistrationClinicalTrials.gov Identifier: NCT01988571

Abstract Lewy pathology can form over decades in patients with Lewy body diseases, but the causal cellular mechanisms associated with this process remain unclear. This project aims to discover proteins that associate with monomeric and/or oligomeric alpha-synuclein during early stages of the aggregation process. To mimic the aggregation processes, cells expressing a synuclein-biotin ligase fusion protein were treated human recombinant pre-formed fibrils and subjected to BioSITe and mass spectrometry. Using a novel split biotin ligase fused to alpha-synuclein facilitated the identification of proteins specifically associated with multimeric alpha-synuclein. A total of 581 proteins were differentiated into potential interactors of monomeric versus multimeric alpha-synuclein in physiological versus aggregated conditions. The data reveal important phosphorylation mechanisms, connections to insulin processing, and a potential interaction with ALS-associated FUS. Interestingly, we identified that loss of specific interactions may contribute to pathology in patients with sporadic onset of Lewy body diseases. Future studies will validate both true interaction of highlighted proteins with alpha-synuclein, and the impact of such proteins on alpha-synuclein aggregation.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Cell Transplantation (HCT) provide expert, multidisciplinary recommendations for autologous and allogeneic HCT based on current evidence. The NCCN Guidelines focus on pretransplant recipient evaluation, hematopoietic cell mobilization, conditioning, and the diagnosis and management of graft-versus-host disease (GVHD), a common complication of allogeneic HCT that is associated with significant morbidity. This selection from the NCCN Guidelines for HCT focuses on the diagnosis, workup, and management of acute and chronic GVHD, as well as important supportive care considerations.

Abstract Background Opioid stewardship policies could adversely affect pain management for patients with cancer. Yet patients with cancer are also at risk for opioid‐related harms. This study sought to determine trends in opioid prescribing by clinical stratum and pain for patients with cancer from 2016 to 2020. Methods A retrospective study was conducted of opioid‐naive adults with newly diagnosed cancer from 2016 to 2020 ( N = 10,232) in a large Connecticut health system. Logistic regression was used to calculate changes in the predicted probability of opioid prescribing from 2016 to 2020. Two subpopulations were examined: patients treated surgically ( n = 4405) and patients with metastatic cancer ( n = 2158). Flowsheet pain scores for patients with metastatic cancer were used to stratify by no pain (all scores, 0) versus any pain. The main outcomes were new (≥1 prescription in the 0–6 months after diagnosis) and additional (0–6 and 7–9 months) opioid prescriptions. Results A decline was observed in the predicted probability of new (71.1% to 64.6%; p < .001) and additional prescribing (27.2% to 24.2%; p = .07 [not significant]) declined. Among surgical patients, the predicted probability of new opioid prescribing fell (96.0% to 88.6%; p < .001), whereas additional prescribing was stable (13%). For patients with metastatic cancer with pain, new opioid prescribing was stable (56%). For those reporting no pain, the predicted probability of new opioid prescribing declined from 61.6% to 36.1% ( p < .001). Conclusions In the context of widespread policy changes, this study showed a modest decline in new and additional opioid prescribing for patients with cancer. In metastatic cancer, prescribing remained stable for patients reporting pain and declined steeply for those reporting no pain.