Annals of Oncology

Sentinel lymph node biopsy (SLNB) is increasingly omitted in early-stage breast cancer, often prompting whole-breast irradiation (WBI). We evaluated partial-breast irradiation (PBI) without axillary surgery among 78 clinically node-negative patients (median age 75) treated from 2014 to 2022. After 53-month median follow-up, no ipsilateral, regional, or distant recurrences occurred. These results demonstrate excellent outcomes and suggest PBI is a feasible, safe alternative to WBI when SLNB is omitted.

Purpose: There are no clinically validated biomarkers to assess recurrence risk and guide treatment de-escalation in Basal-like and HER2-enriched breast cancer. Taxane-based chemotherapy remains a cornerstone of treatment despite significant toxicity. We evaluated the prognostic and predictive utility of the MHCII Immune Activation Score (IA Score) in these subtypes. Experimental Design: We retrospectively analyzed Basal-like and HER2-enriched breast cancers from the NCIC CTG MA.21 trial, which randomized patients with node-positive or high-risk node-negative disease to adjuvant chemotherapy with or without taxanes. MA.21 predated immune checkpoint inhibitors and routine HER2-targeted therapy. Subtype was previously assigned by PAM50. The 36-gene MHCII-IA assay used RNA from formalin-fixed, paraffin-embedded tissue. Multivariable Cox and Kaplan-Meier analyses evaluated associations between IA Score, clinicopathologic variables, tumor-infiltrating lymphocytes (TILs), relapse-free survival (RFS), and taxane benefit. Results: Among Basal-like (N=317) and HER2-enriched (N=155) tumors, higher IA Score was associated with improved RFS independent of lymph node status and provided stronger prognostic discrimination than TILs. Node-negative patients with high IA Score had excellent outcomes (8-year RFS >90%) versus those with low IA Score (8-year RFS <76%). In node-positive disease, high IA Score increased 8-year RFS by >10% relative to low IA Score. IA Score stratified taxane benefit: node-positive IA-low patients benefited, whereas IA-high tumors had favorable outcomes regardless of regimen. Conclusions: MHCII Immune Activation Score is a prognostic and predictive biomarker in Basal-like and HER2-enriched breast cancer. High IA Score identified patients with excellent outcomes before pembrolizumab, trastuzumab, and taxane-based treatment escalation, providing a rationale for prospective risk-adapted de-escalation strategies.

Purpose: Exceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC. Patients and Methods: We identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS. Results: Of 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0/27 [0%] exceptional versus 9/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative. Conclusions: MRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.

Background: Cases requiring 13 or more tissue sections in Mohs micrographic surgery (MMS) demand extended operative time, additional resources, and often specialised closure techniques. Pre-operative identification of such cases would improve surgical scheduling, resource allocation, and patient counselling. We aimed to develop and validate a machine learning prediction tool using pre-operative clinical features to identify cases likely to require13 sections. Objectives: To develop and validate machine learning models for predicting which Mohs procedures will require 13 sections, using pre-operative clinical features, and to identify key predictive factors. Methods: We analysed 408 consecutive Mohs procedures with 16 pre-operative clinical variables. Thirty machine learning algorithms were evaluated, including ensemble methods (Stacking, Voting), gradient boosting (XGBoost, LightGBM, CatBoost), neural networks (3-7 layers), support vector machines, and traditional classifiers. Model performance was assessed using 5-fold stratified cross-validation and independent test set evaluation. Feature importance was determined using SHAP (SHapley Additive exPlanations) analysis. Results: The stacking ensemble achieved the highest cross-validation AUC of 0.891 (95% CI: 0.849-0.934) and test AUC of 0.884. Tumour area (cm2), calculated using the ellipse formula to approximate clinical tumour morphology, emerged as the strongest predictor (SHAP importance: 0.141), followed by tumour size dimensions (0.086 and 0.068), aggressive histopathology (0.046), and recurrence status (0.035). Wide neural network architectures (5-layer) outperformed deeper configurations (7-layer). The model demonstrated 70.7% high-confidence predictions with uncertainty <15%. Conclusions: Machine learning models using pre-operative clinical features can accurately predict which Mohs procedures will require 13 or more sections. The stacking ensemble approach provides robust predictions suitable for clinical decision support. External validation in multi-centre cohorts with diverse patient populations and practice patterns is warranted to assess model generalisability.

Introduction Stark disparities in endometrial cancer (EC) risk and mortality exist between non-Hispanic Black and White women, with Black women experiencing higher incidence and worse survival. This disparity has been attributed to biological and socioeconomic factors, though how these factors interact to influence EC disparities remains unclear. This study modeled EC outcomes using race, area-level socioeconomic deprivation, clinical phenotypes, genetic ancestry, and molecular alterations. Methods We identified 281 cases of EC diagnosed from 2013-2023 in women who underwent clinical genomic sequencing as part of routine care across multiple Northwell Health sites. We estimated genetic ancestry, oncogenic alterations in 324 genes, microsatellite instability, and molecular classification. Geocoded patient addresses were used to derive the state-level Area Deprivation Index to estimate socioeconomic deprivation. Results African ancestry patients were enriched for high-grade disease (89% vs 64%), serous histology (57% vs 26%), and the TP53-mutant molecular classification (71% vs 51%) compared to European ancestry patients (p-value<0.05). Socioeconomic deprivation quintiles were associated with race, with more deprived quintiles enriched for Black patients (p-value<0.001). Both race and genetic ancestry, but not area-level deprivation, were independently associated with differences in progression-free survival. TP53 mutations were enriched in African ancestry patients, while KRAS, PTEN, and ARID1A mutations were enriched in European ancestry patients (q<0.10). Cox proportional hazards modeling, adjusting for these factors, showed that African ancestry patients had worse progression-free survival (HR 1.91, p-value<0.05). Conclusion Our findings indicate that EC disparities persist after adjusting for socioeconomic, clinical, and molecular factors, highlighting the need to further investigate additional drivers of disparity.

Background Erythema nodosum leprosum (ENL) is a severe immune-mediated complication of multibacillary leprosy requiring prolonged immunosuppression. Steroid-sparing agents are essential to reduce relapse and treatment-related morbidity. Methods This longitudinal analytical observational study compared outcomes in patients with ENL treated with prednisolone plus thalidomide (Group A; n=30) and prednisolone plus tofacitinib (Group B; n=31). Patients were followed for 6 months. Primary outcomes included relapse rate and ENLIST ENL Severity Score (EESS). Secondary outcomes were neutrophil-lymphocyte ratio (NLR), Dermatology Life Quality Index (DLQI), steroid dependency, and adverse events. Inter-group comparisons and longitudinal analyses were performed using non-parametric tests. Correlations between NLR, EESS, and DLQI were assessed using Spearmans rank correlation. Results Relapse occurred in 36.7% of patients in Group A and 71.0% in Group B (p=0.007). The mean number of relapses was significantly lower in Group A (0.70{+/-}1.06 vs 1.84{+/-}1.51, p=0.002). At 3 and 6 months, Group A demonstrated significantly lower NLR values (p=0.017 and p<0.001, respectively). DLQI and EESS scores improved in both groups; however, sustained improvement was more consistent in Group A. Steroid-free status at 6 months was achieved in 93.3% of Group A compared with 58.1% of Group B (p<0.001). NLR showed a positive correlation with EESS ({rho}=0.269, p=0.018) and DLQI ({rho}=0.604, p<0.001) at 6 months. On multivariable logistic regression analysis adjusting for baseline confounders, patients receiving tofacitinib had significantly higher odds of relapse compared with those receiving thalidomide (adjusted OR 9.87, 95% CI 1.73-27.12; p = 0.006).Adverse events were predominantly mild to moderate, with differing safety profiles between groups. Conclusion Thalidomide demonstrated superior relapse prevention and steroid-sparing efficacy compared with tofacitinib in ENL. NLR correlated with disease severity and quality of life, supporting its role as a useful biomarker for monitoring disease activity during follow-up.

Background: Trastuzumab deruxtecan (T-DXd) is active in HER2-expressing solid tumours, but trials excluded HER2 immunohistochemistry (IHC) 1+ disease, and data in pretreated ovarian cancer are lacking. We evaluated real-world T-DXd activity and genomic correlates in pretreated ovarian cancer, predominantly high-grade serous (HGSOC). Methods: HER2 expression was assessed in an unselected ovarian cancer cohort (N=74). Fifteen patients receiving off-label T-DXd (14 HGSOC, 1 clear cell; IHC 1+ to 3+) had HER2 status centrally confirmed using gastric-type criteria. Activity was assessed by intra-patient growth modulation index (GMI; progression-free survival [PFS] on T-DXd divided by PFS on the prior line; [&ge;] 1.33 considered meaningful). Patients on treatment at data cut-off were censored. Objective response (RECIST 1.1) was assessed centrally where imaging was available (n=8). Results: Of the 40 HER2-expressing tumours, 15 received T-DXd, limited mainly by reimbursement. Among 14 evaluable patients (median 5 prior lines), 9 reached a GMI [&ge;] 1.33 (median 1.69); 8 remained on treatment at cut-off, making durability preliminary. Confirmed partial responses occurred across the HER2 spectrum. Benefit was independent of homologous-recombination (HR) status: one HR-proficient, CCNE1-wild-type patient achieved prolonged control and was rendered disease-free after radiotherapy to an oligoprogressive lesion. Exploratory analysis showed all four evaluable CCNE1-amplified tumours had reduced or non-durable benefit. Conclusions: T-DXd shows preliminary, clinically meaningful activity in HER2 IHC 1+ ovarian cancer independent of HR status. CCNE1 amplification may attenuate benefit, a candidate biomarker for WEE1-inhibitor combinations. Approval restricted to IHC 3+ disease would exclude most responders in this cohort. Prospective validation is required.

Background The NEO-EXCEL trial hypothesised that aromatase inhibitor (AI)-activity as neoadjuvant endocrine therapy for early-stage breast cancer in postmenopausal women may be enhanced in combination with cyclooxygenase-2 (COX-2) inhibition. Methods NEO-EXCEL was a phase III, placebo-controlled, randomised trial in postmenopausal women with oestrogen receptor (ER)-positive resectable breast cancer with tumours [&ge;]2cm. Women were randomised (1:1:1:1): exemestane (25mg od) plus celecoxib (400mg bid), exemestane (25mg od) plus placebo (bid), letrozole (2.5mg od) plus celecoxib (400mg bid), or letrozole (2.5mg od) plus placebo (bid). Primary endpoint was clinical response (complete/partial) measured by callipers at 16 weeks; a standard assessment method at the time of trial inception. Sixteen-week ultrasound-determined response was the main secondary outcome to verify the calliper-based primary. Analysis was intention-to-treat. Results Due to slow accrual the trial design was redesigned from a definitive 2x2, 1000 patient trial to one randomising 269 patients between 20-Nov-2007 and 29-Apr-2014; 34.9% were human epithelial growth factor receptor 2-positive. AI+celecoxib produced a significantly greater objective clinical response than AI+placebo (72.9% vs 55.6%, P=0.003), which remained after adjustment for AI type and stratification factors (odds ratio = 2.3; 95% CI 1.3-3.8, P=0.003). Ultrasound-determined response was however not significantly enhanced (48.7% [AI+celecoxib] vs 41.2% [AI+placebo], P=0.34). Progression free survival and overall survival remained similar (median follow-up = 5.1 years [range 0.1-7.1]). Conclusions NEO-EXCEL is the first completed, phase III double-blind, placebo-controlled trial testing the addition of celecoxib to AI as neoadjuvant endocrine therapy in early breast cancer. Clinical response showed significant improvement but there was no significant ultrasound-determined response improvement nor any surgical or long-term outcome evidence of AI+COX-2 inhibition improving treatment outcomes for ER+ early resectable postmenopausal breast cancers. Use of short-term celecoxib at 400mg bd for 16 weeks was safe with no excess cardiotoxicity observed.

Background: Cutaneous squamous cell carcinoma (cSCC) accounts for a significant proportion of skin malignancies in India, yet data on patterns of failure, particularly for extremity and truncal primaries remain scarce. We audited a decade of surgically treated cSCC at a tertiary cancer center to characterize failure patterns and associated risk factors. Methods: This retrospective study included 161 patients with histopathologically confirmed cSCC treated surgically between January 2013 and December 2023, comprising 127 upfront/residual and 34 recurrent presentations. Primary sites were extremities (64%), head and neck (26%) and torso (10%). 21 patients had Marjolin's ulcer. Outcomes included local, regional and distant failure, recurrence-free survival and overall survival. Brigham and Women's Hospital (BWH) staging was applied to assess prognostic utility. Statistical analysis was done using Kaplan-Meier and competing-risk methods. Results: Median follow-up was 2.4 years. Regional recurrence was the predominant failure pattern seen in 26 patients, local recurrence was seen in 14 patients and distant metastasis in 13. The 3-year cumulative incidences of local, regional and distant failure were 11%, 19% and 8.4% respectively. Rates of regional recurrence were substantially higher than Western series. Extremity primaries accounted for 19/26 regional recurrences. BWH T2b disease showed the highest regional failure rate (27.6%), exceeding T3 (17.8%) and T2a (6%) with perineural invasion significantly associated with regional failure in T2b/T3 tumors (p<0.001). Median time to regional metastasis was 8.4 months. At 3 years, overall survival was 77% and progression-free survival was 64%. Conclusion: Regional recurrence is the dominant mode of failure in this cohort, at rates higher than most published series, with extremity primaries and BWH T2b staging identifying particularly high-risk subgroups. These findings highlight the need for a comprehensive staging system encompassing non head and neck cSCC and support prospective evaluation of elective nodal staging and adjuvant radiotherapy in high-risk patients, alongside intensified surveillance.

Background The value and optimal timing of circulating tumour DNA (ctDNA) analysis in locally advanced oesophageal adenocarcinoma (OAC) is uncertain. We hypothesised that perioperative detection would predict event-free (EFS) and overall (OS) survival, and that 3-6 months post-operative detection would predict recurrence. Methods In this prospective multi-centre cohort study, tumour-informed ctDNA assays were designed for 49 patients using whole-exome sequencing. Bloods were collected for ctDNA detection up to 8 days prior to surgery, and at 3-6 weeks and 3-6 months post-surgery, then correlated with clinicopathological characteristics, EFS and OS. Results Pre- and early post- surgery ctDNA positivity were associated with worse EFS (HRs 7.97 (95% confidence interval, CI 2.64-24.04), p<0.0001; 8.18 (95%CI 3.23-20.69), p<0.0001) and OS (HRs 7.82 (95%CI 2.22-27.54), p=0.00018; 13.69 (95%CI 4.52-41.49), p<0.0001). In pre-surgery positive patients, post-surgery ctDNA clearance associated with improved EFS and OS, and predicted better OS in those with a poor histopathological response to neoadjuvant treatment. 3-6 month ctDNA-positivity preceded standard-of-care recurrence detection by median 53.5 (interquartile range 39.3-200.0) days. Conclusions Perioperative ctDNA positivity associates with worse EFS and OS in OAC, identifying a subgroup with improved outcomes despite adverse pathological features. ctDNA testing at 3-6 months predicts recurrence earlier than standard-of-care surveillance.

Immune checkpoint therapies have transformed clinical practice; however, reliable biomarkers to predict response remain limited. Tumor mutational burden (TMB) has emerged as an important biomarker because it is thought to reflect neoantigen load, yet its predictive utility has been inconsistent. This limitation may partly arise because TMB primarily captures tumor-intrinsic immunogenicity, which is heterogeneous and does not fully reflect the state of antitumor immunity. To identify transcriptomic surrogates that capture both high mutational burden and antitumor immune activation, we investigated whether mRNA expression of mutagenic APOBEC3 family members could serve as surrogates for high TMB and T cell-rich tumors. Using a pan-cancer computational framework, we evaluated the association of four APOBEC3 genes with mutational burden, neoantigen load, immune infiltration, and immune checkpoint blockade response. Among APOBEC3A, APOBEC3B, APOBEC3G, and APOBEC3H, APOBEC3G emerged as the strongest and most consistent marker of a TMBhighCD8high and NeoantigenhighCD8high tumor phenotypes. Single-cell analyses further demonstrated that APOBEC3G is enriched in both malignant cells and T cells compared with other APOBEC3 family members, with APOBEC3G-positive CD8+ T cells exhibiting elevated activation markers including GZMB and IFNG. Importantly, retrospective analyses of 50 immune checkpoint blockade cohorts showed that APOBEC3G had the most consistent association among APOBEC3 family members with treatment response and clinical outcomes. Together, these findings identify APOBEC3G as a candidate transcriptomic marker of a TMB-associated, T cell-inflamed tumor state linked to immune-checkpoint blockade benefit, warranting further prospective validation.

Introduction: This study aimed to provide population level survival trends during the era in which new systemic therapies transformed treatment guidelines for metastatic cancer, as well as insights on the real world use of these treatments and associated survival. Methods: Adults diagnosed with synchronous metastatic solid cancer in 2008 until 2022 (22 cancer types) were identified from the Netherlands Cancer Registry. Median overall survival (OS) was assessed by five year diagnostic period. For 2018 until 2022, systemic therapy use in any treatment line was analyzed and survival percentiles within treatment and cancer types were estimated with Kaplan Meier survival analyses. Results: Median OS in the overall cohort (n=280,419 patients) improved from 6 to 8 months between the period 2008 until 2012 and 2018 until 2022. Among patients diagnosed in 2018 until 2022, 15% received immunotherapy, 15% targeted therapy, 29% chemotherapy and/or traditional hormone therapy only, and 39% no systemic therapy. In some cancer types, a relatively large proportion of treated patients had longterm survival (e.g., immunotherapy in melanoma: p50 = 67 months). Other cancer types had a smaller subset of treated patients (p10 and p25) with substantially better outcomes than the median (e.g., targeted therapy in NSCLC: p50 = 22 months, p10 = 96 months). Conclusion: Population level survival for patients with synchronous metastatic solid cancer has modestly improved over time. The marked survival heterogeneity within cancer and treatment types highlights both the potential and uncertainty associated with (novel) treatments. Improved prediction of treatment effects and clear communication regarding survival expectation remain critical. Presenting multiple survival scenarios over median survival alone can support decision making.

Population-based mammography screening improves breast cancer outcomes, but its impact on real-world treatment pathways and quality indicators (QIs) remains incompletely described. We conducted a retrospective nationwide cohort study using linked data from the Czech National Cancer Registry and the National Registry of Reimbursed Health Services. Women aged [&ge;]18 years with a first breast cancer diagnosis between 2017 and 2024 were classified as screen-detected (SCR) or diagnostically-detected (DIG) according to the imaging modality preceding histological verification. Outcomes included stage distribution, untreated cases, first-line treatment, main treatment modality, time to treatment, multidisciplinary team discussion (MDT), centralization to Comprehensive Cancer Centres (COCs), and survival patterns. The verified cohort included 47,648 women: 26,817 SCR cases (56.3 %) and 20,831 DIG cases (43.7 %). In this nationwide analysis, SCR breast cancer was associated with earlier stage at diagnosis and better survival patterns, but also with longer time to treatment and longer time to MDT discussion than DIG-detected disease. Although treatment rates were high and centralization improved over time, substantial regional variation persisted in care pathways, MDT use, and access to COCs. These findings support continued strengthening of screening participation, monitoring of care intervals, and quality assurance of MDT reporting and regional oncology care delivery.

Background: Ewing sarcoma (EwS) is a highly aggressive bone and soft tissue cancer mainly affecting children, adolescents, and young adults. The rarity of the disease, relatively small cohort sizes of prior studies, and overall low mutational burden of EwS have limited the ability to establish robust correlations of genomic findings and clinicopathological factors. Methods: To overcome these limitations, we integrated genomic and clinical data from the seven major sequencing studies encompassing 538 EwS patients. Mutational profiles (SNV, indels and CNVs), and their correlation with clinicopathological features in the aggregated cohort were systematically analyzed to provide an integrated view of the EwS genomic landscape. Results: This study compiles the largest EwS genomic dataset reported to date. In the aggregated cohort (n=538) bone tumors were more common (65.4%) than soft-tissue tumors (34.6%), the latter being more frequent in older male patients and associated with poorer outcomes. EWSR1::FLI1 was the most prevalent fusion (87.2%). No major clinicopathological differences were identified between fusion types. The mutational landscape was dominated by STAG2 (15.6%) and TP53 (7.1%) alterations, associated with younger or with older age at diagnosis and poor survival, respectively. Strikingly, the coexistence of STAG2 and TP53 mutations, although rare (n=12), was associated with lethal outcome in all cases. CDKN2A loss (9.1%) was associated with older age, poor survival, and linked to a higher frequency of TP53-mutations in soft tissue EwS. Among frequent CNVs, gain of chr1q (25.2%) and loss of chr16q (21.9%) were per se frequently associated with fatal outcome and their co-occurrence further increased the risk of lethality. Conclusions: We delineate recurrent genomic alterations with important clinicopathological associations, including a uniformly lethal STAG2/TP53 co-mutation and CNV signatures marking aggressive disease. This comprehensive pooled analysis of EwS genomic studies provides a foundation for refined biological risk-stratification.

Background: Breast cancer survivors often experience psychological distress that may increase suicide risk. Marital status, a proxy for social support, may influence this risk, but its role within a competing-risk framework is unclear. This study examined the association between marital status and suicide mortality and assessed modification by socioeconomic and geographic factors. Methods: This is a population-based cohort study using SEER data, including adults diagnosed with primary breast cancer from 2000 to 2022. Marital status was classified as married/partnered or unmarried/non-partnered. Baseline characteristics were balanced using subdistribution inverse probability of treatment weighting (sIPTW). Suicide mortality was analyzed using sIPTW-weighted Fine-Gray competing-risk models, treating non-suicide deaths as competing events. Landmark, subgroup, interaction, and sensitivity analyses were performed. Results: Among 825,047 patients, 40.7% were unmarried. Covariates were well balanced after weighting (SMD <0.01). During follow-up, 529 suicide deaths occurred. Unmarried status was associated with higher suicide mortality (sHR = 1.34, 95% CI: 1.12-1.60). Male sex and estrogen receptor-negative tumors increased risk, while older age and non-White race were protective. Findings were consistent in Cox models (HR = 1.45) and sensitivity analyses (sHR = 1.42). Landmark analyses showed persistent associations at 1, 3, and 5 years. The association was attenuated in the highest income quartile but not modified by rural-urban status. Conclusions: Unmarried breast cancer patients had higher suicide mortality. These findings support integrating psychosocial assessment and targeted suicide prevention into survivorship care, especially for socially vulnerable groups.

Germline pathogenic or likely pathogenic variants (GPVs) in BRCA-1 Associated Protein 1 (BAP1) are associated with a spectrum of tumors, including uveal melanoma (UM). Currently, UM patients with BAP1 GPVs are treated as high-risk class 2 tumors based on mostly empiric data. In the current study, we examined the clinical phenotype of a cohort of 29 UM patients with BAP1 GPVs. We also carried out a systematic review of the literature of UM patients with BAP1 GPVs. We observed that UM patients with BAP1 GPVs have significantly lower median age of diagnosis compared to median age reported in UM patients in the Surveillance, Epidemiology, and End Results Program (SEERS) database. Metastatic risk and overall survival in the UM BAP1 GPVs cohort were statistically significant from those in patients with class 1 tumors, but were comparable to those observed in UM patients with class 2 tumors. In UM BAP1 GPVs treated with radiation (n=12), no secondary cancers were observed in the field of radiation in a median 26.5 months (range, 4-119 months) follow up period. One patient experienced a separate growth of UM at a distinct location within the same eye. These data support managing UM in patients with BAP1 GPVs as aggressive class 2 tumors, following the currently established standard of care for these high-risk tumors.

Breast cancer is a heterogeneous disease whose clinical management relies heavily on accurate molecular subtyping. The murine E0771 mammary carcinoma cell line is widely used in preclinical studies, yet its molecular identity remains controversial, with reports variably classifying it as luminal B or triple-negative. In this study, we performed an integrated molecular and functional characterization of two independently sourced E0771 cell line stocks to resolve this discrepancy. Both stocks were genetically authenticated and exhibited concordant phenotypes. Immunohistochemical and molecular analyses demonstrated absence of oestrogen and progesterone receptors, classifying E0771 as triple-negative. Functionally, E0771 cells showed no transcriptional response to oestrogen and displayed resistance to endocrine therapy both in vitro and in vivo. Collectively, our results establish E0771 as an oestrogen-independent, basal-like triple-negative breast cancer model, supporting its appropriate use in studies of hormone-resistant breast cancer biology.

Background: Cardiotoxicity remains a key concern of HER2-directed therapies, with no proven prevention strategies. The success of cardioprotective interventions will depend not only on efficacy, but on patient acceptability, an underexplored determinant of trial participation and clinical implementation. Objectives: To evaluate willingness to take cardioprotective medication and identify factors influencing decision-making among individuals with HER2-positive breast cancer. Methods: We conducted a cross-sectional online survey of adults with HER2-positive breast cancer in Australia and the United States. The survey assessed willingness, beliefs regarding benefits and risks, and treatment preferences. Multivariable logistic regression examined associations between clinical and demographic characteristics and willingness. Results: Among 74 respondents (Australia n=24; United States n=50), 74.3% reported being likely or very likely to take cardioprotective medication. Physician recommendation emerged as a dominant driver (79.1%). While most participants valued long-term cardiovascular health (72.9%), uncertainty regarding benefit was common (60.4%). Cancer-related outcomes were prioritized over cardiovascular outcomes. Participants demonstrated flexibility regarding treatment burden, including willingness to take multiple medications and continue therapy long term. No demographic or clinical predictors of willingness were identified. Perceived acceptability, appropriateness, and feasibility were consistently high. Conclusions: Willingness to adopt cardioprotective strategies is high but conditional, shaped by cancer priorities, clinician endorsement, and uncertainty regarding benefit. These findings highlight patient acceptability as a critical, and often overlooked, determinant of successful trial participation and downstream clinical implementation in cardio-oncology.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that frequently carries integrated Merkel cell polyomavirus DNA and expresses oncogenic viral small T antigen (sTAg) and truncated large T antigen (tLTAg). We previously reported a mouse model of MCC with skin-targeted expression of sTAg, tLTAg, and the Merkel cell transcription factor ATOH1, combined with deletion of Trp53. Here, we optimized this model to achieve 100% tumor penetrance with lymph node metastases, established four mouse MCC cell lines, and selected one line, mMCC2, for pilot preclinical trials. In immunocompetent C57BL/6J mice, mMCC2 cells reliably produce MCCs and lymph node metastases following subcutaneous or intradermal (orthotopic) injection, and liver and lung metastases after tail vein injection. Mouse MCC allografts resemble parental tumors histologically and express a full complement of MCC differentiation markers. Treatment of allografted mice with anti-PD-1 resulted in variable inhibition of tumor growth. In contrast, treatment with lysine-specific histone Wdemethylase 1 (LSD1) inhibitors, with or without anti-PD-1, led to consistently lower tumor volumes by 5.7-fold in both groups (P < 0.0001) and smaller or undetectable lymph node metastases. Growth-inhibited tumors in all groups showed a marked reduction in proliferating tumor cells and increased infiltration by F4/80+ macrophages and CD8+ T cells. These findings support a role for immune-cell recruitment in treatment response and underscore the importance of immunocompetent preclinical models, even in studies using targeted therapies. This unique virus-positive MCC allograft model, which produces local tumors as well as regional and distant metastases in immunocompetent hosts, provides a critical platform for preclinical evaluation of new therapeutic strategies and sets the stage for much-needed translational studies to inform future clinical trials.

Background Lymph node status and molecular subtype are among the most established prognostic factors in breast cancer. However, the extent to which their prognostic effects vary across different tumor size categories and clinical subgroups remains incompletely understood. We investigated the interplay between nodal status, molecular subtype, and tumor size in a large real world breast cancer cohort and developed a prognostic nomogram for individualized survival prediction. Methods A total of 12,225 women with invasive breast cancer from the Shiraz Breast Cancer Registry were analyzed. Patients were stratified according to tumor size, lymph node status, and molecular subtype. Overall survival (OS) and disease free survival (DFS) were evaluated using Kaplan Meier analyses and subgroup comparisons. Logistic regression was performed to identify predictors of lymph node involvement, while Cox regression was used to determine independent prognostic factors. A nomogram was subsequently developed and internally validated for prediction of 3-year and 5-year OS. Results Of 12,225 patients, 41.7% had lymph node positive disease. Across nearly all tumor size categories and molecular subtypes, nodal involvement was associated with significantly worse OS and DFS. Notably, the survival disadvantage associated with nodal positivity was more pronounced among patients with larger tumors and among those with HER2 positive and triple negative breast cancer (TNBC). Although TNBC demonstrated the lowest rate of lymph node involvement among molecular subtypes (adjusted OR 0.54, 95% CI 0.46-0.63), it appeared to show one of the largest survival gaps between node positive and node negative disease. In the overall cohort, survival outcomes generally ranked from best to worst as Luminal A, Luminal B, HER2 positive, and TNBC. However, survival differences among molecular subtypes were not consistently observed across all tumor size and nodal status subgroups. When significant differences were present, Luminal A and Luminal B tumors consistently showed superior outcomes compared with HER2 positive and TNBC tumors. Multivariable analysis identified lymph node status, tumor size, molecular subtype, lymphovascular invasion, tumor necrosis, type of surgery, radiotherapy, hormone therapy, and adjuvant chemotherapy as independent prognostic factors. A nomogram integrating clinicopathological and treatment variables demonstrated good predictive performance, with time dependent AUCs of 0.749 and 0.751 for 3 year and 5 year OS, respectively, and showed good calibration. Conclusions The prognostic impact of lymph node status is not uniform across breast cancer subgroups and appears particularly pronounced in larger tumors and biologically aggressive subtypes. Despite a lower likelihood of nodal involvement, TNBC showed substantial outcome deterioration when nodal metastasis was present. These findings highlight the importance of jointly considering nodal status, molecular subtype, and tumor burden in prognostic assessment.