Purpose Skin adnexal carcinomas (SACs) are rare and heterogeneous tumors with no established systemic treatment options and poor long-term survival rates in the advanced disease setting. Here, we aimed to characterize the genomic landscape and clinically actionable alterations across SAC subtypes.Methods We analyzed next-generation sequencing data from SACs in the American Association for Cancer Research Project GENIE. Mutations, copy number alterations, and structural variants were annotated using OncoKB. Actionable alterations were defined as Level 1-2 alterations or tumor mutational burden (TMB) >= 10 mut/Mb. TMB was compared across subtypes and with melanoma, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC).Results A total of 224 SACs were analyzed (49% extramammary Paget disease [EMPD], 33% apocrine/eccrine, 17% sebaceous, 1% follicular). In EMPD, the most frequent actionable alterations were in PIK3CA (25.7%) and ERBB2 (22.9%). In sebaceous carcinoma, actionable alterations were mainly in KRAS (10.3%) and PIK3CA (10.3%). Apocrine/eccrine tumors also presented ERBB2 and PIK3CA alterations, but at lower frequencies (5.5% and 8.2%, respectively). TMB-high occurred in 10.1% of EMPD, 28.2% of sebaceous, and 21.9% of apocrine/eccrine tumors, lower than in melanoma (52.1%), CSCC (64.4%), and BCC (63.3%). SAC drivers showed important heterogeneity across subtypes. Overall, 48.2% of SACs harbored at least one potentially actionable alteration.Conclusion SACs frequently harbor clinically actionable alterations in a histotype-dependent manner. The identification of lineage-specific genomic differences underscores the clinical and translational relevance of integrating histology with genomic profiling for guiding therapeutic decision making.
Purpose No curative options are available for medulloblastoma (MB) in the relapse setting. The tumor microenvironment (TME) influences progression and therapy response, presenting a promising target for therapeutic advances. Prior single-cell analyses have characterized the cellular components of the TME but lack spatial context. We hypothesize that spatial architecture, beyond cell composition, influences tumor progression and treatment outcomes.Methods We performed spatial transcriptomic sequencing on 18 pediatric MB samples obtained at diagnosis, including two matched diagnosis-relapse pairs. Samples at diagnosis were stratified into high- and standard-risk groups. Spatial data were analyzed for spatial proximity to other cell types, cell-cell communication networks, and expression of cell cycle dormancy signatures. Findings were validated using immunohistochemistry in the same cohort.Results Our analyses revealed intertumoral and intratumoral heterogeneity within the TME, comprising tumor-associated astrocytes (TAAs), macrophages (TAMs), stromal components, and distinct subpopulations of MB cells at different stages of neuronal differentiation and cell cycle progression. We identified dense regions of quiescent progenitor-like MB cells enriched in patients with high-risk (HR) features and an increase in TAAs, TAMs, and dysregulated vascular endothelium following relapse.Conclusion Our study presents novel insights into the spatial architecture and cellular landscape of the MB-TME, highlighting differential spatial patterns correlating with HR features. Future studies should evaluate their role in relapse and therapy resistance and may lead to uncovering novel therapeutic targets.
PURPOSE Molecular classifications have advanced prognostic stratification in endometrial carcinoma (EC), but they do not explicitly account for cause-specific mortality (CSM) and host-clinical context. We aimed to derive a clinically accessible classification that links demographic/clinicopathologic features, CSM, and molecular landscapes and to test whether it refines molecular-based survival stratification. METHODS We conducted latent class analysis (LCA) on 46,772 cases of primary EC from the SEER program to identify latent characteristic lineages. The resulting LCA scheme was mapped to The Cancer Genome Atlas (TCGA) data. Cumulative incidence functions and Fine-Gray competing risks regression were used to estimate CSM. The Fisher test was employed to evaluate its association with TCGA subtypes. Transcriptomic differential expression analysis and pathway enrichment analysis were performed where data were accessible. Likelihood ratio tests assessed treatment-LCA interactions. RESULTS Five clinically interpretable classes emerged. Class 4 had significantly increased subdistribution hazard for CSM (1.34, P = .031); classes 3/5 trended higher. Classes were associated with TCGA subtypes (P < .001). Specifically, class 3 was associated with copy number (CN)-high enriched sybtype and class 1 was associated with CN-low subtype. Incorporating LCA labels into molecular survival models increased C-index and robustness of prognostic discrimination. Transcriptomics revealed class specific signatures implicating metabolic reprogramming, DNA repair, and immune pathways. Treatment benefit varied by class: compared with surgery alone, class 3 demonstrated the most significant survival advantage with surgery-radiotherapy-chemotherapy. Class 4 exhibited sensitivity to radiotherapy, while class 5 benefited exclusively from the triple therapy. Conversely, class 1/2 did not benefit from combined treatment. CONCLUSION LCA of routine clinical variables identifies subgroups susceptible to CSM and complements TCGA molecular classification, improving survival stratification.
Purpose The prognostic significance of multifocal and multicentric breast cancer (MMBC) with low tumor burden remains controversial, and adjuvant chemotherapy guidelines for these patients are lacking. Materials and Methods Female patients with cT1-T2 MMBC or unifocal breast cancer (UBC) diagnosed between 2010 and 2020 were identified from the SEER database. Propensity score matching (PSM) balanced baseline characteristics. Survival outcomes were evaluated using Kaplan-Meier and Cox proportional hazards models, with subgroup analyses stratified by tumor size in node-negative MMBC. Results After PSM, 9,751 matched pairs of patients with MMBC and UBC were included. Analyses showed MMBC had significantly worse overall survival (OS) and breast cancer-specific survival (BCSS) than UBC (both P < .001). Multivariate Cox regression confirmed chemotherapy improved OS (hazard ratio [HR], 0.583 [95% CI, 0.522 to 0.652]) and BCSS (HR, 0.830 [95% CI, 0.702 to 0.980]) in MMBC. In eligible cases, 1,731 matched pairs with and without chemotherapy were identified. Subgroup analyses showed that in node-negative MMBC, chemotherapy improved OS only when tumors were >= 1 cm (tumor <1 cm: HR, 0.804 [95% CI, 0.506 to 1.275], P = .353; 1-2 cm: HR, 0.577 [95% CI, 0.414 to 0.806], P = .001; >= 2 cm: HR, 0.535 [95% CI, 0.399 to 0.717], P < .001). Conclusion MMBC predicts poorer survival than UBC. In node-negative MMBC, chemotherapy confers benefit only when tumor size is >= 1 cm, suggesting multifocality and multicentricity should guide chemotherapy decisions. Prospective studies are warranted to confirm findings and refine guidelines.
PURPOSE Tovorafenib is an oral, selective, CNS-penetrant, type II inhibitor of BRAF and CRAF. BRAF fusions and CRAF/RAF1 fusions and amplifications are rare oncogenic drivers in many solid tumors. The phase II DAY101-102a substudy of FIRELIGHT-1 (ClinicalTrials.gov identifier: ) investigated the efficacy and safety of tovorafenib monotherapy in recurrent/refractory solid tumors with structural alterations in BRAF or CRAF.PATIENTS AND METHODS Patients >= 12 years of age with a recurrent/refractory solid tumor with a BRAF fusion or CRAF fusion or amplification were enrolled into a melanoma cohort or tumor-agnostic cohort. The primary end point was overall response rate (ORR), as assessed by investigators. Tovorafenib was administered at 600 mg once weekly (adult dose), continuously, in 28-day cycles.RESULTS Twenty-three patients were enrolled; eight in the melanoma cohort and 15 in the tumor-agnostic cohort. The median age was 53 years (range, 21-71), and 57% of patients had >= 2 lines of prior therapy. Fourteen patients had tumors with BRAF fusion, six CRAF fusion, two CRAF amplification, and one CRAF fusions and amplification. The median duration of tovorafenib treatment was 5.3 months (range, 0.8-22.5). The ORR was 43% (10/23 patients), including 50% (4/8) in patients with melanoma and 40% (6/15) in patients with other tumors. The median time to response was 1.8 months. The median duration of response was 9.2 months. The most common treatment-related adverse events (any grade) were anemia (39%), pruritus (30%), increased creatine phosphokinase (26%), and rash (26%).CONCLUSION Tovorafenib demonstrated single-agent clinical activity in solid tumors with BRAF fusions or CRAF fusions or amplification and had a manageable safety profile. Tovorafenib may offer a new targeted treatment option for adult patients with tumors harboring these rare genomic driver alterations.
