Olfactory neuroblastoma (ONB) is a rare head and neck cancer arising from the upper nasal cavity, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to utilize a patient-level genomic repository to identify potential therapeutic targets and improve disease modeling in ONB. Retrospective genomic analysis. Data analysis was performed using the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Patients with confirmed ONB who have undergone targeted sequencing within GENIE. Data were analyzed for recurrent somatic mutations, along with their clinical and demographic correlations, with significance set at p < 0.05. A high prevalence of mutations in TP53 (tumor protein p53) and FRK (fibroblast growth factor receptor kinase) genes was identified. A moderate prevalence of mutations in NOTCH3 (notch receptor 3), SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4), RET (rearranged during transfection), and CTCF (CCCTC-binding factor) was also identified. The mutation patterns differed between pediatric and adult ONB cases. Specific mutations were enriched in metastatic tumors compared with primary tumors. This study provides a genomic profile for ONB, identifying key mutations and potential therapeutic targets. The identification of frequently mutated genes like TP53 and FRK suggests potential targets for novel therapies. The observation that certain genes are mutated in pediatric ONB but not adult ONB (and vice versa), and the presence of specific mutations in metastatic tumors that are absent in primary tumors, offers valuable insights for future precision medicine and the design of targeted therapeutic interventions for these distinct clinical presentations.

Anaplastic ependymoma (AE) is a rare and aggressive central nervous system tumor that predominantly affects children and remains inadequately characterized at the genomic level. This study aimed to delineate the genomic and demographic landscape of histologically defined AE while identifying potential therapeutic targets. We conducted a retrospective analysis of AE cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository via cBioPortal, examining recurrent somatic mutations, copy number alterations, mutation co-occurrence, and exploratory sex- and race-based enrichment using descriptive and non-parametric statistics. The most frequent alterations included mutations in the telomerase reverse transcriptase (TERT) promoter, followed by recurrent changes in lysine methyltransferase 2D (KMT2D), lysine methyltransferase 2A (KMT2A), lysine methyltransferase 2C (KMT2C), E1A binding protein p300 (EP300), additional sex combs like 1 (ASXL1), and SET domain containing 2 (SETD2), indicating significant disruption of chromatin remodeling. Recurrent alterations in tumor protein p53 (TP53), ataxia telangiectasia mutated (ATM), and cyclin-dependent kinase inhibitor 2A (CDKN2A) suggested dysregulation of the p53 and DNA damage response pathways. Additionally, alterations in notch receptor 1 (NOTCH1) and notch receptor 2 (NOTCH2) indicated aberrant NOTCH signaling. Neurofibromin 2 (NF2) mutations were observed in male patients, and exploratory subgroup differences emerged across racial groups. Overall, AE appears to be driven by recurrent alterations in chromatin remodeling, p53, DNA damage response, and NOTCH signaling pathways, highlighting these areas as priorities for future biological validation and therapeutic investigation.

Cancer is a global disease, yet a paradox persists: the most advanced research ecosystems are concentrated in countries with lower disease burden, whereas low- and middle-income countries (LMICs)-carrying 70% of the global cancer burden-face major constraints in research capacity. Closing this gap is essential for equitable progress in cancer prevention, diagnosis, and treatment. Researchers in LMIC are creatively adapting established technologies, research pipelines, and collaborative models from higher-resource settings to local solutions. Here, twenty-five American Association for Cancer Research (AACR) Global Scholar-in-Training Award's recipients from LMICs share how cancer research is advancing within resource-limited settings, focused on: (i) infrastructure and resources, (ii) training and talent retention, (iii) funding and sustainability, and (iv) cultural and social barriers. We identified shared challenges and cross-cutting solutions, discussed gaps and suggested steps to further advancing cancer research. We emphasized locally-led innovation, strategic partnerships, and community engagement. These perspectives offer a framework for inclusive, synergistic approaches to strengthening cancer research and accelerating impact where it is needed most.

Abstract Background: The phosphatidylinositol-3-kinase (PI3K) pathway, driven by the PIK3CA gene, is crucial for tumor initiation, growth, proliferation and therapy resistance. PIK3CA mutations (PIK3CAm) occur in ∼35% of all breast cancers (BC), most commonly in estrogen receptor positive (ER+) and HER2-negative BC. In HER2-positive (HER2+) BC, these mutations are found in ∼25-30% of cases. Although PIK3CAm are linked to lower rates of pathological complete response (pCR) in the neoadjuvant setting for HER2+ patients (pts), the prognostic significance of somatic PIK3CAm remains unclear. In the recently presented phase 3 Destiny Breast09 trial, the presence of a PIK3CAm was identified as a marker of early progression in HER2+ metastatic BC (mBC) on first line therapy with trastuzumab/pertuzumab monoclonal antibody therapy. We, therefore, aimed to evaluate the impact of PIK3CAm status on clinical outcomes in HER2+ BC pts receiving first- and second-line therapy. Methods: We analyzed clinico-genomic data from the BC cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (version 1.2), which includes pts diagnosed between 18-56 years of age who underwent tumor sequencing between 2013 and 2020. We included adult HER2+ BC pts who had received at least one line of therapy. The primary outcomes were overall survival (OS) and progression-free survival (PFS). We used Kaplan-Meier curves to estimate and compare OS and PFS. Univariable and multivariable Cox proportional hazard regressions were used to compare outcomes between patient groups, accounting for line of therapy. Subgroup analysis was performed according to TNM stage and PIK3CA wild type (wt) vs PIK3CAm. Results: We included 212 pts, of which 58 (27.3%) had a documented PIK3CAm. Of the 212, 62 were mBC, of which 15 (26%) had PIK3CAm. The median age at diagnosis was 43. Most patients were White (77%), Non-Hispanic (95%), and initial TNM stage II BC diagnosis (33%). Statistically significant differences between PIK3CAm and PIK3CAwt were observed in use of endocrine therapy (78% vs 62%, p=0.04) as well as the median time to distant metastasis (38 vs 22 months, p= 0.01). The observed median OS for the overall cohort starting from the date of first-line therapy, was 121.8 months. Median OS between pts with PIK3CAm and PIK3CAwt did not significantly differ (121.8 vs. 125.1 months, p=0.42). In the multivariable Cox regression, line of therapy was not significantly associated with an increased risk of death. The observed median PFS for the overall cohort from start of first-line therapy was 14.2 months. These results showed a trend by PIK3CAm status: 20.3 months for PIK3CAwt and 6.9 months for PIK3CAm (p=0.4). Multivariable Cox regression also revealed a higher associated risk of progression for patients with PIK3CAm on their second line of therapy (HR = 2.65, 95% CI 1.02-6.94). These findings were consistent in the subgroup analysis by TNM stage (Stages I-III and Stage IV). Conclusion(s): In this real-world cohort of HER2+ BC patients, PIK3CA mutations were not associated with worse median OS but demonstrated a trend toward shorter median PSF survival in early lines of therapy. Multivariable analysis revealed that patients with PIK3CAm receiving second-line therapy had a statistically significant 2.6-fold increased associated-risk of disease progression. These findings suggest the presence of a PIK3CAm may serve as a negative predictive biomarker for treatment duration in HER2+ disease. Given that approximately 30% of HER2+ BC harbor PIK3CAm, our results support prioritizing clinical investigation of PI3K inhibitors in combination with anti-HER2 therapy in the first-line metastatic setting for HER2+/PIK3CA-mutant BC to optimize treatment sequencing and potentially delay disease progression. Citation Format: N. Stabellini, S. D. de Oliveira, T. Mizukami, A. J. Montero. Impact of somatic PIK3CA Mutations on clinical outcomes in HER2-Positive Breast Cancer [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 PS2-06-23.

Background: Cutaneous squamous cell carcinoma (cSCC) represents one of the most common keratinocyte-derived malignancies encountered in clinical practice; however, its genomic landscape remains far less comprehensively characterized than that of other cutaneous cancers. This study aims to identify key molecular drivers and potential therapeutic targets by comprehensively characterizing the genomic landscape of cSCC using data from the American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) consortium. Methods: A retrospective cohort analysis of cSCC samples was performed utilizing AACR Project GENIE data accessed via the cBioPortal platform (v18.0-public) on 22 November 2025. Analyses included identification of recurrent somatic and copy-number alterations, pairwise gene-gene co-occurrence testing using Fisher's exact tests with Benjamini-Hochberg False Discovery Rate (FDR) correction, and exploratory subgroup comparisons by sex and race, with statistical significance defined as p < 0.05. Results: Recurrent mutations were identified in TP53 (83.5%), NOTCH1 (56.3%), KMT2D (47.0%), CDKN2A (44.4%), TERT (41.4%), ROS1 (34.3%), FAT1 (33.3%), NOTCH2 (31.2%), ERBB4 (28.4%), and KMT2A (24.3%), reflecting disruption of the p53 pathway, cell-cycle control, Notch signaling, epigenetic regulation, telomere maintenance, RTK/MAPK pathways, and Wnt signaling. Statistically significant co-occurrence patterns were observed, and exploratory subgroup analyses evaluated mutation frequency differences by sex and race. Conclusions: This large, multi-institutional genomic analysis defines recurrent mutational and structural alterations in cSCC and highlights an integrated pattern of pathway disruption involving genomic integrity, differentiation, epigenetic control, and proliferative signaling. These findings enhance current understandings of the molecular architecture underlying this common yet genomically understudied malignancy and provide a foundation for future mechanistic studies and development of targeted diagnostic and therapeutic strategies.

We aimed to characterize the somatic mutational landscape of oropharyngeal squamous cell carcinoma (OPSCC) and identify potential genomic drivers of tumor progression and therapeutic resistance using the AACR GENIE database. Retrospective genomic analysis was employed. We used publicly available data from the American Association for Cancer Research (AACR) Project GENIE database accessed via cBioPortal. We analyzed 412 tumor samples from 401 patients diagnosed with OPSCC. Somatic mutations, clinical variables and tumor characteristics were extracted and analyzed. Statistical comparisons of mutation frequencies across gender and tumor stage (primary vs. metastatic) were conducted. Co-occurrence and mutual exclusivity analyses were performed to identify significant genomic patterns. The most frequently mutated genes included TP53 (30.1%), PIK3CA (26.0%), and KMT2D (21.6%). Gender-specific analyses suggested potential enrichment of TP53 and MET mutations in females and of ZNF750 in males. Distinct mutation patterns were observed between primary and metastatic tumors; primary tumors were enriched for mutations in TP53 and CDKN2A, while metastatic lesions harbored unique alterations in genes like CBLB and BUB1B, suggesting pathways involved in immune evasion and chromosomal instability may drive disease progression. Co-occurrence was noted between PIK3CA and FBXW7, and mutual exclusivity between TP53 and CYLD. This study identifies distinct genomic signatures in OPSCC subgroups, highlighting candidate biomarkers in pathways like PI3K/AKT signaling that warrant further investigation. Validating these markers in prospective trials is a critical next step to translate these findings into personalized therapeutic strategies for OPSCC patients.

On December 4, 2025, the American Association for Cancer Research (AACR) released its inaugural AACR Pediatric Cancer Progress Report, which highlights the remarkable scientific and clinical advances transforming outcomes for children (ages 0-14) and adolescents (ages 15-19) with cancer. This first-of-its-kind report encompasses progress against pediatric cancers made over the past decade and chronicles major developments in molecularly targeted therapies, immunotherapies, and genomic profiling that are reshaping pediatric cancer diagnosis, surveillance, and treatment. The report also underscores the enduring challenges that impede progress, including the lack of effective therapies for rarer and aggressive pediatric cancers and the persistent inequities in access to high-quality treatment and supportive care, both in the United States and worldwide. Collectively, these insights reaffirm the urgent need for increased federal investment, strengthened international collaboration, and innovative research strategies to accelerate progress against pediatric cancer. The full report is freely available at PediatricCancerProgressReport.org.

Although KRAS mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely because of a lack of data sets coupling genomic profiling with rich clinical annotations across disease stages. We used American Association for Cancer Research's GENIE Biopharma Consortium Pancreas v1.2 data set to test the association of codon-specific KRAS mutations with clinicogenomic features and patient outcomes in patients with PDAC diagnosed with localized (stages I to III) and advanced disease (stage IV). Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods. Among 1,032 eligible patients, 949 (92%) exhibited mutant KRAS. These mutations were predominantly observed at G12D (n = 390, 41%), G12V (n = 305, 32%), and G12R (n = 149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared with G12D mutation (P = .03). By contrast, patients with G12V mutation who presented with metastatic disease experienced shorter OS compared with those with G12R (P = .04) and G12D mutations (P = .04). Furthermore, no significant differences were observed in the frequencies of coaltered driver genes, including TP53, CDKN2A, and SMAD4, across the different KRAS mutations. These findings demonstrated that codon-specific KRAS mutations affect PDAC outcomes differently based on disease stage at diagnosis. As studies testing KRAS inhibitors continue to emerge and mature, the prognostic variability of individual KRAS mutations must be carefully considered to avoid confounding and ensure accurate evaluation of therapeutic efficacy in early-phase studies.

Characterize the somatic mutations in Oncocytic Carcinoma of the Thyroid (OCA) using a large, multi-institutional database to identify potential therapeutic targets and gain insights into tumor biology. Cross-sectional study. Retrospective nationwide database review. Genomic data from 130 OCA samples, representing 124 adult patients, were retrieved from the American Association for Cancer Research (AACR) Project Genomics, Evidence, and Neoplasia Information Exchange (GENIE) database (v17.0-public). Analysis focused on nonsynonymous somatic mutations identified via whole-genome, whole-exome, or targeted panel sequencing after standardized filtering. Mutation frequencies, enrichment based on gender and metastatic status (primary vs. metastatic), and patterns of co-occurrence or mutual exclusivity were statistically evaluated. The most frequently mutated genes were TERT (33.1%, predominantly promoter mutations), TP53 (20.0%), DAXX (16.2%), KMT2D (13.1%), NF1 (12.3%), and PTEN (10.0%). Significant gender-specific enrichment was identified, notably MST1R mutations exclusive to females (10.7%) and PRKDC mutations exclusive to males (16.7%). Mutations in PC, PCLO, MEN1, and TSC2 were significantly enriched in metastatic samples. DAXX and CDKN1A mutations exhibited significant co-occurrence, whereas TERT mutations were mutually exclusive with DAXX alterations. The genomic landscape of OCA is marked by frequent TERT promoter mutations and distinct mutational patterns associated with patient gender and tumor metastatic status. These findings highlight potential molecular subtypes, reveal pathways potentially driving metastasis (eg, involving MEN1/TSC2), and identify novel sex-specific alterations (MST1R, PRKDC), offering avenues for improved development of targeted therapeutic strategies for OCA.

Thymic carcinoma (TC) is a rare and aggressive malignancy with poor prognosis, and its genomic landscape remains incompletely defined. Identifying the somatic alterations that shape TC biology is essential for improving diagnostic precision, developing targeted therapies, and informing early detection strategies. We performed a retrospective genomic analysis of 141 TC tumor specimens from 134 patients using de-identified data from the American Association for Cancer Research (AACR) Project GENIE® database. Somatic mutations and copy number alterations (CNAs) were characterized, and statistical analyses were conducted to evaluate associations with patient demographics (sex, race) and tumor site (primary vs. metastatic). The cohort was predominantly male (56.7%) and White (56.7%). The most frequently altered genes were TP53 (27.7%), CYLD (17.6%), and CDKN2A (12.1%). Recurrent homozygous deletions at chromosome 9p21.3 involving CDKN2A and CDKN2B were common. Sex-stratified analysis revealed several significant male-specific alterations. Although the Pacific Islander subgroup was small (n = 2), preliminary analysis suggested enrichment of alterations in key cancer-associated genes, including TP53, BRCA1, and STAT5B, underscoring the need for diverse representation in TC genomics. Notably, MTOR mutations were significantly enriched in a subset of local recurrences and lymph node metastases (n = 3; q = 0.013), suggesting a potential role in disease progression. This large-scale genomic analysis reinforces the central involvement of TP53, cell-cycle control, and chromatin-modifying pathways in TC. The identification of sex-associated and race-associated mutational patterns, together with the enrichment of MTOR alterations in recurrent and metastatic disease, highlights biologically plausible mechanisms of progression and potential therapeutic vulnerabilities. These findings support the value of comprehensive genomic profiling in TC and emphasize the need for prospective, multi-omic studies to validate these observations and guide the development of more personalized treatment strategies.

846 Background: There is an alarming rise in early-onset (EO) gastrointestinal (GI) cancers, which may have distinct genomic profiles compared with later-onset (LO) cases. OncoKB is a validated database that provides evidence-based annotation of genomic alterations with therapeutic relevance. Utilizing the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v18.0 and OncoKB annotator, we performed a comprehensive analysis of OncoKB-actionable alterations across all GI tumors. Methods: The AACR GENIE v18.0 database was used to select GI cancers samples by OncoTree code, which were classified by tumor group. We utilized OncoKB to annotate all samples and their somatic mutations, copy number alterations, and structural variants by therapeutic level of evidence (Levels 1-4). We considered a tumor sample to have a potentially actionable alteration if there was at least one Level 1-3B alteration present. We defined EO as age &lt; 50 and LO as age ≥ 50, and excluded samples without age. Chi-square testing compared frequency of actionable alterations between EO and LO tumor groups, and Benjamini-Hochberg procedure controlled for false discovery rate (statistical significance for q&lt;0.05). Results: 43748 samples were analyzed with 19.2% EO and 80.8% LO samples. There were decreased potentially actionable alterations in EO colorectal (43.0% vs 46.3%, q&lt;0.001), gastrointestinal stromal tumor (78.6% vs 93.4%, q&lt;0.001), pancreatic (59.1% vs 67.2%, q&lt;0.001), and stomach/esophagus tumors (50.8% vs 57.2%, q=0.001). No significant differences were observed in other GI tumor groups. The most frequent potentially actionable alterations were in KRAS , PIK3CA , and ERBB2 . Conclusions: To our knowledge, this study represents the largest molecular analysis of actionability of GI tumors. EO GI cancers have decreased frequency of potentially actionable genomic alterations compared to respective LO GI cancers in numerous GI tumor groups. These findings suggest that several EO GI cancers have more limited precision oncology targets, highlighting the need for novel therapeutic strategies. Tumor Group EO samples (n) LO samples (n) EO samples with potentially actionable alterations (n, %) LO samples with potentially actionable alterations (n, %) Most common potentially actionable altered gene q-value Appendix 222 624 103 (46.4%) 282 (45.2%) KRAS 0.85 Colorectal 5274 13989 2270 (43.0%) 6474 (46.3%) PIK3CA &lt;0.001 Gastrointestinal stromal tumor 322 1554 253 (78.6%) 1451 (93.4%) KIT &lt;0.001 Hepatobiliary 589 3995 344 (58.4%) 2274 (56.9%) KRAS 0.64 Neuroendocrine 345 1219 161 (46.7%) 534 (43.8%) ATM 0.52 Other 77 544 37 (48.1%) 295 (54.2%) PTEN 0.52 Pancreatic 614 7874 363 (59.1%) 5290 (67.2%) KRAS &lt;0.001 Small bowel 85 480 62 (72.9%) 351 (73.1%) KRAS 0.97 Stomach/Esophagus 861 5080 437 (50.8%) 2904 (57.2%) ERBB2 0.001

Background and Objectives: Cervical adenocarcinoma (CAC) is a histologically distinct subtype of cervical cancer with a rising incidence in many regions. While the roles of key driver mutations are known, a comprehensive understanding of its genomic landscape, particularly variations across different populations and tumor stages, remains incomplete. This study aims to characterize the somatic genomic landscape of CAC by identifying recurrent mutations, copy number alterations (CNAs), and patterns of co-occurrence, with a focus on variations across racial groups and between primary and metastatic tumors. Materials and Methods: We conducted a comprehensive genomic analysis of 102 tumor samples from 99 patients diagnosed with cervical adenocarcinoma using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Results: The most frequently mutated genes were PIK3CA (25.5%), TP53 (21.6%), ARID1A (20.6%), and KRAS (16.7%). Significant amplification of ERBB2 was also observed (n = 3; 4.83%). Our analysis revealed notable genomic disparities across racial groups, with TP53 mutations being significantly more frequent in White patients compared to Asian and Black patients (p = 0.0236). Furthermore, we identified significant co-occurrence between mutations in KRAS and MSH2 (p = 0.011) as well as ATM and STK11 (p = 0.037). In comparing tumor types, mutations in BCL6 were found to be significantly enriched in metastatic samples. Conclusions: This study validates the primary drivers of cervical adenocarcinoma and reveals novel findings, including notable racial disparities in TP53 mutation frequency and unique patterns of co-occurring mutations. These findings highlight the genomic heterogeneity of the disease and suggest that ancestry and tumor evolution may influence its molecular pathogenesis, offering potential avenues for the development of targeted therapies and personalized biomarkers.

Background/AimT-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers.Materials and MethodsThis study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001.ResultsFrequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations.Conclusion This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.

Chromophobe renal cell carcinoma (chRCC) is a distinct subtype of non–clear cell renal cell carcinoma (ncRCC), arising from intercalated cells of the distal nephron collecting ducts. No standard treatments are specifically approved for chRCC, which is further hindered by lack of a universally accepted grading system. This study sought to find molecular drivers that may aid in the diagnosis or development of treatments for chRCC. A retrospective analysis of chRCC was conducted using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository, accessed through cBioPortal (version 17.0-public) on 21 July 2025. The study examined recurrent somatic mutations and assessed co-occurrence with Benjamini–Hochberg False Discovery Rate (FDR) correction. Additional analyses evaluated mutation by sex and race, with significance set at p < 0.05. The cohort included 180 tumor samples from 170 chRCC patients. Most patients were adults (n = 167, 98.2%) and White (n = 115, 67.6%). Recurrent alterations occurred in genes part of the p53, PI3K/mTOR, Hippo, and NOTCH signaling pathway. Exploratory demographic analyses identified isolated single-patient mutations in select genes across sex and race; however, these rare events are not interpretable as population-level differences. This study provides a comprehensive genomic profile of chRCC across multiple demographic categories.

Seminoma is a malignant germ cell tumor that most commonly involves the testicles but may involve the mediastinum, the retroperitoneum, and other extra-gonadal sites as well. This study aims to investigate the somatic genomic landscape of seminoma. Data for a retrospective observational analysis of seminoma was acquired from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) with clinical and genomic data from 2017 and beyond. Using the R and R Studio software (R 4.5.0), analyses for common somatic mutations and copy number alterations were run with a statistical significance of p < 0.05. The most mutated genes included KIT (22.6%), KRAS (17.1%), and MTOR (5.1%), with significant copy number alterations in CDKN1B (17.2%), KRAS (14.7%), CCND2 (10.3%), and H3F3C (9.8%). These suggest involvement within the KIT/RAS/MAPK and PI3K/AKT/mTOR (PAM) pathways for seminoma development. A novel finding within comparative evaluation of PMS1 and AMER1 mutations were found in Black individuals. Additionally, our findings were consistent with a lower testicular cancer rate among individuals with African ancestry than European ancestry. BRD4 mutations were found only in metastatic samples while KMT2C, STAG2, ALK, AXL, and EGFR were only found in primary samples, suggesting a possible association. This study provided a comprehensive molecular and genetic profiling of seminoma including key genetic alterations, affected pathways, and potential therapeutic strategies. Moreover, overlap between pathways and gene mutations provides the potential for alternative treatment options for seminoma via multiple pathways.

Tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs) are key biomarkers for predicting immunotherapy responses in cutaneous melanoma. The discordance between brisk TIL morphology and absent cytokine signals complicates immune profiling. We examined the interactions between TMB, TIL patterns, cytokine expression, and genomic alterations to uncover immune escape mechanisms and refine prognostic tools. A structure-based BRAF druggability analysis was performed to anchor the genomic findings in a therapeutic context. Primary cutaneous melanoma cases (N = 205) were classified as brisk (n = 65), non-brisk (n = 60), or absent TILs (n = 80) according to the American association for cancer research (AACR) guidelines. Inter-observer concordance was measured using intraclass correlation. Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were graded using immunohistochemistry. Eleven brisk TIL cases lacking TNF-α expression were analyzed using the (Illumina TruSight Oncology 500, Illumina-San Diego, CA, USA). Dabrafenib docking to the BRAF ATP site was performed with Glide SP/XP and rescored with Prime MM-GBSA. Brisk TILs lacking cytokine signals suggested post-translational silencing of TNF-α/IFN-γ. Among the 11 profiled cases, eight exhibited high TMB and copy number alterations, with enrichment of nine metastasis/immune regulation genes. Inter-observer concordance was high (absent TILs, 95%; brisk TILs, 90.7%). BRAF docking yielded a canonical type-I pose and strong ATP pocket engagement (ΔG_bind −84.93 kcal·mol−1). Single biomarkers are insufficient for diagnosis. A multiparametric framework combining histology, cytokine immunohistochemistry (IHC), and genomic profiling enhances stratification and reveals immune escape pathways, with BRAF modeling providing a mechanistic anchor for the targeted therapy.

The 15th Biennial Rivkin Center ovarian cancer research symposium.

American Association for Cancer Research, 25–30 April 2025

Non-small cell lung cancer (NSCLC) harboring mutations in human epidermal growth factor receptor 2 (HER2) represents a challenging lung cancer subtype with limited treatment options and poor outcomes. Trastuzumab deruxtecan, the only HER2-directed antibody-drug conjugate (ADC) approved for the treatment of HER2-mutant NSCLC, is associated with significant toxicities, including interstitial lung disease. In addition, tyrosine kinase inhibitors (TKI) that are not HER2-specific cause EGFR-related toxicities such as diarrhea and rash. The 2025 American Association for Cancer Research (AACR) Annual Meeting and the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featured updates on zongertinib, an oral HER2-selective TKI currently under priority review by the FDA for previously treated patients with HER2-mutant advanced NSCLC. These updates included an oral presentation at AACR that covered efficacy and safety data from the Beamion LUNG-1 Phase Ib trial in three patient cohorts: patients previously treated with double-platinum chemotherapy with or without immunotherapy and HER2 mutations in the tyrosine kinase domain (TKD); patients previously treated with both chemotherapy with or without immunotherapy and, subsequently, HER2-directed ADCs; and patients previously treated with chemotherapy with or without immunotherapy and with HER2 non-TKD mutations. At ASCO, a poster focused on patient-reported outcomes (PRO) from previously treated patients with TKD mutations, examining physical functioning, disease-related symptoms, and treatment tolerability. Together, these presentations demonstrated that zongertinib provides durable clinical activity with a manageable safety profile, and that patients experienced meaningful improvements in symptoms and physical functioning. The data support zongertinib as a treatment option that addresses efficacy, safety, and patient-centered outcomes in previously treated patients with HER2-mutant advanced NSCLC, a patient population that currently has limited therapeutic options.

Sinonasal cancers are malignant neoplasms arising from the nasal cavity and paranasal sinuses, including squamous cell carcinoma (SCC), adenocarcinoma, and undifferentiated carcinoma. Due to their rarity, comprehensive genomic data remain limited. Treatments include surgery, radiation, and chemotherapy, with ongoing trials investigating agents like cetuximab, cisplatin, and Tazemetostat. We analyzed sinonasal cancer cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database via cBioPortal (v16.1-public, accessed July 22, 2024). Common gene mutations, correlations, and mutual exclusivities were assessed using statistical analyses with false discovery rate correction. Of 2,595 head and neck cancer samples, 122 (4.7%) were sinonasal carcinoma: 70 (57.4%) SCC, 31 (25.4%) undifferentiated carcinoma, and 21 (17.2%) adenocarcinomas. The most frequent mutations were TP53 (tumor protein 53; 40%), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; 14%), KMT2D (lysine methyltransferase 2D; 11%), and CDKN2A (cyclin-dependent kinase inhibitor 2A; 9%). Subtype-specific mutations included IDH2 (isocitrate dehydrogenase; 230%) in undifferentiated carcinoma and FAT1 (15%) in adenocarcinoma. TP53 frequently co-occurred with PRKDC (protein kinase, DNA-activated, catalytic subunit; p = 0.020), while KMT2D co-occurred with PIK3CA ( p = 0.018). TP53, PIK3CA, and KMT2D mutations are prevalent in sinonasal carcinoma, highlighting potential targets for therapy. Tazemetostat, targeting KMT2D-related DNA (deoxyribonucleic acid) methylation, and cetuximab, targeting the PIK3CA signaling cascade, may offer therapeutic benefits. Further research on mutation-specific therapies could improve treatment strategies.