Suleiman, Riham

Abstract Background Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma. While localized disease has an excellent prognosis, metastatic EMPD is aggressive with no standardized systemic therapy. This study characterizes the clinicopathologic and molecular landscape of metastatic/recurrent EMPD to identify therapeutic vulnerabilities. Patients and methods We conducted a retrospective cohort study of 26 patients with metastatic or distantly recurrent EMPD treated at Mayo Clinic (2000-2025). Descriptive statistics were used to summarize baseline characteristics. Survival outcomes were estimated using Kaplan–Meier methods, with group comparisons performed using log-rank testing. Continuous variables were compared using nonparametric tests, and categorical variables were analyzed using appropriate comparative tests. Pathway-level genomic correlations with TCGA reference cohorts were assessed using Spearman rank correlation. Treatment responses were retrospectively evaluated from radiologic reports. Results The cohort was predominantly male (73.1%) and White (92.3%), with a median age of 68 (IQR, 53-79). Lymph nodes were the most common metastatic site (61.5%). The median overall survival (OS) was 20.0 months (95% CI, 0-40.4). IHC showed universal CK7 and GATA3 positivity, with 80% androgen receptor (AR) expression. HER2 was positive (3+) or amplified in approximately one-third of cases. NGS revealed frequent mutations in TP53 (68.8%), ERBB2 (50%), and CDKN2A/B (50%). A “triple-hit” deletion at the 9p21 locus (CDKN2A/B/MTAP) was identified in 25% of cases. Genomic profiling showed strong similarity to HER2+ breast and urothelial carcinomas. HER2-directed therapy was associated with longer overall survival (median OS 73.0 months [95% CI, 0-177.9] vs 19.0 months [95% CI, 0-41.4]; HR 0.50 [95% CI, 0.0-177.9], P = .3), although this difference did not reach statistical significance. Conclusion Metastatic EMPD exhibits distinct clinicopathologic and molecular features, including high AR and HER2 expression, TP53 and CDKN2A/B alterations, and similarity to systemic HER2+ malignancies. The observed activity of HER2-directed therapies in this cohort suggests the potential value of further investigating biomarker-guided treatment strategies in metastatic EMPD. NGS-guided profiling may inform precision treatment strategies, including AR-targeted therapy and emerging MTAP-directed approaches.

Purpose To assess how comfortable patients with cancer are in responding to intimate questions on sexual orientation and gender identity (SOGI) and to examine whether question sequencing alters patient-reported comfort. Patients and Methods Patients with cancer were asked to respond to one of two surveys that were provided to patients in a randomized manner and that included seven identical SOGI questions but differed in sequence of responses (upfront vs later debated terms, e.g. “genderqueer”). Using a Likert scale (1 = very uncomfortable to 5 = very comfortable), patients rated comfort. The primary endpoint was the percentage of patients comfortable with the question, “Do you consider yourself to be… [12 response options, including genderqueer]”. Secondary endpoints included differences in comfort based on question sequence or demographics. Write-in comments were captured. Results 74% of patients (95% CI: 70%, 78%) were comfortable when reviewing the primary endpoint SOGI question. Similar comfort levels were reported for the other questions. No significant differences in comfort were observed based on question sequence or demographics. Four themes emerged from write in comments 1) emotional reactions to the questions (“uncomfortable because this question is essentially gender binary”) 2) emotional reactions toward SOGI (“bending over backwards to be politically correct”); 3) concern for privacy and relevance to cancer care (“not sure why this information is needed/necessary”); and 4) constructive remarks (“didn’t know what cisgender was - please define”). Conclusions Most patients with cancer are comfortable in answering SOGI questions. However, their comfort might be enhanced with slight question/response modifications.

Leptomeningeal disease (LMD) is a devastating complication of metastatic melanoma, affecting up to 15% of patients with central nervous system involvement. Despite advances in systemic therapy, LMD carries poor prognosis. Patients with LMD are often excluded from clinical trials. Contemporary real-world data on prognostic factors and treatment outcomes in melanoma LMD are limited. We conducted a retrospective cohort study of patients diagnosed with leptomeningeal metastasis from melanoma between 1 January 2018 and 31 December 2025, across Mayo Clinic sites. LMD diagnosis was made by magnetic resonance imaging showing leptomeningeal enhancement and confirmation from cerebrospinal fluid cytology and clinical presentation. Demographic, clinical, treatment, and outcome data were collected. Overall survival (OS) from LMD diagnosis was the primary endpoint. Forty-four patients were identified (median age: 60.0 years, range: 30.5–82.7). Before diagnosis of LMD, systemic therapy for metastatic disease was given to 91% of patients. BRAF mutations were present in 65.9%. After LMD diagnosis, 88.6% were treated for LMD. Median OS was 2.96 months (95% confidence interval: 1.39–4.53). Poor Eastern Cooperative Oncology Group performance status was independently associated with worse OS (hazard ratio: 2.10, P = 0.036). Any treatment for LMD (hazard ratio: 0.16, P = 0.005) was associated with improved OS. Melanoma-related LMD remains rapidly fatal. Studies of novel treatments are needed to improve outcomes for patients with this diagnosis.

Caudal type homeobox 2 (CDX2) is an intestine-specific transcription factor that serves as a diagnostic marker of enteric differentiation and may also reflect tumor behavior and therapeutic susceptibility. Emerging evidence suggests that CDX2 expression may predict sensitivity to fluoropyrimidine-based therapy independent of tissue of origin. We report a retrospective case series of three patients with metastatic adenocarcinoma (aggressive variant prostate, minor salivary gland, and intestinal-type sinonasal tract) exhibiting strong CDX2 nuclear expression. In all cases, tumors were refractory to or lacked established standard systemic therapy. Treatment decisions were informed by the CDX2-positive enteric phenotype, leading to the initiation of fluoropyrimidine-based regimens. Response was assessed using PET-CT and MRI. All three patients achieved marked metabolic and clinical responses, including a sustained complete metabolic response in the prostate cancer case and durable disease control in the salivary gland and sinonasal tumors. These findings highlight CDX2 as a potential biomarker requiring validation, which may identify tumors intrinsically susceptible to fluoropyrimidines regardless of anatomical origin. CDX2 immunohistochemistry is widely available and inexpensive, and may complement genomic profiling in rare malignancies or in settings where standard treatment algorithms are limited. This report is hypothesis-generating and not intended to estimate response rates or treatment efficacy.

Abstract Background Sarcomatoid carcinomas (SC) are rare tumors with both epithelial and mesenchymal characteristics, linked to aggressive behavior and poor prognosis. Sarcomatoid carcinoma of unknown primary (SCUP) is an exceedingly rare subset with limited literature and no standardized management guidelines. This study aims to characterize the clinical presentations, treatment patterns, and genomic landscape of SCUP. Patients and Methods Data were retrospectively collected from the Mayo Clinic Rochester Cancer of Unknown Primary Registry. Patients included had biopsy-proven SC with no identifiable primary tumor despite comprehensive diagnostic evaluations. Baseline characteristics, immunohistochemistry (IHC) results, next-generation sequencing (NGS) data, and treatment outcomes were analyzed. Statistical analyses included descriptive statistics, Kaplan–Meier survival estimates, and Cox proportional hazards regression. Results Fifty-two SCUP patients were identified, with a median age of 60 years. Most patients presented with widely metastatic disease, particularly lytic bone lesions. Elevated alkaline phosphatase (ALP) was noted in nearly half of the patients. IHC showed high positivity for AE1/AE3 and OSCAR antibodies. Tumor NGS revealed 247 alterations, with TP53 being the most common mutation. Patients receiving definitive therapy had a median overall survival (OS) of 72 months, significantly longer than those receiving systemic therapy (14 months). Immunotherapy was a significant prognostic factor, reducing the risk of death by 90%. Conclusions This study provides essential insights into the clinical and genomic characteristics of SCUP, advocating for the integration of definitive therapy and immunotherapy in treatment protocols. Further prospective studies are needed to validate these findings and improve patient outcomes.

ABSTRACTBackgroundRecurrent squamous cell carcinoma (SCC) of the head and neck (SCCHN) remains a formidable clinical challenge despite available treatments. The phosphatidylinositol 3‐kinase (PI3K) pathway has been identified as a potential therapeutic target, and alpelisib, a selective PI3Kα inhibitor, has demonstrated efficacy in certain malignancies. Combining this targeted therapy with immunotherapy has been suggested in previous studies as a promising strategy to bolster the immune response against cancer.CasesA 69‐year‐old woman with locoregional recurrence of PIK3CA‐mutated SCC of the left maxilla and cervical nodal metastases. Several chemotherapeutic regimens, including cisplatin, docetaxel, 5FU, chemoradiotherapy, and mono‐immunotherapy, resulted in disease progression. Alpelisib combined with pembrolizumab led to a sustained response for 9 months. A 58‐year‐old man with recurrent metastatic PIK3CA‐mutated SCC of the oropharynx, involving the left lung, hilar, and mediastinal lymph nodes. Despite prior palliative radiation and platinum‐based chemotherapy with pembrolizumab and cetuximab, treatment with alpelisib and nivolumab resulted in a partial response. Severe hyperglycemia and rash led to treatment discontinuation.ConclusionOur findings highlight the potential of this innovative therapeutic combination, suggesting a need for further investigations in this setting.

AbstractBackgroundHead and neck cancers (HNC) present diagnostic challenges due to multifocal disease manifestations, posing difficulties in distinguishing between metastatic disease and second primary malignancies (SPM). This complexity underscores the need for advanced diagnostic approaches. Emerging technologies, such as next‐generation sequencing (NGS) and molecular classifier assays, show promise in providing precise insights into the diverse etiologies of HNC.MethodIn this article, we employed NGS and molecular classifier assays to delve into three distinct clinical cases. The objective was to showcase the instrumental role of these technologies in facilitating accurate diagnoses and differentiating between metastatic disease and SPM in HNC cases.ResultsThe results of this series highlight the effectiveness of NGS and molecular classifier assays in enhancing diagnostic accuracy for HNC and contributing to the precise differentiation of disease etiologies. The utilization of these advanced technologies proved instrumental in avoiding unnecessary interventions and paved the way for more targeted and effective treatment strategies.ConclusionOur findings underscore the necessity of incorporating advanced molecular testing technologies into the diagnostic and therapeutic approaches for HNC, thereby championing a more nuanced and effective approach to managing these complex cases.

Metastatic CUP is complex, especially NCUP. Precision oncology is crucial for rare, aggressive cancers. A 54-year-old had HER2+ neuroendocrine carcinoma of unknown origin. T-DXd treatment, response, re-challenge show importance of genomics and caution.

e18807 Background: CUP represents both a diagnostic and a management challenge. Despite improvements through sophisticated imaging modalities, specific and sensitive testing using immunohistochemistry, a concrete determination of the site of origin of the primary tumor can still be a diagnostic challenge Hereby, we described the genomic landscape of patients with CUP treated at our institution. Methods: Retrospective study of patients with CUP treated at Mayo Clinic Rochester MN from 2010 to 2021. Next generation sequencing (NGS) information was abstracted, and alterations were ranked into different levels of actionability following the Onco KB framework. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, we identified 67 (32%) patients in whom NGS was performed. Among patients with available NGS the median age was 64 years (range: 35-86) and 51% were female. the most prevalent histology included adenocarcinoma (39%), carcinoma NOS (31%), and neuroendocrine tumors (12%). NGS on tumor (t-NGS) was available in 56 (84 %) patients, circulating tumor NGS (b-NGS) was available in 12 (18%) patients, and only 1 patient had both testing available. Among the 56 patients with available t-NGS, MSI-high was detected in 9 patients, whereas among the 12 patients with available b-NGS, MSI-high was detected in 8 patients; yielding an MSI-high detection rate of 16% and 67% for t-NGS and b-NGS. In this cohort, there were a total of 474 genomic alterations detected from which 103 (22 %) were able to be ranked into one therapeutic level following the OncoKB framework. Genomic alterations were most observed among patients with carcinoma (n = 50, 48.53%) adenocarcinoma (n = 33, 32.03 %), squamous cell carcinoma (n = 3, 2.91 %) and neuroendocrine tumor (n = 2, 1.94%). Following the OncoKB framework, 39-level 1 genomic alterations were detected in a total of 14 genes. The most common level 1 genomic alterations comprised the BRCA2 (20.51%), NF1 ATM (17.95%) and HER2/NEU (ERBB2) (15.38%) genes. Therapeutic level 2 included 51 genomic alterations in 13 genes of which KRAS (17.65%), BRAF (15.69%), and BRCA2 (15.69%) were the most prevalent mutated genes. Additionally, level R comprised 13 genomic alterations in the following genes: KRAS (69.23) NRAS (23.08%) and PDGFRA (7.69%). Conclusions: CUP are malignancies rich in potentially actionable alterations, and NGS of tissue and blood samples can inform systemic therapy decisions. Alteration-specific targeted therapy may be an option for a substantial proportion of patients. NGS of tumor tissue or blood should be considered for all patients with CUP.

e18803 Background: CUPs are a heterogeneous group of metastatic cancers for which a standardized diagnostic work-up fails to identify the site of origin at the time of diagnosis. CUP accounts for 3%-5% of all cancer diagnoses worldwide, and the natural history of patient with CUP differs from that of patients (pts) with cancer with known primary tumor. Here we report and summarize the clinical features of patients with CUP treated at Mayo Clinic. Methods: Retrospective study of patients treated at Mayo Clinic Rochester MN from 2010 to 2021. Patient demographics, tumor-related variables, treatment-related variables, and clinical data were extracted. Descriptive statistics were used, and all data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 pts, 207 pts were included, as primary tumor site was identified in 7 patients after initial evaluation. The pts in this study were predominantly white (87%) of female (50.2%) gender with a mean age of 63 (SD: 13) without history of smoking (51%) and either private or public insurance (82.6%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (27%), and carcinoma NOS (not otherwise specified) (25%). The most prevalent grade in this cohort was grade III with poorly differentiated tumor cells. All pts had diagnostic imaging and the most used imaging modalities included CT (81.2%), and PET-CT (43.5%). In our cohort, the 3 most common sites of metastases included lymph nodes (57.5%), liver (37.8%), lung (34.3%), and bone (23.7%); and in 64% of pts, there was a specific presentation pattern including liver-predominant (24.6%), lymph node-predominant (24.6%), bone-predominant (7.7%), and peritoneal carcinomatosis (7.7%). The majority of pts received systemic therapy (69%) as first line of therapy and the most frequent first line regimens included platinum-doublet (26.5%), gemcitabine-based regimen (20.7%), 5FU-based regimens (18%) and somatostatin analogs (16.7%); whereas salvage radiation and ablation were offered to 11% of pts and surgery to 17%. The median follow-up time was 22 months (IQR: 45) with a median survival time of 23 months and the 3-year cumulative survival rate was 30%. Conclusions: The heterogenous nature of CUPs and lack of specific immunohistochemical signature prevents primary tissue of origin diagnoses in CUP pts. Without the identification of a primary origin site, treatment is restricted to generic chemotherapy with limited benefit as demonstrated in this cohort.