Citations

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Subglottic stenosis (SGS) may arise from both mechanical and inflammatory airway injury. Patients with mast cell activation syndrome (MCAS) are uniquely vulnerable, due to both direct effects of systemic inflammation and indirect effects of repeated intubation for anaphylaxis that can converge to cause life-threatening airway compromise. We describe a sentinel case of a 34-year-old female with MCAS and multiple prior intubations who presented with progressive dyspnea. Flexible laryngoscopy revealed grade III SGS. She underwent urgent endoscopic intervention, including balloon dilation, carbon dioxide (CO 2 ) laser radial incisions, and steroid injection. Airway patency was restored, and postoperative care focused on optimizing systemic mast cell control with cromolyn, fexofenadine, montelukast, and omalizumab. Literature review supports a mechanistic role for mast cell mediators in airway fibrosis and impaired wound healing, compounding the effects of mechanical trauma in MCAS. This sentinel case highlights clinically significant risk of SGS in patients with MCAS. By integrating case findings with mechanistic insights, this report underscores the urgent need for interdisciplinary awareness, proactive airway evaluation, and research into surveillance and prevention strategies in MCAS and related disorders. Level of Evidence: Level V/Case Report and Narrative Review.

Abstract Purpose: There are limited prospective data on the efficacy, tolerability, and functional impact of treatments for older and frail adults with HER2+ early breast cancer. We report the first-ever, US-based adjuvant trial dedicated to this population. Methods: We conducted a single arm, phase II, multicenter, investigator-initiated study of adjuvant ado-trastuzumab emtansine (T-DM1) in patients aged 60 and older with stage I-III HER2+ breast cancer who either declined standard adjuvant therapy or were deemed by their physician not to be candidates for standard treatment for any reason. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). The primary endpoint was 5-year invasive disease-free survival (iDFS) with a 2-sided 90% confidence interval. Secondary endpoints presented here are toxicity and 3-year iDFS, invasive breast cancer-free survival (iBCFS), and overall survival (OS). All survival analyses were evaluated using Kaplan Meier methods and began at the time of C1D1 of T-DM1. Results: ATOP enrolled 111 evaluable patients during 2015-2020; median follow-up is 4.9 years (IQR 4.2-5.5). The median age was 71 (range 60-88); 50.4% were aged >70 and 11.7% were aged >80. Overall, 69.4% had stage I, 26.1% had stage II, and 4.5% had stage III disease; 70.3% had hormone receptor-positive tumors. The 5-year iDFS = 84.2% (90% CI 77.1-92.0%). The 3-year iDFS = 91.2% (90% CI 85.9%, 96.9%) and iBCFS = 94.1% (90% CI 89.7-98.8%) (see Table for event details); 3-year OS = 96.1% (90% CI 92.4-99.9%). In total, there were 3 distant recurrences and 2 breast cancer-related deaths. Overall, 82% reported grade 2+ toxicity during treatment; the most common grade 2+ events were fatigue (30.6%) and peripheral sensory neuropathy (19.8%). The most frequent grade 3 events were liver function abnormality, anemia, decreased neutrophil count, and neuropathy (<5% for each); one patient (0.9%) had grade 4 thrombocytopenia. Sixty-five (58.6%) completed all 17 cycles of protocol therapy; 27 (24.3%) completed 10-16 cycles, and 19 (17.1%) completed 1-9 cycles. Reasons for early treatment discontinuation in the remaining 41.4% included toxicity (28.8%), patient withdrawal (6.3%), other (3.6%), disease progression (0.9%), death on study (0.9%, deemed unrelated to treatment), and other complicating disease (0.9%). Conclusions: The ATOP trial demonstrated a favorable 5-year iDFS and manageable toxicity among older adults with early stage HER2+ breast cancer. Although iDFS was numerically worse than historical controls (i.e., 5-year iDFS in the ‘ATEMPT’ trial by Tolaney et al. J Clin Oncol, 2024 was 97% [95% 95.2-98.7]), ATOP’s participants had higher-risk cancers, advanced age, and more competing non-breast cancer events. Future endpoints will include in-depth analyses of patient-reported outcomes, biomarkers of aging, and longitudinal functional status. Citation Format: R. A. Freedman, H. Heiling, K. J. Ruddy, L. Rogak, M. Sedrak, A. Dueck, H. Liu, A. Fraettarelli, S. Atanasov, M. DeMeo, P. Lange, A. Perilla Glen, S. Sinclair, D. Dillon, J. Mortimer, M. Fenton, J. Walsh, L. Spring, H. Muss, N. Sinclair, E. Hamilton, C. Dang, S. Giordano, M. Faggen, S. Lo, C. Kuzma, S. Lemke, P. Stella, R. Mowat, M. Wilkinson, J. Rauch, N. Tayob, E. Winer. Adjuvant Ado-Trastuzumab Emtansine (T-DM1) for Older Patients with HER2+ Breast Cancer - Results from the ATOP Study [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 PS3-11-04.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

The iStent series constitutes a range of trabecular bypass minimally invasive glaucoma surgery (MIGS) devices, which offers intraocular pressure (IOP) reduction with favourable safety profiles, in patients with open-angle glaucoma (OAG). Having undergone significant evolution since its initial US FDA-approval in 2012, successive generations address previous limitations, while enhancing IOP-lowering efficacy through device and delivery system design iterations. Longer-term and real-world iStent data demonstrate the durability of IOP- and medication-lowering outcomes with minimal complications, while preliminary studies across a wider spectrum of glaucoma subtypes and severities provide limited evidence of successful outcomes beyond mild-to-moderate OAG, both with and without concomitant cataract surgery. Aqueous humour outflow assessment and novel intra-operative techniques may further facilitate more accurate and effective iStent positioning. Despite typically higher upfront costs, results from both cost-effectiveness and patient-reported outcome studies are encouraging. Combination MIGS with the iStent, leveraging on the multiple mechanisms of actions of various procedures, may provide greater IOP-lowering efficacy without compromising safety. With expanding clinical data and progressive enhancements, iStent technology is likely to remain a key component of the evolving MIGS landscape.

Importance The Surgery as Needed for Oesophageal Cancer (SANO) trial introduced active surveillance as a noninferior alternative to esophagectomy for patients with esophageal cancer who achieve a clinical complete response (cCR) after neoadjuvant chemoradiation (nCRT). However, concerns remain about recurrence risk, long-term survival, and quality-of-life trade-offs with organ-preserving strategies. Objective To evaluate the long-term comparative effectiveness of active surveillance vs standard esophagectomy in patients with cCR following nCRT for locally advanced esophageal cancer, using updated data from the SANO trial. Design, Setting, and Participants This decision analytical model used Markov modeling and probabilities and utility inputs derived from the SANO trial and existing literature. The base case was a 60-year-old male with good functional status and cT3N1M0 esophageal cancer achieving cCR after nCRT. Exposures Standard routine esophagectomy vs active surveillance after neoadjuvant chemoradiation. Main Outcomes and Measures The primary outcome was quality-adjusted life-years (QALYs); the secondary outcome was life-years. Additional model scenarios explored (1) quality-of-life impacts of esophagectomy modeled as a time-varying covariate and (2) 2-year outcomes to align with the SANO trial time horizon. Sensitivity analyses evaluated recurrence probabilities and surgery-related quality-of-life trade-offs. Results At 5 years, standard surgery yielded greater QALYs (1.74 vs 1.34; incremental gain of 0.40 QALYs or ~4.8 months in perfect health) and life-years (3.11 vs 2.41; incremental gain of 0.70 life-years or ~8.4 months) compared with active surveillance. However, at a 2-year horizon, active surveillance was preferred for QALYs (incremental gain of ~15 days), consistent with the SANO trial. Sensitivity analyses revealed the model favored active surveillance when the recurrence probability was less than 43%, the likelihood of local/resectable recurrence was greater than 94%, or the negative quality-of-life impact of esophagectomy was substantial. Modeling esophagectomy’s quality-of-life impact as time limited further strengthened surgery’s long-term QALY benefit. Conclusions and Relevance This study found that while active surveillance offers short-term quality-of-life benefits and may be appropriate in select patients, particularly those at low recurrence risk or with high surgical risk, esophagectomy remains the preferred strategy for maximizing long-term survival and QALYs. These findings support a nuanced, individualized approach to post-nCRT management, balancing organ preservation with long-term oncologic outcomes.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

Purpose: Cutaneous squamous cell carcinoma has a propensity for perineural invasion. Treating perineural spread has involved surgery and adjuvant chemoradiation, and more recently, immune checkpoint inhibitors. This study aims to evaluate motor and sensory functional outcomes in patients with cranial neuropathies from perineural spread of squamous cell carcinoma, particularly those undergoing immunotherapy. Methods: This was a multicenter case series and literature review. Results: Eighteen patients with cranial neuropathies from perineural spread had a mean age of 72.5 ± 9.7 years. Cranial nerves V and VII were most often involved. Treatments included radiotherapy (8/18; 44.4%), chemotherapy (7/18; 38.9%), and/or immunotherapy (11/18; 61.1%), with many receiving a combination of modalities (8/18; 44.4%). Of those receiving immunotherapy, 72.7% (8/11) demonstrated at least partial clinical and/or radiologic tumor response. Among those with functional outcomes documented, half had improvement in sensory/motor nerve function following immunotherapy (4/8; 50%). A literature review identified 55 articles describing 449 patients total with cranial neuropathies from squamous cell carcinoma perineural spread. Combinations of surgery, chemotherapy, and/or radiotherapy were employed, with immunotherapy used in 16 patients. From 5 patients on immunotherapy with documented functional outcomes, all demonstrated at least some improvement. Conclusion: Immunotherapy plays an evolving role in managing advanced squamous cell carcinoma. Functional improvements in cranial neuropathy were demonstrated in 50% of patients receiving treatment with immunotherapy at a mean of 32.6 months of follow-up. This may hold important implications for the timing of surgical intervention, particularly in the case of cranial nerves V and VII palsies.

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.