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4559 Background: Baseline QOL has been linked to survival in mRCC therapy clinical trials (Cella, 2024); however, there is a paucity of prospectively collected real-world QOL data across front-line management strategies. We used data from ODYSSEY to examine the relationship between baseline QOL and early death. Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology); have no prior systemic therapy (ST) or be within 3 months of starting ST; and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Early death was defined as death within 12 months post-enrollment. All pts with non-missing FKSI-19 or FKSI-DRS at enrollment were included. Cumulative event probabilities as a function of time were stratified by either < or ≥ median QoL value and plotted as a step function vs time since enrollment to create cumulative event curves. To determine association between QoL at enrollment and early death, separate Cox proportional hazards models (unadjusted and adjusted) for time-to-first-event as a function of baseline QoL were fit. The adjusted model controlled for the following baseline covariates: IMDC risk (favorable vs intermediate or poor), histology (clear cell vs non). Results: As of 1/5/26, 468 pts were enrolled; 425 had non-missing FKSI-19 or FKSI-DRS at enrollment (329 immediate ST, 96 deferred ST [DST]). ST included 129 IO-IO, 108 IO-TKI, 92 Other. DST included 57 Active Surveillance, 22 Local Therapy Planned, 17 Other/Missing. 209 and 190 pts have < median FKSI-19 (score = 59) and FKSI-DRS (score = 29), respectively; 216 and 235 pts have ≥ median FKSI-19 and FKSI-DRS, respectively. Those below the median have lower rates of nephrectomy, worse IMDC risk and KPS, shorter time since RCC diagnosis, and higher rates of bone metastasis (all p<0.05). Cumulative event probabilities for death at 12 months are 21% and 7% in those < and ≥ median baseline FKSI-19, respectively; and 21% and 7% in those < and ≥ median baseline FKSI-DRS, respectively. For FKSI-19, the unadjusted hazard ratio (HR) for early death is 0.55 (95% CI: 0.43 – 0.70; p<0.001) and adjusted HR is 0.65 (0.49 – 0.85; p = 0.002) per 1 SD higher score. For FKSI-DRS, the unadjusted HR for early death is 0.57 (95% CI: 0.46 – 0.71; p<0.001) and adjusted HR is 0.66 (0.51 – 0.86; p =0.002) per 1 SD higher score (higher score indicates better QOL). Conclusions: Across management strategies in our ODYSSEY cohort of systemic therapy naïve mRCC patients, better baseline QOL was associated with better survival. This is to our knowledge the largest reported real world mRCC cohort with prospectively collected PROs. Future analyses will focus on association of outcomes with longitudinal PROs. Clinical trial information: NCT04919122 .

4178 Background: In the CABINET trial, CABO significantly prolonged progression-free survival (PFS) compared to placebo (PB) in patients (pts) with advanced, previously treated extrapancreatic NET (epNET) or pancreatic NET (pNET) (Chan et al., NEJM, 2025). Here we report outcomes according to functional status based on NET hormone secretion. Methods: Pts with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) before registration, ≥ 1 prior systemic therapy not including somatostatin analogs (SSA). Pts with functional NET due to hormone secretion and non-functional NET were included. In this post hoc subgroup analysis, we analyzed PFS by blinded independent central review and adverse events for pts receiving CABO vs PB based on functional status. Cox regression models were used with stratification on primary tumor site (epNET vs pNET). Subset analyses to evaluate treatment arm differences were conducted in pts with functional and non-functional tumors. Due to small numbers, separate results for those with unknown functional status are not included. Results: Of the total 298 pts enrolled in both cohorts, 74 had a functional NET (CABO, n = 47; PB, n = 27); 179 had a non-functional NET (CABO, n = 123; PB, n = 56); 45 had unknown functional status (CABO, n = 28; PB, n = 17). For functional NET, primary tumor sites were GI tract (n = 50; 68%), pancreas (n = 15; 20%), unknown (n = 4; 5%), lung (n = 3; 4%), and thymus (n = 2; 3%). Secreted hormones that were reported included serotonin (55%), somatostatin (18%), gastrin (16%), glucagon (4%), insulin (4%), ACTH (1%), and vasoactive intestinal peptide (1%). For non-functional NET, primary tumor sites were pancreas (n = 75; 42%), GI tract (n = 42; 23%), lung (n = 30; 17%), unknown (n = 17; 9%), thymus (n = 8; 4%), and other (n = 7; 4%). Concurrent SSA was received by 91% and 53% of pts with functional and non-functional NET, respectively. In both subgroups, CABO was associated with improved PFS compared to PB (for functional NET: stratified hazard ratio [sHR], 0.40; 95% confidence interval [CI]: 0.20-0.82, P = 0.012; for non-functional NET: sHR, 0.26; 95% CI: 0.17-0.41, P < 0.001). The most frequent grade 3/4 adverse events (AEs) attributed to CABO vs PB in pts with functional NET included hypertension (21% vs 11%), diarrhea (9% vs 11%), and fatigue (2% vs 15%); in pts with non-functional NET, grade 3/4 AEs included hypertension (21% vs 4%) and fatigue (18% vs 4%). Conclusions: Subset analyses of the CABINET trial suggest that CABO is an effective treatment option for pts with functional and non-functional epNET or pNET. Efficacy and safety results for pts with functional or non-functional NET treated with CABO are consistent with results for the entire trial. Clinical trial information: NCT03375320 .

3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)

OBJECTIVE Historically, craniopharyngioma (CP) was divided into adamantinomatous CP (ACP) and papillary CP (PCP) subtypes based on histopathological features. However, each harbors a unique genetic profile and progressively differing treatment paradigms, leading to their reclassification by the WHO in 2016 as two distinct entities. Descriptive in nature, this large multi-institutional study aimed to establish current differences between the presentation, treatment patterns, and clinical course of these pathologies to serve as a baseline for future studies as new treatment paradigms emerge. METHODS The authors queried the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, which encompassed patients from 14 participating institutions across the United States between 2000 and 2024. The database was screened for adult patients who underwent initial CP treatment with a confirmed histopathological diagnosis of ACP or PCP. Patient demographic characteristics, clinical course, tumor treatment, and outcomes data were collected and compared by CP type. RESULTS The final analysis included 273 ACP and 99 PCP adult patients who underwent initial surgical treatment. ACP patients presented younger on average (mean 48.3 vs 52.8 years, p = 0.034). PCP patients were more likely to present with hypothyroidism (33.3% vs 20.5%, p = 0.010), hyperlipidemia (25.3% vs 15.8%, p = 0.036), fatigue (28.3% vs 17.6%, p = 0.024), temperature intolerance (9.1% vs 1.5%, p < 0.001), and cardiac arrhythmia (6.1% vs 1.1%, p = 0.006). The groups demonstrated similar postsurgical and neuroendocrinological outcomes. Postoperative median (IQR) progression-free survival did not significantly differ between groups (19.0 [7.0–37.0] for ACP vs 5.0 [3.5–7.5] months for PCP, p = 0.972). ACP patients were more likely to receive radiation after surgery (27.8% vs 15.2%, p = 0.012). CONCLUSIONS This large multicenter descriptive study aimed to characterize similarities and differences between the clinical courses of molecularly distinct ACP and PCP, which has not previously been described. The findings should serve as a baseline to inform future studies, particularly with the recent introduction of targeted therapy for PCP.

SUMMARY Aging is accompanied by profound changes in bladder function, leading to increased urinary frequency and incontinence that impair quality of life in humans and are recapitulated in mouse models. Bladder filling and emptying rely on precise mechanosensory feedback, yet how aging alters this sensory control remains unclear. PIEZO ion channels convert mechanical forces into cellular signals essential for bladder fullness sensation. Using inducible smooth-muscle specific Piezo1 deletion, we find that loss of Piezo1 attenuates aging-related bladder dysfunction. Dietary enrichment with margaric acid, a membrane-active fatty acid previously shown to inhibit PIEZO channels, reduced urinary dysfunction in aged mice. In humans, genotype–phenotype analyses reveal an association between a PIEZO1 gain-of-function variant and early-onset neuromuscular bladder dysfunction. Together, these findings define a smooth-muscle, PIEZO1-mediated mechanosensory basis for aging-related bladder dysfunction and introduce a non-invasive strategy for targeting PIEZO channels in vivo .

Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Abstract Background Older adults remain underrepresented in prospective trials of immunotherapy for advanced lung cancer. To estimate pembrolizumab adverse events, we conducted a multicenter, nonrandomized, open-label phase 2 trial of oncologist-choice first-line pembrolizumab with or without chemotherapy for older adults with advanced lung adenocarcinoma. Methods Alliance for Clinical Trials in Oncology A171901 enrolled patients aged 70 years and older with stage IV or recurrent lung adenocarcinoma starting oncologist’s choice of first-line pembrolizumab with or without carboplatin and pemetrexed. The primary endpoint was the proportion of patients experiencing a solicited grade 3 or greater adverse event within 6 months. Secondary endpoints included overall survival, quality of life, and association of a geriatric assessment toxicity risk score with severe adverse events. Results Among 95 evaluable patients, 43 (45.3%) received pembrolizumab and 52 (54.7%) received pembrolizumab plus chemotherapy. Median age was 77 years (range = 70-92 years); 11.6% had an E Performance Status of 2 or higher. During 6 months of treatment, 25.6% (95% CI = 13.5% to 41.2%) experienced a solicited grade 3 or greater adverse event in the monotherapy group and 42.3% (95% CI = 28.7% to 56.8%) in the combination group. Median overall survival was 16.4 months (95% CI = 10.1 to not estimable) with monotherapy and 29.9 months (95% CI = 16.4 to not estimable) with combination therapy. Quality of life worsened during treatment. The geriatric assessment toxicity risk score was not associated with severe adverse events with pembrolizumab with or without chemotherapy. Conclusions Older adults with advanced lung adenocarcinoma receiving pembrolizumab with or without chemotherapy had comparable adverse event rates to those in prior registration trials that excluded medically frail patients. These findings can inform shared decision making and support inclusion of older adults in future trials. Clinical Trial NCT04533451 (https://clinicaltrials.gov/study/NCT04533451)

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

PURPOSE For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR) but extends treatment duration. This phase III trial investigated whether boost delivery during WBI versus after WBI provides noninferior IBR and preserves cosmetic appearance. METHODS NRG/RTOG 1005 randomly assigned patients at higher risk for IBR after lumpectomy and axillary surgery to either a sequential boost of 12 Gy in six fractions(F) or 14 Gy in 7F after WBI of 50 Gy in 25F or 42.7 Gy in 16F (sequential arm) or a concurrent boost of 8 Gy in 15F of 0.53 Gy per day with WBI of 40 Gy in 15F (concurrent arm) using 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT. Based on 1.59% 5-year IBR for the sequential arm, defining the noninferiority margin as a hazard ratio upper limit on the 90% CI of 2.12, 2,312 patients provide 80% power for noninferiority of IBR as first recurrence for the concurrent arm. Secondary end points included disease-free survival and overall survival, adverse events (AEs), and cosmetic outcomes. RESULTS Between May 24, 2011, and June 20, 2014, 2,354 patients were randomly assigned, with 2,255 eligible for analysis (sequential arm, n = 1,118; concurrent arm, n = 1,137). With median follow-up of 7.3 years, there were 56 IBR events; 5- and 7-year IBR were 2.1% and 2.2% on the sequential arm and 1.9% and 2.6% on the concurrent arm, respectively. The noninferiority criterion was met: HR (90% CI): 1.31 (0.84 to 2.04), P = .037. No differences were observed in AEs, cosmetic outcomes, or survival between arms. CONCLUSION Concurrent boost during WBI results in noninferior IBR compared with sequential boost without worsening toxicity or cosmetic outcomes and reduces overall treatment time.