Citations

e16586 Background: Guideline-discordant care disproportionately affects racial minorities, uninsured, and underinsured patients, yet prior studies lack quantification of absolute survival time lost. We evaluated equity-adjusted survival penalties from non-adherence to guideline-concordant therapy in muscle-invasive bladder cancer (MIBC). Methods: From the National Cancer Database, we identified patients with non metastatic muscle invasive bladder cancer (cT2 to T4a, N0 or N1, M0). Overall survival was defined from diagnosis to death or last contact. Guideline-concordant therapy was defined as radical cystectomy (± perioperative systemic therapy) or trimodality therapy (definitive bladder radiotherapy with chemotherapy); all other patterns were classified as discordant. Of 55,873 eligible patients, 28,025 received concordant therapy (27,401 cystectomy; 524 trimodality therapy) and 27,848 received discordant careInverse probability of treatment weighting (IPTW) was used to balance demographic, socioeconomic, facility, tumor, and temporal covariates. We analyzed survival using weighted Kaplan-Meier and Cox models censored at 36 and 60 months. Equity-adjusted survival penalties were calculated as the difference between observed survival and counterfactual survival predicted from concordant-only models. Restricted mean survival time losses were extrapolated to years lost per 1,000 patients. Results: Guideline concordance was associated with significantly improved survival (36-month HR 0.64; 60-month HR 0.68; both p < 0.01). Among concordant modalities, radical cystectomy conferred an early survival advantage over trimodality therapy at 36 months (HR 0.23; p < 0.05) which dissipated by 60 months (HR 0.53; p > 0.05). Survival penalties were most severe for vulnerable populations. At 36 months, uninsured patients incurred a 0.90-month survival penalty (75.0 life-years lost per 1,000 patients). By 60 months, penalties widened: uninsured patients lost 1.94 months (161.7 life-years/1,000), Filipino patients lost 1.53 months (127.0/1,000), Medicaid beneficiaries lost 0.97 months (80.8/1,000), and patients at community cancer programs lost 0.21 months (54.1/1,000). Conclusions: In this national cohort of 55,873 patients, guideline concordance reduced the propensity-weighted risk of death by 32% to 36% at 3 and 5 years. However, non-adherence results in substantial absolute survival losses for marginalized groups. By quantifying these "survival penalties," we demonstrate that targeting the factors underlying discordance offers a direct opportunity to reduce inequities and achieve measurable population-level survival gains in MIBC.

e16564 Background: Urothelial carcinoma (UC) predominantly affects older adults with a high burden of comorbidities, particularly chronic kidney disease (CKD), which affects 30–40% of patients at diagnosis and is more prevalent in advanced disease. Enfortumab vedotin plus pembrolizumab (EV+P) has become a frontline standard for advanced UC; however, patients with moderate-to-severe CKD were underrepresented in pivotal trials. Enfortumab vedotin targets Nectin-4 expressed in renal tubular epithelium, and immune checkpoint inhibitors are associated with immune-mediated nephrotoxicity, raising concern for renal vulnerability in patients with reduced renal reserve. Real-world data evaluating renal and clinical outcomes of EV+P in patients with baseline CKD are limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adult patients with UC treated with EV+P between January 2020 and December 2025. Baseline CKD status (stages 3–5; eGFR < 60 mL/min/1.73 m²) was determined by diagnostic codes and laboratory data obtained prior to EV+P initiation.Patients were stratified into CKD and non-CKD cohorts. Propensity score matching (1:1) was performed for demographics, comorbidities, laboratory values, and prior therapies. Outcomes assessed within 180 days of treatment initiation included overall survival (OS), major adverse kidney events (MAKE; composite of acute kidney injury, dialysis initiation or dependence, or death), and selected treatment-related toxicities. Kaplan–Meier and Cox proportional hazards models were used. Results: After matching, 386 patients were included in each cohort (median age 75 years), with well-balanced baseline characteristics (all post-matching standardized mean differences < 0.1). Prior to matching, patients with CKD had a higher burden of cardiovascular comorbidities. Baseline renal function differed by design, with lower mean eGFR and higher serum creatinine in the CKD cohort. Overall survival was similar between CKD and non-CKD cohorts (HR 0.96; 95% CI, 0.69–1.35; p = 0.83), with 180-day survival rates of 79.9% and 79.3%, respectively. Patients with CKD had a higher incidence of MAKE, reflected by lower 180-day event-free survival (49.4% vs 59.1%; HR 1.41; 95% CI, 1.13–1.76; p = 0.002). Treatment-related toxicities were also more frequent in the CKD cohort (HR 1.35; 95% CI, 1.05–1.74; p = 0.020), with a higher mean number of toxicity events (4.3 vs 3.4). Conclusions: In this large real-world analysis, EV+P use was associated with comparable short-term overall survival in UC patients with and without CKD but with higher rates of renal events and treatment-related toxicities among patients with baseline CKD. These findings support the use of EV+P in select UC patients with CKD, with close monitoring of renal function and treatment-related toxicity.

e14017 Background: The role of stereotactic radiosurgery (SRS) is well established in the setting of one to four brain metastases (BM), offering effective control with reduced neurocognitive toxicity compared with whole-brain radiotherapy (WBRT). However, for patients with five or more BM, the optimal radiation strategy remains uncertain, and comparative outcome data are limited. We performed a systematic review and meta-analysis to compare overall survival (OS) between SRS and WBRT in patients with ≥ 5 BM. Methods: A systematic review was conducted to identify comparative studies of SRS versus WBRT in patients with ≥5 brain metastases. Retrospective and prospective studies reporting median OS with available cohort sizes were included. Comparative survival was summarized using pooled ratios of median survival within a random-effects meta-analytic framework. Results: Five comparative studies were included, comprising 226 patients treated with SRS and 261 treated with WBRT, including both retrospective and prospective cohorts. Sample-size–weighted summary (with reported medians) showed median OS was 8.1 months with SRS and 7.7 months with WBRT. Pooled analysis demonstrated no significant difference in OS between treatment strategies (ratio of median survival, 1.03; 95% CI, 0.73–1.46; p = 0.81). Conclusions: Among patients with ≥5 BM, SRS and WBRT were associated with comparable OS. These data suggest that OS alone may not guide treatment choice in this population, emphasizing the importance of careful patient selection. As focal therapies are increasingly incorporated into clinical practice for patients with higher intracranial disease burden, prospective, multi-institutional randomized clinical trials are needed to better define optimal management strategies. Summary of included studies reporting median overall survival (OS). Study Study Design SRS (n) WBRT (n) Median OS in SRS cohort (months) Median OS in WBRT cohort (months) Kim et al., 2009 Retrospective 29 39 5.6 7.2 Mizuno et al., 2019 Retrospective 24 20 7.3 7 .2 Li et al., 2020 Prospective, randomized 35 34 7.8 8.9 Bodensohn et al., 2023 Prospective, non-randomized 40 70 10.4 6.5 Aizer et al., 2025 Prospective, randomized 98 98 8.3 8.5

e14016 Background: Postoperative stereotactic radiosurgery (SRS) is utilized following resection of brain metastases (BM), however use is limited by target delineation uncertainty and an increased risk of leptomeningeal disease (LMD). Preoperative SRS allows for precise targeting and is being increasingly utilized in treatment paradigms of resectable BM. Reported outcomes across studies are promising and there are several phase 3 trials which are underway. Therefore, we pooled multiple studies and conducted a meta-analysis to estimate 1-year local control (LC), LMD incidence, and overall survival (OS) following single-fraction preoperative SRS for resectable BM. Methods: We systematically searched PubMed, Embase, and Scopus to identify studies of single-fraction preoperative SRS for resectable BM. For each cohort, data for 1-year LC, 1-year LMD, and 1-year OS, along with corresponding sample sizes, were extracted. A proportion-based meta-analysis was performed to derive pooled estimates and 95% confidence intervals (CIs), with between-study heterogeneity quantified using I². Results: Ten studies published between 2016 and 2025, including both prospective trials and retrospective cohorts, met the inclusion criteria. There were 617 patients treated with single-fraction preoperative SRS. The median age was 60.8 years (range 58-65 years), and the median prescribed dose was 15.8 Gy (range 14.5-17.0 Gy). The pooled 1-year LC rate was 81.9% (95% CI, 76.9-85.9; I² = 43.4%). The pooled 1-year incidence of LMD was 4.6% (95% CI, 2.8-7.4; I² = 0%), and the pooled 1-year OS rate was 60.2% (95% CI, 55.5-64.8; I² = 0%). Sensitivity analyses showed stable pooled estimates, with no single study driving the results. Conclusions: Single-fraction preoperative SRS is associated with low rates of LMD and acceptable LC and OS. In the context of historically reported postoperative SRS outcomes, these results suggest that preoperative SRS represents a promising strategy in selected patients. Randomized trials are needed to define the comparative role and optimal patient selection for preoperative SRS, with ongoing studies (NCT05341739, NCT03741673) expected to clarify its role in the management of resectable BM. Study characteristics and reported outcomes of single-fraction preoperative SRS for BM. Study Study design Number of patients Median age (years) Median dose (Gy) 1-year LTC (%) 1-year LMD (%) 1 year OS (%) Agarwal, 2024 Trial 47 59 NR NR 4.8 NR Higazy, 2025 Trial 35 61 17 82 2.86 NR Li, 2022 Retrospective 24 64 NR 87.6 NR NR Mallela, 2024 Retrospective 26 64.5 NR 77.2 NR NR Murphy, 2024 Trial 35 63 NR 76.6 NR 59 Patel, 2018 Retrospective 12 57.5 NR 49.1 10 74.1 Patel, 2016 Retrospective 66 58.2 14.5 84.1 3.2 NR Prabhu, 2025 Retrospective 124 NR 17 87.2 1.7 64.5 Prabhu, 2025 Retrospective 183 NR 15 86.4 7.3 58.1 Prabhu, 2020 Retrospective 65 NR NR 77.1 4.2 56.3

7062 Background: MCL is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable. Bruton tyrosine kinase (BTK) inhibitors are an established standard of care for R/R MCL. However, comparative effectiveness data for different BTK inhibitors for R/R MCL are limited. This study evaluated the real-world effectiveness of zanu and acala in US patients with R/R MCL based on overall survival (OS) and time to next treatment (TTNT). Methods: A retrospective cohort study was conducted using Komodo health administrative claims data. Eligible patients were adults (aged ≥18 years) with ≥2 MCL diagnoses and continuous enrollment or activities within 1 year prior to and 3 months following the index date. Patients were required to initiate monotherapy with zanu (index period: November 2019 to August 2025) or acala (index period: October 2017 to August 2025) as a second-line or later (2L+) treatment, with index date defined as the first observed claim for zanu or acala. Patients with evidence of clinical trial participation, end stage renal disease or prior stem cell transplant were excluded. Outcomes included OS (time from index date to all-cause mortality) and TTNT (time from index date to subsequent therapy with an allowable gap of 120 days). If an outcome was not observed, patients were censored at the date of last activity or enrollment end date. Survival analyses were conducted using Kaplan-Meier estimates and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was adjusted for age, sex, US region, treatment initiation year and Charlson Comorbidity Index (CCI). Results: In total, 2219 patients (zanu, n=931; acala, n=1288) were eligible and included in the study. The mean age was higher in the zanu (72.3 years; SD, 9.4) vs acala cohort (71.4 years; SD, 9.7). Most patients were male (zanu, 71%; acala, 75%), non-Hispanic white (zanu, 73%; acala, 74%), and the mean CCI was 3.5 (SD, 3.2) and 3.6 (SD, 3.1) in the zanu and acala cohorts, respectively. Median follow-up was 14.8 and 18.2 months in zanu and acala cohorts, respectively. Median TTNT was 26.7 months for zanu and 20.8 months for acala. Median OS was not reached for zanu and was 60.6 months for acala. In the unadjusted model, zanu had a longer TTNT (HR, 0.86; 95% CI, 0.76-0.97; P =.012) and OS (HR, 0.74; 95% CI, 0.62-0.88; P <.001). After IPTW adjustment, TTNT and OS favored zanu treatment (TTNT: IPTW-adjusted HR, 0.86; 95% CI, 0.76-0.98; P =.025; OS: IPTW-adjusted HR, 0.81; 95% CI, 0.68-0.98; P =.03). Conclusions: In this real-world analysis of US health claims data, zanu monotherapy demonstrated significantly longer TTNT and improved OS compared with acala in patients receiving 2L+ therapy for MCL. These findings support zanu as an effective BTK inhibitor for R/R MCL.

6501 Background: Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell (RBC) production and contributes to anemia onset and severity. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Methods: RALLY-MF (NCT05320198) is an ongoing Phase 2, open-label study conducted in the US. The primary aim is to evaluate DISC-0974 efficacy in participants with MF and anemia. Secondary aims include evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD). Eligible participants are ≥18 years of age with primary or secondary MF and hemoglobin (Hgb) <10 g/dL or RBC transfusion requirement. Participants enroll into 3 cohorts based on RBC units transfused in the 84 days prior to screening: non-transfusion dependent (nTD, 0 units and Hgb <10 g/dL), low transfusion burden (TD low, 1-2 units), high transfusion burden (TD high, 3-12 units). Stable dose of concomitant Janus kinase inhibitor (JAKi) is allowed. DISC-0974 is administered subcutaneously at 50 mg monthly for up to 6 doses, with escalation to 75 mg for inadequate or lost response. Primary endpoints include major hematologic response defined as transfusion independence (TI) during any consecutive 16 weeks (TD low) or 12 weeks (TD high), or a mean Hgb increase of ≥1.5 g/dL from baseline for ≥12 weeks (nTD). Secondary endpoints include PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results: At data cut (16 Oct 2025), 47 participants enrolled in the nTD (n=30), TD low (n=10), and TD high (n=7) cohorts, with 53% on concomitant JAKi therapy. DISC-0974 led to sustained hepcidin reduction and iron mobilization across cohorts. DISC-0974 resulted in meaningful hematologic responses among evaluable participants: 50% of nTD participants achieved a mean Hgb increase of ≥1.5 g/dL for ≥12 weeks, 71% of TD low participants achieved TI for ≥16 weeks, and 67% of TD high participants experienced a ≥50% reduction in transfusion burden, with follow-up ongoing. Major hematologic response rates were 50% for participants on and off concomitant JAKi therapy (n=18 and n=16, respectively). DISC-0974 was associated with meaningful improvement in FACIT-Fatigue scores for nTD and TD low participants. Serious adverse events (AEs, n=9) and ≥Grade 3 AEs (n=16) were considered unrelated to DISC-0974. There were no early withdrawals due to AEs. Conclusions: DISC-0974 was well tolerated and shows a favorable safety profile. Anemia response and fatigue scores improved across patients with MF and anemia, including those receiving JAKi therapy. These data validate hepcidin reduction as a promising approach to treating anemia in MF. Clinical trial information: NCT05320198 .

590 Background: The landmark FAST-Forward trial demonstrated that ultra-hypofractionated whole-breast irradiation with 26 Gy in 5 fractions over 1 week was non-inferior to 40 Gy in 15 fractions for local control (HR 0.67, 95% CI 0.38–1.16), with similar normal tissue effects at 5 years. In response, major international guidelines incorporated 26 Gy in 5 fractions as a standard approach or recommended option for selected patients. Despite robust randomized evidence and guideline endorsement, U.S. real-world adoption patterns and equity of uptake across patient populations remain incompletely characterized. This study evaluated national trends in 5-fraction breast radiotherapy and sociodemographic differences from 2020 to 2023. Methods: The National Cancer Database radiotherapy fractionation fields were used to identify radiotherapy (RT) courses with evaluable fraction counts, and a binary indicator for 5-fraction RT (yes/no) was created. Temporal trends by diagnosis year (2020–2023) were assessed, and associations between 5-fraction RT and sociodemographic factors (primary insurance, urban or rural status, neighborhood income quartile, and race) were examined using chi-square testing. Results: Among 536,783 RT courses with complete data from 2020 to 2023, use of 5-fraction RT increased substantially over time: 4.3% in 2020, 8.1% in 2021, 12.7% in 2022, and 17.4% in 2023, resulting in an overall adoption rate of 10.7% (p < 0.001). In the subset eligible for fractionation (5, 15–16, 25–28 fractions; N = 31,448), 5-fraction RT accounted for 11.7% and differed significantly by insurance type (p < 0.001): Medicare 17.4%, Private 7.6%, Medicaid 5.9%, and Uninsured 6.9%. Geographic variation was notable (p < 0.001), ranging from 7.3% in mid-size metropolitan areas (250,000–1 million population) to 17.7%–18.1% in more remote or non-adjacent areas; large metropolitan areas (≥1 million) had 12.8% uptake. Neighborhood income showed a gradient (p < 0.001): 10.1% in the lowest quartile compared to 12.5% in the highest. Race was also associated with uptake (p < 0.001), with lower use among Black patients compared to White patients (9.4% vs 12.2%). Conclusions: In routine U.S. practice, adoption of 5-fraction breast RT increased rapidly from 2020 to 2023, with the most pronounced growth after 2021, reflecting the swift translation of trial evidence into clinical practice. However, uptake varies by insurance, geography, income, and race, indicating that diffusion is not uniform. Given the potential benefits of ultra-hypofractionation in reducing treatment burden and supporting timely completion, targeted implementation strategies, such as provider education, reimbursement alignment, and facility-level operational support, may be necessary to ensure equitable access as 5-fraction regimens become more widely adopted and potentially become the standard of care.

4589 Background: Recent years have seen a shift in aUC management following approval of enfortumab vedotin–pembrolizumab (EV-P) and gemcitabine/cisplatin plus nivolumab (GC-NIVO) as first-line therapies. Despite improved clinical outcomes, their relative economic value remains uncertain. Herein, we conducted a cost-effectiveness analysis of current 1L regimens in aUC from a U.S. payer perspective using 2026 pricing. Methods: A partitioned survival model with three health states (progression-free [PF], progressed disease [PD], and death) was developed over a 10-year horizon from a U.S. payer perspective. Analyses focused on cisplatin-eligible patients. Survival data were reconstructed from published Kaplan–Meier curves and extrapolated using parametric survival models. Treatment dosing, schedules, and duration were modeled according to trial protocols. Patients receiving gemcitabine/cisplatin without progression were modeled to receive avelumab maintenance (GC→AVEL). Subsequent-line therapy costs were applied at incident progression, and grade ≥3 adverse event costs and disutilities were applied as one-time events. Drug acquisition costs (2026 USD) were based on average sales prices from the Centers for Medicare & Medicaid Services. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually. Incremental cost-effectiveness ratios (ICERs) and net monetary benefit (NMB) were evaluated at willingness-to-pay (WTP) thresholds of $100,000, $150,000, and $200,000 per QALY. Parameter uncertainty was characterized using probabilistic sensitivity analysis. Results: In the base-case analysis, total discounted costs and QALYs were $90,269 and 1.62 for GC→AVEL, $131,836 and 2.09 for GC-NIVO, and $1,451,885 and 2.77 for EV-P. Compared with GC→AVEL, GC-NIVO gained 0.46 QALYs at an incremental cost of $41,567, resulting in an ICER of $89,501 per QALY and positive NMB across all evaluated WTP thresholds. Compared with GC→AVEL, EV-P gained 1.15 QALYs at an incremental cost of $1.36 million (ICER $1.19 million per QALY). Compared with GC-NIVO, EV-P gained 0.68 QALYs at an incremental cost of $1.32 million (ICER $1.93 million per QALY), exceeding all evaluated WTP thresholds. In a scenario analysis limiting EV-P to 10 treatment cycles, total costs decreased to $287,360, with ICERs of $172,000/QALY versus GC→AVEL and $225,000/QALY versus GC-NIVO, remaining above the $150,000/QALY threshold. Conclusions: Using updated 2026 pricing, GC-NIVO is likely to be the most cost-effective first-line regimen for cisplatin-eligible patients with aUC. EV-P offers the greatest clinical benefit but is not cost-effective at current prices. A major limitation of this study is cross-trial variability in study populations and design, limiting the validity of head-to-head economic comparisons.

Alzheimer’s disease (AD) is characterized by profound metabolic dysfunction and disturbances in gut–brain axis signaling. Ketogenic diet (KD) has demonstrated metabolic and cognitive benefits in both preclinical and clinical studies. However, factors that determine individual responsiveness or non-responsiveness to KD interventions remain poorly understood. Emerging evidence suggests that gut microbiome composition plays a critical role in modulating these factors. This study examined how KD responsiveness, determined by fecal microbiota transplantation (FMT) derived from human KD responders (RES) or non-responders (nRES)- influences cognition, gut barrier function, neuroinflammation, and microbial structure in 3xTg-AD mice. We further evaluated whether supplementing KD with a novel Synbiotic Yogurt (SY) formulated by our team could augment or restore responsiveness. We hypothesized that RES microbiota would confer superior KD-driven benefits and that KD-SY would synergistically improve metabolic and neurobiological outcomes, particularly among nRES recipients. Adult 3xTg-AD mice were antibiotic-cleansed and randomized to receive Control-, RES-, or nRES – FMT, while maintained on KD for four weeks. A second cohort received KD supplemented with SY or non-fat milk along with RES- or nRES-FMT. Behavioral tests, gut permeability assay, serum inflammatory markers, brain amyloid beta (Aβ), intestinal morphology, gene expression, and 16S rRNA microbial profiling were measured. RES-FMT recipients showed early improvements in spatial memory (Y-maze and novel object recognition) and consistently lower Aβ accumulation in cortex and hippocampus. They also showed higher synaptophysin and IL-10 expression. In contrast, nRES-FMT mice exhibited distinct microbiome clustering, lower microbial diversity, enrichment of Proteobacteria, and impaired gut barrier function relative to RES-FMT recipients. Functionally, specific taxa like Enterococcus, Enterobacter, and Paenibacillus were associated with greater vulnerability to AD-related pathology, while Akkermansia, Bifidobacterium, and Muribaculum were linked with lower vulnerability. SY supplementation improved metabolic and gut barrier indices across groups characterized by increased circulating ketone levels, lowered fasting glucose and glucose-ketone index, and decreased gut permeability. nRES-SY mice showed the strongest gains in recognition memory and reductions in brain Aβ1–42 burden. SY increased expression of barrier- and inflammation-modulating genes, including occludin, APLP2, and IL-10. Microbiome analysis demonstrated higher microbial diversity and enrichment of beneficial genera such as Paralactobacillus, Eubacterium, and Muribaculum. These findings show that KD responsiveness is strongly determined by gut microbiota composition and that SY supplementation can enhance or rescue metabolic, cognitive, and microbial outcomes, particularly in nonresponders. This supports a precision-microbiome strategy combining metabolic and Synbiotic interventions to improve gut–brain axis function in AD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.