Browse Articles

Global trends in leukemia incidence by age, sex, and sociodemographic index: A GBD 2023 Joinpoint analysis, 2000–2023.

e18547 Background: Leukemia remains a major contributor to the global cancer burden, with incidence patterns varying by age, sex, and sociodemographic development. Long-term, subgroup-specific global incidence trends have not been comprehensively characterized. Methods: We analyzed global leukemia incidence using Global Burden of Disease (GBD) 2023 estimates from 2000 to 2023. Incidence rates were expressed per 100,000 population with corresponding 95% confidence intervals (CIs). Temporal trends were evaluated using Joinpoint regression, estimating annual percent change (APC) and average annual percent change (AAPC) overall and stratified by sex, age group (<20, 20–54, >55 years), and Sociodemographic Index (SDI) categories. Results: Globally, leukemia incidence declined steadily from 2000 to 2023, with an overall AAPC of −1.08% (95% CI, −1.11% to −1.06%). By sex, incidence declined more steeply among females (AAPC −1.30%, 95% CI, −1.32% to −1.27%) than males (AAPC −0.93%, 95% CI, −0.96% to −0.90%). Across age groups, all strata experienced declining incidence, with the steepest reduction among adults aged 20–54 years (AAPC −1.13%, 95% CI, −1.17% to −1.09%), followed by individuals <20 years (AAPC −1.10%, 95% CI, −1.16% to −1.05%). Adults >55 years showed a sustained but comparatively slower decline (AAPC −1.01%, 95% CI, −1.04% to −0.97%). Across SDI strata, the largest long-term decline occurred in high SDI regions (AAPC −1.10%, 95% CI, −1.14% to −1.07%), while low SDI regions exhibited the slowest overall reduction (AAPC −0.46%, 95% CI, −0.50% to −0.43%), with periods of increase before recent declines. Conclusions: From 2000 to 2023, global leukemia incidence declined across all population subgroups. The slowest reductions were observed among males, adults aged >55 years, and populations in low SDI regions, highlighting persistent disparities despite overall downward trends.

Baseline circulating tumor cells and association with early resistance in patients with metastatic breast cancer undergoing palbociclib therapy.

1111 Background: Palbociclib has significantly improved outcomes in metastatic breast cancer (MBC); however, a substantial proportion of patients experience early treatment resistance. Reliable biomarkers to identify high-risk patients prior to therapy initiation remain limited. Our previous work has demonstrated that circulating tumor cell (CTC) and ctDNA monitoring is associated with poor prognosis in MBC (ASCO 2025 #1042; AACR 2025 #3613). Here, we report new findings of the association between baseline CTC level and timing of resistance in patients receiving palbociclib. Methods: This study included 178 patients with ER+/HER2− MBC treated with palbociclib at the Robert H. Lurie Cancer Center between 2016 and 2025 (IRB: NU16B06), all of whom developed treatment resistance. Time to resistance was defined as the interval from treatment initiation to first documented resistance; the median follow-up period was 8.0 months. Patients were stratified a priori into early resistance (≤6 months; n = 71) and later resistance ( > 6 months; n = 107). Baseline CTCs were enumerated prior to treatment using FDA-approved CELLTRACKS system (Menarini). Associations between baseline CTC levels and time to resistance were assessed using Spearman rank correlation, treating CTC as a continuous variable and analyzing early and later resistance groups separately. Results: Among patients with early resistance, the median time to resistance was 3.25 months (range, 0.16–6.0), compared with 16.0 months (range, 6.5–57) among those with later resistance. Patients with early resistance exhibited higher baseline CTC levels on average than those with later resistance (mean CTC: 36.7 vs 25.8), although CTC distributions were highly right-skewed with substantial overlap between groups. Within the early resistance group, 29 of 71 patients had baseline CTC ≥5, with markedly higher mean CTC levels compared with patients with CTC < 5 (88.6 vs 0.8). In contrast, baseline CTC ≥5 was not associated with timing of resistance among patients with later resistance. Using Spearman rank correlation, higher baseline CTC levels were significantly associated with earlier resistance among patients with early resistance (ρ = −0.24, P = 0.043), whereas no association was observed in patients with resistance occurring beyond 6 months (ρ = 0.04, P = 0.71). Conclusions: Baseline CTC levels were associated with the timing of treatment resistance in patients with metastatic breast cancer receiving palbociclib, with a significant inverse correlation observed exclusively among patients experiencing early resistance within 6 months. These new findings suggest that elevated baseline CTC burden reflects aggressive disease biology underlying rapid treatment failure. Time-dependent assessment of CTC may provide clinically relevant insights into early resistance risk and inform clinical decision-making.

Spin‐State Engineering of Ni Centers by Dual‐Ligand Competitive Coordination for Superior Oxygen Evolution Reaction

ABSTRACT Modulating electronic spin states of metal active centers is an effective strategy to address the sluggish oxygen evolution reaction (OER) kinetics. Herein, we utilize a dual‐ligand competitive coordination strategy to induce lattice expansion, generate abundant oxygen vacancies and unsaturated coordination sites, and restructure the NiO 6 octahedron. This triggers a pivotal transition of Ni from intermediate‐spin (Ni 2+ ) to high‐spin (Ni 3+ ) states, which enhances adsorption of OH − and oxygen‐containing intermediates, but also tailors the interfacial microenvironment by enriching free water, thus accelerating OER kinetics. In situ x‐ray adsorption spectroscopy further verifies the accelerated adsorption and transformation of oxygen intermediates enabled by this spin reconfiguration. Consequently, the optimized nickel‐thiophene‐2,5‐dicarboxylic acid 0.6 ‐1,4‐dicarboxybenzene 0.4 dual‐ligand metal‐organic framework catalyst (marked as Ni‐TDC 0.6 BDC 0.4 ) delivers excellent OER performance (230 mV@10 mA cm −2 ). Using Ni‐TDC 0.6 BDC 0.4 as the anode, the assembled anion exchange membrane water electrolyzer achieves a low cell voltage of 2.40 V at 1.5 A cm −2 and maintains stability for 500 h at 300 mA cm −2 . Its photovoltaic‐integrated overall water splitting device also attains a 13.23% solar‐to‐hydrogen efficiency with robust stability. This work provides an innovative synthesis pathway for designing high‐performance OER electrocatalysts by tailoring electron spin states.

Carbon-based quantum dots in oncology: Properties and applications in cancer therapy and diagnosis

Ionic‐Liquid‐Triggered Amorphization Engineers Symmetry‐Breaking <i>p</i> ‐Block Bismuth Oxides with Electric Dipole Domains for Practical Lithium‐Sulfur Batteries

ABSTRACT The practical application of lithium‐sulfur batteries is severely hindered by the sluggish sulfur redox kinetics and the notorious lithium polysulfides (LiPSs) shuttle effect. Herein, we report a strategy utilizing an Fe‐based ionic liquid to trigger amorphization, engineering symmetry‐breaking p ‐block bismuth oxides on carbon nanofibers (CNFs) with electric dipole domains and asymmetric Fe 1 ‐O‐Bi electronic bridges (Fe 1 ⊂A/C‐Bi 2 O 3 @CNFs). The amorphous phase induces significant electronic delocalization, facilitating substantial orbital overlap and creating electron transport channels for rapid redox of LiPSs. Specifically, the asymmetric Fe 1 ‐O‐Bi electron bridges lower the p ‐band center through 3 d ‐2 p ‐6 p multi‐orbital coupling, optimizing the chemical adsorption of LiPSs and preventing active site poisoning. The electronic dipole domain functions as an electron/Li + “pump” to enhance charge transfer and Li + diffusion. In addition, the electric dipole domain induces dipole‐dipole interactions, facilitating Li─S bond polarization and cleavage. As a result, the Fe 1 ⊂A/C‐Bi 2 O 3 ‐based cell achieved a cyclability of 698 mAh g −1 at 1.0 C over 1000 cycles with a degradation rate of 0.026% per cycle, and a high areal capacity of 6.8 mAh cm −2 under a sulfur loading of 7.4 mg cm −2 . The strategy of constructing an electronic dipole domain through amorphization provides a new direction for the rational design of efficient catalysts for sulfur redox reactions.

Autophagic pathway is responsible for selective degradation of cytosolic enzymes formaldehyde and formate dehydrogenases in the methylotrophic yeast Komagataella phaffii

Abstract In the methylotrophic yeast Komagataella phaffii (formerly Pichia pastoris ), several methanol-induced enzymes are rapidly degraded upon a shift to glucose. We studied how deletion of autophagy-related genes affects turnover of two cytosolic enzymes, formaldehyde dehydrogenase (Fld1) and formate dehydrogenase (Fdh1), following the shift from methanol to glucose as a carbon source. GFP-tagged Fld1 and Fdh1 were expressed in wild-type and atg1Δ , atg6Δ , and atg15Δ strains, lacking, respectively, Atg1 (a serine/threonine kinase required for autophagosome formation), Atg6 (a subunit of phosphatidylinositol 3-kinase complexes I and II), and Atg15 (a phospholipase B required for lysis of autophagic bodies). Enzyme activities, Western blots, and fluorescence microscopy were used to monitor degradation. In wild-type cells Fld1 and Fdh1 levels and activities declined rapidly after the shift, whereas all atg1Δ , atg6Δ and atg15Δ mutants retained substantially higher Fld1/Fdh1 activity, similar to the peroxisomal enzyme alcohol oxidase, and cytosolic GFP signal. These data show that Atg1, Atg6 and Atg15 are required for efficient vacuolar degradation of cytosolic enzymes of methanol metabolism Fld1 and Fdh1. We conclude that these cytosolic enzymes are cleared via selective autophagy upon cell shift from methanol to glucose, underscoring the essential role of the autophagy–lysosome pathway in proteome remodeling of K. phaffii .

From beach culture to burden: Analysis of skin cancer trends in Australasia using the GBD database (1980–2023).

e22607 Background: Australasia (Australia and New Zealand) bears a disproportionate burden of skin cancer, driven by high levels of ultraviolet radiation, outdoor lifestyles, and a largely fair-skinned population. Despite extensive public health campaigns promoting sun protection and early screening, the incidence of skin cancer remains high, and mortality has not declined at the same pace in all demographic groups. Using Global Burden of Disease estimates, this study aims to quantify the trends for skin cancer in Australasia from 1990 to 2023. Methods: Using data from the Global Burden of Disease (GBD) 2023 study, temporal trends in Skin Cancers across Australasia incidence, mortality, and Disability-Adjusted Life Years (DALYs) were analyzed. Join point regression analysis was employed to assess Average Annual Percentage Change (AAPC) and Annual Percentage Change (APC). Results: Skin cancers in Australasia has affected both sub-regions differently, with Australia showing decreasing overall trend with AAPC of -0.25% (95% CI -0.46 to -0.04, p value = 0.018785), however the Age-standardized Death Rate (ASDR) was 3.80 in 1980, which rose minimally to 3.99 in 2023. Whereas, for New Zealand, ASDR spiked from 3.58 to 4.67 from 1980 to 2023. The overall trend was also a stark contrast from Australia with an upward trend [AAPC = 0.58% (95% CI 0.60 to 1.11, p value = 0.028733)]. During 1990-2023, Disability-adjusted life years (DALYs) attributed to skin cancers in Australasia declined and were similar across both Australia [146.50 (1990) to 93.41(2023)] and New Zealand [142.25 (1990) to 134.49(2023)]. The trend however was downward with statistically significant AAPC of -1.33% (95% CI -1.75 to -0.91, p value &lt; 0.000001) for Australia, and non-significant -0.20% (95% CI -0.63 to 0.22, p value = 0.345527). In contrast to DALYs, the incidence of Skin cancers in both sub-regions is on the rise with inclining trend, as reflected by statistically significant Age-standardized Incidence Rate (ASIR) -AAPC of 0.25% (95% CI 0.67 to 0.45, p value = 0.007894) for Australia and 1.44% (95% CI 1.06 to 1.82, p value &lt; 0.00001). Similarly, the prevalence has also increased with a statistically significant trend seen in New Zealand with AAPC of 1.57% (95% CI 1.18 to 1.95, p value &lt; 0.000001), while Australia showed a linear trend with AAPC of 0.48%. Conclusions: Skin cancer trends in Australasia differ by sub-region, with Australia showing declining mortality while New Zealand’s mortality continues to rise. Efforts to raise public awareness appear to have been fruitful, contributing to improved outcomes in Australia, particularly. Despite reductions in DALYs, both countries experienced increasing incidence and prevalence, highlighting the need for better health policies.

Navigated embedded supportive care via telehealth (NEST): A community-partnership model for rural oncology supportive care access.

e13534 Background: Rural Tennessee experiences disproportionately high cancer morbidity and mortality, yet utilization of palliative and supportive oncology services remains low. Although these are available in rural clinics within Tennessee Oncology (TO), fewer than 5% of rural patients receiving oncologic treatment access these services. NEST (Navigated, Embedded, Supportive care via Telehealth) was developed to address this gap through implementation with full community partnership using community-based participatory research (CBPR) approach. Methods: With funding from Tennessee State Health Department, and the support of TO leadership, we established and partnered with 3 Community Advisory Boards (CAB) in 3 rural communities. Each CAB consisted of 8-10 community members that included people with breast cancer, caregivers, and community leaders. The CABs reviewed our project objectives, participated in focus group recruitment, reviewed focus group findings, and based on these, made programmatic recommendations which they then rank-ordered. Since the majority in rural Tennessee are white, we established a Latino CAB and a Black American CAB to ensure that their perspectives and recommendations are also incorporated into our final program. Results: Despite regional differences, all 3 CABs independently converged on 9 recommendations, with five rank-ordered as key: (1) Dedicated nurse navigation, (2) Repeated, multimodal patient and caregiver education, (3) Telehealth as an option, not a replacement for in-person care, (4) Expansion of supportive care services to include palliative care, psychosocial oncology, integrative medicine, peer support, support groups and spiritual care, and (5) Structured caregiver support with skills training and emotional guidance. We incorporated all top five community-based priorities into our program. Programmatic changes included (1) Deployment of nurse navigators, (2) Standardized education delivered through written material, in-person teaching, and videos, (3) Redesigned telehealth workflows preserving monthly in-person supportive care access, and (4) Expansion of supportive care offerings to include: (5) Caregiver support groups, peer networks, and on-demand spiritual care. (6) Cultural and linguistic adaptations, including Spanish-language navigation and materials were incorporated. Conclusions: Community partnerships across multiple rural regions were feasible to implement and sustain. All CABs revealed a convergence of priorities for supportive oncology care delivery. Translating these shared recommendations into our program, demonstrates that it is possible to build a supportive care framework that is responsive to the needs of rural communities. The CBPR partnership approach offers a scalable strategy to address persistent gaps in palliative and supportive care utilization.

Understanding the impact of gold and silver signals on ERAS applications: A survey of hematology/oncology fellowship program directors.

9007 Background: Since transition to virtual interviews, application and interview inflation have increased the work burden of GME recruitment. In 2021, AAMC ERAS implemented a process that allows applicants to assign signals to top programs of interest. There is a paucity of guidance on optimal use of ERAS signals (ES), resulting in apprehension and uncertainty amongst applicants and program directors (PD). For the 2026 ERAS cycle, Hematology/Oncology programs (HOP) had the option to participate in ES, in which applicants are provided 5 gold (G) signals and 15 silver (S) signals. First-hand knowledge on how ES was utilized by HOP, as well as PD perceptions about ES, may guide best practices on ES. Methods: During the ASCO Oncology Training Program Leadership Retreat in November 2025, an anonymous survey, assessing HOP utilization and perception of ES, and the impact of ES on recruitment practices, was launched. One PD from each HOP was invited to complete the survey while onsite. Results: 88 HOP (46% of ACGME HOP) are represented. 97% (n=85) utilized ES. Of HOP who used ES, 74% are academic. 32% are small (1-9 fellows), 43% medium (10-19 fellows), and 25% large (20+ fellows). 79% received 400+ applications. 69% reviewed applications without signals but gave higher consideration to signaled applicants. 25% only reviewed applications with signals. 28% used ES when creating rank list; 45% think ES utilization is appropriate during ranking. 85% reported ES did not alter their approach to applicants requiring visa sponsorship. 78% felt ES made the interview selection process easier. 66% were more satisfied with this year’s recruitment process compared to years without ES. The most requested change to ES was reduction of allowed signals, especially silver. 98% will use ES next year. Conclusions: Despite limited knowledge on ES impact on recruitment, nearly all surveyed HOP participated in ES this past year and will continue. Most HOP view ES positively though many desire changes, particularly with the number of signals. Most HOP consider all applications regardless of ES. However, some HOP with larger applicant pool are using ES as inclusion criteria for interview consideration. Signals are a strong predictor for interview invitation when internal selection criteria are met. The “borderline” applicant may be the greatest benefactor from ES, viewed similarly to the non-signaled applicant who meets internal selection criteria. Sharing PD perspectives and real-life data from this year’s ES process breeds opportunities for further improvement and increased confidence with ES. Likelihood HOP offer interview invitation based on quality of application and signals (%, n=85). Internal Selection Criteria Signal Extremely Likely Likely Neutral Unlikely Extremely Unlikely Met G 73 22 5 0 0 S 42 47 8 2 1 None 8 27 24 22 19 Nearly met G 4 35 39 19 3 S 0 9 52 28 11 Not met G 0 2 12 41 45 S 1 1 6 30 62

Phase II randomised placebo-controlled trial of melatonin for the management of sleep disturbance in women with early breast cancer on adjuvant endocrine therapy.

e12533 Background: Sleep disturbance is common among women on endocrine therapy for early breast cancer. This study investigated the effect of prolonged-release melatonin on sleep disturbance in women with early breast cancer on adjuvant endocrine therapy. Methods: In a multi-centre, randomised, double-blind, placebo-controlled Phase 2 trial, women with stage I-III breast cancer on adjuvant endocrine therapy experiencing sleep disturbance defined by Pittsburgh Sleep Quality Index (PSQI) score ≥5, were randomised 2:1 to receive prolonged-release melatonin 2mg or placebo daily for 12 weeks. Participants completed: Patient Reported Outcome Measures (PROMs) at baseline, week 6, 12 and 24; actigraphy at baseline and week 12. The primary endpoint was the effect of melatonin on sleep quality (proportion of women with ≥ 3-point decrease in PSQI score from baseline to week 12). Analyses were on an intention-to-treat basis. All statistical tests were two-sided. Results: Between September 2022 and July 2025, 53 participants were recruited and randomly assigned to melatonin (n = 36) or placebo (n = 17), with a mean age of 56 years (SD 9.1, range 39-79); most had stage one (42%) or two (42%) disease; 33% on tamoxifen; 67% aromatase inhibitor; 19% ovarian function suppression; 45% had received adjuvant chemotherapy. The baseline PSQI score was 11.6 (SD 3.3). The proportion achieving a ≥3 point decrease in PSQI score at week 12 compared to baseline was 55% (17/31) in the melatonin group and 46% (6/13) in the placebo group (p = 0.6). There was no significant difference in the number of poor sleepers (PSQI ≥5) for melatonin at baseline 97% (35/36) and week 12 81% (26/34), versus placebo 100% (17/17) and 100% (13/13) respectively ( p = 0.3); or the mean PSQI score for melatonin at baseline, 11.6 (SD 3.3) and week 12, 8.16 (SD 3.1), versus placebo 11.4 (SD 3.3) and 8.1 (SD 3.1) respectively ( p = &gt; 0.05). Overall, the mean FACT-ES total score and FACT-F subscale score for the total group significantly improved from baseline to week 6, 12 and 24 ( p = &lt; 0.001); however, there was no significant difference between melatonin and placebo ( p = &gt; 0.05). One patient (3%) receiving melatonin reported a grade 3 treatment-related adverse event, with headache leading to study drug discontinuation. Conclusions: Prolonged-release melatonin did not improve sleep quality compared with placebo in women with early breast cancer on adjuvant endocrine therapy. Although the trial did not meet its primary endpoint, the findings provide important insights into the management of sleep disturbance in this population. Clinical trial information: ACTRN12619001284156.

Synergistic antitumor activity of GLIX1, a small molecule TET2 activator, in combination with PARP inhibition across multiple cancers.

e13129 Background: Poly(ADP-ribose) polymerase (PARP) detects single-stranded DNA breaks and marks them for repair. PARP inhibitors (PARPi) interfere with PARP activity, stabilizing single-stranded DNA breaks, inducing synthetic lethality in tumors with defects in homologous recombination repair. These inhibitors have limited activity in most homologous recombination (HR)–proficient cancers. Expansion of PARPi utility into HR-proficient cancers requires strategies that increase tumor-selective DNA damage and dependence on PARP-mediated repair. Ten-Eleven Translocation methylcytosine dioxygenase 2 (TET2) catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine -- the latter two species are substrates for base excision repair generating a single-stranded DNA break. Cancers have an increase in hypermethylated regions and TET2 is inhibited. GLIX1 is a small-molecule activator of TET2 that is designed to promote tumor-selective DNA single-strand breaks through increased DNA oxidation and base excision repair. Mechanistically, GLIX1 is expected to increase the formation of tumor-selective single-stranded DNA breaks, while PARP inhibition is expected to stabilize these lesions, resulting in enhanced cancer cell death. Methods: In vitro combination studies were performed across a panel of cancer cell lines representing multiple tumor types. GLIX1 was evaluated in combination with a range of clinically relevant PARPi using dose–response matrices and quantitative synergy modeling. Results: The combination of GLIX1 with PARPi produced strong and reproducible synergistic cytotoxicity across a range of cancer cell lines and tumor subtypes, including those not typically sensitive to PARP inhibition. Synergy was observed across multiple PARPi with differing chemical scaffolds and trapping potency, supporting a class effect rather than compound-specific activity. Conclusions: These data demonstrate broad in vitro synergy between GLIX1 and PARP inhibition across diverse cancers. The complementary mechanisms of GLIX1-mediated DNA modification and PARP-dependent DNA repair provide a strong mechanistic rationale for combination therapy and support further translational and clinical evaluation.

Inpatient outcomes and cost utilization by surgical approach for elective non-metastatic colon cancer resection in the United States, 2018–2023.

e23189 Background: Minimally invasive colectomy is commonly used for colon cancer resection, with increasing adoption of robotic platforms. Contemporary national data comparing inpatient outcomes and costs across open, laparoscopic, and robotic approaches in elective non-metastatic colon cancer are limited. Methods: A retrospective, serial cross-sectional analysis was performed using the 2018–2023 Healthcare Cost and Utilization Project National Inpatient Sample. Adult hospitalizations undergoing elective colectomy for non-metastatic colon cancer were identified using ICD-10-CM and ICD-10-PCS codes. Surgical approach was classified as open, laparoscopic, or robotic-assisted. Outcomes included in-hospital mortality, postoperative complications, length of stay (LOS), and hospitalization cost estimated using cost-to-charge ratios. National estimates accounted for survey weighting, clustering, and stratification. Multivariable survey-weighted regression models compared outcomes across approaches, adjusting for age, sex, race and ethnicity, payer type, income quartile, hospital characteristics, calendar year, and severity of illness. Temporal trends in minimally invasive surgery utilization were evaluated using survey-weighted logistic regression. Results: An estimated 225,690 elective colectomy hospitalizations for non-metastatic colon cancer were identified nationally. Utilization of minimally invasive surgery increased over time (odds ratio per year 1.18, 95% CI 1.16–1.20), driven primarily by growth in robotic surgery. Unadjusted in-hospital mortality was highest for open colectomy (1.13%) compared with laparoscopic (0.44%) and robotic (0.49%) approaches. Postoperative complications occurred in 26.5% of open, 16.8% of laparoscopic, and 15.4% of robotic hospitalizations. Mean LOS was 5.9 days for open colectomy, 4.1 days for laparoscopic, and 3.8 days for robotic approaches. In adjusted analyses, laparoscopic (adjusted OR 0.47, 95% CI 0.35–0.65) and robotic colectomy (adjusted OR 0.51, 95% CI 0.36–0.72) were associated with lower odds of in-hospital mortality compared with open surgery. Adjusted LOS was shorter for laparoscopic (−0.29 days) and robotic (−0.38 days) approaches relative to open colectomy (p &lt; 0.001 for both). Mean hospitalization costs were $21,599 for laparoscopic, $24,682 for open, and $27,588 for robotic colectomy. Conclusions: In this national inpatient analysis of elective non-metastatic colon cancer resections, minimally invasive surgical approaches were associated with lower in-hospital mortality and shorter length of stay compared with open colectomy, with higher costs observed for robotic-assisted surgery. These findings provide contemporary benchmarking data on utilization patterns, short-term outcomes, and inpatient costs across colectomy approaches.

Platinum re-challenge in platinum-resistant ovarian cancer: Real-world patterns and outcomes.

5566 Background: Platinum-resistant ovarian cancer (PROC), defined as recurrence within 6 months of completing platinum-based chemotherapy, has limited treatment options and poor outcomes. Although guidelines recommend non-platinum therapy, platinum rechallenge still occurs in real-world practice, despite limited evidence. This study examines real-world patterns and outcomes of platinum rechallenge versus non-platinum therapy at first PROC occurrence overall and by biomarker status, prior therapy, and time to PROC. Methods: Using the US-based, EHR-derived deidentified Flatiron Health Research Database, ovarian cancer patients diagnosed after January 1, 2017 (data cutoff August 31, 2025) were selected. Patients with PROC, defined as progressing ≤ 6 months after platinum, that received subsequent therapy were included; primary platinum refractory patients (&lt; 3 months) were excluded. Patients were grouped by first PROC therapy (platinum rechallenge vs non-platinum therapy), and rwPFS and rwOS were assessed overall and by BRCA/HRD status, use of prior first-line maintenance (1LM), number of prior platinum lines, and time to PROC. Associations were assessed using Kaplan-Meier estimates and IPTW-adjusted Cox models accounting for demographics, ECOG PS, practice type, insurance, index year, biomarkers, and prior 1LM and platinum exposure. Results: Among 29,194 patients with ovarian cancer, 2,907 had PROC. Of these, 528 received platinum rechallenge and 2,379 received non-platinum therapy (71% received chemotherapy ± bevacizumab) as subsequent treatment. Baseline characteristics in both groups were similar; the platinum rechallenge group had fewer patients with BRCA mutations (BRCAm) (9.3% vs 12%) and no residual disease (36% vs 40%) but more with only one prior platinum line (56% vs 48%). Median rwPFS was 5.8 mo with platinum rechallenge vs 3.9 mo with non-platinum therapy (adjusted HR 0.72, 95% CI, 0.64 to 0.81; P &lt; .001), and median rwOS was 13 vs 11 mo (adjusted HR 0.81, 95% CI, 0.72 to 0.92; P = .001). In adjusted analyses, rwPFS advantage of platinum rechallenge was consistent across major subgroups, including biomarker-defined populations (BRCA-wild type and HRD-positive non-BRCAm), prior 1LM and platinum exposure, and time to PROC. rwOS benefit was more limited, confined to patients with BRCAm, earlier recurrence, and more heavily pretreated disease, with limited events in several subgroups. Conclusions: In this large real-world cohort, platinum rechallenge improved rwPFS and rwOS vs non-platinum therapy in PROC. Consistent rwPFS benefits across most subgroups and selective rwOS advantages, particularly in BRCAm, highlight heterogeneity within PROC populations and support individualized decisions for platinum rechallenge beyond a strict 6-month platinum-free interval. Prospective studies are required to identify patients most likely to benefit from platinum rechallenge.

Association between HER family expression and clinical outcomes with trastuzumab deruxtecan (T-DXd) in patients with hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC).

1030 Background: T-DXd improves outcomes in HR+/HER2- mBC, yet response remains heterogeneous. Treatment selection is based on HER2 IHC. Preclinical models suggest signaling from HER family dimerization partners like EGFR drive resistance; specifically, EGFR overexpression impairs T-DXd internalization by favoring EGFR/HER2 heterodimerization. Because clinical data linking HER dimerization partners to T-DXd outcomes are limited, investigation is warranted to understand how expression of these partners may serve as predictive biomarkers. Methods: The Tempus Lens Platform was used to identify and analyze a cohort of patients (pts) with HR+/HER2- mBC treated with T-DXd (n = 224) and sacituzumab govitecan (SG) (n = 81, comparator) who underwent RNA (Tempus xR) and DNA (Tempus xT) sequencing within one year of treatment initiation. HER family gene expression ( EGFR/ERBB1, ERBB2/3/4 ) was quantified as transcripts per million (TPM) and reported as log2(TPM+1). High vs low groups were defined using median expression. Median real-world time to next treatment (rwTTNT) with T-DXd and real-world overall survival (rwOS) were calculated using Kaplan–Meier curves and compared using log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazards models. Results: The cohort (n = 305) had a median age of 60; 83% of pts’ race was reported as White, 9.6% Black or African American, 2.7% Asian, 7.6% Hispanic or Latino, and 4.3% unknown. Median HER family gene expression values were: ERBB1 ( EGFR ): 3.92; ERBB2 7.75; ERBB3 7.65; ERBB4 4.72. EGFR RNA expression was negatively correlated with ERBB2/3/4 (p &lt; 0.0001). ERBB2/3/4 RNA expression was positively correlated with one another (p &lt; 0.0001). Among pts treated with T-DXd, the EGFR -high group had shorter median rwTTNT (7.76 vs 13.25 months; HR = 2.17 95% CI 1.42-3.34, p &lt; 0.001) and rwOS (13.71 vs 22.55 months, HR = 2.21; 95% CI 1.50-3.24, p &lt; 0.001) compared to the EGFR -low group. In contrast, increased RNA expression of other HER family members was not associated with a significant difference in rwTTNT or rwOS. Among pts treated with SG, the EGFR -high group did not have significantly different rwTTNT (median 4.34 vs 5.56 months; HR = 1.30 95% CI 0.72-2.36, p = 0.4) or rwOS (median 14.47 vs 11.28 months; HR = 0.86, 95% CI 0.47-1.55, p = 0.6) compared with the EGFR -low group. Conclusions: Among pts with HR+/HER2- mBC treated with T-DXd, elevated EGFR , but not ERBB2/3/4 , RNA expression was associated with worse outcomes. EGFR overexpression did not modulate outcomes in pts treated with SG, highlighting a potential differential impact based on antibody target rather than payload. Further research is needed to confirm the utility of pre-treatment EGFR expression as a predictive biomarker for T-DXd treatment.

Phase I/II study to evaluate AZD9750, a novel androgen receptor proteolysis-targeting chimera, alone and in combination with other anticancer agents in patients with metastatic prostate cancer (ANDROMEDA).

TPS5146 Background: The androgen receptor (AR) is a key driver of prostate cancer progression. AR pathway inhibitors (ARPIs) are standard of care for metastatic prostate cancer, but acquired resistance is inevitable and often involves reactivation of AR signaling via AR gene alterations such as amplifications or ligand binding domain mutations. The need remains for alternative strategies to target the AR. AZD9750 is a novel oral proteolysis-targeting chimera that potently degrades wild-type, mutant, and amplified forms of the AR. Preclinical data also showed significant antitumor benefit with AZD9750 as monotherapy and combined with the PARP1 selective inhibitor saruparib (AZD5305). ANDROMEDA (NCT07336446) is a first-in-human, phase I/II, open-label, multicenter study investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD9750 as monotherapy and combined with saruparib in patients (pts) with metastatic castration-resistant prostate cancer. Methods: This study follows a modular design in which pts receive AZD9750 as monotherapy (Module 1) or combined with saruparib (Module 2; Table). Each module has 2 parts: monotherapy dose escalation or combination dose finding (Part A) and dose optimization and expansion (Part B). Eligible pts are ≥18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease with serum testosterone level ≤50 ng/dL, evidence of disease progression, and ECOG performance status of 0 or 1. Pts should have previously received ARPIs and taxane-based chemotherapy, with the exception of no prior taxane-based chemotherapy in Module 1 Part B3. Primary endpoints include occurrence of dose-limiting toxicities (Part A only), incidence of adverse events (AEs) and AEs leading to treatment discontinuation (Parts A and B), and preliminary efficacy (ie, ≥50% decrease in prostate-specific antigen [PSA]; Part B only). Secondary endpoints include preliminary efficacy (ie, ≥50% and ≥90% decrease in PSA, objective response rates and progression-free survival per RECIST v1.1 and PCWG3 criteria, change in target lesion size per RECIST v1.1 criteria, time to PSA response, and time to PSA progression per PCWG3 criteria) and pharmacokinetic parameters (Parts A and B). This study is currently recruiting for monotherapy dose escalation. Clinical trial information: NCT07336446 . Study part Module 1: AZD9750 monotherapy Module 2: AZD9750 plus saruparib Part A A1. Dose escalationA2. Backfill cohorts Combination dose finding a Part B B1. Dose optimization a B2. Dose expansion b B3. Dose expansion b Combination dose expansion c a Recommended doses determined in Module 1 Part A; b To be opened once recommended phase II dose identified in Module 1 Part B1; c To be opened once combination dose identified in Module 2 Part A.

Leveraging E7386 phase 1 trials for cardiac safety: Gaining concentration-QTc insights to inform early-stage oncology development.

e24005 Background: E7386 is a novel oral anticancer agent that inhibits the interaction between β-catenin and CREB-binding protein. Phase 1 studies provide an efficient approach to cardiac safety assessment by using data across a range of doses to model the concentration-QTc (C-QTc) relationship; such modeling enables early detection of cardiac risk. The analysis described herein was conducted to evaluate cardiac safety and assess the potential effect of E7386 on ECG parameters, including the QTcF interval. Methods: C-QTc analyses were performed using E7386 plasma concentrations and continuous Holter ECG data collected on C1D1 and C1D8 (at steady state) from two phase 1 monotherapy studies in patients (pts) with solid tumors: Study 101 (NCT03264664; data available from 25 pts treated with E7386 at doses ranging from 10-120 mg twice daily [BID]) and Study 103 (NCT03833700; data available from 18 pts treated at the E7386 monotherapy RP2D of 120 mg BID). The relationship between E7386 plasma concentrations and change-from-baseline QTcF (ΔQTcF) was investigated using a linear mixed-effects modeling approach. The concentration level at which the upper bound of the 2-sided 90% CI of model-predicted ΔQTcF exceeded 10 ms was determined. Results: E7386 showed no clinically significant impact on cardiac conduction parameters (PR and QRS intervals) or heart rate across the studied dose ranges. Observed changes on heart rate were minimal and unlikely to influence the C-QTc analysis. The absolute slopes of QTcF vs RR were minimal, indicating negligible effect on the C-QTc assessment. Consequently, additional heart rate correction methods were not warranted. Hysteresis was not present. Neither the fixed intercept nor the slope for the E7386 ─ C-QTc relationship were statistically significant. C-QTc analysis showed no clinically meaningful QTc effect (ΔQTcF &gt;10 ms) for E7386 concentrations up to 2650 ng/mL in Study 103. Consistent results were seen in Study 101 with exclusion of a QTc effect up to E7386 concentrations of 2300 ng/mL. Results from the C-QTc analyses in Study 103 and 101 indicate substantial cardiac safety margins of ~5.70 and ~3.36‐fold, respectively, over corresponding clinical C max,ss values reported for the E7386 RP2D of 120 mg BID (Study 103, 464.8 ng/mL; Study 101, 684.0 ng/mL). Conclusions: Phase 1 C-QTc evaluations of E7386 offer critical insights on cardiac safety that inform dose selection and monitoring strategies for further clinical development. The predicted mean ΔQTcF and its 90% CI upper bound remained below 10 ms for concentrations up to 2650 ng/mL, based on C-QTc analysis of two phase 1 studies. No significant cardiac safety concerns were identified at the studied dose levels. Clinical trial information: NCT03264664 , NCT03833700 .

Brigatinib after lorlatinib and/or chemotherapy following first-line alectinib in ALK-rearranged NSCLC: Cohort B of the WJOG11919L/ABRAID study.

8606 Background: As survival improves in ALK-rearranged NSCLC, patients increasingly receive multiple lines of therapy; however, evidence to guide later-line ALK-TKI sequencing in the third line and beyond remains limited. Brigatinib has activity against multiple ALK resistance mutations, yet data on its effectiveness after progression on first-line alectinib and subsequent lorlatinib and/or chemotherapy—and on associated plasma ctDNA biomarkers—remain scarce. Methods: WJOG11919L/ABRAID Cohort B is a prospective, multicenter observational study enrolling patients with ALK-rearranged NSCLC who received brigatinib after lorlatinib and/or chemotherapy following first-line alectinib. Effectiveness and safety were summarized descriptively. Pretreatment plasma ctDNA was analyzed with the PGDx Elio Plasma Resolve panel. The data cutoff was September 26, 2024. Results: Twenty-five patients were analyzed (median age, 64 years; all adenocarcinoma); ECOG PS was 0-1/2-3 in 22 (88.0%)/3 (12.0%). Baseline CNS metastases were present in 10 patients. After alectinib, 13 patients received lorlatinib and 14 received platinum-based chemotherapy (overlap, n=2). Median follow-up was 12.7 months. Efficacy outcomes overall and by prior lorlatinib exposure are summarized in the Table. 23 patients had discontinued brigatinib, including 21 due to PD. Pretreatment ctDNA was evaluable in 24 patients: ALK mutations were detected in 4 (including 3 with prior lorlatinib), and compound ALK mutations (G1202R/I1171M/L1204V and D1203N/L1196M) were identified in 2, both after lorlatinib. In exploratory analyses, among the 3 patients with prior lorlatinib and detectable ALK mutations, all experienced early progression or death within 10 weeks of brigatinib initiation. Pneumonitis/ILD occurred in 1 patient (4%; grade 4). No new safety signals were observed. Conclusions: Brigatinib showed clinically meaningful activity with a manageable safety profile, providing durable disease control in a subset of patients previously treated with alectinib followed by lorlatinib and/or chemotherapy. Outcomes appeared less favorable after prior lorlatinib, although some patients derived benefit. In exploratory plasma ctDNA analyses among patients with prior lorlatinib, detectable ALK mutations were associated with less favorable outcomes and should be validated in larger cohorts. Clinical trial information: UMIN000042439. Efficacy outcomes overall and by prior lorlatinib exposure. Endpoint Overall (n=25) Prior lorlatinib (n=13) No prior lorlatinib (n=12) ORR, % (95% CI) 32.0 (14.9–53.5) 30.8 (12.7–57.6) 33.3 (13.8–60.9) DCR, % (95% CI) 60.0 (38.7–78.9) 38.5 (17.7–64.5) 83.3 (55.2–95.3) mPFS, mo (95% CI) 4.8 (2.2–12.7) 2.2 (1.2–18.8) 8.9 (2.3–15.6) 12-mo PFS, % 32.0 30.8 33.3 mOS, mo (95% CI) 13.7 (7.29–NR) 10.8 (3.7–NR) 16.2 (7.1–NR) 12-mo OS, % 56.0 38.5 75.0

Immune checkpoint inhibitor therapy in patients with advanced cancer and chronic viral infections: Real-world clinical experience.

e20589 Background: Patients with chronic viral infections, including human immunodeficiency virus (HIV) and viral hepatitis, have historically been excluded from pivotal immune checkpoint inhibitor (ICI) trials due to concerns regarding safety and efficacy. As ICIs are widely used in non–small cell lung cancer (NSCLC) and melanoma, real-world evidence is needed to better understand outcomes in this underrepresented population. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, comprising de-identified electronic health records from 170 healthcare organizations. Adult patients with NSCLC or melanoma treated with ICIs, including pembrolizumab, nivolumab, ipilimumab, atezolizumab, or durvalumab, were identified. Among patients eligible for propensity score matching, 4,153 patients with documented HIV and/or viral hepatitis (Cohort A) and 98,495 patients without viral infection (Cohort B) were included. Propensity score matching was performed in a 1:1 ratio based on demographics and baseline clinical characteristics, resulting in 4,153 matched patients in each cohort. All outcome analyses were conducted in the matched population. Outcomes were assessed beginning one day after the index event, defined as the first qualifying cancer diagnosis with ICI exposure. The primary outcome was overall survival. Secondary outcomes included inpatient hospitalization and emergency department visits. Kaplan–Meier survival analysis and measures of association were performed. Results: After propensity score matching, baseline characteristics were well balanced between cohorts, including age, sex, race, ethnicity, and liver-related comorbidities. Kaplan–Meier analysis demonstrated no statistically significant difference in OS between viral and non-viral cohorts (HR 1.05; 95% CI, 0.99-1.12; p = 0.83). The cumulative risk of death was comparable (44.9% vs. 45.8%), with no significant differences in risk ratio (RR 0.98; 95% CI, 0.94-1.03) or odds ratio (OR 0.96; 95% CI, 0.88-1.05). Median OS was 723 days in the viral cohort vs 818 days in the non-viral cohort (log-rank p = 0.12). Furthermore, healthcare utilization was comparable, with no significant differences in the risk of inpatient hospitalization (39.6% vs. 39.4%; p = 0.45) or emergency department utilization. Conclusions: In this large real-world analysis, patients with NSCLC or melanoma and concomitant HIV or viral hepatitis treated with ICs did not demonstrate a statistically significant difference in OS healthcare utilization compared with matched patients without viral infection, suggesting that chronic viral infections should not necessarily preclude the use of ICs in patients with solid tumors. Prospective studies are warranted to further characterize safety and efficacy in this historically underrepresented population.

Cellular consequences of a germline <i>SMC5</i> variant enriched in medulloblastoma.

e14112 Background: Pediatric brain tumors are the second most common pediatric malignancy and are associated with a germline risk of approximately 15%. Medulloblastoma is a high-grade pediatric brain tumor with four subtypes, of which group 3 portends the worst outcomes and has the least molecular determinants identified. To this end, our work is the first to report the putative germline association of SMC5 variants in children with group 3 medulloblastoma in a large pediatric cancer predisposition study. SMC5 , encoding Structural Maintenance of Chromosome 5 (SMC5), is a core component of the SMC5/6 complex, essential for DNA replication, DNA damage repair, cell-cycle regulation, and chromosome maintenance. Tumor data show the occurrence of a second somatic hit in SMC5 with a tumor DNA mutational signature of late replication error, implicating the pathogenicity of SMC5 in medulloblastoma. Although germline variants in SMC5 have not been linked to cancer predisposition, biallelic alteration of SMC5 causes a neurodevelopmental disorder, Atelis Syndrome-2. In addition, somatic mutations in SMC5 have commonly been observed in adult cancers. These data suggest an important role of SMC5 in neurodevelopment and cancer biology, which is understudied and not well understood. Our study aims to elucidate the role of SMC5 in brain tumor biology by leveraging disease-relevant SMC5 mutations with the potential to shed light on the DNA repair vulnerability of these tumors. Methods: We assessed the function of SMC5 using the disease-relevant N940Y mutation in an iPSC and transiently overexpressed FLAG-tagged SMC5 wild-type and N940Y models. Baseline protein expression, cell cycle analysis, SMC5/6 complex integrity, and DNA damage signaling were assessed in wild-type and N940Y mutant models using molecular, immunofluorescence, and immunoprecipitation–mass spectrometry assays (IP-MS). Results: N940 SMC5 demonstrated unchanged protein expression compared to wild-type in the overexpression model. EdU-based flow cytometric analysis of cell cycle in isogenic and N940Y SMC5 iPSCs revealed no significant differences in cell-cycle distribution at baseline. To determine whether the N940Y mutant disrupts the formation of the SMC5/6 complex, which comprises eight proteins, we performed IP-MS and observed preserved complex formation in the N940Y mutant compared with wild-type. We next tested the effect of SMC5 dysfunction on DNA damage by immunofluorescence and demonstrated reduced 53BP1 foci in N940Y mutant iPSCs compared with wild-type iPSCs, suggesting that N940Y is unable to trigger DNA damage signaling. Conclusions: These data suggest that SMC5 N940Y preserves SMC5/6 complex integrity and cell cycle progression but impairs DNA damage signaling, warranting further investigation into the role of SMC5 in pediatric brain tumor biology.

Whole genome sequencing to identify novel, clinically relevant findings missed by standard of care for patients with myelodysplastic syndrome.

6570 Background: Genomic analysis is critical for accurate diagnosis and risk stratification for patients with myeloid malignancies. Whole genome sequencing (WGS) has the ability to capture a breadth of alterations and has the potential to complement or replace current genomic profiling techniques. We sought to validate the molecular findings from Tempus xH, a WGS based assay, with standard of care [SOC] results from a major academic institution (MDACC). Methods: We retrospectively sequenced 43 patient samples from MDACC using the Tempus xH WGS assay. SOC data from cytogenetics (karyotype +/- FISH), 81-gene panel sequencing, and/or optical genome mapping OGM (n=10), was regarded as the source of truth. We performed a two-part study: an initial unblinded analysis (n=10) comparing WGS to SOC, followed by a blinded unbiased comparative review (n=33). Clinically relevant alterations were compared between the SOC and xH reportable range workflows. We excluded mutations with &lt;= 10% VAF and filtered copy number alterations (CNAs) &lt; 5Mb, and combined OGM and cytogenetics (10&gt;= metaphases). Structural variants (SVs) were included if they overlapped orthogonal truth or were recurrent myeloid fusions. Results: In the unblinded analysis (n=10), WGS detected 53 clinically reported alterations, yielding 94% sensitivity. Single nucleotide variants (SNVs) had 100% sensitivity, and 18/20 CNA events and 6/7 SVs were detected. The single missed SV event was a derivative chromosome (chr), between chr1 and chr20, identified by cytogenetics with breakpoints over the masked centromere region of the WGS. However, WGS detected CNAs in chr arms of 1 and 20, signalling the event was captured yet not resolved as a derivative chr. Two copy losses on chr 19 (complete loss and p-arm) and an ASXL1 frameshift were detected by WGS but not by SOC. In the blinded study (n=33), WGS detected 143 events, including 124 true positives and no alterations from SOC went undetected by WGS demonstrating 100% sensitivity. WGS identified 24/24 of the CNAs detected by cytogenetics. Among all specimens, 21 novel, high confidence variants were identified in 11 specimens (39%) by WGS that were not detected by SOC; including 14 CNAs, two SNVs, and five SVs, including diagnostically and/or prognostically critical alterations: 2 MECOM rearrangements, 1 KMT2A -PTD, an 11MB deletion in chr 17p ( TP53 locus), and a focal RUNX1 deletion highlighting the potential clinical benefit of WGS. Conclusions: WGS accurately recapitulates results from targeted NGS panels, OGM and cytogenetics and advances our understanding of MDS biology. xH WGS uncovered a significant number of novel, clinically relevant and potentially targetable findings undetected by SOC. WGS provides a complementary view of the genome, identifying actionable and prognostic markers helping clinicians make more informed treatment decisions.