Alliance Data (United States)

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.

41 Background: Surrogate endpoints of overall survival (OS) are increasingly used as the basis of cancer drug approvals, but a strong association between their treatment effects is essential for validation as appropriate surrogates. We summarize the current evidence landscape for meta-analytic validation of surrogate endpoints in colorectal cancer (CRC) and assess surrogacy evaluation quality through a novel framework to inform the selection of primary endpoints in future trials. Methods: We developed a framework to grade the quality of surrogate endpoints in oncology. We then searched MEDLINE to identify meta-analytic validation studies of endpoints in CRC at the trial level. We consulted a research librarian to develop a search strategy in PubMed using keywords and MeSH terms. Articles published before 07/06/2024 were included and two reviewers independently evaluated each. Grades were assessed according to seven evidence domains: data source (A-B), disease population (0-3), surrogate and true endpoint definitions (0-3), number of trials evaluated (0-4), quality and strength of individual (0-2) and trial-level associations (0-8). Discordance in blinded assessments was resolved by consensus decision. Results: Eighteen articles were identified containing 39 evaluations of 12 unique endpoints. Results are presented for disease-free survival (DFS), Progression-free survival (PFS), overall response rate (ORR), time to progression (TTP) and disease control rate (DCR). PFS was most frequently assessed (n=11). Surrogates were primarily evaluated in stage IV disease (n=34) and analyses of biologic agents (n=29). Individual patient data (IPD) was used in 13 evaluations. A23 was the highest endpoint quality score assigned using IPD and B6 was the lowest using summary trial data (SD). Only DFS consistently demonstrated high-quality surrogacy for OS at the trial level using IPD (≥A18, R 2 ≥ 0.70). Conclusions: DFS consistently shows high quality of surrogacy, whereas other endpoints show inconsistent surrogacy evaluation ranging from low to moderate quality in contemporary CRC trials. Standardizing the methodology of endpoint validation using IPD may improve surrogacy estimates. Assessment of new, or revision of prior surrogate endpoints may be warranted, particularly in the context of metastatic disease. Endpoint Data source (frequency) Treatment setting (frequency) Treatment era (frequency) Trial-level association, R 2 (range) Surrogate quality score (range) DFS (n=5) IPD: 5 Adjuvant Pre-biologics: 4Post-biologics: 1 0.70-0.93 A18-23 PFS (n=11) IPD: 3SD: 8 Metastatic Pre-biologics: 2Post-biologics: 9 0.34-0.99 B6-A22 ORR (n=9) IPD: 1SD: 8 Metastatic Pre-biologics: 1Post-biologics: 8 0.03-0.74 B6-A13 TTP (n=5) SD: 5 Metastatic Post-biologics: 5 0.27-0.65 B7-11 DCR (n=2) SD: 2 Metastatic Post-biologics: 2 0.82-0.89 B7-8

TPS279 Background: A total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone in those with locally advanced rectal cancer. Recent data indicate that optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to improve complete response rates. The use of FOLFIRINOX has shown to improve response and outcomes compared to CRT and surgery alone. Data have also shown that patients with clinical complete response (cCR) after TNT may be managed with a watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to improve cCR rates has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. We designed this NCI-sponsored study of chemotherapy intensification to address this and to increase cCR rates, provide opportunity for organ preservation, and survival outcomes. Methods: In this multigroup randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N+) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N+ vs N0) and distance from anal verge (0–4; 4–8; 8–12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX (control arm)) or triplet chemotherapy (FOLFIRINOX (experimental arm)) for 3–4 months. LCRT in both arms involve 4500 cGy in 25 fractions over 5 weeks +900 cGy boost in 5 fractions with a fluoropyrimidine. Patients will undergo assessment 8–12 (±4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha=0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include overall survival, organ preservation time, time to distant metastasis, and adverse event rates. This study completed accrual as of July 2025 and is investigating exploratory correlatives (e.g., ctDNA). Support: U10CA180821, U10CA180882, U24 CA196171. https://acknowledgments.alliancefound.org. Clinicaltrials.gov ID: NCT05610163. Clinical trial information: NCT05610163 .

622 Background: Colorectal small and large cell neuroendocrine carcinoma (SCNEC and LCNEC) comprise &lt;1% of colorectal cancers and have poor prognosis. Detailed survival information is limited due to rarity. We analyzed survival outcomes using Survival, Epidemiology, and End Result (SEER) database (2000-2022) and compared with NETs and adenocarcinoma (AC). Methods: All patients with SCNEC, LCNEC, NETs or AC with colorectal primaries were extracted. AJCC stage was calculated with 8 th ed. TNM classification. Kaplan-Meier estimator, log-rank test, and Cox regression (including AJCC stage, surgery, radiation, and chemotherapy variables) were used to analyze survival outcomes. Results: Comparing colon and rectal primaries, the only significant mOS difference was in stage IV SCNEC (2 vs 7 months, p&lt;0.0001). Comparing LCNEC and SCNEC, the only significant mOS difference was in stage IV colon SCNEC and LCNEC (2 vs 5 months, p&lt;0.0001). Stage III and IV colorectal SCNEC and LCNEC had significantly shorter mOS than stage III and IV AC and NETs. In multivariate Cox regressions, surgery and chemotherapy were associated with significantly improved survival for both SCNEC and LCNEC at both primaries (p&lt;0.001), while radiation was never significant. Conclusions: Most colorectal SCNEC and LCNEC patients present with stage IV disease. Stage IV colon SCNEC had significantly shorter mOS than both stage IV colon LCNEC and stage IV rectal SCNEC. Further research should explore early diagnosis and effective therapies for this rare, aggressive malignancy. Median overall survival (months) Colon SCNEC (n/mOS) Colon LCNEC (n/mOS) Colon NETs (n/mOS) Colon AC (n/mOS) SCNEC vs NETs in colon: P-value LCNEC vs NETs in colon: P-value SCNEC vs AC in colon: P-value LCNEC vs AC in colon: P-value SCNEC vs LCNEC in colon: P-value Rectal SCNEC (n/mOS) Rectal LCNEC (n/mOS) Rectal NETs (n/mOS) Rectal AC (n/mOS) SCNEC vs NETs in rectum: P-value LCNEC vs NETs in rectum: P-value SCNEC vs AC in rectum P-value LCNEC vs AC in rectum SCNEC vs LCNEC in rectum: P-value Colon SCNEC vs rectal SCNEC P-value Colon LCNEC vs rectal LCNEC: P-value Stage I 19/32 17/122 4496/NA 114,213/144 &lt;0.0001 &lt;0.0001 &lt;0.0001 0.34 0.25 27/23 10/28 5185/NA 54,702/160 &lt;0.0001 &lt;0.0001 &lt;0.0001 0.00047 0.88 0.99 0.24 Stage II 17/38 30/49 259/NA 121,757/106 0.0015 &lt;0.0001 0.4 0.0068 0.65 17/16 3/NA 33/NA 38,417/106 &lt;0.0001 0.57 &lt;0.0001 0.87 0.3 0.065 0.55 Stage III 40/14 107/13 582/184 104,793/82 &lt;0.0001 &lt;0.0001 &lt;0.0001 &lt;0.0001 0.48 50/19 37/17 103/102 46,687/107 &lt;0.0001 &lt;0.0001 <j

Abstract. Over the last 20,000 years, Northern Hemisphere vegetation underwent major shifts in response to orbital changes, rising CO₂, and ice sheet retreat. Using the large-scale pollen-based tree cover reconstruction by Schild et al. (2025), we evaluate the performance of the MPI-ESM Earth System Model in simulating tree cover dynamics from the Last Glacial Maximum to the present. Although the model reproduces the broad increase in tree cover during deglaciation and decrease throughout the Holocene, it fails to simulate the mid-Holocene maximum observed in the reconstructions. The model does capture the shift from energy-limited conditions during deglaciation to water-limited conditions in the early to mid-Holocene, and then back to energy-limited conditions in the late Holocene, but regional discrepancies remain substantial. MPI-ESM simulates too much forest in sparsely forested areas and too little forest in densely forested areas, particularly in mid- and high-latitude regions. Statistical analyses indicate that summer temperature dominates simulated high-latitude forests, while precipitation is critical in most other regions, contrasting with reconstructions that highlight cold-season temperature in temperate and boreal forests. Areas of model-data agreement show largely linear responses to climate drivers, whereas regions of disagreement exhibit non-linear dynamics to the temperature of the warmest month and over-sensitivity of the plant-physiological CO₂ response. Employing an emulator with a bias-corrected climate reduces the mismatch in the forest steppe transition zones, but does not lead to an overall improvement of the model-data agreement. In particular, the mismatch in the boreal region remains unresolved, suggesting structural limitations in the model. Improving dynamic vegetation models for simulating climatic transitions in both, past and future contexts, requires integrating realistic soil and permafrost processes, dynamic biome thresholds and disturbance regimes. Trait-based approaches could lead to better representation of the vegetation response to climate changes.

The National Comprehensive Cancer Network guidelines recommend tumor phenotyping for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 at initial breast cancer diagnosis, with repeat biopsy considered at disease progression. This study assessed the frequency, timing, regional variation, and predictors of repeat biopsies among patients with metastatic breast cancer (mBC) treated at community oncology practices in the United States. A weighted random sample of 911 mBC patients was selected from 15 practices within the ONCare Alliance network. The data included demographics, clinical characteristics, number and types of biopsies, and associated findings. Multivariate negative binomial regression, adjusted for disease duration, was used to identify predictors of biopsy frequency. Among the cohort, 42.2% had a history of early-stage disease, while 57.8% were diagnosed with de novo stage IV mBC. After adjusting for disease duration, patients with prior early-stage disease underwent significantly more biopsies (mean: 3.9; 95% CI: 3.7-4.0) than those with de novo mBC (mean: 2.2; 95% CI: 2.1-2.3; P<0.001). Factors associated with fewer biopsies included non-Black, non-Asian minority status (RR=0.80, P<0.001), longer time to metastatic progression (RR=0.93, P<0.001), poor performance status, and geographic region. A substantial proportion of patients with mBC, particularly those with de novo disease, did not undergo repeat biopsy at progression. These findings reveal disparities in biopsy practices and underscore the need for improved adherence to guideline-based care in community oncology settings.

3504 Background: Among patients with resected node-positive colon cancer, nearly 30% will relapse despite standard adjuvant chemotherapy. Analysis of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may enable risk stratification for tumor recurrence and inform adjuvant treatment decisions. Methods: Postsurgical ctDNA was analyzed in patients with stage III colon carcinoma who participated in a phase 3 trial of adjuvant FOLFOX alone or combined with cetuximab (n = 3084) [NCCTG N0147]. We utilized a tissue-free epigenomic assay for ctDNA detection (Guardant Reveal) with sampling prior to start of adjuvant therapy. Among ctDNA positives, epigenomic tumor fraction (TF) was estimated and ctDNA genotyping was done with Guardant360 (panel of 739 genes). Median follow-up was 6.1 years (yr). Study endpoints included time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan–Meier method. Multivariable Cox proportional hazards models were used to assess prognostic utility of ctDNA status adjusting for confounders. Interaction between ctDNA and clinicopathological features were assessed. Results: Among 2260 patients with evaluable ctDNA data, 461 (20.4%) were ctDNA positive.Tumors were significantly associated with higher T, N stage, BRAF V600E , high grade, obstruction/perforation, and worse performance status. Positive vs negative ctDNA was significantly associated with shorter TTR (hazard ratio [HR] 4.33, 95% confidence interval [CI] 3.65-5.13, P &lt; 0.0001), poorer DFS (HR 3.74, CI 3.18-4.39, P &lt; 0.0001] and OS (HR 3.17, CI 2.63-3.83, P &lt; 0.0001), adjusting for covariates and tissue MMR, KRAS and BRAF V600E . ctDNA positive vs negative patients had 3y DFS of 36.4% (95%CI 32.2-41.2%) vs 82.5% (95% CI 80.0-84.4%), respectively. Adverse prognosis was consistent across subgroups (all P &lt; 0.05), with stronger detrimental effects for positive ctDNA in N1 (vs. N2), T1/2 (vs T3 or 4), and mismatch repair deficient tumors [interaction P = 0.0002 to 0.041). Among patients with positive ctDNA, TF in those who recurred/died within 3 yr was double of those who remained recurrence-free ( P = 0.0001). High vs. low ctDNA TF ( &gt; vs ≤ median) further stratified TTR (HR 1.48, CI 1.17-1.88, P = 0.0011), DFS (HR 1.52, CI 1.21-1.92, P = 0.0004) and OS (HR 1.58, CI 1.21-2.07, P = 0.0009), adjusting for confounders. ctDNA positive cases, . Analyses of ctDNA detection by site of recurrence, ctDNA clearance, and genomic variant detection are ongoing. Conclusions: In the largest study evaluating tissue-free epigenomic-based MRD detection, we demonstrate a robust prognostic utility of postsurgical ctDNA. Tumor fraction provided further patient stratification and analysis is ongoing to identify a subgroup based on TF that may be unlikely to clear ctDNA despite adjuvant chemotherapy.

A method for mass-producing graphene without a substrate or catalyst has not yet been developed. Consequently, combined with the tendency of graphene to stack easily, there are currently no applications that effectively exploit its structure and functionality. We address these issues by investigating the preparation of graphene using hot isostatic pressing (HIP) and the mechanism of this process. We developed a method for mass-producing vapor-phase-grown graphene by first heating a resin material such as phenolic resin under conditions that control the amount of residual hydrogen and then treating the product with argon or nitrogen using HIP equipment. After heating, the resin powder changed to carbon powder containing small quantity of residual hydrogen and oxygen. In the HIP method, the carbonized powder generates hydrogen and hydrocarbons from inside the powder particles. These create a concentration gradient near the carbonized powder surface by hydrostatic pressure due to HIP, and a thermal chemical vapor deposition reaction occurs due to the heating, which results in the radial formation of flower-like graphene on the carbonized powder surface. The results show that in the formation of vapor-phase-grown carbon, when the HIP treatment temperature is 1300–1500 ℃, thin two-dimensional growth is preferred over three-dimensional growth, and graphene grows in the same manner as carbon nanotubes without a catalyst.

LBA531 Background: Muscle-invasive urothelial carcinoma (MIUC) is an aggressive disease with high relapse rates. Neoadjuvant platinum-based chemotherapy (NAC) is the standard of care in patients (pts) who are cisplatin (Cis)-eligible. However, many pts are Cis-ineligible or have persistent muscle-invasive disease after NAC and surgery. We evaluated pembrolizumab (Pembro) as adjuvant therapy in pts with high-risk MIUC following surgical resection. Methods: The AMBASSADOR study is an open-label, randomized, phase III trial that enrolled pts with histologically confirmed MIUC of the bladder, upper tract, or urethra who (1) had ≥ pT2 and/or pN+ or margins+ at surgery (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) following NAC or (2) ≥ pT3 and/or pN+ or margins+ at surgery without NAC and were either Cis-ineligible or declined adjuvant Cis-based therapy. Pts were registered ≥4 to 16 weeks after surgery and randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The dual primary endpoints were disease-free survival (DFS) and overall survival (OS) with a target sample size of 739 pts and required 387 DFS and 320 OS events for final analysis. Secondary objectives included evaluation of DFS and OS in PD-L1-positive and -negative pts and assessing safety. Here we present the interim DFS and OS results. Results: Between 09/2017 and 08/2021 a total of 702 pts were randomized prior to early closure due to US FDA approval of nivolumab for MIUC pts: 354 pts to Pembro and 348 pts to Obs; 13.0% vs 21.6% withdrew from study without event in the Pembro vs Obs arms, respectively. 74 pts (21%) in the Obs arm received an immune checkpoint inhibitor. Median follow-up was 22.3 months (mos) for DFS and 36.9 mos for OS. The DFS endpoint (based on 319 events needed for interim analysis) crossed the efficacy boundary. Median DFS was 29.0 months (95% confidence interval (CI) 21.8‒not evaluable (NE)) with Pembro and 14.0 months (95% CI 9.7‒20.20) with Obs (hazard ratio (HR) 0.69 [95% CI 0.55–0.87]; p=0.0013). At the interim analysis (n = 257 events), median OS was 50.9 months (95% CI 43.9‒NE) with Pembro and 55.8 months (95% CI 53.3‒NE) with Obs (HR 0.98 [95% CI 0.76–1.26]; p=0.88). Grade 3+ adverse events occurred in 48.4% and 31.8% of pts in the Pembro and Obs arms, respectively. Conclusions: Adjuvant Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs Obs for high-risk MIUC pts after radical surgery. The OS endpoint may have been impacted by pts on the Obs arm receiving a checkpoint inhibitor. Pembro was tolerable with no new safety signals. These results support adjuvant Pembro as a new therapeutic option for pts with MIUC with high risk for recurrence. Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and ctDNA analyses. Clinical trial information: NCT03244384 .