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Manipulation of X‐Ray Persistent Radioluminescence in Core–Shell–Shell Nanoparticles for Energy‐Discriminated Chromatic 3D Imaging
ABSTRACT Lanthanide‐doped fluoride nanoparticles with tunable persistent radioluminescence (persistent RL) have emerged as promising scintillators for 3D X‐ray delay imaging. However, its core challenges persist in developing a highly‐discriminative imaging detection technologies for complex structures composed of materials with similar density. Here, a persistent RL‐assisted energy‐discriminated approach is developed to realize high‐resolution chromatic X‐ray 3D imaging for visualizing material specificity in complex structures. We demonstrated highly differentiated, energy‐dependent, precisely persistent RL multicolor tuning within a single Core–Shell–Shell (CSS) heterogeneous nanoparticles. We uncover the fundamental mechanism underlying persistent RL decay kinetics, establishing a mechanistic framework that links X‐ray energy to color dynamics. This mechanistic insight enables to establish a general design principle for color‐engineered persistent RL nanocrystals and achieving precise discrimination of energy through color‐based information. Moreover, flexible imaging detector incorporating the CSS nanoparticles with the ability to self‐repair, be recycled, and record images, and demonstrated chromatic 3D imaging capable of resolving complex objects with subtle distinctions at a low X‐ray dose rate of 15.1 uGy/s. These findings not only elucidate the photophysical origins of color‐tunable persistent RL, but also pave the way for next‐generation efficient X‐ray imaging systems with broad potential across medical, industrial, and scientific applications.
Contemporary real-world outcomes of mantle cell lymphoma in Colombia: Results from an expanded multicenter cohort.
e19077 Background: Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma with limited contemporary real-world data from Latin America. We report treatment patterns and outcomes in an expanded multicenter cohort from Colombia. Methods: We conducted a multicenter observational cohort study of adult patients with MCL treated at three tertiary referral centers in Colombia. The primary endpoint was overall survival (OS), estimated using the Kaplan–Meier method and compared with log-rank tests. Secondary endpoints included treatment patterns and response (overall response rate [ORR], complete remission [CR]). Results: A total of 152 patients were included. Median age at diagnosis was 64 years (IQR 56–72), and 73.7% were male. Advanced disease was common, with Ann Arbor stage IV in 83.0% and high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) in 51.3%. Classical morphology predominated (70.4%), followed by blastoid variants (11.3%). Comprehensive molecular profiling was not uniformly available, among patients with available data, complex karyotype was identified in 12.6%, SOX11 overexpression in 45.9% and 10.1% had p53 mutations. Cytarabine-based chemoimmunotherapy was the most common first-line approach, most frequently R-CHOP alternating with R-DHAP (45.3%). Among 65 patients eligible for ASCT, 53 (81.5%) underwent ASCT as first-line consolidation. ORR to first-line therapy was 81.5%, including complete remission in 58.9%. With a median follow-up of 51.8 months (reverse Kaplan–Meier; 95% CI 42.9–71.7), the estimated 5-year overall survival (OS) was 58.4% (95% CI 48.6–66.9%). Patients who underwent ASCT experienced significantly improved OS (log-rank p<0.001). In multivariable analysis, high Ki-67 (≥50%; HR 2.20; 95% CI 1.04–4.62; p=0.038) and ECOG performance status ≥2 (HR 2.93; 95% CI 1.33–6.47; p=0.008) were independently associated with inferior OS. Conclusions: In this large multicenter real-world cohort, patients with MCL frequently presented with advanced and high-risk disease. Despite incomplete molecular characterization, access to intensive frontline therapy, including high utilization of ASCT, achieved durable survival. Clinical risk factors, particularly Ki-67 and ECOG remained independently associated with overall survival, highlighting their prognostic value and practical relevance for risk stratification and treatment decision making in routine care within resource-limited settings. Baseline characteristics, treatment, and outcomes. Baseline characteristics Age (median, years) 64 (56–72) Male sex, n (%) 112 (73.7%) Ann Arbor stage IV, n (%) 122 (83.0%) High-risk M-IPI, n (%) 78 (51.3%) Classical morphology, n (%) 100 (70.4%) Cytarabine-based induction,n (%) 68 (45.3%) ASCT, n (%) 53/65 (81.5%) 5-year overall survival, % (95% CI) 58.4 (48.6–66.9) Overall response rate (ORR), % 81.5%
Insights from patients with early-stage, hormone positive breast cancer (BC) using an artificial intelligence (AI)–driven digital navigation platform.
e12554 Background: Patients with BC navigate complex treatment decisions influenced by tumor biology, disease extent, and personal values. Early-stage hormone receptor-positive BC, the most common subtype, involves multi-year hormone therapy decisions. We examined how an AI-powered navigation platform supports BC patients in understanding their diagnosis, treatment and side effect management options. Methods: We used Claude Sonnet 4.5 to analyze patient-initiated conversations with the Manta Cares platform (ASCO 2025 Abst e13713),which includes a multistation cancer map and a “fenced garden” AI tool. We characterized conversation themes, treatment-related queries, and indicators of patient empowerment in clinical decision-making. Results: From 11/27/2025 through 1/26/2026 we analyzed 20 patient conversation threads originating with patients aged 40-75 years. Themes are ordered in the table starting with most common. Conclusions: An AI-powered digital navigation platform has utility for early stage BC patients seeking to understand their treatment and side effect management options. By delivering subtype-tailored guidance, the Manta Cares platform addresses knowledge gaps that undermine confidence in treatment decisions. This approach may enhance shared decision-making and patient engagement in their breast cancer care, particularly for complex decisions surrounding long-term endocrine therapy adherence. Oncologists and their teams should address these concerns early and continuously in the patient’s course. Conversation Theme Conversation Description User Impact Hormone therapy side effects Hot flashes, joint pain, fatigue, mood changes, vaginal dryness Affects quality of life and treatment adherence Emotional Health Depression, anxiety, fear of recurrence, post-treatment adjustment Common 5+ months post-treatment; often unpredictable waves Sexual/relationship impact Libido changes, early menopause effects Long-term concern given 5-10 year treatment duration Treatment decisions Understanding test results, receptor status, why hormone therapy needed Users need clarity on estrogen and progesterone receptor positive implications Treatment duration concerns Tolerating 5-10 years of therapy Balancing prevention benefits vs. quality of life Healthcare navigation Coordinating specialists, preparing appointments Need for symptom tracking and communication tools
Intravenous oncolytic virus IDOV-Safe in pMMR/MSS metastatic colorectal cancer.
3536 Background: Proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC) is largely resistant to immune checkpoint inhibitors, with limited options after standard therapies. IDOV-Safe is a systemically deliverable, vaccinia virus-based oncolytic virotherapy. This phase 1 clinical trial evaluated the safety and preliminary efficacy of intravenous IDOV-Safe combined with toripalimab and fruquintinib in patients with pMMR/MSS mCRC (NCT06380309). Methods: Patients with pMMR/MSS mCRC who had progressed on or were intolerant to ≥2 prior systemic therapies were enrolled. Dose escalation used a 3+3 design across four dose levels (1×10 9 , 3×10 9 , 1×10 10 , and 3×10 10 PFU). In expansion, three combination strategies with immune-target therapy were evaluated: sequential, early, and IO free combinations using fruquintinib with or without toripalimab. Primary endpoints were safety and objective response rate (ORR). Results: Fifty-five patients were enrolled; 80% had received ≥3 prior treatment lines. Dose-limiting toxicities at 1×10 10 PFU led to selection of 1×10 9 and 3×10 9 PFU for expansion. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 62% of patients, most commonly fever, thrombocytopenia, and neutropenia; grade ≥3 immune-related events were infrequent (2%), and no grade ≥3 TRAEs were attributed to fruquintinib. In sequential combination cohorts, objective responses occurred only after initiation of combination therapy. ORR was 33.3% at 1×10 9 PFU (IIA1) and 30.0% at 3×10 9 PFU (IIA2), with disease control rates (DCRs) of 50.0% and 70.0%, respectively. In early combination cohorts, objective responses were observed at 3×10 9 PFU (IIC2; ORR 16.7%), with high DCRs (83.3% in IIC1 and 91.7% in IIC2). The DCR in the IO-free cohort (IID) was 50.0%. Median progression-free survival (mPFS) across five cohorts was 5.4 (IIA1), 8.7 (IIA2), 5.4 (IIC1), 5.5 (IIC2), and 4.6 months (IID). Conclusions: Intravenous IDOV-Safe demonstrated a favorable safety profile and encouraging preliminary antitumor activity when combined with toripalimab and fruquintinib, particularly using a sequential combination strategy in heavily pretreated patients with pMMR/MSS mCRC. Clinical trial information: NCT06380309 . Response to IDOV-safe and immuno-targeted therapy. Response IIA1 1×10 9 IIA2 3×10 9 IIC1 1×10 9 IIC2 3×10 9 IID 3×10 9 Best overall response — n (%) Partial response 2 (33.3) 6 (30.0) 0 2 (16.7) 0 Stable disease (SD) 1 (16.7) 8 (40.0)* 5 (83.3) 9 (75.0) 3 (50.0) Progressive disease 3 (50.0) 5 (25.0) 0 1 (8.3) 2 (33.3) Not evaluable 0 1 (5.0) 1 (16.7) 0 1 (16.7) ORR—Percent (95% CI) 33.3 (4.3, 77.7) 30.0 (11.9, 54.3) 0 16.7 (2.1, 48.4) 0 DCR —Percent (95% CI) 50.0 (11.8, 88.2) 70.0 (45.7, 88.1) 83.3 (35.9, 99.6) 91.7 (61.5, 99.8) 50.0 (11.8, 88.2) *One patient in IIA2 cohort had unconfirmed SD.
Additional health-related quality of life (HRQoL) analysis from DESTINY-Gastric04 (DG-04), a randomized phase 3 study of trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) unresectable/metastatic gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA).
4111 Background: In DG-04 (NCT04704934), a statistically significant and clinically meaningful improvement in overall survival was seen with T-DXd vs RAM + PTX in pts with HER2+ unresectable/metastatic GC/GEJA in the second-line setting. Patient-reported HRQoL was also maintained with T-DXd. We report additional HRQoL results from DG-04. Methods: Pts with unresectable/metastatic GC/GEJA who were HER2+ (IHC 3+, IHC 2+/ISH+) by local or central testing received T-DXd 6.4 mg/kg or RAM + PTX. Patient-reported outcomes were assessed at prespecified time points using the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) scale and the EuroQol 5-dimension, 5-level (EQ-5D-5L) visual analog scale (VAS). Time to first deterioration (TTFD) and mean change from baseline (CFB) were assessed. Mixed model for repeated measures (MMRM) was used to analyze CFB of the FACT-Ga scale. Results: At data cutoff (October 24, 2024), median TTFD favored T-DXd (n = 246) vs RAM + PTX (n = 248) for the EQ-5D-5L VAS (3.5 vs 3.0 mo; hazard ratio [HR], 0.79; nominal P = 0.063), FACT-General (G) total score (3.5 vs 2.8 mo; HR, 0.74; nominal P = 0.015), and FACT-Ga emotional well-being (EWB; 5.1 vs 3.7 mo; HR, 0.74; nominal P = 0.026) and social well-being (SWB; 3.8 vs 2.5 mo; HR, 0.71; nominal P = 0.006) subscales. Additional TTFD results, including TTFD in gastric cancer subscale (GaCS) and physical well-being (PWB), are in the Table. Mean CFB scores remained stable in all FACT-Ga subscales, with no clinically meaningful changes associated with T-DXd. MMRM analysis of CFB results favored T-DXd vs RAM + PTX for the FACT-G total score (nominal P = 0.023), and the FACT-Ga functional well-being (FWB; nominal P = 0.045) and SWB (nominal P = 0.004) subscales. Conclusions: These findings support patient-reported HRQoL was maintained with T-DXd in pts with HER2+ unresectable/metastatic GC/GEJA. TTFD was not negatively impacted with T-DXd; mean CFB in all FACT-Ga subscales showed pt symptoms and functioning remained stable, with some subscales favoring T-DXd vs RAM + PTX. Clinical trial information: NCT04704934 . T-DXdn=246 RAM + PTXn=248 HR (95% CI)Nominal P Value EQ-5D-5L VAS, median TTFD (95% CI), mo 3.5 (2.7-5.0) 3.0 (2.1-3.5) 0.79 (0.62-1.01)0.063 FACT-Ga scale, median TTFD (95% CI), mo FACT-G (EWB + FWB + PWB + SWB) 3.5 (2.2-4.4) 2.8 (2.1-3.5) 0.74 (0.58-0.95)0.015 FACT-Ga total score (FACT-G + GaCS) 4.4 (3.5-5.7) 4.4 (3.5-6.5) 0.95 (0.73-1.24)0.700 EWB 5.1 (4.2-8.7) 3.7 (2.4-5.0) 0.74 (0.57-0.97)0.026 FWB 2.3 (2.1-3.2) 2.3 (2.1-3.5) 0.89 (0.70-1.13)0.338 PWB 2.8 (2.1-3.7) 2.2 (2.1-3.1) 0.79 (0.62-1.00)0.052 SWB 3.8 (2.6-5.3) 2.5 (2.1-3.5) 0.71 (0.55-0.91)0.006 GaCS 4.9 (3.7-6.3) 5.8 (4.8-7.4) 1.11 (0.84-1.47)0.462
Clinical and metabolic predictors of complete response after neoadjuvant immune checkpoint blockade in resectable gastroesophageal adenocarcinoma (GEC).
e16149 Background: Perioperative durvalumab + FLOT improves overall survival and is a new treatment option for patients with resectable GEC. FDG-PET SUV decline of ≥35% is commonly used as a benchmark of treatment response. We correlated FDG-PET and endoscopic response with pathologic outcomes to evaluate their utility in selecting patients for non-operative management (NOM). Methods: Patients with localized MSS GEC treated with curative intent ICB+chemotherapy at MSK between 2020-2025 were retrospectively analyzed. Association of primary tumor baseline FDG avidity and %SUV change with surgical pathological outcomes [pathologic complete response (pCR), defined as absence of residual carcinoma; ypT3-4; and ypN+] was determined. High avidity was defined as SUV > 8, metabolic response as 35% reduction in FDG, and clinical complete response (cCR) as a negative biopsy on post-neoadjuvant therapy endoscopy (EGD). Results: Among 48 patients (20 gastric, 28 GEJ) who received neoadjuvant FLOT (n = 30) or FOLFOX (n = 18) + ICB, 43 underwent surgery. pCR occurred in 7/43 [16.3%; pCR with FOLFOX+ICB 1/13 (7.7%); 6/30 (20%) with FLOT+ ICB]. 35/48 underwent FDG PET at baseline and after therapy and had FDG-avid disease at baseline (SUV > 5). Median baseline SUV was 8.7 (range 5.1-37.5) with median %SUV change -55% (range +12% to -100%) after therapy. Baseline SUV (≥8 vs < 8), %SUV reduction (≥35% vs < 35 and ≥75% vs < 35%), and residual post-therapy avidity were not associated with pCR, ypT3–4 disease, or ypN+ disease. Findings were consistent by site (gastric vs GEJ/esophagus) and among patients receiving triplet chemotherapy. Compared to patients without cCR or pCR (n = 26 PET evaluable), patients with cCR or pCR (n = 9 PET evaluable) had significantly reduced median post-treatment avidity (SUV 2.8 vs 4.1; p = 0.03), however the groups did not significantly differ in median percent reduction in avidity or percent with post-treatment SUV < 3. Among 6 patients with complete resolution of PET avidity, 2/6 had pCR, 1/6 had cCR and proceeded to NOM, and 3/6 had residual disease including 2 with ypT4aN+ disease. 12/48 patients had an EGD after neoadjuvant therapy; 5 had cCR of whom 3 had residual FDG avidity on post-treatment PET. 1/5 of the cCR had pCR; the other 4 proceeded to NOM. In both cases of complete metabolic resolution and cCR, patients proceeded to NOM with no evidence of recurrence after minimum follow up of 3 years. Conclusions: Percent reduction in primary tumor PET avidity following neoadjuvant chemoimmunotherapy in resectable GEC was not associated with surgical pathology outcomes in our cohort. The combination of PET and endoscopy may better select patients for NOM paradigms, though higher resolution tools to assess for residual disease are needed. Multimodal predictive models for surgical pathology and long-term survival outcomes are being developed.
Failure to rescue following colorectal cancer surgery at minority-serving hospitals: A National Inpatient Sample analysis.
e23067 Background: Given persistent disparities in surgical outcomes, this study examines patient- and system-level factors associated with differences in failure-to-rescue (FTR) rates after colorectal cancer (CRC) surgery between minority-serving hospitals (MSHs) and non–minority-serving hospitals (non-MSHs). Methods: A retrospective cohort analysis was conducted using the National Inpatient Sample (NIS) database from 2016 to 2022. FTR, defined as mortality following a complication among patients undergoing CRC surgery, was identified using ICD-10 diagnostic and procedural codes. MSHs were defined as hospitals in the top quintile for the proportion of Black or Hispanic patients treated. Univariate and multivariable regression analyses were performed to assess disparities in FTR between MSH and non-MSH cohorts. Results: Among 4,173,403 hospitalizations for CRC surgery, 25% occurred at MSHs. Patients treated at MSHs compared with non-MSHs were younger (mean age 57.2 vs. 61.1 years), male (49.0% vs. 46.6%), and non-Hispanic Black (23.5% vs. 8.0%) or Hispanic (28.0% vs. 6.1%). On univariate analysis comparing MSHs versus non-MSHs, FTR and inpatient mortality were higher at 1.9% vs 1.8% (OR 1.06; 95% CI, 1.02-1.11) and 2.0% vs 1.8% (OR 1.06; 95% CI, 1.02-1.10), respectively. On multivariable logistic regression, after adjustment for clinical and surgical factors, MSH status remained independently associated with increased odds of FTR (aOR 1.08; 95% CI, 1.03-1.14). Additionally, hospitalizations at MSHs were associated with longer length of stay (7.2 vs. 6.6 days) and higher total hospitalization costs ($114,799 vs. $93,208). Secondary complications occurred more frequently at MSHs, including shock (OR 1.15, p<0.001), cardiac arrest/CPR (OR 1.33, p<0.001), CVA (OR 1.22, p<0.001), DVT (OR 1.23, p<0.001), and relaparotomy (OR 1.41, p<0.0001). Conclusions: Patients admitted to MSHs experienced disproportionately higher complications, mortality, and FTR rates following CRC surgery compared to non-MSHs. Notwithstanding poorer clinical outcomes, MSHs had longer hospitalizations and higher costs. Taken together, this evidence emphasizes the need to address the disparities in surgical outcomes at MSHs. Understanding the patient and system-related factors that play a role in these differences is critical to facilitating earlier identification of complications, which may improve postoperative mortality and FTR.
Single-institution clinical outcomes with pembrolizumab plus neoadjuvant radiation (SARC032 regimen) with or without neoadjuvant doxorubicin/ifosfamide in high grade soft tissue sarcomas.
e23552 Background: SARC032 therapy (pembrolizumab plus neoadjuvant XRT, PD-1 + XRT) represents an appealing perioperative option for patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma (dLPS) who are not candidates for doxorubicin/ifosfamide (AI) adjuvant chemotherapy. However, safety and efficacy of PD-1 + XRT in sequence with AI for fit patients deemed high-risk by Sarculator overall survival (OS) predictions has not been studied. Here we report our institution’s experience of PD-1 + XRT treatment with or without neoadjuvant AI in patients with high grade soft tissue sarcomas (STSs). Methods: IRB waiver of consent was obtained to retrospectively review clinical outcomes of patients from 2010 to 2025 receiving neoadjuvant PD-1 + XRT. Patient demographics, disease characteristics, Sarculator estimated OS, and treatment outcomes (including % tumor necrosis at surgery) were obtained from clinical records. Differences between PD-1 + XRT or AI/PD-1 + XRT groups were evaluated using students unpaired t-tests. Results: 18 patients met criteria for evaluation. Represented STS types included UPS (n=9), myxofibrosarcoma (n=3), XRT-associated sarcoma (n=1), pleomorphic liposarcoma (pLPS, n=2), and pleomorphic rhabdomyosarcoma (pRMS, n=3). Represented tumor sites included extremity (n=12), trunk (n=2), intrapelvic (n=3) and retroperitoneal (RP, n=1). 8 patients received 3 or 4 cycles of chemotherapy (AI=7, A/cyclophosphamide=1) followed by PD-1 + XRT (AI/PD-1 + XRT). Significant differences in baseline characteristics between patients that received chemotherapy compared to PD-1 + XRT alone included age (50.5 yrs vs 68.7 yrs, p = <0.01), baseline tumor size (15.5 cm vs 8.8 cm, p = 0.03), and Sarculator ESTS estimated 10-year OS (38% vs 71%, p = 0.02). No difference in Sarculator RPS 5-year OS or % tumor necrosis at resection were seen (61% vs 71%, p=1; 65% vs 75%, p = 0.94). One patient with pRMS had 100% treatment effect at resection with no evidence of residual tumor (AI/PD-1 + XRT). Patients with pLPS had tumor necrosis of 30% (AI/PD-1 + XRT) and 60% (PD-1 + XRT). No additional toxicity with AI/PD-1 + XRT was observed outside of that expected from chemotherapy or PD-1 + XRT alone. Conclusions: Our data suggest feasibility and efficacy with real-world application of XRT/pembrolizumab with or without AI for patients with extremity, intrapelvic, and RP localized high grade STSs, including pLPS and pRMS which were not included in outcomes from SARC032. Significant baseline differences were noted between the AI/PD-1 + XRT and PD-1 + XRT cohorts, driven by clinical judgement and associated with Sarculator high-risk status. This observation warrants consideration in the future design of clinical trials of PD-1 + XRT to assess incorporation of AI chemotherapy.
FOLFOXIRI/bevacizumab in microsatellite stable (pMMR/MSS) <i>RAS</i> and <i>BRAF</i> wild-type “gene-altered” metastatic colorectal cancer (mCRC): The HYPERTRIBE study.
3560 Background: Negative hyperselection may allow patient refinement for the use of anti-EGFRs in chemo-naïve pMMR/MSS, RAS and BRAF wild-type (wt) mCRC patients. However, outcomes are poor with both doublets/anti-EGFRs and doublets/bevacizumab (bev) among patients with gene-altered tumors. We investigated the efficacy of chemotherapy intensification with FOLFOXIRI/bev in this subgroup. Methods: We prospectively selected mCRC patients with pMMR/MSS, RAS and BRAF wt tumors harbouring at least one genomic alteration potentially implied with anti-EGFR resistance in published studies ( ERBB2 / PIK3CAexon20 / PTEN / AKT1 / NTRKs / ERBB3 / NF1 / MAP2K1-2-4 / AKT2 / EGFR / subclonal RAS mutations; ERBB2 / MET / ERBB3 / FGFR2 / IGF1R / KRAS / ARAF / AKT1-2 amplification; ALK / ROS1 / NTRKs / RET fusions; EGFR rearrangements; PTEN / NF1 loss), treated with upfront FOLFOXIRI/bev in 11 Italian centres. Assuming that the use of FOLFOXIRI/bev could lead to an increase in median PFS (mPFS) from 9 (as observed with doublets/anti-EGFRs) to 16 months (mos), with one-sided α and β errors of 0.10 and 0.20, respectively, 33 patients were needed. Secondary endpoints were overall survival (OS) and objective response rate (ORR). Outcomes were paired with a propensity score-matched external cohort of pMMR RAS and BRAF wt gene-altered patients treated with doublets/anti-EGFRs in clinical trials. Results: 35 patients were included. Main patients' characteristics were: median age 54 years, ECOG PS 0 83%, left-sided tumours 54%. Amplification in ERBB2 and MET genes accounted for 26% and 6% of cases, respectively. The most frequent mutant gene was ERBB2 (17%), followed by MAP2K1 (9%) , PTEN (9%), NF1 (6%), PIK3CAexon20 (3%), EGFR (3%). Subclonal RAS mutations were found in 14% of tumors. Fusions, detected in ALK and RET genes, accounted for 6% of cases. FOLFOXIRI/bev resulted into a mPFS of 12.3 mos (80% CI: 9.2 – 14.3 mos, Brookmeyer-Crowley test p = 0.023), an ORR of 74% and a mOS of 35.9 mos. PFS and OS with FOLFOXIRI/bev were longer than those achieved in the propensity score-matched cohort of patients treated with doublets/anti-EGFRs (mPFS: 12.3 vs 10.3 mos, HR: 0.74, 95% CI: 0.45 – 1.21, p=0.226; mOS: 35.9 vs 27.2 mos, HR: 0.57, 95% CI: 0.32 – 1.03, p=0.058). Similarly, a numerical advantage in ORR was reported (74% vs 63%, OR: 1.69 95% CI 0.61 – 4.88, p=0.303). No interaction (int) between the effect of treatment and primary tumor location was evident (p intPFS =0.267; p intOS =0.459; p intORR =0.866). Conclusions: Waiting for efficacy results about the upfront use of targeted treatments directed against specific molecular subgroups, FOLFOXIRI/bev may be the preferred first-line option for clinically fit pMMR/MSS RAS and BRAF wt mCRC patients harbouring at least one genomic alteration of potential resistance to anti-EGFRs, regardless of primary tumor sidedness.
Structural determinants of cancer risk: Healthcare violence, mental health, and cancer-related risk behaviors among transgender individuals in Brazil.
e13728 Background: Transgender and gender-diverse populations experience disproportionate exposure to healthcare-related violence, which may adversely affect mental health and engagement in cancer prevention behaviors. However, quantitative data integrating healthcare violence, mental health, and cancer-related risk behaviors remain scarce, particularly in middle-income countries. Methods: We conducted a cross-sectional analytic study among transgender, travesti, and non-binary adults in Brazil using an online self-administered questionnaire. Primary exposures included healthcare-related violence, consistent use of social name, and regular access to healthcare. Mental health was evaluated as a key intermediate construct in the conceptual model, and cancer-related risk behaviors included tobacco use, alcohol consumption, illicit drug use, and risky sexual behavior. Associations were estimated using Poisson regression with robust variance, adjusted for sociodemographic characteristics and healthcare access. Results: A total of 170 participants were included. Nearly half of the sample reported a mental health condition (46.6%), with prevalence exceeding 50% in some gender identities. Frequent healthcare violence was independently associated with mental health problems (adjusted prevalence ratio [aPR] 1.68; 95% CI, 1.05–2.68). Mental health conditions were strongly associated with illicit drug use (aPR 2.15; 95% CI, 1.25–3.70). Tobacco use and risky sexual behavior—both highly relevant for cancer risk—demonstrated marginal associations with mental health after multivariable adjustment, suggesting a potential link attenuated by socioeconomic and access-related factors. Conclusions: Violence in healthcare services emerges as a structural determinant associated with mental health among transgender and gender-diverse individuals, with findings consistent with a pathway connecting psychological distress to behaviors related to cancer risk. Although some adjusted associations with smoking and risky sexual exposures were marginal, the high prevalence of these outcomes suggests relevant implications for equity in cancer prevention. Interventions to reduce institutional violence, expand affirmative practices (including respect for chosen names), and strengthen mental health support may represent low-cost, high-impact strategies for prevention and screening in transgender populations.
BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinoma: Final outcomes of the EXPEL PANC trial.
4201 Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to immune checkpoint inhibitors, in part due to a cold tumor immune microenvironment (TME). BXCL701 (‘701) is a small molecule inhibitor of dipeptidyl peptidases 4, 8, 9 and fibroblast activation protein. We have shown that combinations of ‘701 and anti-PD1 antibodies lead to tumor regression in murine PDAC models due to 1) activation of the inflammasome and expression of CXCL9 to attract and activate CXCR3+ lymphocytes, 2) tumor invasion of CD8+ T cells and other effector cells, 3) induction of adaptive immunity, and 4) reduced fibrosis in the PDAC TME. We sought to evaluate the efficacy of this combination in patients (pts) with previously-treated advanced PDAC. Methods: In this phase II clinical trial (NCT05558982), pts with second-line advanced PDAC received ‘701 at a 0.2 mg PO BID dose on days 1-7 and then 0.3 mg BID on days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID on days 1-14 every 21 days in all subsequent cycles, administered with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective was to determine the 18-week progression-free survival rate (PFS 18weeks ) in pts with advanced PDAC treated in the second-line setting. We estimated that the historical second-line PFS 18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and a power of 80%, if the true rate is 50%, we would need 19 pts in stage 1 and 20 pts in stage 2 (a total of 39 evaluable). Seven of 19 evaluable pts would need to be progression-free at 18 weeks to trigger stage 2. Results: Twenty-one pts were enrolled. Four out of 18 evaluable pts (22%) were alive and progression-free at 18 weeks. Three had partial responses (PR, 17%), and 4 had stable disease (SD, 22%), for a disease control rate of 39%. One responder had MSI-H PDAC, while the other 2 had MSS disease. Median follow-up was 4.5 months. Median PFS was 2.3 months (95% CI 1.6 – 5.3), and median overall survival was not reached (NR, 95% CI 4.5 – NR). Three pts (14%) had PFS exceeding 6 months (2 PR, 1 SD). No new safety signals have been identified. Baseline and on-treatment tumor biopsies will be analyzed to understand the mechanisms underlying therapeutic benefit and to examine the characteristics of responders vs. non-responders. Conclusions: ‘701 plus pembrolizumab in second-line advanced PDAC did not reach the preliminary efficacy endpoint to trigger the second stage. However, there were encouraging signs as this combination induced objective responses in 2 MSS pts, and PFS exceeded 6 months in 3 pts. Ongoing correlative studies should elucidate predictive markers of efficacy and resistance to this novel immunotherapy combination. Clinical trial information: NCT05558982 .
Comparative effectiveness of ALK tyrosine kinase inhibitors in ALK-positive non–small cell lung cancer: A systematic review and network meta-analysis.
e20753 Background: Next generation ALK tyrosine kinase inhibitors (TKIs) have transformed ALK positive advanced non-small cell lung cancer (NSCLC). However, the relative efficacy of newer agents compared with established standards remains unclear. We conducted a network meta-analysis (NMA) to evaluate comparative effectiveness of firstline ALK-TKIs. Methods: We searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and oncology conferences for randomized trials evaluating ALK-TKIs or chemotherapy in advanced ALK positive NSCLC. The primary outcome was progression-free survival (PFS). A Bayesian random effects NMA was performed using crizotinib as reference. Results: Fifteen trials comprising 4,392 patients and nine ALK TKIs were included. All next-generation TKIs significantly improved PFS versus crizotinib. Lorlatinib ranked highest (HR 0.19, 95% CrI 0.13-0.27; SUCRA 0.91), followed by foritinib (HR 0.23) and iruplinalkib (HR 0.31). Alectinib showed consistent benefit with high-certainty evidence (HR 0.39, 95% CI 0.31-0.49). Lorlatinib demonstrated greatest intracranial efficacy (intracranial PFS HR 0.07). OS analyses were limited by crossover, though alectinib showed OS benefit versus crizotinib (HR 0.67, 95% CI 0.53-0.85). Risk of bias was low to moderate; certainty ranged from high to low across comparisons. Conclusions: Next-generation ALK-TKIs significantly outperform crizotinib. Lorlatinib demonstrated greatest PFS and intracranial benefit, while alectinib showed durable efficacy with high-certainty evidence, supporting current guidelines. First-line pfs network meta-analysis results. Treatment HR vs Crizotinib (95% CrI) SUCRA Lorlatinib 0.19 (0.13–0.27) 0.91 Foritinib 0.23 (0.14–0.38) 0.84 Iruplinalkib 0.31 (0.22–0.44) 0.72 Alectinib 0.39 (0.31–0.49) 0.61 Envonalkib 0.47 (0.34–0.64) 0.50 Brigatinib 0.49 (0.35–0.68) 0.48 Crizotinib Reference 0.24
Stage-specific circulating tumor DNA (ctDNA) positivity and minimal residual disease (MRD) decision making in colorectal cancer (CRC) in the prospective INTERCEPT program.
3623 Background: ctDNA positivity is a strong prognostic biomarker for recurrence after curative-intent procedures for CRC and defines MRD in the absence of radiographic disease. Our aim was to assess stage-specific positivity rates across follow-up intervals and the clinical actions associated with ctDNA+. Methods: The INTERCEPT program enrolled patients undergoing curatively intended procedures for stage I-IV CRC at MD Anderson Cancer Center. Tumor informed MRD assays (Signatera) were drawn postoperatively and every 3 months according to reimbursement guidelines. ctDNA draws were grouped into 6-month intervals from completion of definitive therapy. Clinical decisions after the first ctDNA+ result in the MRD window were classified as: MRD-trial, systemic therapy, diagnostic escalation, early follow-up, ctDNA confirmation, or no change. Results: The final cohort included 1,603 patients (40% stage IV, 32% stage III, 20% stage II, 8% stage I). Median follow-up was 18.4 months. Patients that were ctDNA- on first post-definitive draw had longer recurrence-free survival (RFS) than ctDNA+ patients (median RFS 62.6 vs 4.8 months, HR 11.6 [95% CI 9.6-14.1]), remaining significant in stage subgroups. Among all patients 28% were ctDNA+ at any post-definitive timepoint, the rates were highest for stage IV, followed by stage III, II, and I (Table). ctDNA+ rates were highest in early follow-up and got lower at later intervals (21% to 5%), with similar patterns for all stages. Among 271 patients that were ctDNA+ in the MRD window the initial therapeutic approach was MRD trial screening for 59 (22%), diagnostic escalation in 73 (18%), early follow-up in 57 (21%), confirmation of ctDNA+ by repeat testing in 23 (8%), no change in management for 38 (14%), and 21 (8%) patients started other systemic therapy. MRD trials were discussed prior to recurrence with 144 (53%) of the patients. Conclusions: ctDNA positivity is more common in higher stage tumors and becomes less frequent during follow-up. ctDNA positivity confirms its established prognostic value and meaningfully impacts clinical management, including diagnostic workup and MRD trial enrollment. Even within a single center, heterogeneity in initial management of ctDNA+ patients and timing for MRD trial enrollment is evident. Stage-specific ctDNA+ rates during follow-up after definitive therapy. All Stage IV Stage III Stage II Stage I p Any time 444 / 1,603 (28%) 313 / 646 (48%) 87 / 513 (17%) 40 / 322 (12%) 4 / 122 (3%) <0.001 <6 months 329 / 1603 (21%) 249 / 646 (39%) 57 / 513 (11%) 21 / 322 (7%) 2 / 122 (2%) <0.001 6 to <12 months 151 / 1,018 (15%) 97 / 349 (28%) 36 / 351 (10%) 17 / 230 (7%) 1 / 88 (1%) <0.001 12 to <18 months 75 / 672 (11%) 50 / 197 (25%) 15 / 250 (6%) 10 / 161 (6%) 0 / 64 (0%) <0.001 18 to <24 months 16 / 264 (6%) 10 / 71 (14%) 3 / 94 (3%) 3 / 71 (4%) 0 / 28 (0%) 0.019 ≥24 months 9 / 147 (6%) 5 / 41 (12%) 2 / 58 (3%) 1 / 33 (3%) 1 / 15 (7%) 0.259
Multiomic machine learning integration of DNA and RNA features to predict immunotherapy benefit in MSS-CRC and other rare cancers.
2531 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the oncology landscape, yet remain constrained by imprecise predictive biomarkers (i.e., PD-L1, TMB, MSI), which fail to capture the complexity of the tumor microenvironment. The Immune Profile Score (IPS), an AI/machine learning (ML) driven DNA-/RNA-based molecular signature addresses this gap in translational molecular biomarkers of ICI response. IPS integrates TMB, single-gene RNA features and RNA signatures, and was independently validated for prognostic utility in > 1,500 advanced solid tumor patients (pts) treated with FDA-approved ICI. Here we evaluated the ability of IPS to accurately stratify ICI treatment outcomes in two independent cohorts representing traditionally ICI-resistant populations. Methods: From our multimodal real-world database, we used the ML-derived IPS algorithm to analyze two cohorts of high unmet need for which ICI is not approved: 1) microsatellite stable colorectal cancer (MSS CRC); and 2) rare solid cancer as defined by FDA ( < 200,000 cases/year) treated with off-label ICI. Pts were categorized as IPS-H and IPS-L using a previously independently validated and published threshold. Cox proportional hazards models were fit to demonstrate prognostic utility for real-world overall survival (rwOS). Association with time-to-next-treatment (TTNT) on prior chemotherapy (CT) was compared in the same pts to rwOS on subsequent ICI therapy to assess ICI-specific predictive value of IPS . Results: IPS-H consistently identified a subset of pts with improved clinical outcomes across both cohorts. In the MSS-CRC cohort (n = 46): IPS-H pts (6/46 = 13%) had longer rwOS than IPS-L pts (40/46 = 87%) (HR 0.22; 90% CI: 0.04-1.16). No difference was observed in TTNT between IPS-H and IPS-L for prior CT (HR 1.07; 90% CI: 0.60-1.91), while there was improvement in rwOS IPS-H vs IPS-L on subsequent ICI therapy (HR 0.21; 90% CI: 0.04-1.22). In the rare cancer cohort (n = 90): there were 26 solid tumor subtypes without an FDA-approved ICI label; carcinosarcoma (n = 19, 21%) and pancreatic ductal adenocarcinoma (n = 17, 19%) were the most commonly represented. IPS-H pts (16/90 = 18%) had longer rwOS than IPS-L pts (HR 0.26, 95% CI: 0.09-0.73). In this rare cancer cohort, IPS remained significant even when restricted to subtypes with representation from both IPS-H and IPS-L (HR = 0.18, 95% CI: 0.04-0.69). Conclusions: IPS is a novel multiomic genomic signature that identifies a subset of advanced MSS-CRC and rare solid cancer patients who may benefit from ICI therapy. By integrating multimodal genomic features, IPS emerged as a possible predictive biomarker in a population where ICI is not currently approved. IPS suggests a paradigm shift toward AI/ML-driven signatures to refine ICI candidate selection and personalize clinical decision-making in oncology.
Spatiotemporal evolution of immune evasion: Divergent resistance mechanisms in primary refractory versus new primary cutaneous squamous cell carcinomas during anti-PD1 therapy.
e21553 Background: While anti-PD1 therapy is effective in advanced cutaneous squamous cell carcinoma (cSCC), ~50% of patients exhibit primary resistance. A distinct, paradoxical clinical phenomenon involves emergence of new primary tumors arising during therapy (NPADTs), representing de novo malignancies evolving under systemic immune pressure. We hypothesized that these disparate clinical failures represent fundamentally divergent evolutionary trajectories, requiring distinct therapeutic solutions. Methods: We performed an integrated single-cell RNA sequencing (Chromium Flex) and subcellular-resolution spatial transcriptomics (Nanostring CosMx) analysis on a cohort of 14 patients with cSCC treated with cemiplimab or pembrolizumab [primary responders (n = 4), primary non-responders (n = 5), NPADTs (n = 5), healthy skin (n = 7)]. The dataset comprised > 110,000 single cells. Cellular neighborhoods were mapped via spatial transcriptomics integrated with multiplex immunofluorescence. Resistance archetypes were defined using differential composition analysis (Bayesian framework using sccomp to control for biological variability and compositionality), pathway inference (PROGENy), and spatial neighborhood analysis. Results: Transcriptional profiling revealed two distinct resistance phenotypes. Primary resistant tumors are ‘immune-excluded’, characterized by a paucity of intratumoral CD8+ T cells (differential compositional analysis using sccomp; False Discovery Rate < 0.05) and stromal fibrosis. This exclusion was driven by TGF-ß pathway activation and enrichment of myofibroblastic cancer-associated fibroblasts (myCAFs: ACTA2+COL1A1+ ), forming a barrier to T-cell ingress. In contrast, NPADTs exhibited an ‘immune-dysfunctional’ phenotype. Despite high infiltration of CD8+ T cells comparable to responders, these tumors remained refractory. Mechanistic analysis identified a chronic Type I Interferon signature driven by plasmacytoid dendritic cells (pDC). This chronic inflammatory state was associated with expansion of immunoregulatory mature dendritic cells (mregDCs; LAMP3+BIRC3+IDO1+ ). Spatial analysis revealed that mregDCs function as cellular hubs, recruiting FOXP3+ regulatory T cells (Tregs). We observed a significant spatial correlation between mregDCs and Tregs (Pearson r > 0.5), establishing localized immunosuppressive niches that neutralized effector T cells. Conclusions: This study delineates divergent paths for immunotherapy resistance in cSCC: structural exclusion driven by myCAFs in primary resistance versus functional suppression driven by a pDC-IFN-mregDC axis in NPADTs. These findings offer a precision medicine framework for sequencing therapies in cSCCs.
PSA nadir–stratified outcomes of ARPI doublet and docetaxel triplet therapy in metastatic prostate cancer.
e17096 Background: Therapy intensification has expanded combination strategies in metastatic prostate cancer (mPC) with improved outcomes in clinical trials. However, it remains unclear which patients derive incremental benefit from the addition of upfront docetaxel to androgen receptor pathway inhibitor (ARPI)–based doublet therapy. Methods: We identified adults with prostate cancer in the Patient360 Prostate dataset, a U.S.-based de-identified data source derived from electronic health records, linked claims, and mortality data. Patients initiating ARPI doublet (ARPI + androgen deprivation therapy [ADT]), docetaxel doublet (docetaxel + ADT), or triplet (ARPI + ADT + docetaxel) were included. Patient characteristics and treatment regimens were summarized descriptively; overall survival (OS) was estimated using Kaplan–Meier methods. Results: Patients with mPC were diagnosed between 1990 and 2025. Among patients without privacy-compliant date of birth suppression, median age was 67 years; 79.4% were White and 14.3% Black. ECOG performance status was 0–1 in 86.4%. ARPI doublet was the most common regimen (n = 7,676), followed by triplet (n = 1,389) and docetaxel doublet (n = 1,282; total n = 10,347). Compared with ARPI doublet, patients who received docetaxel-containing regimens had higher prevalence of adverse baseline features, including de novo metastatic disease (triplet 65.7%; docetaxel doublet 68.4% vs ARPI doublet 55.2%), liver metastases (14.8% and 17.9% vs 8.7%), and high-grade disease (Gleason 8–10: 55.5% and 57.2% vs 49.2%). Bone-supportive therapy use was also higher (66.7% and 73.4% vs 56.9%, respectively). A PSA nadir < 0.2 ng/mL was achieved in 42.9%, 29.1% and 30.2% of patients receiving ARPI doublet, docetaxel doublet and triplet, respectively. Median OS from regimen start was 109 months (mo) for ARPI doublet, 79 mo for triplet and 64 mo for docetaxel doublet. When stratified by PSA nadir < 0.2 ng/mL, median OS was substantially longer across all regimens (202, 128 and 104 mo, respectively), whereas among patients not achieving PSA nadir < 0.2 ng/mL, differences between regimens were attenuated (86, 71 and 59 mo, respectively). In multivariable Cox regression, baseline disease characteristics independently associated with worse OS included de novo metastatic disease (HR 3.71), liver metastases (HR 1.87), baseline PSA > 200 ng/mL (HR 1.39), and Gleason score 8–10 (all p < 0.0001). Conclusions: In the largest cohort to date comparing ARPI doublet and triplet therapy, ARPI doublet was the most common regimen and was associated with more favorable outcomes, even after multivariable adjustment. Non-achievement of PSA nadir identifies a population with poorer survival in whom docetaxel triplet therapy may be associated with improved outcomes, supporting the rationale underlying the TRIPLE-SWITCH (SWOG/CCTG-PR26) clinical trial.
Incidentally discovered lung cancer in explanted lungs at the time of lung transplantation: Management and outcomes.
e20087 Background: Lung transplantation is an established therapy for end-stage pulmonary disease. Occult lung cancer is incidentally identified in 2% of explanted lungs at time of transplant. Pre-operative detection of cancer is particularly challenging in patients (pts) with ILD, where radiographic findings may obscure malignancy. We report a single-center series of pts with lung cancer incidentally discovered in explanted lungs and describe tumor characteristics, management, and clinical outcomes. Methods: We retrospectively reviewed adult lung transplant recipients at the University of Pennsylvania Health System (2015–2025). Pts with lung cancer identified in explanted lungs were confirmed by chart review. Clinical features, pathologic staging, oncologic and immunosuppressive management, and outcomes post-transplant were abstracted. Results: Eleven pts, all male, were identified. Median age was 65.1 years. Median follow-up post-transplant was 27.1 months. Ten pts (91%) had a smoking history (median 30 pack-years). Transplant indications included fibrotic ILD (45%), CPFE(18%), and COPD (36%). Adenocarcinoma was the most common identified cancer (64%), followed by squamous (27%) and adenosquamous (9%) histologies. Most tumors were early stage (pT1, 64%); nodal disease was present in 36% (all N1) and one pt had M1a disease involving the contralateral lung and pleura. One KRAS G12C mutation was identified. Management included surveillance (55%) or adjuvant chemotherapy (27%); two pts died before discharge after transplantation (excluded from table). Immunotherapy was avoided in adjuvant and recurrent settings. Immunosuppression was modified in 55%, mostly by holding mycophenolate. Chemotherapy was poorly tolerated; only one pt completed therapy. Lung cancer recurred in 27%. Six patients (55%) died, including 2 from lung cancer. Conclusions: We report one of the largest single-center series of incidentally discovered lung cancer in explanted lungs, a high-risk entity with important oncologic management implications. In this series, immunotherapy was not given, immunosuppression was modified, and adjuvant chemotherapy was poorly tolerated. Lung cancer recurred in a quarter of these pts. Pt # Lung Disease Histology Stage Management Time to recurrence (mo) Time to death (mo) Time to last contact (mo) 1 ILD secondary to scleroderma adenocarcinoma pT3, pN1, M0 adjuvant chemo 41 46 2 hypersensitivity pneumonitis squamous pTxpN1M0 adjuvant chemo 44 3 CPFE adenocarcinoma pT1c, cN0, M0 surveillance 29 4 IPF adenocarcinoma cT4, cN1, M1a adjuvant chemo 14 15 6 CPFE with secondary pulmonary hypertension adenocarcinoma pT1b, pN0, M0 surveillance 18 8 mixed COPD/fibrosis squamous pT1aN0M0 surveillance 28 9 COPD adenocarcinoma pT1aN0M0 surveillance 127 10 COPD adenosquamous pT1b, cN0, M0 surveillance 23 11 mixed COPD/fibrosis adenocarcinoma pT1aN0M0 surveillance 17 27
Incremental clinical yield of serial large NGS panel liquid biopsies in routine care: Analysis of the STING study.
3046 Background: Plasma ctDNA profiling is increasingly repeated over the disease course to capture tumor evolution and newly targetable alterations. However, the incremental clinical yield of serial ctDNA profiling in routine practice remains incompletely characterized. Methods: This analysis was conducted within the prospective STING study (ClinicalTrials.gov identifier: NCT04932525), a program that aims to identify actionable molecular targets in patients with advanced solid tumors. Eligible patients were adults with advanced solid tumors and provided written informed consent for molecular analyses. Circulating tumor DNA (ctDNA) profiling was performed using an FDA-approved hybrid-capture next-generation sequencing assay, enabling to analyze over 300 genes, and assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) from plasma samples. All molecular results were reviewed during a weekly institutional Molecular Tumor Board to assess clinical relevance and therapeutic implications. For the present study, patients with ≥2 FMI liquid biopsies were included. The earliest ctDNA test was defined as baseline (BL1), and the second earliest as BL2. Actionable alterations were classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). The primary objective was to determine the proportion of patients in whom repeat ctDNA testing identified new actionable alterations not detected at BL1, and their ESCAT tier distribution. Results: Among 1,565 patients (3,494 liquid biopsies), the median number of tests per patient was 2 (range 2–6). The most common tumors were lung (26.4%), breast (13.1%), prostate (10.9%), colorectal (CRC) (8.0%), pancreas (6.7%), and thyroid (4.1%). The median BL1→BL2 interval was 313.5 days (range 2–2,279). At BL1, 470 patients (30.0%) harbored ≥1 actionable alteration (ESCAT I–III); excluding TMB-high, 23.9%. Repeat testing identified ≥1 new actionable alteration in 316 patients (20.2%); excluding TMB-high, 10.7%. Notably, 227 patients (14.5%) converted from no actionable alteration at BL1 to ≥1 actionable alteration on later testing (8.1% excluding TMB-high). Newly detected actionable alterations were distributed as ESCAT II (54.3%), ESCAT I (26.1%), and ESCAT III (19.7%); 93 patients (5.9%) gained at least one new ESCAT I alteration. The yield of new actionable alterations varied by tumor type (~29% CRC, 25.9% breast, 23.5% lung, 14.6% prostate). Conclusions: In a large real-world cohort, serial ctDNA testing provided clinically meaningful incremental detection of actionable alterations in ~1 in 5 patients, including new ESCAT I findings in ~6%. These data support serial ctDNA profiling to capture evolving tumor genomics and expand therapeutic opportunities. Prospective studies should define optimal timing and confirm downstream clinical impact.
Prognostic value of <i>ESR1</i> mutation status in patients with metastatic breast cancer receiving second-line therapy: A real-world evidence study.
e13140 Background: ESR1 mutations emerge during endocrine therapy and are associated with endocrine resistance in HR+/HER2-metastatic breast cancer (mBC). The independent prognostic value of ESR1 mutations in patients starting second-line (2L) therapy remains unclear in real-world settings. Methods: We conducted a retrospective cohort study using Flatiron Health EHR-derived de-identified database (range: 02/01/2015-12/31/2024) of patients with HR+/HER2- mBC receiving first-line (1L) CDK4/6 inhibitor plus aromatase inhibitor and had ESR1 testing within 90 days of 2L therapy initiation. ESR1 status was classified as Mutated (any positive test within window), or Not Detected (ND, negative test with no prior positive). Primary endpoints were real-world progression-free survival (rwPFS; composite of progression or death) and overall survival (rwOS). Multivariable Cox proportional hazards models adjusted for age, ECOG, calendar year, demographics, metastatic burden, prior adjuvant AI, treatment-free interval,1L duration, practice setting, and sample type (Model A), with additional adjustment for 2L treatment (Model B). Stratified analyses by sample type (blood vs tissue) were also performed. Results: Of 40,437 patients identified, 480 met eligibility criteria with valid ESR1 results (170 ESR1 Mutated [35.4%], 310 ESR1 ND [64.6%]). Blood samples comprised 56% of tests, tissue 42%, other 2%. Patients with ESR1 mutation detected had significantly longer treatment-free interval (median 34 vs 10 months, p = 0.023) and 1L duration (20 vs 12 months, p < 0.001) than patients without ESR1 mutation detected. Median rwPFS was 5.9 months (95% CI: 5.1-9.0) for ESR1 Mutated vs 6.2 months (5.3-8.5) for ESR1 ND; median rwOS was 19.4 months (17.0-26.4) vs 24.0 months (19.3-30.5). In multivariable models, ESR1 Mutated status was associated with significantly worse rwPFS (Model A: HR = 1.60 [1.11-2.31], p = 0.011; Model B: HR = 1.79, [1.21-2.64], p = 0.004) and rwOS (Model A: HR = 1.76, [1.14-2.72], p = 0.011; Model B: HR = 1.93, [1.21-3.09], p = 0.006). Sample type stratification demonstrated the prognostic effect was significant in blood samples (rwPFS Model B: HR = 2.27, [1.36-3.78], p = 0.002; rwOS Model B: HR = 2.09, [1.26-3.47], p = 0.004) but not in tissue samples (rwPFS Model B: HR = 1.20, [0.60-2.39],p = 0.60; rwOS Model B: HR = 1.77, [0.77-4.09], p = 0.18). Conclusions: In this real-world cohort of patients with HR+/HER2- mBC, ESR1 Mutated status demonstrated significant prognostic value for worse rwPFS and rwOS after 1L CDK4/6i plus AI therapy, with effects independent of 2L treatment choice. Sample type stratification revealed that the prognostic signal was driven by blood-based testing, with no effect observed in tissue samples. These results have important implications for interpretation of ESR1 status.
Healthcare utilization and health expenditures among U.S. adults by cancer and atherosclerotic cardiovascular disease status.
e23191 Background: Improvements in cancer prognosis have led to a growing population of cancer survivors who are at increased risk for noncancer comorbidities, particularly atherosclerotic cardiovascular disease (ASCVD). While ASCVD and cancer are major contributors to rising healthcare costs and utilization, less is known about differences in healthcare utilization and health expenditures across individuals with cancer, ASCVD, both conditions, or neither. Methods: Using the Medical Expenditure Panel Survey (2008-2023), we identified adults aged ≥18 years and categorized participants into four groups based on self-reported cancer and ASCVD (myocardial infarction, stroke, coronary heart disease, or angina) status. Healthcare utilization outcomes included ≥2 hospitalizations, emergency department, outpatient, and office-based visits, and any prescription medications purchased or refilled in the past year. Health expenditures reflected annual total direct payments for the same sources of care. Among individuals with any expenditures, annual mean spending was estimated using generalized linear models with a gamma distribution and log link. Multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for healthcare utilization, adjusting for sociodemographic characteristics. Results: Among 334,240 adults, 2.4% had both cancer and ASCVD (representing 5.5 million individuals annually). Compared to individuals without cancer or ASCVD, those with both conditions had substantially higher healthcare utilization, including hospitalizations (aOR, 6.55 [95% CI, 5.76-7.44]) and emergency department visits (aOR, 4.24 [95% CI, 3.83-4.69]). Individuals with cancer or ASCVD alone also had higher utilization, though estimates were consistently greatest among those with both conditions. Similar gradients were observed for outpatient visits (aOR, 2.70 [95% CI, 2.52-2.89]), office-based visits (aOR, 3.51 [95% CI, 3.16-3.88]), and prescription medication use (aOR, 7.05 [95% CI, 5.87-8.47]) among individuals with both cancer and ASCVD, compared to those without either condition. Mean annual total direct healthcare expenditures increased stepwise across groups, from $3,652 among those without cancer or ASCVD to $7,156 among those with cancer alone, $8,174 among those with ASCVD alone, and $9,992 among those with both conditions (absolute difference: $6,340; p < 0.001). Conclusions: Individuals with co-existing cancer and ASCVD experienced the greatest burden of healthcare utilization and health expenditures compared to those with either condition alone or neither condition. Given the growing population of cancer survivors at increased risk of ASCVD, targeted efforts to manage shared cardiometabolic risk factors may help reduce healthcare utilization and prevent adverse cardiovascular events.