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Patient demographics and germline mutation patterns across breast cancer molecular subtypes in a tertiary academic medical center: A retrospective study (October 2023–October 2025).
e13142 Background: Breast cancer is the most commonly diagnosed malignancy among women in the United States and continues to be a leading cause of cancer-related mortality. Despite advancements in screening and treatment, disparities in outcomes persist, particularly in underserved populations. The literature estimates that germline mutations account for 5-10% of breast cancer cases. Hereditary susceptibility involves pathogenic variants in multiple cancer-predisposing genes. Characterizing germline mutation patterns across different breast cancer subtypes can enhance genetic risk assessment, counseling, and personalized management. This study examines patient demographics and germline mutation patterns across breast cancer subtypes at a tertiary academic medical center from October 2023 to October 2025. Methods: We conducted a descriptive, retrospective study of women aged 18 years and older with breast cancer who underwent germline genetic testing at a tertiary academic medical center between October 2023 and October 2025. A total of 107 patients were included in the study. Data were extracted from electronic medical records to identify breast cancer subtypes, patient demographics, and germline testing results. Patients with incomplete genetic testing results or insufficient clinical data were excluded. Germline testing was performed using commercially available certified laboratories, primarily with multigene hereditary cancer panels. Results: The age at diagnosis ranged from 35 to 91 years, with a mean age of 57 years. In this study, African American patients represented the largest group, making up 43% of the sample, with the majority demonstrating negative germline testing results. Among those with positive results in this group, variants of uncertain significance (VUS) were most commonly found in the ATM gene. Hispanic patients represented the second largest group at 37%, showing a predominant positive test result for germline mutations, characterized mainly as VUS in BRCA2 and CHEK2. The ER+/PR+/HER2− breast cancer subtype was the most common, accounting for 51% of cases, and the dominant ethnic group in this subtype was Hispanic. Triple-negative breast cancer was the second most common subtype at 13%, which was observed more frequently among African American patients, the majority of whom did not have a germline mutation. Conclusions: Patients at our tertiary academic center face substantial socioeconomic barriers, including restricted access to genetic testing. This study provides insight into an underserved, multiethnic population that is often underrepresented in clinical trials. These findings highlight the ongoing challenges in interpreting germline results and underscore the necessity for improved access to genetic counseling and testing to support equitable, personalized care.
Survival outcomes of patients with grade 4 IDH mutant astrocytomas: The UT MD Anderson experience.
e14092 Background: The WHO 2021 Classification of CNS Tumors distinguished IDH mutant (IDHmt) Grade 4 astrocytomas from IDH wild type glioblastomas based on presence of microvascular proliferation or necrosis, or CDKN2A/B loss in the setting of IDH mutation. These tumors are reported to have relatively better outcomes compared to their IDH wild-type counterparts; however, the heterogeneity of such outcomes within this subtype highlights the need for a better understanding of the factors that affect overall survival. Previous investigations have suggested that homozygous loss of CDKN2A/B portends a worse prognosis in IDHmt astrocytomas independent of pathologic grade. Other mutations that may worsen prognosis include other alterations in the RB1 pathway and in the RTK-PI3K-mTOR pathway. A small subset of these patients also present with tumors that have a histologically evident primitive neuronal component, which appears to be associated with early recurrence and rapid leptomeningeal spread leading to poor outcomes, but with no known molecular drivers. Methods: In this single institution retrospective cohort analysis, we aimed to identify patient- and tumor-specific factors that influence overall survival in patients with Gr 4 IDHmt astrocytomas using the PROACTIVE bio- and data protocol at MD Anderson. We collected data regarding patient demographics and tumor markers from targeted next-gen sequencing from a patient cohort that presented to MD Anderson between 2021-2025. Results: We identified 44 patients (31 male, 13 female) with Gr 4 IDHmt gliomas with median age at diagnosis of 36.5 (range 24-62), of which 36 were Grade 4 at the time of initial diagnosis (25 male, 11 female) and the remainder were previously treated lower grade tumors that underwent malignant transformation. Of tumors that were Gr 4 at initial diagnosis, 31 had the canonical IDH1 R132H mutation whereas 5 had non-canonical mutations (3 IDH1 R132S, 2 IDH1 R132G); one tumor had homozygous CDKN2A/B loss and 2 demonstrated heterozygous loss. MGMT promoter methylation was seen in 11 tumors (3 transformed), and was not reported in 19 tumors (3 transformed); the other 14 tumors (2 transformed) were considered to be MGMT unmethylated. Median follow-up time for the entire cohort was 20.7 months. There were no deaths in the CDKN2A/B homozygous deletion or hemizygous deletion subgroups. One patient with the presence of MGMT promoter methylation (32 yo female) was deceased at 30.3 months (median follow-up 6.3 months for subgroup). Two patients with MGMT promoter unmethylated status were deceased: one patient (34 yo male) died at 6.2 months, and one patient (33 yo male) died at 25.4 months after diagnosis; median follow-up time was 17.4 months for MGMT unmethylated subgroup. Conclusions: Ongoing studies are assessing the significance of additional mutations within this cohort and their relationship with overall survival and will be presented at the conference.
Glucagon-like peptide-1 receptor agonist for primary prevention of hepatocellular carcinoma in high-risk patients: A real-world analysis across metabolic, viral, alcoholic, and hereditary liver disease.
10522 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. While antiviral and metabolic therapies have reduced incidence, scalable pharmacologic strategies for primary prevention (PP) remain a critical unmet need. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated preclinical antitumor activity and the potential to mitigate hepatic lipotoxicity while promoting metabolic reprogramming to stabilize cirrhosis. However, while chemoprevention signals are observed in metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, the efficacy of GLP-1RAs for PP across diverse liver disease etiologies remains underexplored. To address this gap, we conducted a global, multicenter analysis on the efficacy and safety of GLP-1RAs for the PP of HCC in a pan-etiology high-risk cohort. Methods: A retrospective cohort study was conducted using the TriNetX database (150M patients across 108 health organizations). Adults 18–90 years at elevated HCC risk with ≥ 1 risk factor (chronic viral hepatitis, cirrhosis, MASLD, alcohol use disorder, or hereditary liver disorders) were identified. Cohort A (≥3 months of GLP-1RA) was propensity score-matched 1:1 with Cohort B (non-users) on demographics, HbA1c, BMI, and MELD-Na scores. The primary endpoint was incident HCC, and secondary endpoints were incidence of gastrointestinal (GI) side effects. We employed a 3-month lag period to mitigate immortal time bias. Time-to-event outcomes were assessed via Kaplan-Meier analysis and Cox proportional hazards models. Sensitivity & subgroup analyses were performed to confirm robustness across non-metabolic etiologies. Results: After matching, 592,718 patients were analyzed (296,359 per cohort). Median follow-up was 2,450 days for GLP-1RA users vs 2,114 days for non-users. GLP-1RA use was associated with a 73% reduction in incident HCC (140/296,345 events vs 432/296,198) [HR 0.271 (0.224-0.328)], (NNT=1,015). Notably, the protective effect was most pronounced in non-diabetics [HR 0.179 (0.140-0.229)] and lean patients (BMI < 29) [HR 0.161 (0.103-0.252)]. Risk reductions were sustained across all etiologies, including alcohol liver disease (HR 0.379), cirrhosis (HR 0.456), chronic viral hepatitis (HR 0.477), and MASLD (HR 0.605). GLP-1RA use was associated with a significant increase in GI adverse events. Conclusions: GLP-1RA use was associated with a 73% reduction in incident HCC, consistent across subgroups. The enhanced benefit in non-diabetic and lean cohorts suggests a direct anti-neoplastic mechanism independent of weight loss or glycemic control. The NNT of 1,015 highlights the substantial public health impact of GLP-1RA therapy in preventing a high-mortality malignancy. These findings warrant prospective validation.
Vepdegestrant, a proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus atirmociclib (ATI) in ER+/HER2− advanced breast cancer (ABC): TACTIVE-K phase 1b/2 results.
1075 Background: There is unmet need for therapies that improve clinical outcomes in patients (pts) with ER+/HER2− ABC and disease progression on existing endocrine therapies (ETs). Both vepdegestrant, and ATI, a selective cyclin-dependent kinase (CDK) 4 inhibitor (CDK4i), have shown antitumor activity in pts with ER+/HER2− ABC previously treated with CDK4/6i plus ET. This study evaluated the efficacy and safety of vepdegestrant plus ATI in pts with ER+/HER2− ABC. Methods: This open-label, multicenter, phase 1b/2 study (NCT06206837) enrolled pts with ER+/HER2− ABC who received >1 (phase 1) or 1–2 (phase 2) prior lines of therapy in the ABC setting; 1 prior CDK4/6i-based regimen in any setting was required in phase 2. The study included a dose escalation/de-escalation phase 1b to select recommended doses, and a randomized phase 2 to further assess efficacy, safety, and PK. Baseline ESR1 mutation status (via ctDNA) and its association with efficacy outcomes were also assessed in phase 2. Results: As of Sep 5, 2025, 70 pts (median age, 60 y) received vepdegestrant 200 mg daily plus ATI 100 mg BID (ATI100; n = 36), or 300 mg BID (ATI300; n = 34). Pts received a median of 1.0 prior regimens in the ABC setting. Most pts previously received an aromatase inhibitor (ATI100, n = 33, 91.7%; ATI300, n = 26, 76.5%) and/or a CDK4/6i (ATI100, n = 36, 100%; ATI300, n = 32, 94.1%). Confirmed objective response rate (ORR), clinical benefit rate (CBR; complete response, partial response, or stable disease for ≥ 24 wks), and median progression-free survival (mPFS) are shown in the Table. Efficacy outcomes for pts with baseline ESR1 mutations (n = 27) were consistent with the total population (Table). Two dose-limiting toxicities were reported in phase 1b: a grade (G) 3 platelet count decreased (ATI100) and a G3 neutrophil count decreased (ATI300). Most treatment-related adverse events (TRAEs) were G1/2; G3/4 TRAEs were mainly neutropenia (ATI100, 16.7%; ATI300, 35.3%). PK parameters including AUC tau and C max for vepdegestrant and ATI100/300 at steady state were consistent with previous reports, indicating no clinically impactful drug-drug interactions. Conclusions: In previously treated pts with ER+/HER2− ABC, vepdegestrant plus ATI showed clinical activity in the full pt population and in pts with ESR1 mutations. The safety profile of the combination was consistent with each agent. Clinical trial information: NCT06206837 . Vepdegestrant + ATI 100 mg Vepdegestrant + ATI 300 mg Pts with measurable disease at baseline n = 31 n = 33 Confirmed ORR, % (95% CI) 16.1 (7.1–32.6) 24.2 (12.8-41.0) All pts n = 36 n = 34 CBR, % (95% CI) 44.4 (29.5–60.4) 52.9 (36.7–68.5) mPFS, mo (95% CI) 9.3 (5.4–NE) 11.5 (7.2–NE) Pts with ESR1 mutation n = 13 n = 14 Confirmed ORR, % (95% CI) 15.4 (4.3–42.2) 21.4 (7.6-47.6) CBR, % (95% CI) 46.2 (23.2–70.9) 64.3 (38.8–83.7) mPFS, mo (95% CI) NR (3.0–NE) NR (3.7–NE) NE, not estimable; NR, not reached.
Phase 1 evaluation of the PRAME-targeted ImmTAC brenetafusp in advanced melanoma (Mel).
9527 Background: Brenetafusp (brene) is an ImmTAC bispecific (PRAME × CD3) therapy that promotes T cell recruitment into tumors. Initial Phase (Ph) 1 data showed acceptable safety, robust T cell activation at target doses (TD) ≥ 20 mcg and promising clinical activity in multiple tumors including heavily pretreated cutaneous melanoma (CM) (Hamid 2022, 2024; NCT04262466]). We present updated monotherapy (mono) and PD1 immune checkpoint inhibitor (ICI) combination (combo) safety and efficacy results supporting brene dose selection in Mel (CM, mucosal [Mu] or acral [Ac]). Methods: HLA-A*02:01+ Mel patients (pts) who exhausted standard treatments were eligible. Primary objectives: safety and recommended dose; additional objectives included efficacy, biomarkers and ctDNA response. Brene mono was administered intravenously weekly (QW) with 1-2 step-up doses to TD; TD 40 and 160 mcg were evaluated in expansion. Combo was 160 mcg brene QW + 400 mg pembrolizumab (pembro) Q6W. Molecular response: ≥ 0.5 log [68%] ctDNA reduction by week 9 (Hamid 2024). T cell fitness defined as 3-gene (TESPA1, CD28 and GPR183) signature in blood (Sacco 2024). Tumor PD-L1 measured by immunohistochemistry, beta2 microglobulin (B2m) by immunofluorescence. Results: As of Oct 2025, 66 pts with Mel (median 2.5 prior lines, 100% prior PD1, 30% PD1 refractory [progression <6 mo post start of first anti-PD1], 68% St IV-c/IV-d) received brene mono (TD 40, n=16; TD 160, n=24; other TD 10-320 mcg, n=26). The 40-mcg cohort had more favorable baseline prognostic factors (ECOG PS, tumor burden, ctDNA, prior treatment) and T cell fitness. Ten pts (median 2.5 prior lines, 90% prior PD1, 50% prior BRAF/MEKi, 70% St IV-c/IV-d) received brene + pembro. Safety was similar at TD 40 and 160 mcg with Gr1/2 CRS (56% vs 42%) and rash (44% vs 42%) initially. Gr3/4 events occurred in 25% vs 54%: mainly transient lymphocyte decrease, consistent with mechanism. Of 10 pts with prior ICI Gr3/4 irAE, none had recurrence. Combo profile resembled each agent alone. No new safety signals observed. Disease control, RECISTv1.1 response and ctDNA molecular response rates were numerically higher at 160 vs 40 mcg (Table), with similar rates across subgroups typically less responsive to anti-PD1. Overall survival was associated with baseline T cell fitness and tumor B2m, but not with PD-L1 status. Conclusions: Brene shows promising monotherapy activity in late-line Mel, including difficult to treat populations, without causing ICI-like irAEs, and can be safely combined with pembro. Ph1 results support 160 mcg as the selected dose in the Ph3 PRISM-MEL trial evaluating brene with nivolumab versus standard nivolumab regimens (NCT06112314). Clinical trial information: NCT04262466 . N DCR% (PR + SD) ORR% 6mo OS% ctDNA-evaluableN ctDNA response% Brene mono 66 52 12 83 50 38 40 mcg 16 56 6 81 10 20 160 mcg 24 67 17 79 15 33 PD1 refractory 20 55 10 70 15 53 Ac / Mu 7 57 14 86 5 40 Sum target lesions >10 cm 25 44 12 80 19 32 Brene + pembro 10 70 20 80 5 40 PD1 refractory 6 67 33 67 2 50
Impact of neighborhood socioeconomic deprivation and diet quality on immune checkpoint blockade outcomes.
1545 Background: Immune checkpoint blockade (ICB) has significantly improved survival across multiple advanced malignancies; however, outcomes remain heterogeneous. While socioeconomic disadvantage (SED) is known to adversely affect cancer outcomes through delayed diagnosis and access to care, impact of SEDupon ICB efficacy remains incompletely characterized. The Area Deprivation Index (ADI) is a validated, neighborhood-level measure of SED. We evaluated the association between ADI and clinical outcomes to ICB across a large, multi-state integrated cancer network. Methods: We identified 1,699 adult patients with advanced cutaneous melanoma (CM), renal cell carcinoma (RCC), or urothelial carcinoma (UC) treated with first-line ICB (monotherapy or combination) between 2013–2025 within the UPMC Hillman Cancer Center network (>70 sites across four states). ADI scores were derived from 9-digit ZIP codes at ICB initiation using the Neighborhood Atlas and categorized into quartiles, with higher quartiles indicating greater SED. Primary endpoints were time-to-next therapy (TTNT) and overall survival (OS), measured from ICB initiation to initiation of subsequent systemic therapy or death, respectively. Outcomes were analyzed by ADI quartile using Kaplan–Meier methods and Cox proportional hazards models adjusted for relevant clinical covariates. Analyses were limited to first ICB exposure. Results: Across 2,156.3 person-years follow-up, patients in highest ADI quartile experienced a significantly higher incidence of TTNT events compared with lowest quartile (31.1% vs 22.8%; χ² p=0.008), without a corresponding increase in deaths (39.2% vs 38.4%; χ² p=0.86). Highest ADI status was independently associated with inferior TTNT after first-line ICB in CM (HR 1.51; 95% CI 1.01–2.27; p=0.04), RCC (HR 1.58; 95% CI 1.02–2.45; p=0.04), and UC (HR 2.02; 95% CI 1.11–3.68; p=0.01). Association between ADI status and OS were not statistically significant after adjustment for confounding variables. Univariate and multivariate analyses were performed to control for confounding variables, and confirmed independent prognostic impact of highest ADI quartile upon inferior TTNT. Within a subset of ICB-treated CM patients with available dietary intake data, highest ADI quartile had lowest Healthy Eating Index (HEI) scores (Wilcoxon p=0.01). Conclusions: Neighborhood-level SED is associated with inferior durability of response to first-line ICB across multiple solid tumors. These findings suggest that SED may influence ICB effectiveness beyond treatment access alone and underscore the need to identify biologic and care-delivery mechanisms—potentially including diet, comorbidities, and the gut microbiome—through which deprivation impacts ICB outcomes. Prospective, pan-cancer studies integrating social, clinical, and biological variables are warranted.
Cancer patients’ knowledge and willingness for biospecimen donation at Prisma Health.
e22569 Background: Despite advances in precision medicine, cancer disparities persist among racial and ethnic minorities in the United States. African Americans have the highest mortality for several cancers, while Latinos—especially first-generation immigrants—face elevated risks for specific malignancies. Although biorepository biospecimens are essential for advancing precision medicine, they disproportionately represent individuals of White European ancestry, limiting generalizability. This study examines how knowledge of biospecimen donation relates to willingness to donate. Methods: We conducted a cross-sectional survey of 30 adult cancer patients at the Prisma Health Cancer Institute. Participants completed a structured questionnaire soliciting respondents’ sociodemographic characteristics, cancer type, prior knowledge and perceived benefits of biospecimen donation, trust in medical institutions, and willingness to donate biospecimen for research. Data was analyzed using SAS 9.4. Frequencies and chi-square tests examined associations between knowledge and demographic variables (race, education, and income). Results: The sample was predominantly female (83 %) and White (77 %); 23 % identified as Black. Sixty-three percent reported no previous knowledge of biospecimen donation, yet 93 % expressed willingness to donate for medical research. Most participants believed donation benefits scientific advancement (96 %) and trusted medical institutions to protect privacy (97 %). Among those with prior awareness of donation opportunities, 43 % learned through healthcare providers, while 3 % noted learning through educational institutions. Chi-square analyses revealed no statistically significant differences in knowledge by race (χ² = 0.26, p = 0.61), education (χ² = 0.79, p = 0.68), or income (χ² = 1.29, p = 0.52). Conclusions: Findings demonstrate an opportunity to develop patient friendly education about biospecimen donation as a high willingness to donate biospecimen was self-reported among the cancer patients despite previous low awareness about biospecimen donation. While a disparity among races in willingness to participate in biospecimen was not observed in our participants, engaging trusted healthcare professional’s stakeholders to develop appropriate materials may be used to encourage overrepresentation of minority racial and ethnic groups as a step towards equitable representation in biorepositories. This preliminary data may inform subsequent inclusive engagement and equitable participation in biobanking and cancer research.
Intracranial pharmacokinetics and resistance mechanisms of tucatinib in patients with HER2+/mutant solid tumors and brain metastasis: Results from the WinHER2 study (NCT05892068).
2031 Background: Tucatinib, a potent HER2-selective tyrosine kinase inhibitor approved for the treatment of HER2-positive (+) metastatic breast cancer (MBC) and colorectal cancer (CRC), has demonstrated activity in stable and active brain metastasis (BrM). However, intracranial pharmacokinetics and specific mechanisms of resistance driving BrM progression remain unknown. Methods: This window-of-opportunity, prospective, non-randomized study evaluated tissue and serum levels of tucatinib ([Tt], [Ts]) in patients undergoing BrM resection for HER2+/mutant (mut) MBC, NSCLC, CRC or gastroesophageal cancer. HER2+ MBC patients were enrolled in 2 parallel cohorts: those with progressing BrM while on tucatinib (A) and tucatinib-naïve patients (B); cohort C was comprised of patients with GI malignancy, NSCLC and mutHER2 MBC. All patients received tucatinib 300 mg BID for 4 days preoperatively. [Tt/s] were measured by mass spectrometry in resected BrM and serum at screening and 3 intraoperative timepoints; CSF [T] was collected when available by optional lumbar puncture. BrM tissue was used for correlative studies including WGS, scRNA-seq, and electron microscopy. The primary endpoint compared BrM-to-serum tucatinib ratios between cohorts A and B with lower ratios hypothesized in cohort A. [T] was reported as median and interquartile range (IQR). Results: 9 female patients enrolled between 7/2023 and 12/2025: 3 in cohort A, 5 in cohort B, and 1 HER2+ CRC patient in cohort C. Median age was 48.5 years (43-65). One patient from cohort B was unevaluable due to lack of viable recurrent disease on pathologic examination. Total tucatinib levels in resected BrMs ranged from 2.22 to 192.87 ng/mg, (median=30.82; IQR=16.52-111.84) in cohort A and from 1.5 to 4.21 ng/mg (median=3.04; IQR=1.93-4.05) in cohort B. The median tucatinib serum concentration was 1158.3 ng/mL (range=229.2-3440; IQR=693.78-2299.17) and 365.52 ng/mL (range=167.23-731.03; IQR=176.47-596.37), in cohorts A and B, respectively. The BrM/serum ratio did not differ between cohorts A and B (median=9.7; range=9.0-166.5; IQR=9.43-102.77] vs 7.36 [range=3.77-22.28; IQR=5.26-12.30]). The single cohort C patient had tucatinib BrM level of 1.66 ng/mg and BrM/serum ratio of 7.41. CSF [T] was available in two cohort A patients: it was undetectable in one and 35.71 ng/mL in the other (BrM/CSF ratio: 5401). Conclusions: Patients with progressing BrM while receiving tucatinib had BrM/serum tucatinib ratios similar to those of patients receiving tucatinib for the first time in the trial. These data indicate that intratumoral drug concentration alone is unlikely to account for intracranial acquired resistance. Correlative analyses investigating potential genomic and microenvironmental mechanisms of resistance are ongoing, and results will be presented at the meeting. Clinical trial information: NCT05892068 .
Trends in income-related lung cancer disparities since the introduction of USPSTF screening guidelines.
8072 Background: In 2013, the USPSTF introduced guidelines for lung cancer screening to promote earlier detection. Prior screening programs have unintentionally widened disparities due to limited access in vulnerable populations. We examined national US administrative data to explore the effect of lung cancer screening according to area levels of income. Methods: We studied adults with lung cancer in the SEER 21 Registries Database diagnosed between 2005-2022 over two time periods (pre-screening: 2005-2013; screening: 2014-2022). We evaluated outcomes of survival and stage distribution over varied levels of county median household income (MHI). We calculated descriptive statistics for our sample and used a Cox PH model to evaluate the interaction of time period and MHI while adjusting for other covariates. Results: We identified 485,763 cases in the pre-screening era and 487,001 cases in the screening era, with the median age for each group in the 60-69 years range. Sex, race, rurality, MHI and stage are reflective of US lung cancer demographics. Compared to the pre-screening era, cases in the screening era were more likely to be diagnosed at a localized stage in all MHI groups. The lowest MHI group saw a 24.6% increase in proportion of cases detected at a localized stage, while the highest MHI group saw a 37.5% increase. Median survival increased for all MHI groups with a positive association between MHI and survival gains. In a multivariable Cox PH model, a time period and MHI interaction term indicated that the income-related survival disparity between the highest and lowest MHI groups is 12.2% larger in 2014-2022 than in 2005-2013 (HR = 1.122, p < 0.001). Conclusions: Since the introduction of USPSTF lung cancer screening guidelines in 2013, lung cancers are detected at earlier stages and survival has improved. These changes have been experienced across all income groups, but the income-related disparities in survival have widened. These results indicate a need for additional efforts to ensure that the benefits of lung cancer screening are distributed across all populations regardless of wealth. MHI Year of Diagnosis 3-Year OS 5-Year OS Median OS (Months) Change in Median OS (Months) < $60,000 2005-2013 19.4% (19.2-19.6) 13.8% (13.6-14.0) 8 (7.89-8.11) 2 2014-2022 25.5% (25.1-25.9) 18.3% (17.9-18.7) 10 (9.84-10.16) $60,000 - $69,999 2005-2013 21.8% (21.6-22.0) 15.9% (15.7-16.1) 9 (8.88-9.12) 2 2014-2022 29.2% (28.8-29.6) 21.8% (21.4-22.2) 11 (10.80-11.20) $70,000 - $79,999 2005-2013 22.6% (22.4-22.8) 16.7% (16.5-16.9) 9 (8.89-9.11) 4 2014-2022 31.4% (31.0-31.8) 23.9% (23.5-24.3) 13 (12.78-13.22) $80,000 - $99,999 2005-2013 23.9% (23.7-24.1) 17.7% (17.5-17.9) 9 (8.87-9.13) 6 2014-2022 33.8% (33.4-34.2) 25.8% (25.4-26.2) 15 (14.77-15.24) ≥ $100,000 2005-2013 27.3% (26.9-27.7) 20.6% (20.2-21.0) 11 (10.81-11.19) 8 2014-2022 38.6% (38.2-39.0) 30.1% (29.7-30.5) 19 (18.66-19.35)
Imatinib-related toxicity profile in patients with gastrointestinal stromal tumors seen over a twenty-year period in Ile-Ife, Nigeria.
e23513 Background: The use of Imatinib mesylate in the first-line setting has changed the treatment landscape of GISTs. Imatinib mesylate-related toxicities have been widely reported in previous studies in other populations, but there is a paucity of data on the Nigerian population. Pharmacogenomic studies done in Nigerian patients have revealed remarkable unique differences in the metabolism of Imatinib mesylate, which may suggest different treatment outcomes and related toxicity profiles. It is unclear if Imatinib-related toxicities in the Nigerian population are different from what has been reported in other populations. We set out to investigate Imatinib treatment outcomes and related toxicity profile in Nigeria in patients with GISTs. Methods: This was a retrospective cohort study carried out at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria. Medical records of 135 patients diagnosed with GISTs from January 2003 to December 2023 were reviewed. The primary endpoint was the toxicity profile, and the secondary endpoint was the objective response rate. Grade of toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0, and objective response was evaluated using the RECIST criteria version 1.1. Descriptive statistics were used to summarize patient characteristics, treatment responses, and toxicity profiles. Results: Of all patients reviewed, 124 (96.9%) received standard first-line Imatinib at 400mg/day. One year after the commencement of Imatinib, four patients (3.1%) achieved a complete response, and 15 patients (11.5%) achieved a partial response to Imatinib treatment. Sixty-three patients (48.5%) had stable disease, and 13 patients (10.0%) had progressive disease. Most treatment-related toxicities were mild to moderate (80%), with the majority (77.6%) experiencing non-hematological toxicities, including peripheral oedema (44.7%) and hypopigmentation (35.6%). Neutropenia was the most common hematological toxicity (62.5%). Conclusions: Imatinib mesylate is a tolerable treatment option for patients with GISTs in Nigeria. Defaulting from regular clinic visits was the most common reason for poor drug adherence. The presence of a unique molecular mutation profile in Nigerian patients with GISTs may also have contributed to the observed low objective response rate.
A retrospective cohort study evaluating cetuximab super-responders with recurrent or metastatic squamous cell carcinoma of the head and neck.
e18009 Background: Cetuximab is a key targeted therapy in squamous cell carcinoma of the head and neck (SCCHN), supported by near-universal EGFR overexpression. Early studies established its use with platinum-based chemotherapy and as post-platinum monotherapy, though outcomes remain modest: in platinum-refractory disease, response rates are ~13% with median progression of 2–3 months. Since the advent of immune checkpoint inhibitors, cetuximab is primarily used in later-line or combination settings. Despite limited efficacy, rare exceptional responses lasting 12 months to over 5 years have been reported. Here, we evaluated 13 patients across two academic health systems—the largest series reported to date—to identify features associated with durable benefit. Methods: We conducted a retrospective observational study of relapsed/metastatic SCCHN patients treated with cetuximab for ≥6 months at two academic centers (VCU and FHCC). Thirteen patients were identified through IRB-approved informatics queries and underwent detailed chart review. Treatment duration ≥6 months was defined as durable benefit. Results: Dates of diagnosis ranged from April 15, 2009, to June 7, 2022, with a median disease-free survival of 9.5 months. First-line R/M therapy yielded an ORR of 46.2%, increasing to 71.4% among patients treated with cetuximab plus chemotherapy. Four patients achieved radiographic complete responses, three with cetuximab-based combinations. Median PFS was 7 months and median OS was 35 months, with 69.2% alive at 12 months. Nine patients received second-line therapy, with an ORR of 22% and median PFS of 6 months. Conclusions: Sustained disease control beyond 6 months with cetuximab is uncommon, as historical trials report median treatment durations of 4–5 months. In this multi-institutional series, a subset of patients demonstrated exceptionally durable responses that exceeded historical expectations. Limited benefit from prior therapies argues against indolent disease biology, while deep and durable responses to platinum–cetuximab combinations suggest a biologically distinct subgroup. These findings support further investigation using integrated molecular and tumor microenvironment profiling to better define cetuximab “super-responders.” Line Patients (n) Therapy ORR CR Median PFS (months, 95% CI) Progressions Median OS (months, 95% CI) 1-yr OS (95% CI) First-line 13 Any therapy 46.2% (6/13) 4 7 (4–NA) 8 35 (12–NA) 69.2% (48.19%, 99.5%), First-line 7 Cetuximab + chemo 71.4% (5/7) 3 — — — — Second-line 9 Cetuximab ± chemo 22% (2/9) 0 6 (3–NA) 5 —
Concordance of <i>EGFR</i> and <i>KRAS</i> mutation status between primary non–small cell lung cancer and corresponding metastases: A systematic review and meta-analysis.
e20563 Background: Accurate molecular profiling is critical for NSCLC treatment selection. Metastatic tissue is frequently used for genotyping when primary samples are unavailable. However, reported concordance of driver mutations between primary tumors and metastases varies. We conducted a meta-analysis to quantify concordance rates for EGFR and KRAS alterations. Methods: We searched PubMed, Embase, and Scopus till January 2026 for studies reporting paired primary metastatic testing for EGFR and/or KRAS in NSCLC. Random effects meta analyses were performed using generalized linear mixed models. Subgroup analyses evaluated metastatic site and detection method. Risk of bias was assessed using adapted QUADAS-2; certainty using GRADE. Results: Thirty studies comprising 1,668 paired samples were included. Seventeen studies (1,015 pairs) evaluated EGFR concordance, yielding 86.5% (95% CI, 78.1–91.9; I² = 60.3%). Concordance varied by metastatic site: 78.4% in brain to 91.2% in lymph nodes, though differences were not statistically significant. Eleven studies (369 pairs) assessed KRAS concordance at 85.4% (95% CI, 76.3–91.4; I² = 59.2%). EGFR protein expression and gene amplification showed lower concordance (76.4% and 73.0%). Certainty was moderate for EGFR and low for KRAS. Conclusions: EGFR and KRAS mutation status demonstrates high but imperfect concordance between primary NSCLC and metastases. Clinically meaningful discordance persists, supporting cautious interpretation and consideration of repeat testing when feasible. GRADE summary. Outcome Pairs Estimate (95% CI) Certainty EGFR mutation 1,015 86.5% (78.1–91.9%) Moderate KRAS mutation 369 85.4% (76.3–91.4%) Low EGFR IHC 195 76.4% (66.3–84.1%) Low EGFR FISH 89 73.0% (62.9–81.2%) Low
Longitudinal associations between patient and caregiver quality of life following hematopoietic stem cell transplantation.
12087 Background: Caregivers of patients undergoing hematopoietic stem cell transplantation (HSCT) experience high rates of psychological distress, yet patient-level factors most strongly associated with caregiver outcomes over time remain poorly understood. We evaluated longitudinal associations between patient and caregiver quality of life (QoL) following HSCT. Methods: We conducted a secondary analysis of the PROTECT randomized trial of integrated palliative care during HSCT. Among enrolled patient-caregiver dyads, we measured patient (FACT-BMT) and caregiver (CarGOQoL) QoL at baseline, week 2, and months 3, 6, and 12. Only patient-caregiver dyads that completed both measures were included in analyses at each timepoint. Linear mixed-effects models were used to assess the relationship between changes in patient QoL and changes in caregiver QoL, adjusting for time and treatment arm. Results: Among 186 enrolled patient-caregiver dyads, patients had a mean age of 55.2 ± 12.4 years and 65% were male. Mean CarGOQoL remained stable from baseline through month 12 (range: 74.1–75.9). FACT-BMT declined at week 2 (91.9 ± 20.4) compared to baseline (105.0 ± 18.8), then recovered and improved by month 3 through month 12 (Table 1). In multivariable mixed-effects modeling, within dyads, visits where the patient’s QoL exceeded their usual level were associated with higher caregiver QoL (β = 0.11 per 1-point above the patient’s mean; p < 0.001), adjusted for time and arm. Conclusions: While average caregiver QoL remained stable throughout the follow-up period despite changes in average patient QoL, individual caregiver QoL closely tracked their patient's QoL over the post-HSCT follow-up period. Patient-reported QoL represents a clinically meaningful marker to identify at-risk caregivers. Interventions targeting patient QoL may yield dual benefits for patient-caregiver dyads. Clinical trial information: NCT03641378 . Patient and caregiver quality of life by timepoint. Outcome Baseline (n = 183) Week 2 (n = 157) Month 3 (n = 126) Month 6 (n = 112) Month 12 (n = 109) Patient FACT-BMT (mean +/- SD) 105.0 +/- 18.8 91.9 +/- 20.4 107.0 +/- 18.4 111.0 +/- 19.6 112.0 +/- 19.9 Caregiver CarGOQoL (mean +/- SD) 74.1 +/- 12.0 74.1 +/- 12.7 75.9 +/- 12.8 75.8 +/- 13.8 75.7 +/- 14.8 Spearman 0.37 (p < 0.001) 0.27 (p < 0.001) 0.25 (p = 0.004) 0.40 (p < 0.001) 0.38 (p < 0.001)
Comparative safety and efficacy of obinutuzumab versus rituximab in combination with chemotherapy for follicular lymphoma: A systematic review and meta-analysis.
7068 Background: Follicular lymphoma is one of the most common non-Hodgkin lymphoma subtypes, typically presenting with advanced-stage disease and a relapsing-remitting course. Over the past two decades, anti-CD20 monoclonal antibodies combined with chemotherapy have significantly improved outcomes. Rituximab, a first-generation anti-CD20 antibody, has been the standard of care since approval. Obinutuzumab, a type II glycoengineered anti-CD20 antibody with enhanced antibody-dependent cellular cytotoxicity and direct cell death mechanisms, is a newer option with potential efficacy advantages. While individual randomized trials have shown promising results with obinutuzumab, comparative data on safety and efficacy remain limited. Methods: A systematic search of PubMed, ClinicalTrials.gov, Scopus, Embase, and Cochrane CENTRAL identified relevant English-language randomized controlled trials and observational studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models based on heterogeneity. Statistical significance was set at p<0.05, and heterogeneity was assessed using the I² statistic. Analyses were performed using Review Manager version 5.3, following PRISMA guidelines. Results: Three studies met inclusion criteria, including two retrospective observational studies (Claustre et al., 2023; Berger et al., 2023) and one randomized controlled trial (Marcus et al., 2017). The pooled sample included 1,482 patients, of whom 53% were female. Compared with rituximab, obinutuzumab was associated with higher partial response rates (OR=0.66; 95% CI: 0.50–0.89; p=0.006) and improved disease progression outcomes (OR=0.64; 95% CI: 0.49–0.86; p=0.002). No significant differences were observed in overall response rate (OR=1.18; 95% CI: 0.84–1.65; p=0.34) or complete response (OR=0.82; 95% CI: 0.63–1.06; p=0.13). Obinutuzumab was associated with a higher incidence of adverse events during induction (OR=1.56; 95% CI: 1.04–2.33; p=0.03) and maintenance (OR=1.48; 95% CI: 1.13–1.93; p=0.004). Treatment discontinuation, dose reduction, or interruption due to adverse events occurred more frequently with obinutuzumab (OR=1.65; 95% CI: 1.13–2.42; p=0.01), as did neutropenia (OR=1.38; 95% CI: 1.12–1.71; p=0.002). Conclusions: This meta-analysis demonstrates that obinutuzumab provides improved efficacy, including higher partial response rates and reduced disease progression, compared with rituximab in follicular lymphoma. However, this benefit is accompanied by increased toxicity. Treatment selection should balance efficacy gains against safety risks.
Phase I/II study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in combination with LB4330, a long-acting IL-10, in patients with advanced solid tumors.
2626 Background: LB1410 is an anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Bio Co., Ltd., Shanghai, China. In an ongoing phase I study in patients (pts) with advanced solid tumors (NCT05357651), LB1410 demonstrated an excellent safety profile (RPIID 20 mg/kg) and promising efficacy in various anti-PD-1-resistant solid tumors: ORR 9.1%; DCR 54.5%; n = 66 as of Jan 4, 2026. Antitumor activity was especially notable in anti-PD-1-resistant ccRCC (ORR 11.1%; DCR 77.8%; n = 9) and anti-PD-1-resistant CC (ORR 38.5%; DCR 69.2%; n = 13). LB4330 is a novel, long-acting IL-10 developed by L&L Bio Co., Ltd., Shanghai, China. It is generated by fusing IL-10 to a high-affinity anti-CLDN18.2 antibody and exhibits a significantly extended T 1/2 of 2.3 days. In a completed phase I study (NCT05707676), LB4330 effectively enhanced CD8+ T cell proliferation and activation in cancer pts and achieved a DCR of 36.4% (12/33) in pts with PDAC, CRC and other anti-PD-1-resistant tumors. Given their complementary mechanisms and potential to better enhance antitumor immune activity, a phase I/II study has been launched to evaluate LB1410 in combination with LB4330 in pts with advanced solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG PS 0-1. Pts received LB1410 at 15 or 20 mg/kg in combination with LB4330 at 0.2-0.4 mg/kg IV Q2W, with a maximum of 6 doses of LB4330. A 3+3 dose-escalation design was used to assess safety and tolerability. The selected doses of LB1410 at 15 or 20 m/kg plus LB4330 at 0.4 mg/kg were used for the efficacy expansion study in pts with anti-PD-1-resistant ccRCC and HCC. Results: As of Jan 14, 2026, 15 patients (1 CRC, 1 HCC, 3 NSCLC, 4 CC and 6 ccRCC) had been enrolled: median age 58.5 yrs (42-71 yrs); 57.1% male; 85.7% with prior anti-PD(L)1-based therapies. TRAEs occurred in 13 pts (92.9%), the most common (≥ 20%) being fever, platelet count decreased, pruritus, elevated ALT, elevated AST, elevated creatinine, cough, rash and anemia. Most TRAEs were related to the MOA of LB4330 and were manageable. Grade 3-4 TRAEs occurred in 5 pts (35.7%), including decreased platelet count in 2 pts and IRR, shock symptom and immune-mediated myocarditis in 1 pt each. No DLTs were observed. Among all pts with on-treatment scans, the overall ORR per RECIST 1.1 was 15.4% (2/13) with 2 confirmed PR ; DCR was 30.8% (4/13). Notably, the 5 pts with anti-PD-(L)1-refractory favorable-risk ccRCC showed an ORR of 40.0% and a DCR of 80.0%. 50% ccRCC pts with PR/SD (2/4) had been on treatment for nearly one year or longer. Conclusions: The combination of LB1410 and LB4330 exhibited a manageable safety profile consistent with that observed with each monotherapy. Clinical data in pts with favorable-risk ccRCC support the characteristics and efficacy of LB4330 as an immune-enhancing agent. Efficacy expansion studies are ongoing. Clinical trial information: NCT06468358 .
A phase Ib, open-label, clinical trial of JAB21822 combined with second-line chemotherapy for metastatic colorectal cancer with <i>KRAS</i> G12C mutation.
3544 Background: Glecirasib (JAB-21822), a novel, covalent, small molecule KRAS G12C-GDP covalent inhibitor, has been shown to be effective and safe as monotherapy or in combination with cetuximab in treating patients with refractory, unresectable locally advanced or metastatic colorectal cancer (mCRC) harboring KRAS G12C mutation. There are few data regarding the efficacy and safety of KRAS G12C inhibitor in the second-line setting. This multicenter, phase Ib, open label, single arm study aims to investigate the efficacy and safety of glecirasib in combination with the standard second-line chemotherapy and bevacizumab in patients with mCRC with KRAS G12C mutation who failed first-line treatment (NCT06838338). Methods: Patients (pts) with mCRC harboring KRAS G12C mutation were enrolled and treated with glecirasib (800mg QD) combined with standard second-line chemotherapy (FOLFIRI or FOLFOX) and bevacizumab until disease progression or intolerable toxicity or patient-initiated withdrawal from the study. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), duration of response (DoR) and safety. Results: As of Dec 10, 2025, 26 pts were enrolled and received glecirasib combined with chemotherapy and bevacizumab in four centers. The median age was 58 years with female (54%)/male (46%), ECOG 0 (8%)/1 (92%). A total of 20 subjects had at least one post-baseline tumor assessment. The confirmed ORR and DCR were 50% (10/20) and 100% (10/20), respectively. Median DoR was 10.1 months (95%CI: 2.9, NE), median PFS was 11.5 months (95%CI: 5.5, NE). Any grade treatment-related adverse events (TRAEs) occurred in 23/26 (88.5%) pts, the most common ones (>20%) being diarrhea, nausea and anemia. Grade 3-4 TRAEs occurred in 6 (23.1%) pts. No grade 5 TRAEs occurred. Conclusions: Glecirasib in combination with the second-line standard chemotherapy and bevacizumab demonstrated encouraging efficacy and tolerable safety in the second-line treatment of mCRC patients with KRAS G12C mutation. Clinical trial information: NCT06838338 .
Predictivity of coagulation markers in diagnosing acute promyelocytic leukemia.
e18544 Background: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by life-threatening coagulopathies and bleeding. Rapid diagnosis is critical for prompt initiation of all-trans retinoic acid as confirmatory testing can take days to result. Further evaluation using readily available laboratory tests can aid early rule out of APL in patients presenting with acute leukemia. Methods: A single-center retrospective chart review of adult patients diagnosed with APL and non-APL acute myeloid leukemia (NP-AML) was conducted. All patients diagnosed with APL, confirmed by t(15;17) via FISH or PML-RARα by PCR from 2001 to October of 2025 at Stony Brook University Hospital were included in the analysis, while a similar number of NP-AML were also included. Baseline demographic and laboratory parameters including age, sex, complete blood count (CBC), creatinine, INR, PTT, fibrinogen, and D-dimer were collected and compared using the Mann–Whitney U test for continuous variables or Fischer’s exact tests for categorical variables. Sensitivity and specificity were calculated. Results: 42 patients with APL and 41 patients with NP-AML between 2001 to the present were included in the analysis. Compared with NP-AML, APL patients had significantly lower median platelet counts (16 ×10⁹/L [IQR 11-41] vs 61 ×10⁹/L [IQR 35-128], p<0.00001), white blood cells (3.27 vs 11.46 ×10⁹/L, p=0.007), ANC (0.585 vs 1.17 ×10⁹/L, p=0.044), aPTT (27.45 vs 29.1 seconds, p=0.008), and fibrinogen levels (242 mg/dL [IQR 161-343] vs 552 mg/dL [IQR 449-700], p<0.000027). Median d-dimer was significantly higher in the APL group (5922 ng/mL [IQR 2957-11694] vs 792 ng/mL [IQR 375-2231], p<0.00001). There was no significant difference in gender, hemoglobin, creatinine, INR or PT levels. D-dimer levels > 500 ng/mL were seen in all evaluable APL cases (40/40), corresponding to a sensitivity of 100%. Platelet count <150 ×10⁹/L was present in 41 of 42 APL patients (sensitivity 97.6%). Fibrinogen >250 mg/dL was observed in 40 out of 41 NP-AML patients (specificity 97.6%). Conclusions: When confirmatory diagnosis for subtypes of acute myeloid leukemia is pending, our study showed that D-dimer <500 mg/dL or platelet count >150 ×10⁹/L is highly sensitive in ruling out APL at presentation. Fibrinogen levels <250 mg/dL is also highly specific in excluding NP-AML.
Making telehealth delivery of cancer care at home effective and safe: A pragmatic cluster randomized trial.
TPS1680 Background: Telehealth (TH) use for cancer care has rapidly expanded, both during and following the COVID-19 pandemic. However, evidence regarding safety, feasibility, effectiveness, equity, stakeholder satisfaction, and implementation of telehealth-enabled oncology care remains limited. We seek to assess the impact of TH on these outcomes in breast and prostate cancer patients. Methods: The MATCH-UP pragmatic cluster randomized trial is being conducted at Memorial Sloan Kettering Cancer Center to compare alternate models of TH use in oncology practice. Sixty-two physician practice clusters in breast and prostate medical oncology are randomized 1:1 to enhanced telehealth (ET) or usual practice (UP), stratified by disease type and clinic volume. ET emphasizes TH with expanded home services designed to deliver as many components of care as desired in patients’ homes. Usual care involves routine practice with TH visits at the discretion of the patient and MD or APP. Eligible patients have >=3 prior medical oncology visits and are not enrolled on a therapeutic trial. Automated enrollment is triggered by a routine oncology visit with waiver of informed consent. The ET intervention includes EHR-enabled telehealth scheduling defaults for routine follow-up visits, optional home phlebotomy, structured support for home administration of select injectable medications, and digital support for patients with TH access barriers. The primary endpoint is the proportion of routine medical oncology visits conducted in person among all routine medical oncology visits over 1 year. Secondary outcomes include healthcare utilization, no-show and late cancellation rates, and overall survival. Patient-reported outcomes include: quality of life, healthcare costs, experience of care, and preferences for use of TH at future visits. Clinician-reported outcomes include: experience of care and preferences for TH use at future visits. For patients in the ET arm only, telehealth accessibility, intervention uptake and efficiency, and implementation outcomes, including acceptability, appropriateness, and feasibility, are also being collected. The primary endpoint will be analyzed using generalized linear mixed models with a logistic link, accounting for repeated visits within patients and clustering within randomized practice units and adjusting for stratification factors. Enrollment will continue through March 2026 with follow-up for 12 months. To date, 7256 patients have been enrolled, with 3641 patients assigned to ET, (n=2437 [67%] breast cancer; n=1204 [33%] prostate cancer and 3,615 assigned to UP (n=2252 [62%] breast cancer; n=1363 [38%] prostate cancer). MATCH-UP will generate pragmatic evidence on the effectiveness, patient-centeredness, implementation, and equity-relevant barriers of a scalable, EHR-embedded enhanced telehealth model for breast and prostate oncology care. Clinical trial information: NCT06954337 .
Distinct multi-omic signatures that underlie <i>KRAS</i> variants and survival in <i>KRAS</i> G12R pancreatic cancer.
4234 Background: KRAS mutations are the dominant oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). While KRAS G12D/V variants are associated with aggressive disease and poor prognosis, the biological basis for survival differences among KRAS variants remains incompletely defined. We leveraged a comprehensive multi-omics dataset to characterize variant-specific molecular signatures associated with survival. Methods: Tissue and plasma samples from 72 patients with Stage I/II resectable PDAC were retrospectively analyzed using the Aseesa Stars multi-modal integrated platform. Multi-omic profiling included targeted DNA sequencing, whole-transcriptome RNA sequencing, tissue and plasma proteomics, lipidomics, and computational pathology, generating 6,363 features linked to overall survival (OS). Analyses focused on KRAS wild-type (n=7) and the most prevalent KRAS variants: G12R (n=12), G12D (n=21), and G12V (n=13). Results: Patients with KRAS G12R who underwent upfront resection demonstrated significantly longer OS compared with G12D/V variants (median OS 37.5 vs. 18.9 months; HR 0.50 [95% CI 0.23–1.09]; log-rank p=0.047). Compared with KRAS-WT, combined KRAS-mutant tumors exhibited significant alterations in neutrophil degranulation, apoptosis, protein transport, cell adhesion, and oxidative phosphorylation (OXPHOS) pathways (p<0.05). A total of 381 molecular signatures differed significantly (p<0.05) between G12R and G12D/V cohorts. In direct G12R vs. G12D comparison, 110 features were unique to high OS (p<0.05). KRAS G12R, G12D and G12V shared activation of PI3K/AKT, MET, and PTPN11 signaling, consistent with a common aggressive phenotype. In contrast, KRAS G12R tumors demonstrated significant alterations in major mRNA splicing and OXPHOS pathways (p<0.05). Splicing regulators PLRG1 and RBM8A were reduced in G12R patients by 6% (p<0.03). Six OXPHOS-related signatures also favored high OS, lipid hexosylceramide 24:1 was decreased by 14.59% (p=0.016). Tissue protein ACADS decreased by 5.38% (p=0.025) in G12R high OS, but increased in G12D high OS. Conclusions: KRAS G12R defines a molecularly distinct PDAC subtype with improved survival, characterized by suppressed mRNA splicing signatures and coordinated metabolic remodeling, highlighting variant-specific metabolic and molecular divergence. These findings underscore the importance of KRAS variant stratification for prognostication and future development of variant-specific precision therapeutic strategies.
Timing and prognostic impact of thromboembolic events in lung cancer patients treated with immune checkpoint inhibitors: A time-dependent real-world analysis.
11124 Background: Thromboembolic events (TEEs) are complications associated with malignancy, and emerging evidence suggests immune checkpoint inhibitors may further increase thrombotic risk; however, the prognostic impact of thromboembolic events in the era of immune checkpoint inhibitors, where inflammation and vascular toxicity may be amplified, remains unclear. We analyzed the incidence, timing, and impact on survival of thromboembolic complications in lung cancer patients treated with immunotherapy at a single tertiary academic institution. Methods: We conducted a retrospective study of adult lung cancer patients treated with immunotherapy at a single rural academic center (2015–2025). Thromboembolic events were classified as arterial (myocardial infarction, stroke) or venous (deep vein thrombosis, pulmonary embolism). Clinical characteristics and VAN Index scores were compared by TEE status, and overall survival was assessed using Kaplan-Meier and time-dependent Cox regression to address immortal time bias. Results: Altogether, 505 lung cancer patients received immunotherapy during the study period; patients were predominantly White (76.6%) and male (56.4%), with 21.4% identifying as Black. 22.8% experienced at least one TEE. Histologic subtypes included 59% with non-small cell lung cancer and 41% with small cell lung cancer. The mean age at diagnosis was 65 years. Among patients with TEE, 63.5% experienced arterial and 40.0% venous events. Some patients experienced both venous and arterial events during follow-up. The mean time to first TEE was 404 days, with venous events occurring earlier in the disease course. Patients with TEE had significantly higher comorbidity burden (9.28 vs 6.51) and thrombotic risk by VAN Index (31.99 vs 23.69; both p < 0.001). While unadjusted Kaplan-Meier analysis showed no survival difference (22 vs 19 months; p = 0.126) and multivariable Cox models treating TEE as a baseline exposure showed no independent association with survival (aHR 1.05, 95% CI 0.80-1.38), time-dependent Cox modeling demonstrated a significantly increased mortality risk following TEE (aHR 2.45, 95% CI 1.85-3.26; p < 0.001). Conclusions: Thromboembolic events occurred in nearly one-quarter of lung cancer patients treated with immunotherapy and were associated with higher comorbidity and thrombotic risk. Although standard analyses showed no survival difference, time-dependent modeling demonstrated significantly increased mortality following TEE. These findings demonstrate that failure to account for TEE as a time-varying exposure may substantially underestimate its prognostic impact, underscoring the need for prospective dynamic risk assessment and thromboprophylaxis strategies during immunotherapy.