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Impact of molecular profile on switch maintenance to paclitaxel plus ramucirumab (PTX-RAM) versus continuation of first-line fluoropyrimidine and oxaliplatin (FOX) chemotherapy (ChT) in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: An exploratory endpoint of the ARMANI phase 3 randomized trial.

4060 Background: The ARMANI trial proved the superiority of PTX-RAM switch maintenance over continuation of FOX first-line ChT in patients with advanced HER2-negative G/GEJ cancer. Here, we present the prognostic and predictive impact of baseline gene alterations. Methods: ARMANI was an Italian, multicenter, open-label, randomized phase 3 trial in which patients with HER2-negative G/GEJ cancer who achieved disease control after 3 months of induction FOX chemotherapy were randomized to either PTX-RAM switch maintenance or continuation of FOX. Pre-induction chemotherapy samples were sequenced by means of FoundationOne CDx, a panel comprising 324 cancer-related genes. Variants of unknown significance were filtered out. Presence of at least one pathogenic alteration was used to classify samples as altered or wild-type for the respective pathway (Cell cycle, PI3K, RAS, RTK, TGFβ, TP53 and WNT). Homologous repair deficiency (HRD) positivity was defined as the presence of a positive HRD signature (HRDsig+) as defined by FoundationOne CDx. Results: Sequencing data was available for 130 patients, with 65 patients treated in each arm, and 103 were evaluable for HRDsig. The most frequently altered pathways were TP53 (69.2%), Cell cycle (43.1%), PI3K (24.6%), RTK (24.6%) and RAS (23.1%). Presence of at least one alteration in the WNT pathway was observed for 22/130 patients (16.9%) and was associated with significantly higher rate of objective response to maintenance regimen (55.6% vs 17.3%, p = 0.002), longer mPFS (8.8 vs 6.0 months; HR = 0.54, 95%CI: 0.33-0.89; p = 0.017) and longer mOS (18.1 vs 14.1 months; HR = 0.53, 95%CI: 0.31-0.91, p = 0.021). TP53 pathway status was predictive for OS as switching maintenance to PTX+RAM improved OS in patients without TP53 pathway alterations (mOS 16.8 vs 8.8 months; HR 0.40, 95% CI 0.20–0.78) but not in those with at least one TP53 pathway alteration (mOS 14.7 vs 17.4 months; HR 0.94, 95% CI 0.60–1.48) (p for treatment interaction = 0.044). Ten out of 103 (9.7%) were HRDsig+. HRDsig+ status was not associated with neither PFS nor OS advantage (p = 0.676 and p = 0.623) and was not predictive of better outcomes in the FOX arm (p for treatment interaction for PFS = 0.919 and p for treatment interaction for OS = 0.558). Conclusions: Alterations in the WNT pathway have a positive prognostic significance in patients with G/GEJ cancer who achieved disease control after 3 months of FOX. TP53 pathway alterations bear potential for guiding the choice of PTX+RAM switch maintenance. HRDsig+ is not predictive of sensitivity of FOX in this setting. Clinical trial information: NCT02934464 .

Impact of germline <i>BRCA</i> pathogenic or likely pathogenic variants on fertility potential and reproductive outcomes in young women with breast cancer: A systematic review and meta-analysis.

10606 Background: In young women with a diagnosis of breast cancer (BC), the impact of germline BRCA ( gBRCA ) pathogenic or likely pathogenic variants (PVs) on their reproductive reserve and fertility outcomes remains uncertain. This systematic review and meta-analysis assessed the influence of harboring gBRCA PVs on ovarian reserve, efficacy of fertility preservation (FP) techniques, and pregnancies after BC diagnosis. Methods: A systematic PubMed/MEDLINE search was conducted with no date restrictions up to June 30 th , 2025 (CRD420251114990). Eligible studies included retrospective and prospective case-control or cohort studies and clinical trials, comparing at least one of the following outcomes between gBRCA carriers vs. non-carriers: ovarian reserve parameters [i.e., anti-Müllerian hormone (AMH) levels or antral follicle count (AFC)] at BC diagnosis (objective 1); efficacy of FP techniques (i.e., number of total and mature retrieved oocytes, and cryopreserved oocytes before chemotherapy) (objective 2); likelihood of conceiving after treatments (objective 3). Pooled mean differences and risk ratios (RRs) with 95% confidence intervals (CI) were calculated using a random-effects model. Results: Out of 5,325 screened records, 18 studies met the inclusion criteria and were included in the final analysis (2,631 patients, of whom 737 gBRCA carriers). Mean age of patients at BC diagnosis was 32.6 years for gBRCA carriers and 33.1 years for non-carriers. Among 12 studies (n=1,529 patients) reporting on objective 1, gBRCA carriers (n=399) showed significantly lower AMH levels compared with non-carriers, with a mean difference of -0.5 (95% CI -0.8; -0.2) ng/mL, and a numerically lower AFC count (-0.8; 95% CI -2.3; +0.8). Among the 11 studies (n=1,027 patients) addressing objective 2, gBRCA carriers (n=318) had a lower median number of total oocytes (-1.8; 95% CI -3.3; -0.3), retrieved mature oocytes (-1.6; 95% CI -2.8; -0.3), and numerically lower cryopreserved oocytes (-1.1; 95% CI -2.7; +0.6). Subgroup analyses showed that reductions in ovarian reserve and FP outcomes were mainly driven by BRCA1 carriers (n=184), whereas reproductive outcomes in BRCA2 carriers (n=125) were comparable to those of non-carriers. Regarding objective 3, only one study (n=75 patients) reported the likelihood of conceiving after BC using assisted reproductive technologies (ART) and showed no differences between gBRCA carriers (n=20) and non-carriers (RR 0.28; 95% CI 0.04; 2.04). Conclusions: Young patients with BC harboring gBRCA PVs showed reduced AMH levels and lower FP efficacy, while no differences were observed in pregnancy rates after BC through ART, although evidence remains limited. Prospective studies are needed to optimize oncofertility counselling young gBRCA carriers.

A prospective phase II clinical study of different time-delivered drugs combined with intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.

6061 Background: To compare the effects of combining intensity-modulated radiotherapy administered at different times on the toxic side effects, quality of life (QoL) and long-term survival of patients with locally advanced nasopharyngeal carcinoma (LA-NPC). Methods: A total of 160 patients with LA- NPC were randomized into the experimental group and the control group of 80 patients each, both groups received 2 cycles of TPF (docetaxel, cisplatin, and 5- fluorouracil) induced chemotherapy sequential synchronous radiochemotherapy, the experimental group received chrono- chemotherapy, while the control group received conventional chemotherapy. Primary study endpoints included Grade ≥ 3 acute adverse reactions, Secondary study endpoints included quality of life and 8- year overall survival (OS), progression- free survival (PFS), distant metastasis- free survival (DMFS), and local recurrence- free survival (LRFS). Results: As of October 10, 2024, the incidence rates of grade ≥ 3 acute vomiting, oral mucositis, leukopenia, and neutropenia in the experimental group were 3.75%, 6.25%, 27.5%, and 35.0%, while those in the control group were 15.0%, 16.25%, 47.5%, and 52.5%, and the differences were statistically significant (P &lt; 0.05). In the experimental group, the incidence rates of Grade 1- 2 xenosomia and hearing impairment were 63.2% and 23.5%, respectively, compared to 80% and 48.6% in the control group, with a statistically significant difference (P &lt; 0.05), and no Grade 3- 4 late toxicities were reported in either group. The experimental group demonstrated significantly higher overall QoL scores compared to the conventional group, with statistically significant differences in vomiting, general health status, and quality of life scores between the two groups (P &lt; 0.05). However, no statistically significant differences were observed in 8-year OS, PFS, DMFS, or LRFS between the groups (P &gt; 0.05). Conclusions: The integration of chronotherapy with IMRT significantly reduced adverse reactions and improved quality of life with LA-NPC, without compromising long-term survival outcomes. Clinical trial information: NCT02937519 .

Neuroendocrine tumors: Real-world evidence from a national cancer institute in Panama.

e16324 Background: Neuroendocrine tumors (NETs) are rare and heterogeneous malignancies with limited epidemiologic data from Central America. This study describes demographic patterns, tumor characteristics, metastatic burden, and survival outcomes among patients with NETs treated at the National Cancer Institute of Panama. Methods: We conducted a retrospective observational study of patients with histologically confirmed NETs managed between 2016 and 2023. The protocol received institutional ethics approval before data extraction. Overall survival (OS), defined from histologic diagnosis to death or last follow-up, was the primary endpoint. Eligible patients were adults &gt; 18 years with pathologically or immunohistochemically confirmed NET. The primary endpoint was overall survival (OS). Survival was estimated using the Kaplan–Meier method and evaluated across age groups, grade, and anatomical site. Results: A total of 340 patients with NETs were identified. Mean age at diagnosis was 59 years, and females comprising 56.2% of the cohort. Metastatic disease at presentation was observed in 46.8% of cases. Tumor grade distribution was 48.8% G1, 21.8% G2, and 27.1% G3 tumors. The most common primary sites were colorectal (17.6%), lung (14.4%), pancreas (13.8). Median OS was 43 months, with a mean survival of 50 months. Survival differed by age group, with 5-year OS of 68.9% ( &lt; 40 years), 44.5% (40–59 years), 41.6% (60–80 years), and 11.7% ( &gt; 80 years). OS also varied by tumor grade, with 5-year OS of 75.6% for G1 tumors, 27.7% for G2, and 13.7% for G3. Survival by primary site showed the highest 5-year OS in appendiceal (92.3%) and breast NETs (88.0%), followed by small bowel (64.8%), duodenum (63.5%), stomach (54.9%), and colorectal tumors (49.1%), while lung (31.6%), pancreatic (26.9%), indeterminate (23.5%), and other sites (23.4%) demonstrated the poorest outcomes. Conclusions: This real-world cohort highlights a substantial burden of neuroendocrine tumors in Panama, characterized by a high proportion of metastatic disease at diagnosis and marked heterogeneity in survival across age groups, tumor grade, and primary site. Favorable outcomes observed in low-grade and appendiceal tumors contrast with the markedly poor survival of high-grade, pancreatic, and elderly patients. These findings underscore the need for earlier detection, standardized diagnostic pathways, and strengthened registry-based strategies to inform and improve NET care in Latin America.

Endocrine adverse events associated with immunotherapy: A retrospective cohort study.

e23387 Background: Immunotherapy (IT) are a cornerstone of cancer therapy but are associated with immune-related adverse events (AEs). Real-world studies often lack a comparative control group, limiting causal inference. We evaluated the incidence &amp; risk of endocrine (Endo) AEs in patients receiving IT versus non-IT therapies. Methods: We conducted a retrospective cohort study of adult cancer patients (n = 5,556) treated between January 2010 &amp; December 2022 within the Cleveland Clinic health system in Ohio. Patients receiving IT were compared with non-IT patients. Anti–PD-1/PD-L1 &amp;/or anti–CTLA-4 agents accounted for 99.9% of IT exposure. Follow-up began at first systemic therapy until Endo-AE, death, or last follow-up. Endo-AEs included hypothyroidism, thyrotoxicosis, hypophysitis, primary adrenal insufficiency, &amp; hyperglycemia. Cumulative incidence rates (CIR) were estimated by first-line IT exposure. Cox models treated IT as a time-dependent covariate. Incidence rates per 100 person-years were calculated using the Poisson distribution. Results: Among 5,556 patients,1,291 (23%) received first-line IT &amp; 948 (17%) received second-line IT. Median age was 66 years; 38% were female &amp; 87% White. The cohort was predominantly composed of patients with advanced lung cancer, including stage IV non–small cell lung cancer (29%) &amp; advanced small cell lung cancer (11%). Other common malignancies included esophageal/gastric cancers (stages II–III, 14%; stage IV, 11%), bladder, kidney, endometrial, &amp; other advanced solid tumors. Median follow up of 14 months (CI: 6-34), a total of 120 endocrine-AE were observed (Table 1), including hypothyroidism (n = 84; IT: 51 vs non-IT: 33), hyperglycemia (n = 14; IT: 8 vs non-IT: 6), primary adrenal insufficiency (n = 13; IT: 10 vs non-IT: 3), thyrotoxicosis (n = 7; IT: 4 vs non-IT: 3), &amp; hypophysitis (n = 4; IT: 3 vs non-IT: 1). Among hypothyroidism cases, 76% were CTCAE grade 2; 35% required hormone replacement, 6% required treatment discontinuation, 1% were central, &amp; 32% subclinical. Conclusions: IT is associated with a significantly increased incidence of Endo-AEs that may occur beyond the first year of treatment. Events were predominantly grade 1–2, rarely required immune-modulating therapy, &amp; infrequently resulted in permanent treatment discontinuation, supporting the overall safety of IT with appropriate monitoring. Characteristic IT group (n=1,291) Non-IT group (n=4,265) Endocrine: absolute number of AE 74 46 Endocrine: Incidence rates per 100 person years (95% CI) 0.30 (0.23-0.37) 0.04 (0.03-0.05) Endocrine: 24-month CIR (95% CI) 8.0 (6.1-9.8) 1.2 (08-1.6) Endocrine: Time dependent Cox HR 13.7 (8.6-22), P&lt;0.001 Ref Hypothyroidism: absolute number of AE 51 33 Hypothyroidism: Incidence rates per 100 person years (95% CI) 0.20 (0.15-0.26) 0.03 (0.02-0.04) Hypothyroidism: 24-month CIR (95% CI) 5.6 (4-7) 0.7 (0.4-1) Hypothyroidism Time dependent Cox HR11.8 (6.9-20), P&lt;0.001 Ref

mTOR activation and racial disparity in early breast cancer survival.

569 Background: Black women have lower survival rates following a diagnosis of estrogen receptor-positive (ER+) early breast cancer (EBC) compared with White women, with 80% higher mortality and more frequent genomically high-risk tumors (Hoskins et al, JAMA Oncol, 2021). A whole-transcriptome comparison of 412 luminal tumors from Black women with EBC and age-matched White women showed increased mTOR signaling in tumors from Black patients (Hoskins et al. J Clin Oncol 2021, 39:15_suppl, 1009-1009), suggesting a molecular driver of the survival disparity. This study aimed to confirm increased mTOR pathway activation at the protein level in Black patients with an independent cohort, and to explore factors responsible for racial differences in luminal tumor biology. Methods: A breast tumor tissue microarray (TMA) comprising primary tumor cores from diverse patients with EBC was analyzed with multiplex immunofluorescence staining to quantify protein markers of mTOR pathway activation (pS6K and pAkt). Image segmentation was performed with pan-cytokeratin staining to delineate tumor cells from stromal cells. Halo HighPlex image analysis software was used for automated digital image analysis to calculate an H-score for each tumor core. Ancestry admixture analysis was performed with ancestry informative markers that are located within coding regions of genes using RNAseq data generated from tumors represented on the TMA. Data on contextual factors was obtained by geocoding patients’ residential address at the time of diagnosis and linking to a census tract-level measure of neighborhood disadvantage (Area Deprivation Index-ADI). mTOR pathway activation levels were compared by self-identified race, proportion of African ancestry, body mass index (BMI), insurance status, and ADI. One-sided t-tests evaluated mean H-scores for pS6K and pAkt in tumor cells for various comparisons. Results: Analysis of 70 ER+ primary tumors from Black patients and 43 tumors from White patients showed mean pS6K staining in pan-cytokeratin-positive cells was significantly higher in tumor cores from Black compared with White patients (p-value = .05). Ancestry admixture analysis (dichotomized by the proportion of African ancestry &gt; 0.4 vs. &lt; 0.4) showed significantly increased pS6K staining in patients with greater proportion of African ancestry (p-value = .04). There was no association with ADI (p-value = .30). Analyses of association with insurance status and BMI, multivariable analyses, and survival analyses are ongoing and results will be presented, along with data on pAkt staining. Conclusions: This study demonstrated increased mTOR pathway activation at the protein level in Black women with ER+ EBC, confirming the result of a prior gene expression analysis. The underlying cause of this racial difference is unknown, but findings support development of clinical trials targeting the mTOR signaling pathway to mitigate racial disparity in EBC survival.

Evaluation of butyrate and chenodeoxycholic acid (CDCA) for anti-inflammatory and hepatoprotective effects in various liver cancer models.

e16257 Background: The gut-liver relationship plays an important role in maintaining the intestinal barrier, regulating immune response, and proliferation of hepatocytes, along with modulating the biochemical profile. Perturbation in the gut results in gut dysbiosis, leading to leaky gut, and immune disorders in the gut, liver and in the host physiology on the whole. Any or all these changes may trigger the occurrence of hepatocellular carcinoma (HCC) in the host. Butyrate (NaBu) is a potent antioxidant, anti-inflammatory, pro-apoptotic, histone deacetylase inhibitor, has a role in Cell cycle arrest, can activate the GPCR, and promotes gut health. Chenodeoxycholic acid (CDCA) can activate Farnesoid-X-Receptor, act as an anti inflammatory, inhibit angiogenesis, maintain glucose homeostasis and insulin resistance, and help in regulating the gut microbiome. NaBu is a SCFA, secondary metabolite produced by the gut microflora; and CDCA, a bile acid metabolite could restore the dysbiotic state of the gut and altered bile acid mechanism respectively and may potentially work on the Gut-Liver axis. Methods: In vitro anti-proliferative efficacy of NaBu and CDCA was determined on HepG2 cells compared with 5-flourouracil (5-FU). Various assays like Cell viability assay by MTT, gene expression study and ROS assay was performed. Reversal potentials of NaBu and CDCA was evaluated in chemical induced HCC male rats. Efficacy was determined by serum biochemical, histopathological, gene expression, HPLC and cytokine studies. Results: The IC50 of NaBu, CDCA and 5-FU are mentioned in the Table. The expression studies showed NaBu was more efficacious than CDCA and 5-FU. The potential concentration of NaBu and CDCA was further given to in-vivo model to check their efficacy and toxicity. The histopathological analysis of NaBu group when compared with diseased control showed at par results with 5-FU. The cytokine levels showed an altered in disease control and was restored in treatment groups. Gut dysbiosis as identified in HPLC analysis showed reversal in Butyrate groups as compared to CDCA group. Conclusions: We can conclude that with the treatment of Butyrate, and CDCA are beneficial for the reversal of HCC with an improved bile acid mechanism and restored gut dysbiosis. The combination effect of butyrate and CDCA showed synergistic effects which can be a potential strategy in treating liver cancer. IC 50 values for 5-fluorouracil, butyrate, and chenodeoxycholic acid (CDCA). 5-Flourouracil IC 50 Butyrate IC 50 CDCA IC 50 131 ± 21µg 672.8 ± 54µg 232.2 ± 21µg

Impact of HSPA6 on lenvatinib resistance in HCC via phase separation–mediated TXNRD1 stabilization and ferroptosis suppression.

4119 Background: Lenvatinib is a first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is frequently limited by intrinsic and acquired resistance. The underlying molecular mechanisms remain incompletely understood, and strategies to overcome resistance are urgently needed. Methods: We integrated genome-wide CRISPR/Cas9 screening, transcriptomic profiling of lenvatinib-resistant HCC cells, and proteomic analysis of patient tumors to identify key mediators of resistance. Results: Heat shock protein family A (Hsp70) member 6 (HSPA6) emerged as a central driver of both intrinsic and acquired resistance, was consistently upregulated in resistant models, and was associated with poor response and reduced survival in lenvatinib-treated patients. Functional studies demonstrated that HSPA6 knockdown sensitized HCC cells and xenograft tumors to lenvatinib, whereas HSPA6 overexpression conferred resistance both in vitro and in vivo . Mechanistically, HSPA6 recruited the deubiquitinase ubiquitin-specific protease 9X (USP9X) to stabilize thioredoxin reductase 1 (TXNRD1), thereby suppressing lenvatinib-induced ferroptosis. Moreover, lenvatinib enhanced HSPA6 liquid–liquid phase separation (LLPS) through its intrinsically disordered region 1 (IDR1), facilitating the formation of HSPA6–USP9X–TXNRD1 condensates that reinforced TXNRD1 stability. Through structure-based virtual screening, we identified canagliflozin, an FDA-approved sodium–glucose cotransporter 2 (SGLT2) inhibitor, as a direct HSPA6 binder that disrupted this complex, restored ferroptosis sensitivity, and synergized with lenvatinib in preclinical models. Conclusions: Our study defines a novel HSPA6-driven resistance axis that integrates chaperone function, phase separation, and redox homeostasis to suppress ferroptosis in HCC. Targeting this axis with canagliflozin represents a promising therapeutic strategy to overcome lenvatinib resistance.

Anti-tumor activity and safety of SYN429, a synthetic type I IFN.

e14561 Background: Immune checkpoint inhibitors (ICIs) are effective for some types of cancer; however, a large population of patients fail to respond or develop resistance. Therefore, there remains an unmet need for patients that don’t respond to ICIs. Type I interferon (IFN) signaling is central to antitumor immunity through activation of antigen-presenting cells (APCs), promotion of T cell priming and effector function, and induction of PD-L1 that sensitizes tumors to anti–PD-1/PD-L1 therapy. Type I IFNs have demonstrated efficacy in the clinic and are approved in multiple cancers; however, the utility of type I IFNs is limited by toxicity. To address these limitations, we developed synthetic interferons (SYNs) designed to improve the anti-tumor properties of type I IFN while improving safety. SYN molecules are partial agonists composed of bispecific antibody domains that engage IFNAR1 and IFNAR2, enabling tunable activation of the IFN pathway with distinct biological outcomes. Methods: STAT phosphorylation in human peripheral blood mononuclear cells (PBMCs) was assessed by flow cytometry. Mixed lymphocyte reactions (MLR) were performed using primary monocyte-derived dendritic cells and T cells. Antitumor efficacy was evaluated using syngeneic mouse tumor models. Results: In preclinical studies, the SYN429 molecule activated the type I IFN pathway to mediate anti-tumor activity while showing reduced induction of CRS-associated inflammatory cytokines and reduced anti-proliferative activity compared to IFN-α in vitro. This is consistent with the profile of SYNs which show an improved safety profile compared to IFN-α in vitro and in vivo. The lead SYN429 molecule increased PD-L1 and HLA expression on tumor cells in a dose-dependent manner in vitro. SYN429 enhanced T cell activation in MLR assays with greater potency compared to IFN-α, and the observed SYN429-dependent T cell activation was further increased by combination with ICIs. In the MLR assays, SYN429 induced IFN-γ production without inducing cytokines associated with CRS, including IL-6 and TNF-α. In addition, SYN429 promoted activation of APCs, as indicated by upregulation of CD80 as well as other activation markers. In syngeneic mouse tumor models, SYN429 demonstrated anti-tumor activity as a monotherapy that was comparable to ICIs, while SYN429/ICI combinations profoundly enhanced tumor growth inhibition. Mice that achieved complete tumor regression rejected subsequent tumor re-challenge, indicating induction of durable, protective antitumor immunity. Conclusions: These findings demonstrate that SYN429 exhibits potent anti-tumor immunity as a monotherapy and shows potential synergy in combination with immune checkpoint blockade in preclinical models. SYN429 represents a promising therapeutic approach that harnesses the type I IFN pathway to drive new biology for improved efficacy and safety.

Molecular profiling and perioperative management of inflammatory myofibroblastic tumors at a single institution.

e23519 Background: Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm often driven by kinase fusions, most commonly involving anaplastic lymphoma kinase (ALK). Although tyrosine kinase inhibitors (TKIs) have demonstrated activity in unresectable IMT, the role of targeted therapy perioperatively is not well established. We evaluated the molecular profiles and clinical outcomes of IMTs at a single institution, describing the prevalence of actionable gene fusions and use of neoadjuvant targeted therapy. Methods: We performed a retrospective review of all patients with IMT at Columbia University Irving Medical Center from 2005 to 2025. Clinical and treatment data were analyzed. RNA-based fusion testing was performed on archival tumor specimens when available, and prior DNA/RNA sequencing results were reviewed when available. Results: Twenty-seven IMT patients were included. 59% were male and the average age at diagnosis was 41 years (range 1.5-81). Tumors arose in multiple sites, including the lung (22%), kidney (15%), head and neck (15%), and gastrointestinal tract (15%). 14 tumors underwent successful RNA-based sequencing, of which 12 (86%) harbored kinase fusions. ALK fusions were present in 9 (64%), ROS1 in 2 (14%), and a VCAN-IL23R fusion in one case. FN1-ALK was the most common fusion subtype (n=3), all occurring in bladder IMTs. Surgical resection was the primary treatment for 26/27 patients. Four patients received neoadjuvant therapy. Two patients with ALK-rearranged IMTs were treated with neoadjuvant ALK inhibition, resulting in one complete metabolic response (alectinib) and one partial response (crizotinib) prior to resection. The VCAN-IL23R case demonstrated recurrence and progression despite multimodal therapy. Two additional patients developed recurrence managed surgically. Conclusions: Kinase fusions were common (86% of sequenced tumors) and molecularly diverse in this IMT cohort, supporting routine use of RNA-based fusion profiling. Despite the high prevalence of actionable alterations, TKI use remained limited. The favorable responses to neoadjuvant ALK inhibition demonstrate the potential role for perioperative targeted therapy. The aggressive clinical phenotype seen in the VCAN-IL23R fusion case suggests that rare non-ALK fusions may represent biologically distinct IMT subsets with limited treatment options. Together, these findings support earlier incorporation of molecular testing with expanded investigation of rare gene fusions and highlight the need for prospective evaluation of perioperative TKI strategies. IMT molecular fusion profiles. Fusion Type N (%) Fusion partner(s) Tumor location Age range ALK 9 (64) FN1 (3), CLTC, MCC, TMP4, CLIP2, CSTF3, KIF5B Bladder (3), lung (3), head/neck (2), breast 2-77 ROS1 2 (14) FN1, TFG Lung, small intestine 13-18 IL23R 1 (7) VCAN Liver 12 No fusion detected 2 (14) N/A Epididymis, head/neck 70-78

Immune-mediated toxicities (irAEs) in immune checkpoint inhibitor (ICI) therapy in various combinations: A real-world sample.

e23376 Background: ICI either alone or in combination with other ICI, tyrosine kinase Inhibitors (TKI), or chemotherapy (CTX) are standard of care for many cancer types. We studied rates of irAEs in a diverse, real-world cohort treated with ICI alone and in various combinations. Methods: We analyzed a real-world clinical dataset of all patients (pts) treated with ICI within the MedStar Health system from 2011-2020. Data regarding treatment regimens and irAEs were obtained from a previously created and curated GU Immunotherapy registry. Initial ICI regimens were subdivided into ICI monotherapy (Mono), ICI+ICI, ICI+CTX, and ICI+TKI. Results: 1927 pts were analyzed, 44.1% female (n = 850), 32.5% African American (n = 626), 56.6% White (n = 1090), average age 65 (16-95). Compared to Mono, rates of most irAEs including rash (32.6% vs 14.4%, p = 0.0001), hepatitis (26.4% vs 6.5%, p = 0.0001), and colitis (16.7% vs 7.0%, p = 0.0001) were significantly higher with ICI+ICI. The ICI+ICI group was comprised of majority melanoma (57.3%) pts. Pneumonitis was higher with ICI+CTX (9.6% vs 5.5%, p = 0.0074) and endocrine irAEs were more common in ICI+TKI (36.1% vs 10.4%, p = 0.0001), especially hypothyroidism (27.8% vs 7.6%, p = 0.0001). Pneumonitis (21.0% vs 5.5%, p = 0.0001) and overall toxicity (65.6% vs 43.3%, p = 0.0001) was higher in durvalumab compared with other Mono agents. The durvalumab group was comprised of pts with lung cancer (98.3%) and a smoking history (100%). Rates of thyroid toxicity (7.3% vs 8.7 %, p = 0.4228) and rash (11.3% vs 14.4%, p = 0.2008) were numerically lower in the ICI+CTX group. Within a lung cancer subgroup, thyroid toxicity was still lower in ICI+CTX (6.5% vs 10.1%, p = 0.0954); however, rash was slightly higher (12.9% vs 11.7%, p = 0.6322). Conclusions: Our results show variability in incidence of toxicity in pts receiving ICI Mono compared with various ICI combinations in a large, diverse, real-world sample representative of a more general pt population. We highlight the potential for enhancing irAEs in combination regimens of multiple ICI agents and ICI combined with TKIs. We also highlight a unique aspect of ICI+CTX where, there is a trend toward lower irAEs suggesting less immune activation with such regimens. Further, the heterogeneity in irAEs observed from various treatment regimens appear to be heavily influenced by the comorbidities common to distinct cancer types. Thyroid Colitis Pneumonitis Hepatitis Rash Mono 119/1363 (8.7%) 96/1363 (7.0%) 75/1363 (5.5%) 88/1363 (6.5%) 192/1363 (14.4%) ICI+ICI 48/227 (21.1%) 38/227 (16.7%) 11/227 (4.8%) 60/227 (26.4%) 74/227 (32.6%) p=0.0001 p=0.0001 p=0.6855 p=0.0001 p=0.0001 ICI+CTX 22/301 (7.3%) 27/301 (9.0%) 29/301 (9.6%) 22/301 (7.3%) 34/301 (11.3%) p=0.4228 p=0.2475 0.0074 p=0.5900 p=0.2008 ICI+TKI 11/36 (30.6%) 4/36 (11.1%) 0/36 (0%) 4/36 (11.1%) 2/36 (8.3%) p=0.0001 p=0.3497 p=0.1480 p=0.2661 p=0.1438

AI-derived tumor microenvironment features and recurrence risk in microsatellite-stable colon cancer after adjuvant chemotherapy.

3646 Background: Despite adjuvant chemotherapy, a substantial number of patients with stage II–III microsatellite stable (MSS) colon cancer relapse. While clinicopathologic and circulating tumor DNA (ctDNA) analysis can be used for risk stratification, there is a need for further improvement in risk prediction. Here, we utilized artificial intelligence (AI) applied to hematoxylin and eosin (H&amp;E) slides, which enables efficient and comprehensive assessment of tumor microenvironment (TME). Methods: We retrospectively analyzed TME of high-risk stage II and III colon cancer patients treated with surgery and adjuvant fluoropyrimidine and oxaliplatin chemotherapy. AI-based quantification of tumor area, stromal area, and TME cells (lymphocytes, fibroblasts, macrophages, and endothelial cells) was performed using Lunit SCOPE IO. We developed a generalized linear model with a backward elimination process integrating AI-derived TME features with conventional clinicopathologic variables (T stage, N stage, tumor differentiation, lymphatic invasion, venous invasion, and perineural invasion). The optimal cutoff for distinguishing between high-risk and low-risk patients for relapses was determined using the Youden index derived from the model's receiver operating characteristic curve. We evaluated how the model stratified the risk group in the training cohort and validated it in an independent cohort. Results: In the training cohort (n = 390), high stromal lymphocyte density (HR 0.42, 95% CI 0.26 – 0.68), high tumor-stromal ratio (HR 0.46, 95% CI 0.29 – 0.73), and low stromal area per fibroblast (HR 0.33, 95% CI 0.21 – 0.53) were associated with favorable DFS among the TME features. In the multivariate analysis, high stromal lymphocyte density (adj HR 0.57, 95% CI 0.35 – 0.95) and low stromal area per fibroblast (adj HR 0.58, 95% CI 0.33 – 0.99) showed significant associations with DFS independent of clinicopathological covariates. The final TME-integrated model, incorporating N stage, lymphatic invasion, stromal lymphocyte density, and stromal area per fibroblast, stratified patients into high- and low-risk groups with 3-year DFS rates of 72.3% and 93.8%, respectively (adjusted HR for high risk 3.29, 95% CI 1.98 – 5.46). The model identified high-risk patients irrespective of clinicopathological risk features. For example, high-risk status was associated with worse outcomes among patients with N2 disease (adjusted HR 6.57, 95% CI 1.58 – 27.34), and also among patients with N0 or N1 disease (adjusted HR 2.49, 95% CI 1.27 – 4.87). The model was validated in an external independent cohort (n = 260; adjusted HR for high-risk 3.68, 95% CI 1.60 – 8.48). Conclusions: TME-integrated model combining AI-derived TME features with clinicopathologic factors significantly improved recurrence risk stratification in MSS colon cancer receiving adjuvant chemotherapy.

Self-supervised reservoir computing with spatial-temporal encoding for identifying critical transitions

HIV lymphomas in the safety-net setting: A decade of experience at a single institution.

e19113 Background: Safety-net hospitals treat disproportionately more HIV patients than other hospitals. HIV patients are at increased risk for aggressive lymphomas requiring concurrent chemotherapy and antiretroviral therapies (ART). Trial-based data largely exclude patients with poor performance status (PS), and the proportion of patients not offered chemotherapy is underreported. We evaluated characteristics and outcomes of HIV-associated lymphomas treated at JPS Health Network, a large safety-net system in North Texas. Methods: We conducted an IRB-approved retrospective study using the JPS tumor registry and Epic EHR, including patients diagnosed with HIV-associated aggressive B-cell lymphomas between January 1, 2013, and December 31, 2022. Data regarding HIV status/treatment, stage of lymphoma, compliance with ART/chemotherapy, and survival parameters were abstracted. Cox regression analysis was used to analyze the association between variables and survival. Results: Fifty patients were included in the study. The median age was 47 years; 76% were male. Racial/ethnic distribution was 50% Black, 28% Hispanic, and 22% non-Hispanic White. Fifty percent were uninsured, and the median zip-code-based household income was $54,988 (vs 2022 US median of $74,580). Hepatitis B and C coinfection occurred in 10% and 8%, respectively; 44% had psychiatric comorbidities. Diffuse large B-cell lymphoma (DLBCL) was the most common (68%), followed by Hodgkin (14%) and Burkitt lymphomas (10%). Stage distribution for DLBCL was 11.7%, 8.8%, 20.6% and 55.9% for stages 1, 2, 3, and 4, respectively. Median International Prognostic Index was 3. Seventy-four percent had PS &gt;1 at diagnosis. Chemotherapy was administered to 86% (n=43) of patients, 79.1% (n=34) completed the frontline regimen with 86% treatment compliance. Delays occurred in 21 patients, most commonly due to neutropenia; 27.6% (n=12) developed opportunistic infections. All patients received ART. Overall survival (OS) with 95% CI was 0.82 (0.68, 0.90) at 3 months, 0.72 (0.57, 0.82) at 1 year, 0.68 (0.53, 0.79) at 2 years, and 0.62 (0.45, 0.74) at 5 years; median OS was approximately 9 years, 3304 days. Progression-free survival (PFS) at 1 year was 0.68 (0.53, 0.79), 2 years was 0.66 (0.51, 0.77), and 5 years was 0.61 (0.46, 073); median PFS was approximately 9 years, 3289 days. The complete response rate was 76.9% for all patients and 60% for DLBCL. Four patients relapsed, two received salvage chemotherapy none received transplant or CAR T. Conclusions: Despite a high proportion of patients with poor PS, long-term outcomes for HIV-associated aggressive lymphomas at JPS are comparable to published literature. The initial 3–6 months after diagnosis are critical to overall survival, underscoring the importance of offering chemotherapy to all patients. Multidisciplinary collaboration is essential to ensure the best outcomes in resource-constrained safety-net settings.

Racial disparities in risk of second primary malignancies in esophageal cancer survivors: Insights from a population-based database.

e16090 Background: Racial disparities shape outcomes in esophageal cancer, yet their role in second primary malignancies (SPMs) remains underexplored. Using a population-based database, this study investigates variations in SPM risk among racial groups, providing critical insights into inequities that influence survivorship, guide surveillance, and inform strategies to reduce disparities. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) database, comparing secondary cancer rates among esophageal cases diagnosed from 2000 to 2022. A second primary malignancy was defined as a malignancy developing six or more months after an index HCC diagnosis. We used the SEER MP-SIR session to obtain the p-value, observed/Expected (O/E) ratio, and absolute excess risk (AER) per 10,000. We excluded patients with unknown race. Results: total of 67,461 SPMs were observed in our extracted cohort. The collective standardized incidence of SPMs was 1.13 (95% CI 1.12-1.14) compared to the US population, with an AER of 21.40 per 10,000 individuals. Most common sites of SPMs included colorectal (SIR 2.17, CI 2.13-2.21), lung (SIR 1.11, CI 1.90-1.14), kidney (SIR 1.11, CI 1.06-1.16), thyroid (SIR 1.67, CI 1.57-1.76), and chronic myeloid leukemia (CML) (SIR 1.21, CI 1.08-1.37). Based on race, the highest risk of SPM was observed in non hispanic American Indian/Alaska native (SIR 1.97 CI 1.77-2.20), while the lowest risk of SPM was observed in hispanic (SIR 1.03 CI 1.01-1.06). Non hispanic whites had an SIR of 1.10 (CI 1.09-1.11), non hispanic blacks SIR 1.22 (CI 1.19-1.25), while non hispanic asian or pacific islander SIR 1.41 (CI 1.37-1.45). Conclusions: Our findings highlight significant racial disparities in second primary malignancy risk among esophageal cancer survivors. In our study, highest incidence of SPMs were found in NHAIAN and NHAPI populations. These differences underscore the need for tailored surveillance strategies and equitable access to care. Addressing such inequities is essential to improving outcomes, guiding prevention efforts, and shaping policies that advance health equity in survivorship.

Investigator-initiated phase II trial of ABSK043, an oral PD-L1 inhibitor, in patients with angiogenic sarcoma.

TPS11593 Background: Angiogenic sarcomas (AS) represent a group of rare mesenchymal malignancies arising from the vascular endothelium. Patients with locally advanced or metastatic disease have poor outcomes due to limited availability of effective systemic treatment options. Emerging data suggest that immune checkpoint blockade (ICB) has activity in select patients, but prospective data is lacking for ultra-rare subtypes of AS including intimal sarcoma and epithelioid hemangioendothelioma (EHE). Methods: This is a single institution phase II investigator-initiated open label trial of ABSK043, an oral PD-L1 inhibitor in patients with AS. The primary endpoint is objective response rate. Secondary endpoints include progression free survival, overall survival and incidence of treatment emergent adverse events. Exploratory objectives include tissue- and blood-based correlative analyses to identify molecular biomarkers associated with ICB response/resistance in AS. Key inclusion criteria include histologically proven EHE, intimal sarcoma or scalp angiosarcoma with evidence of disease progression, age ≥18 years, ECOG performance status 0-2, adequate organ function, and measurable disease by RECIST v1.1. Exclusion criteria include ongoing systemic immunosuppressive therapy, active autoimmune disease, prior treatment with PD-(L)1 directed therapy, untreated brain metastases, or gastrointestinal conditions that may impair oral drug absorption. Participants will receive ABSK043 800mg orally twice daily until disease progression or unacceptable toxicity. Radiologic assessments by CT or MRI will be performed every 12 weeks. Research bloods will be collected prior to treatment initiation and with radiologic assessments, and biobanked for future correlative analyses (including longitudinal ctDNA assessment). Archival tissue or a fresh biopsy will be collected during screening for all patients. Patients who achieve partial response will undergo on-treatment and post-progression biopsies for correlative analyses (including whole genome and transcriptome sequencing and multiplex immunohistochemistry). This study opened in August 2025 and is actively recruiting. Planned enrollment is 20 patients, with accrual expected to complete by June 2027. Clinical trial information: NCT07014137 .

Becotatug vedotin plus pucotenlimab as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma: A phase II clinical trial.

TPS6130 Background: Epidermal growth factor receptor (EGFR) is highly expressed in approximately 85% of nasopharyngeal carcinoma (NPC) cases and plays a critical role in tumor cell proliferation. Becotatug vedotin (MRG003) is a novel EGFR-targeted antibody-drug conjugate (ADC) with promising anti-tumor activity in NPC. Pucotenlimab is a recombinant humanized programmed cell death protein-1 (PD-1) inhibitor. Although platinum-based chemotherapy combined with a PD-1 inhibitor represents the current standard first-line treatment for recurrent or metastatic (R/M) NPC, treatment-related toxicities and suboptimal efficacy remain significant challenges. Preclinical and early clinical data have demonstrated synergistic anti-tumor activity of MRG003 combined with pucotenlimab in platinum-refractory R/M NPC. However, the efficacy and safety of this platinum-free combination as a first-line therapy for R/M NPC remain uncertain. This study aims to evaluate the efficacy and safety of becotatug vedotin plus pucotenlimab as a novel first-line treatment for patients with R/M NPC. Methods: This is an open-label, single-arm, phase II trial enrolling patients with R/M NPC eligible for first-line systemic therapy. Inclusion criteria include: age 18 to 75 years; ECOG performance status score of 0 or 1; histologically or cytologically confirmed NPC; stage IVB (UICC/AJCC 8th edition) or locoregional recurrence not amenable to curative local therapy; at least one measurable lesion per RECIST v1.1; and adequate organ function. Key exclusion criteria include severe uncontrolled pulmonary disease, active autoimmune disease, or a history of autoimmune disease requiring systemic immunosuppressive therapy. Eligible patients receive becotatug vedotin (2.0 mg/kg, IV, D1, Q3W) and pucotenlimab (200 mg, IV, D1, Q3W) until disease progression, unacceptable toxicity, or death. Dose adjustments are permitted based on toxicities. The primary endpoint is progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death from any cause. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), treatment-related safety, and predictive biomarkers. Research Sponsor: Lepu Biopharma Co., Ltd. Clinical trial information: NCT07381699 .

Follow-up of outpatients taking oral anticancer drugs in the multidisciplinary community hospital ONCORAL care plan.

1507 Background: The increasing use of oral anticancer drugs (OADs) has shifted cancer care toward outpatient and home-based management, raising major challenges related to treatment adherence, drug-related problems (DRPs), and coordination between hospital and community healthcare professionals. ONCORAL is a structured multidisciplinary community-hospital care plan designed to secure OAD use through coordinated personalised pharmacist-nurse-oncologist follow-up, by face-to-face consultations and phone-calls. The present study aims to assess the impact of ONCORAL over the course of treatment. Methods: This prospective real-life cohort study included adult outpatients treated by OADs and followed within ONCORAL between October 2021 and April 2024 in a tertiary referral hospital within the Hospices Civils de Lyon (Lyon, France). The 6-months follow-up was structured in two sequential phases from initiation, with hospital-led consultations, to community monitoring. The primary outcome was the number and nature of nurse and pharmacist interventions (NPIs), classified between DRPs and coordination issues. The secondary outcome was relative dose intensity (RDI), defined as the ratio of prescribed to theoretically approved dose, assessed at months 1 (M1), 3 (M3), and 6 (M6). Based on the literature, a RDI target range of 80-85% is associated with OAD efficacy. Descriptive analyses were performed at both patient and treatment follow-up levels. Results: Five hundred and thirty-six patients were included: mean age 69 ± 13 years; M/F ratio 0.8; 52.4% women; 55.8% with solid tumours. Targeted therapies accounted for 55.2% of treatments. Overall, 71.3% of patients received OADs for ≥ 6 months. Mean RDI was above 80% throughout follow-up for 86.1% at M1, 84.3% at M3, 83.5% at M6. Four hundred and eighty-one patients (90.0%) had at least 1 NPI during follow-up, for a mean of 4.8 NPIs per patient. DRPs (88.5%) were identified in 426 patients (79.5%): patient-reported symptoms and adverse effects (37.5%), drug-drug interactions (DDIs) (30.1%), and adherence issues (20.4%). Clinically relevant DDIs were identified in almost more than 1 in 3 patients (n = 145; 27%), with respectively 26.2% and 43.4% of DDIs potentially reducing OAD efficacy or increasing toxicity. Most NPIs concerned information relay to community healthcare professionals (64.2% of patients), and pharmaceutical counselling on side-effects management and treatment schedules (58.4%). Conclusions: This longitudinal evaluation demonstrates that the ONCORAL multidisciplinary community-hospital program enables safe outpatient management of OADs, with sustained dose intensity and early detection of DRPs. Pharmacist-nurse collaboration plays a crucial role in securing treatment pathways and optimising the use of anticancer therapies in a real-world setting.

Final analysis of the TiNivo-2 phase 3 trial: Long-term outcome of tivozanib (Tivo) in patients with metastatic renal cell carcinoma (mRCC).

4555 Background: TiNivo-2 results showed that immune checkpoint inhibitor (ICI) rechallenge did not offer benefit to patients with mRCC, regardless of treatment sequencing ( Lancet , 2024; 404:1309). However, the data highlights activity for Tivo monotherapy in the post-ICI setting. Long term outcomes of the TiNivo-2 study are reported here. Methods: TiNivo-2 trial design and primary-endpoint results were previously reported: patients with mRCC were randomized to treatment with Tivo 0.89 mg once daily for 21/28 days plus Nivolumab (Nivo) at 480 mg every four weeks (Tivo/Nivo) or Tivo 1.34 mg once daily for 21/28 days. Here, long term progression free survival (PFS), overall survival (OS), and the safety profile are reported at final analysis. Results: At the data cutoff of 17 October 2025, 172 patients were randomized to Tivo (171 treated) and 171 patients were randomized to Tivo/Nivo (168 treated); median (m) follow up was 28.4 mo (95% CI 27.0-29.8) in Tivo versus 27.2 months (mo) (95% CI 26.1-28.5) in Tivo/Nivo. Survival outcomes and hazard ratios (HR) for the ITT population, 2L, and 3L populations are summarized in Table 1. In 2L, mPFS favored Tivo over Tivo/Nivo (9.23 mo [7.29, 11.04] vs 5.95 mo [5.42, 7.95]). Across subgroups, there were no differences in mOS. No new safety signals were observed with prolonged administration; the most common ≥ Grade 3 TEAE was hypertension occurring in 39 (22.8%) and 38 (22.6%) and of patients in the Tivo and Tivo/Nivo groups respectively. Other ≥ Grade 3 TEAEs included diarrhea (2.3% and 3.6%) and palmar-plantar erythrodysaesthesia (0.6% and 1.2%) in the Tivo and Tivo/Nivo groups respectively. Treatment Related SAEs occurred in 15 (8.8%) and 18 (10.7%) of patients in Tivo and Tivo/Nivo groups respectively. Conclusions: This final analysis of patients in the TiNivo-2 study highlights the sustained efficacy Tivo in mRCC with a consistent safety profile. Together, these findings support durable clinical benefit and tolerability of Tivo in the post-ICI treatment setting in RCC, an area of high unmet need (NCT04987203). Clinical trial information: NCT04987203 . Parameter By ITT 2L setting 3L setting Tivo (0.89mg) /Nivo (n=171) Tivo (1.34mg) (n=172) Tivo (0.89mg) /Nivo (n=111) Tivo (1.34mg)(n=105) Tivo (0.89mg) /Nivo (n=60) Tivo (1.34mg)(n=67) mPFS, months (95% CI) 5.72(4.37-7.43) 7.43(5.52-9.23) 5.95(5.42, 7.95) 9.23(7.29, 11.04) 5.45(3.15, 9.56) 5.44(2.10, 7.36) mPFS HR 0.96 (0.76, 1.21) 1.08 (0.80, 1.46) 0.77 (0.52, 1.15) mOS, months (95% CI) 23.85(19.71-NR) 22.93 (18.14-NR) 29.50(21.06, NR) 23.52(18.33, NR) 19.71(10.81, 31.90) 22.70(11.79, NR) mOS HR 0.95 (0.70, 1.28) 0.78 (0.53, 1.16) 1.13 (0.70, 1.81) NR, not reached.

Evaluation of whole-exome and whole-genome sequencing tumor-informed circulating tumor DNA MRD assays in patients with early triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) with or without olaparib: A prospective sub-study of the PARTNER trial.

570 Background: Detection of molecular residual disease (MRD), using circulating tumor DNA (ctDNA), following treatment for early-stage TNBC is associated with a high risk of recurrence. ctDNA clearance in response to NAC has shown potential for predicting pathologic compete response (pCR) and improving the prognostic ability of pCR status. PARTNER is a prospective, phase II-III, randomized controlled clinical trial, which recruited early-stage basal TNBC BRCA1/2 wild-type patients (Nature April 2024). Control regimen was neoadjuvant carboplatin–paclitaxel followed by anthracycline-based NAC. Experimental arms added olaparib to the platinum-taxane backbone. A sub-study of serial blood samples for ctDNA analysis during NAC and post-op were analyzed with 2 tumor informed MRD assays using primary tumor and germline sequencing: 1) whole-exome sequencing (WES) to select ≤200 variants and 2) whole-genome sequencing (WGS) to select 400-5000 variants for the two bespoke MRD assays, respectively. Both assays were independently used to assess available plasma samples collected for the presence or absence of ctDNA. Methods: This prospective sub study included TNBC patients enrolled within PARTNER with serial blood collections at baseline (prior to NAC), mid-NAC, post-NAC, 2-4 weeks post-op, 3 months post-op and 12 months post-op. Germline and somatic DNA were provided via the Personalised Breast Cancer Program. The primary objective was to determine the association of ctDNA positivity post-op with distant recurrence-free interval (DRFI). The distribution of DRFI by ctDNA status was compared using the log-rank test. The Cox proportional hazards regression model was used to estimate the strength of the relationship between ctDNA positivity and DRFI. Results: Median WES MRD assay panel size was 159 variants (range 47 – 200). At baseline ctDNA was detected in 50 of 55 patients (91%). After NAC, 4 of 63 patients had detectable ctDNA. 24 of 28 non-pCR patients were ctDNA negative and 0 of 35 pCR patients were ctDNA positive. Of 61 post-op patients available to assess DRFI distant recurrences developed in 8 patients (13.1%) within a median follow up of 5 years. Post-op 5 patients were ctDNA positive and 3 developed distant recurrences (log-rank p &lt; 0.0001, HR = 20.2, 95% CI = 4.3, 95.1). In addition, 56 were ctDNA negative and 51 (91%) were distant recurrence free. Median WGS MRD assay panel size was 2962 variants (range 552 - 5000). At baseline ctDNA was detected in 46 of 47 patients (98%). Additional WGS MRD results are being generated and will be presented at the meeting. Conclusions: Post-op detection of ctDNA using a WES MRD assay was highly prognostic for distant recurrence in TNBC patients following NAC. WGS MRD improved baseline detection.