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Neoadjuvant penpulimab combined with taxanes and carboplatin in triple-negative breast cancer: Updated efficacy and safety results from the phase II NeoTAPPL study.

600 Background: The KEYNOTE-522 and IMpassion031 trials established that adding immune checkpoint inhibitors to neoadjuvant chemotherapy significantly improves pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC). In our previously reported phase II NeoTAPPL trial, an anthracycline-free neoadjuvant regimen of penpulimab (anti-PD-1 antibody), carboplatin, and taxanes demonstrated promising efficacy and manageable safety. Here, we present updated efficacy and safety outcomes from the full trial cohort. Methods: In this open-label, multi-center phase II study, patients with untreated, histologically confirmed TNBC in stage II-III were enrolled. Patients received 6 cycles of neoadjuvant therapy with penpulimab (200 mg, d1, q3w) plus taxanes (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2, d1, q3w) and carboplatin (AUC=6, d1, q3w). Patients who either completed or discontinued the neoadjuvant treatment would undergo breast surgery. Adjuvant chemotherapy and immunotherapy were at the discretion of the treating physician, and radiation therapy was per standard of care. The primary endpoint was the rate of pCR based on the definition of ypT0/Tis ypN0. Secondary endpoints included residual cancer burden (RCB), event free survival (EFS), overall survival (OS), adverse events (AE), and immune response biomarkers. Results: 64 patients were enrolled, all of whom received neoadjuvant treatment and underwent surgery. The median age was 53 years (range, 32-73). At diagnosis, 54 patients (84.4%) had stage II disease. pCR was achieved in 41 of 64 patients (64.1%; 95% CI, 51.1%-75.7%), and 50 patients (78.1%; 95% CI, 66.0%-87.5%) achieved RCB 0-1. The objective response rate (ORR) and disease control rate (DCR) were 93.8% (95% CI, 84.8%-98.3%) and 98.4% (95% CI, 91.6%-100%), respectively. Subgroup analyses revealed pCR rates of 64.8% (35/54) in patients with stage II disease and 60.0% (6/10) in those with stage III disease. The pCR rate was 64.9% (24/37) in node-negative patients and 63.0% (17/27) in node-positive patients. Treatment-emergent adverse events (TEAEs) of any grade occurred in all 64 patients, with grade ≥3 TEAEs reported in 24 patients (37.5%). The most common grade ≥3 TEAEs were alopecia (20.3%), anemia (14.1%), neutropenia (10.9%), and leukopenia (10.9%). Conclusions: The NeoTAPPL trial demonstrates that an anthracycline-free neoadjuvant regimen is an effective and tolerable treatment strategy for patients with TNBC. The regimen achieved a high pCR rate, which remained consistent across key prognostic subgroups, including disease stage and nodal status. The safety profile was manageable, with no new safety signals identified. Clinical trial information: ChiCTR2300071925 .

Comparison of genomic landscapes at single cell resolution of pulmonary and salivary adenoid cystic carcinomas.

e18152 Background: Primary pulmonary adenoid cystic carcinomas (PACCs) are rare salivary-gland-like neoplasms associated with poor long-term survival outcomes. How these cancers compare to primary salivary gland adenoid cystic carcinomas (SACCs) remains poorly understood. Recent attempts to elucidate biomarkers and actionable mutations of PACCs through bulk RNA sequencing studies have been met with some success. However, no study to date has compared composition of PACCS and SACCs on single cell RNA level. Methods: We identified two publicly available scRNA sequencing datasets in GEO processed on Illumina NovaSeq 6000 platform. GSE217084 dataset obtained from paraffin embedded samples derived from a patient with primary SACC and adjacent normal head and neck tissue, as well as a patient with 3 lung SACC metastases and adjacent normal lung tissue. GSE245170 dataset was derived from paraffin embedded tissue from a patient with primary PACC, adjacent normal lung tissue, and peripheral blood. Data analysis performed using R v.4.4.3 and Seurat v.5.2, and clustering was performed using Uniform Manifold Approximation and Projection (UMAP) approach. Each dataset analyzed separately, and then in combination with the blood sample removed. Harmony v.1.2.3 was used for batch correction of patient specific effects. Results: UMAP analysis of the primary and metastatic SACC with adjacent normal tissue resulted in clear visual overlap of SACC with related SACC lung metastases and normal head and neck tissue. A distinct clustering pattern from normal lung tissue appeared in close proximity to clusters of lung metastases as well as some cells segregated from the other three tissue types with similar cellular origins. PACC tissue from the GSE245170 dataset demonstrated a discrete pattern, unique from adjacent normal lung tissue and blood. Combined analysis of PACC, SACC and metastatic lung tissue scRNA from the two datasets with the exclusion of the blood sample and after batch correction resulted in a UMAP plot showing PACC cells cluster closely with lung metastases and normal lung tissue. Separate clusters are formed uniquely from primary SACC cells in close proximity to metastatic SACC cells, normal head and neck tissue, and PACC cells. Conclusions: Using UMAP approach to graphically plot scRNA sequencing data we identified varying degrees of overlap in molecular features across tissue samples from PACC, SACC with metastasis to lung, and normal lung, head and neck. ScRNA sequencing data from PACCs most closely resembled that from SACC lung metastases, with additional similarity to primary SACC and normal head and neck tissue. This raises the question of whether primary PACC diagnoses are instead oligometastatic SACCs without clear identification of primary head and neck disease either due to primary tumor regression, cramped head and neck anatomy, or aggressive nature of an early metastatic process.

Transcriptomic validation of <i>ALK</i> fusions by RNA STEP with associated NaPi2b enrichment in lung adenocarcinoma.

e20763 Background: The RNA Salah Targeted Expression Panel (RNA STEP) is an exploratory clinical transcriptomic assay capable of directly quantifying transcripts of 204 oncogenic, pre-selected genes in clinical samples. This study analyzes RNA STEP gene expression of ALK fusion positive ( +) samples to investigate RNA STEP as an orthogonal and complementary assay to next-generation sequencing (NGS). SLC34A2 is a gene that codes for the sodium-phosphate cotransporter 2B (NaPi-IIb), crucial for regulating phosphate levels (homeostasis) by transporting sodium and phosphate ions across cell membranes, mainly in lung alveolar cells for surfactant production. SLC34A2 mutations are linked to the rare lung disease pulmonary alveolar microlithiasis (PAM) with calcium phosphate buildup. SLC34A2 is frequently overexpressed in various cancers, including lung cancer, with promotion of cell growth and metastasis. Methods: Primary lung cancer samples (N = 524 total, 24 ALK +) were tested with both clinical NGS (Illumina TSO500 platform) and RNA STEP (nanoString platform). Gene expression by RNA STEP (log2 ratio) versus ALK fusion unique supporting reads by NGS were compared with Pearson correlation. Four RNA STEP cutoffs were compared for positive percentage agreement and accuracy with NGS. Differences in gene expression were compared for the ALK + versus ALK- samples with box and whisker plots and Mann-Whitney U test for significance. Results: Strong correlation was observed for ALK gene expression by RNA STEP versus supporting reads by NGS (R = 0.777 for 24 ALK+ samples). An ALK RNA STEP cutoff of log2 ratio ≥2 yielded a positive percentage agreement of 87.5% and accuracy of 97.9%. RNA STEP and NGS results correlated and were concordant with each other (optimized cut-off: log2 ratio ≥2), supporting the accuracy and value of RNA STEP as an orthogonal and complementary assay to NGS. Median expressions of the ALK , ROS1 , and SLC34A2 genes were significantly higher in the ALK + samples versus ALK- samples (p &lt; 0.001). Some ALK inhibitors also inhibit ROS1 and that when both ALK and ROS1 gene expression are high in an ALK fusion positive lung cancer, perhaps an inhibitor that targets both might be considered. Conclusions: Wild-type ALK gene expression correlated with ALK fusion supporting reads and positive gene expression demonstrated strong concordance with ALK fusion presence. RNA STEP provides clinically useful orthogonal transcriptomic validation of ALK fusions, particularly in cases with borderline results or atypical fusion partners or breakpoints beyond classic EML4::ALK . ROS1 and SLC34A2 (NaPi2b) expression were high in the ALK+ cohort in agreement with the literature, highlighting these markers as possible therapeutic targets for patients with ALK + lung adenocarcinoma.

Implementation of a multidisciplinary committee within a national oncology society: An educational and quality improvement initiative.

e23033 Background: Multidisciplinary care is fundamental to improving quality, safety, and patient-centered outcomes in oncology. However, despite its recognized importance, multiprofessional teams are often underrepresented in the governance and educational structures of medical oncology societies. The Brazilian Society of Clinical Oncology (SBOC), founded in 1981, lacked a formal multidisciplinary committee until recently. Methods: In August 2024, SBOC launched its first Multidisciplinary Committee as a quality improvement and educational initiative. The committee was structured to formally integrate diverse healthcare professionals involved in cancer care, aiming to enhance interprofessional education, improve communication strategies, and promote collaborative oncology practice nationwide. Results: Since its implementation, the committee has led key educational and organizational actions, including the modernization of SBOC’s website and digital communication channels, the development and recording of educational podcasts targeting oncology professionals, and the organization of a dedicated multidisciplinary roundtable at the Brazilian Congress of Clinical Oncology. These initiatives expanded access to multiprofessional perspectives, strengthened educational outreach, and increased engagement among society members. Conclusions: The SBOC Multidisciplinary Committee represents a significant quality improvement, established 43 years after the society's founding. Early outcomes demonstrate the feasibility and value of formally integrating multiprofessional teams into a national oncology society. This experience highlights an effective model to enhance education, collaboration, and quality of oncology care, with potential applicability to other oncology organizations globally.

Pathologic response in relation to total neoadjuvant therapy sequence, completion, and extra consolidation chemotherapy in locally advanced rectal cancer.

e15648 Background: Total neoadjuvant therapy (TNT) is widely used in locally advanced rectal cancer (LARC); however, the effect of TNT sequencing, treatment completion, and additional consolidation chemotherapy on pathologic response remains unclear. We evaluated the association between different TNT delivery patterns and pathologic complete response (pCR) and modified Ryan tumor regression grade (TRG). Methods: We retrospectively analyzed 161 patients with LARC treated with chemoradiotherapy (CRT)-based TNT followed by surgery. TNT delivery was categorized using three complementary classification schemes: (1) six predefined sequence/completion patterns (TNT1) including complete CRT-chemotherapy (CT), complete CT-CRT, additive CT-CRT-CT while awaiting surgery, incomplete CRT-CT, incomplete CT-CRT, and incomplete additive CT-CRT-CT; (2) ordinary (complete CRT-CT or CT-CRT) versus aberrant (any incomplete and/or additive patterns) (TNT2); and (3) extra consolidation chemotherapy (additive complete CT-CRT-CT), incomplete chemotherapy (failure to complete planned systemic therapy), and ordinary (TNT3). Continuous variables were compared using non-parametric tests and categorical variables using chi-square or Fisher’s exact tests. Multivariable logistic regression models were constructed for pCR. Results: Median age was 63 years. pCR was achieved in 22 patients (13.7%). Modified Ryan TRG distribution was TRG0 13.7%, TRG1 24.2%, TRG2 50.9%, and TRG3 11.2%. pCR rates did not differ significantly across TNT1 (p = 0.613), TNT2 (p = 0.271), or TNT3 (p = 0.378). Modified Ryan TRG distributions were comparable among all TNT grouping strategies (TNT1 p = 0.953, TNT2 p = 0.712, TNT3 p = 0.682). Significant differences across TNT groupings were observed for selected baseline and treatment-related variables, including locoregional lymph node involvement (TNT1 p = 0.023), neoadjuvant chemotherapy regimen (TNT1 p = 0.002), total neoadjuvant chemotherapy cycles (TNT1 p &lt; 0.001; TNT2 p = 0.007; TNT3 p &lt; 0.001), and carcinoembryonic antigen (CEA) after TNT (TNT1 p = 0.031; TNT2 p = 0.030; TNT3 p = 0.027). Across three multivariable models adjusted for clinical T4 status and locoregional lymph node involvement, TNT1, TNT2, and TNT3 classifications were not independently associated with pCR. Conclusions: In this real-world cohort, TNT sequence was not associated with differences in pCR or modified Ryan tumor regression, and extra consolidation chemotherapy did not improve pCR rates. These findings suggest that TNT sequence and intensification do not translate into superior pathologic response. De-escalation and sequencing modifications based on patient clinical status may be feasible, which should be evaluated in future prospective studies to better define the optimal TNT strategy.

Intracranial efficacy and safety of trastuzumab deruxtecan in HER2-positive and HER2-low metastatic breast cancer with central nervous system involvement: A systematic review and proportional meta-analysis.

1053 Background: Central nervous system (CNS) metastases and leptomeningeal disease (LMD) are major drivers of morbidity and mortality in metastatic breast cancer (MBC). Trastuzumab deruxtecan (T-DXd) has demonstrated intracranial activity across multiple studies; however, evidence remains fragmented across heterogeneous CNS subgroups. We conducted a systematic review and meta-analysis to assess intracranial efficacy and survival outcomes, along with interstitial lung disease (ILD) risk with T-DXd monotherapy in CNS-involved HER2-positive and HER2-low MBC. Methods: Following PRISMA guidelines, prospective trials and retrospective cohorts reporting CNS outcomes with T-DXd monotherapy were included. Fifteen unique cohorts met eligibility criteria. The primary endpoint was intracranial objective response rate (iORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Safety analysis included ILD incidence. Random-effects proportional meta-analyses and prespecified subgroup and sensitivity analyses were performed (RevMan 5.4.1). Results: In patients with active brain metastases (11 cohorts), pooled iORR was 0.61 (95% CI 0.55–0.66; I²=0%). Similarly, in stable brain metastases (6 cohorts), pooled iORR was 0.61 (95% CI 0.50–0.71; I²=75%); exclusion of an influential cohort increased pooled iORR to 0.65 (95% CI 0.55–0.75) and reduced heterogeneity. In LMD (3 cohorts), pooled CNS response was 0.53 (95% CI 0.35–0.70; I²=0%). HER2-low cohorts demonstrated a pooled iORR of 0.51 (95% CI 0.33–0.69), which did not differ significantly from HER2-positive CNS subgroups (p=0.75). Where comparative data were available, treatment with T-DXd was associated with improved PFS (HR 0.33, 95% CI 0.19–0.58) and overall survival (log HR −0.32, 95% CI −0.55 to −0.09; ≈HR 0.73). Safety analyses showed a pooled incidence of ILD (any grade) of 0.12 (95% CI 0.09–0.15), with higher rates observed in high-risk (0.16) and intermediate-risk (0.13) cohorts compared with low-risk cohorts (0.04). Conclusions: Across 15 cohorts, T-DXd demonstrates consistent and clinically meaningful intracranial activity in active and stable brain metastases, substantial activity in LMD, and a survival signal where comparative data exist, with quantifiable ILD risk. These findings support T-DXd as a key systemic therapy for CNS-involved HER2-positive and HER2-low MBC and underscore the need for standardized CNS endpoints and ILD mitigation strategies in future studies.

National burden and distribution of febrile neutropenia among hospitalizations with pancreatic cancer, 2016-2022.

e16409 Background: Febrile neutropenia (FN) is a potentially life-threatening complication of myelosuppressive chemotherapy and a common cause of hospitalization among patients with pancreatic cancer. Despite the widespread use of intensive cytotoxic regimens in this population, contemporary data describing the national burden of FN, its demographic and health-system distribution, and associated inpatient outcomes are limited. Methods: We analyzed adult pancreatic cancer hospitalizations in the Nationwide Inpatient Sample from 2016-2022 using ICD-10-CM codes in any discharge diagnosis position. Febrile neutropenia (FN) was ascertained using validated diagnostic codes. Survey-weighted analyses were used to compare baseline characteristics and outcomes between hospitalizations with and without FN, and survey-weighted multivariable logistic regression was performed to evaluate the association between FN and in-hospital mortality after adjustment for demographics, hospital characteristics, and Elixhauser comorbidity burden. Results: Among an estimated 742,745 pancreatic cancer–related hospitalizations in the United States, 13,820 (1.9%) were complicated by FN. Patients with FN were slightly younger than those without FN (mean age 66.7 vs 68.4 years, P &lt; 0.001), with a modest shift toward the 45–64-year age group. FN-associated hospitalizations occurred more frequently among White patients (75.2% vs 70.8%, P &lt; 0.001). Although Medicare was the predominant payer in both groups, FN-associated hospitalizations had a higher proportion of privately insured patients (31.4% vs 26.2%, P &lt; 0.001). From a health-system perspective, FN admissions were less frequently managed at urban teaching hospitals (74.6% vs 79.4%) and more often occurred in urban non-teaching and rural hospitals (P &lt; 0.001). Overall comorbidity burden was slightly higher among FN admissions (Elixhauser score 5.46 vs 5.32, P = 0.015). After multivariable adjustment for demographics, hospital characteristics, and comorbidity burden, FN was independently associated with increased in-hospital mortality (aOR 1.63, 95% CI 1.35–1.98). Conclusions: In a nationally representative cohort, febrile neutropenia complicates approximately 1 in 50 hospitalizations among patients with pancreatic cancer and is concentrated in younger patients and tertiary-care centers. The persistence of increased mortality after adjustment for comorbidity burden underscores FN as an independent marker of vulnerability in pancreatic cancer, rather than merely a surrogate of baseline illness severity. These findings emphasize the importance of proactive risk stratification, appropriate use of growth-factor prophylaxis, early sepsis recognition, and system-level supportive-care pathways to mitigate the substantial mortality burden associated with FN in this high-risk oncologic population.

Baseline telomere length and prediction of cognitive recovery after chemotherapy in patients with breast cancer: An NCORP prospective cohort study.

12149 Background: Chemotherapy-related cognitive impairment (CRCI) affects up to 70% of breast cancer survivors, yet recovery varies. Telomere length (TL), a marker of biological aging, may reflect biological resilience to CRCI. We evaluated whether baseline TL predicts longitudinal cognitive recovery following chemotherapy. Methods: In a nationwide prospective cohort study across 19 NCORP-affiliated community oncology clinics (URCC 10055), 185 women with stage I–IIIC breast cancer were assessed before chemotherapy (T1), post-chemotherapy (T2), and 6 months post-chemotherapy (T3). Baseline TL was measured by qPCR, normalized, and categorized into three groups: Short (S, n = 63, 34.1%), Average (A, n = 75, 40.5%), and Long (L, n = 47, 25.4%). Perceived cognitive function was assessed using the Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog; minimum clinically important difference for total ≈7 pts), including total score and subscales for perceived cognitive impairments (PCI), perceived cognitive abilities (PCA), comments from others (OTH), and impact on quality of life (QoL). Changes from T1→T2 and T2→T3 were evaluated using repeated-measures mixed-effects analysis of covariance models adjusted for baseline values. Results: Baseline FACT-Cog total scores were similar across TL groups. At T2, all groups experienced comparable acute PCI (FACT-Cog change: S = −13.2, A = −13.3, L = −18.7). By T3, recovery differed by TL. While all groups remained below baseline, patients with long TL demonstrated substantially greater recovery, with a smaller overall decline from T1 (L = −8.6) compared with persistent impairment in Short (S = −14.0) and Average (A = −11.4) groups. This reflected a clinically meaningful improvement in cognitive function from post-chemotherapy to 6-month of +10.0 pts in the Long group (p = .016), whereas changes in the other two groups was not clinically or statistically significant. This recovery pattern was supported by clinically significant improvement in PCI (+7.2) and statistically significant change in OTH (+1.0; p = .003) in the Long group from T2 to T3, while it was attenuated in the Average and Short groups. In contrast, PCA showed minimal change across groups. Impact on quality of life also improved significantly in the Long group over the same period (FACT-Cog QoL T3–T2 change = +2.0; p = .019), reinforcing a coherent cognitive recovery phenotype. Conclusions: Baseline TL does not determine susceptibility to acute chemotherapy-related toxicity but strongly predicts cognitive recovery over time. Patients with longer telomeres demonstrate clinically meaningful recovery of cognition, whereas those with shorter telomeres show more persistent perceived cognitive impairment. TL may identify patients at higher risk for long-term impairment who could benefit from early supportive and rehabilitative interventions.

Cyclin amplification in biliary tract cancer: Integrated profiling to evaluate immune exclusion, drug sensitivity, and prognosis.

4153 Background: The impact of cell cycle regulator amplifications on the tumor microenvironment (TME) and clinical outcomes in biliary tract cancer (BTC) remains undefined in the chemo-immunotherapy era. This study characterizes the genomic, transcriptomic, and clinical landscape of cyclin-amplified BTC (CCNE/CCND family). Methods: We analyzed 263 BTC patients (pts) via comprehensive genomic/transcriptomic sequencing. Cohorts were stratified into Cyclin-Amplified (Amp, N = 71, Copy Number ≥6) and non-amplified Control (Ctrl, N = 192). We compared demographics, DNA co-alterations, and survival (Kaplan-Meier/Log-Rank). Transcriptomic profiling utilized 29 established gene signatures (Bagaev et al, Cancer Cell 2021) quantifying immune cell infiltration and stromal features. Differential gene expression assessed markers of chemotherapy resistance. Results: Cyclin amplification defined a distinct subgroup characterized by younger age (median 56 vs 65 years, p &lt; 0.001). The Amp cohort (N = 71) consisted of CCNE1 (N = 30), CCND1/2/3 (N = 29/2/7), and CCNE1/D1 co-amplification (N = 3). Amp pts had significantly inferior overall survival (OS) compared to Ctrl (median 21.2 vs 28.3 m, p = 0.009). In stage 3-4 disease, Amp pts demonstrated worse OS (19.2 vs 25.5 m, p = 0.035). While adding immunotherapy (IO) to chemotherapy significantly improved OS in the control group (36.1 vs 23.0 m, p = 0.001), it provided no OS benefit in the Amplified group (median 19.2 m [Chemo+IO] vs 24.1 m [Chemo only], p = 0.80). Amp tumors exhibited high genomic instability, dominated by TP53 (67%), IRS2 (13%), ARID1A (11%), KRAS (11%), and ATM (11%) mutations. Frequent co-amplifications included FGF19/4 (35%), MYC (23%), ERBB2 (19%), EGFR (16%), and MET (16%). Transcriptomic profiling revealed a profound "immune desert" phenotype in Amp tumors, characterized by widespread depletion of adaptive and innate immunity: B-cells (p &lt; 0.001), NK cells (p = 0.002), T-cells (p = 0.008), and Th1/Th2 signatures (p &lt; 0.01) were significantly downregulated compared to Ctrl. Amp tumors exhibited intrinsic chemotherapy resistance via upregulation of gemcitabine targets (RRM1, p = 0.04) and platinum efflux pumps (ABCC2, p = 0.04), alongside a trend toward increased tumor proliferation (p = 0.053). Conclusions: Cyclin amplification identifies a biologically distinct, aggressive BTC subtype characterized by intrinsic resistance mechanisms to standard chemo-immunotherapy. This resistance is driven by a profound "immune desert" microenvironment limiting immunotherapy efficacy and the upregulation of genes associated with chemotherapy resistance. Comprehensive genomic profiling in this subgroup provides prognostic context and reveals a landscape of frequent co-occurring actionable drivers, highlighting the complex biological underpinnings of this high-risk population.

Real-world (RW) characteristics, management, and outcomes of genomically defined mismatch repair deficient (MMR-d) and aggressive variant prostate cancer (AVPC).

e17042 Background: AVPC (≥ 2 alterations in PTEN / TP53 / RB1 ) and MMR-d are genomically distinct subsets of prostate cancer with poor response to androgen-pathway therapies (ARPi) and docetaxel (DTx). Methods: This prospective RW multicenter study (Alberta, Canada) investigates the incidence, characteristics, systemic treatment (tx), and outcomes of pts with metastatic (m) and/or castration resistant prostate cancer (CRPC) receiving genomic testing (2018-2025). Pts with AVPC or MMR-d were compared with pts with no biomarker detected (NBD: lacking AVPC, MMR-d and HRD). Pt characteristics, time to CRPC (tCRPC) from androgen deprivation therapy (ADT) initiation, survival post-mCRPC (OS), time to PSA progression (TTPP), and radiographic PFS (rPFS) were assessed using univariate tests of association and Kaplan-Meier analyses. Results: Of 178 cases, 19 (12%) were AVPC (18 PTEN, 4 RB1, 17 TP53), 19 (12%) MMR-d (4 EPCAM, 3 MLH1, 6 MSH2, 6 MSH6, 2 PMS2), and 140 (76%) NBD. HRD was observed concurrently in 42% (8/19) each of AVPC [ATM/PTEN/TP53 (n = 2); BRCA2/PTEN/TP53 (n = 3); BRCA2/TP53/RB1 (n = 2); PALB2/PTEN/TP53 (n = 1); RAD51C/TP53/RB1 (n = 1)] and MMR-d [ATM/MLH (n = 1); ATM/EPCAM/MSH6 (n = 1); BRCA2/MSH6 (n = 1); BRCA2/MSH2 (n = 2); CDK12/MSH6 (n = 1); CDK12/MSH2 (n = 1); 1 PALB2/MSH6 (n = 1)]. Excluding concurrent HRD, 11 AVPC (11 PTEN, 2 RB1, 9 TP53), 11 MMR-d (3 EPCAM, 1 MLH1, 2 MSH2, 4 MSH6, 2 PMS2), and 140 NBD were analyzed. Concurrent HRD did not impact tCRPC or OS for AVPC or MMR-d. Clinicopathological features (age, Gleason ≥8, disease volume, visceral or de novo metastases, pathology, PSA) were similar across groups. tCRPC was 16.6, 18.4 and 29.9 mo for AVPC, MMR-d and NBD, respectively (p = 0.6). AVPC had a significantly shorter OS (11.9 mo), compared to MMR-d (13.6 mo) and NBD (37 mo); p &lt; 0.01). 97/178 pts with mCSPC received treatment intensification (66 ARPi [26 APA; 31 ABI; 9 ENZA), 19 ARPi + DTx [8 ABI; 11 DARO], and 12 DTx). 1L mCRPC tx consisted of 82% (41/50) ARPi [2 APA; 20 ABI; 19 ENZA), 16% (8/51) DTx, and 2% (1/50) platinum chemotherapy (P). 2L for mCRPC pts was 77% (39/55) DTx, 24% (13/55) ARPi [6 ABI; 7 ENZA], 3% (2/55) cabazitaxel, and 2% (1/55) P. Conclusions: This RW study identified a high proportion of pts harbouring AVPC or MMR-d were also concurrently HRD. Yet, AVPC is a distinct aggressive subtype with poor outcomes, demonstrating a short OS and tCRPC, and rapid TTPP and rPFS on both ARPi and Dtx. No pts received AKT inhibitors and a single pt with MMR-d (PMS2) received a self-funded immune checkpoint inhibitor, underlining the need for earlier comprehensive biomarker testing in M1 or CRPC and further trial development in these unique subtypes. AVPC n (%) MMR-dn (%) NBDn (%) p 1L Single Agent ARPi N 9/11(81) 8/11 (72) 90/126 (71) 0.3 TTPP 8.3 14.8 26.6 &lt;0.01* R-PFS 8.2 10.3 21.4 &lt;0.01* 2L DTx N 4/7 (57) 5/6 (83) 34/47 (72) 0.8 TTPP 1.4 11.1 10.2 &lt;0.01* R-PFS 4.2 3.0 7.1 0.5

Real-world implementation of an integrated exercise medicine model within routine oncology care.

1577 Background: Exercise is an evidence-based intervention for people with cancer, with demonstrated benefits for physical function, symptom burden, and treatment tolerance. Despite international guideline recommendations, exercise remains inconsistently implemented as a prescribed medical treatment in routine oncology care. This study describes the real-world implementation of an integrated Exercise Medicine model embedded within a supportive oncology service. Methods: This descriptive implementation study reports on the Lift Model of Care, a clinician-led supportive cancer care service established in Australia in 2018. Exercise Medicine is delivered as a core, medically prescribed intervention and integrated with Physiotherapy, Psychology, Dietetics, and subspecialty services across the cancer continuum. Exercise prescriptions are individually tailored and dosed by qualified clinicians in accordance with Clinical Oncology Society of Australia exercise guidelines and delivered in a medically supervised environment. Routinely collected service data were analysed descriptively. The primary outcome was annual service reach and treatment volume from 2018 to 2025. Secondary outcomes included patient-reported experience measures related to Exercise Medicine. Results: Annual service reach increased from 607 individuals in 2018 to 1,353 individuals in 2025. Delivery of Exercise Medicine increased from 2,077 to 12,255 treatments annually, reflecting sustained growth in access and longitudinal engagement. Concurrent increases in Physiotherapy, Psychology, Dietetics, and Lymphoedema services were observed, supporting coordinated multidisciplinary care delivery. Patient-reported experience data demonstrated high acceptability, with over 90% of respondents reporting high satisfaction and perceived improvements in fatigue, strength, functional capacity, and ability to tolerate cancer treatment. Conclusions: This real-world implementation study demonstrates the feasibility of embedding Exercise Medicine as a prescribed treatment within routine oncology care at scale. The model provides a pragmatic framework for integrating guideline-recommended exercise into standard cancer pathways and may inform broader adoption across health systems.

Efficacy and tolerability of talimogene laherparepvec in treatment of solid tumors: A systematic review.

e14554 Background: Talimogene laherparepvec (T-VEC) is an oncolytic virus engineered to selectively replicate within tumor cells, leading to cell lysis and enhanced systemic antitumor immunity through expression of granulocyte-macrophage colony-stimulating factor (GM-CSF). Since its FDA approval in 2015 for the treatment of unresectable melanoma, T-VEC has generated interest for its potential application in other malignancies. However, a comprehensive synthesis of response rates, survival outcomes, and adverse events associated with T-VEC across non-melanoma solid tumors is lacking. This systematic review aims to synthesize available evidence on the efficacy and safety of T-VEC across a range of solid tumors to better define its clinical utility beyond melanoma. Methods: A systematic literature search of PubMed, Embase, and Scopus was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Peer-reviewed clinical studies reporting outcomes of T-VEC therapy in non-melanoma solid tumors were included. Extracted variables included patient age, cancer type, T-VEC dosage, treatment duration, survival outcomes, treatment response, and adverse events. Median overall survival (OS), complete response rates, and grade ≥ 3 adverse events were compared across studies. Results: Of 1,664 identified records, 10 clinical studies met inclusion criteria, encompassing outcomes across 11 cancer types. These included breast cancer (n = 5), sarcomas (n = 3), basal cell carcinoma (n = 1), pancreatic cancer (n = 1), and colorectal cancer (n = 1). Clinical outcomes varied by tumor type. Partial response or stable disease was achieved in 76% of sarcoma patients, while complete responses were observed in 33% of patients with breast cancer and basal cell carcinoma. No cases of progressive disease were reported among basal cell carcinoma patients. Median OS ranged from 3.8 to 30 months, with the shortest survival observed in colorectal cancer and the longest in a breast cancer cohort. The most frequently reported grade ≥ 3 adverse events were hematologic, cardiovascular, and constitutional or administration site–related. Conclusions: T-VEC demonstrated promising efficacy and an acceptable safety profile in basal cell carcinoma and sarcomas, with more heterogeneous responses observed in breast cancer. Further studies are warranted to better characterize the clinical outcomes of T-VEC in non-melanoma solid tumors, particularly in combination with other immunotherapeutic agents.

A bidirectional cohort study of chemotherapy-targeted alternating therapy on outcomes of third-line metastatic colorectal cancer.

e15607 Background: CSCO guidelines recommend trifluridine/tipiracil (TAS-102) plus bevacizumab as standard third-line therapy for metastatic colorectal cancer (mCRC). An alternating strategy combining TAS-102 with small-molecule anti-angiogenic agents has emerged in practice but lacks real-world evidence. This study compared TAS-102+regorafenib group (REG) with TAS-102+bevacizumab group (BEV). Methods: This single-center bidirectional cohort included patients initiating TAS-102-based third-line therapy. Patients received TAS-102+REG (TAS-102 35 mg/m², Maximum single dose: 80 mg, orally, bid, days 1–5; REG 80–120 mg, orally, qd, days 6–15, repeated every 15 days) or TAS-102+BEV (Recommended dosing regimen per guidelines). Primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints were time to treatment discontinuation (TTD) and adverse events (AEs). Outcomes were analyzed using Kaplan–Meier, log-rank tests, and Cox models. Results: Fifty-one patients were enrolled (REG n = 30; BEV n = 21). Median follow-up was 390 days (95% CI 232–441). Median PFS was 199 days（95% CI 165.46-232.54） vs 125 days（95% CI 84.68-165.32）, median OS 584 days（95% CI 388.75-NR）vs 322 days（95% CI 34.74-NR）, and median TTD 149 days（95% CI 80.13–217.87） vs 232 days（95% CI 198.01–265.99）for REG and BEV, respectively. Median PFS was prolonged in the REG group compared with the BEV group (199 vs. 125 days). No significant differences were observed (PFS p = 0.084; OS p = 0.831; TTD p = 0.294). Cox analysis showed an HR for PFS of 0.55 (95% CI 0.28–1.09; p = 0.088), suggesting a trend toward reduced progression risk with REG. HRs for OS and TTD were 0.89 (95%CI 0.30–2.66, p = 0.83) and 1.49 (95%CI 0.70–3.14, p = 0.30). AE incidence was 76.4% (REG) and 71.4% (BEV). Grade ≥3 AEs were infrequent (6.7% vs 9.5%). Myelosuppression was more common with REG (56.6% vs 38%), while fatigue was the most frequent AE in both groups (33.3% vs 23.8%).20% of the REG group had hypertension and 14.2% of the BEV group had nausea, all grade 1–2. Conclusions: No statistically significant differences in PFS, OS or TTD were found among TAS-102-based regimens in this study. Nevertheless, TAS-102+regorafenib group was preliminarily shown to have at least equivalent efficacy to TAS-102+bevacizumab group in real-world practice with potential advantages, which deserves further verification in large prospective studies.

Body mass index as a prognostic factor for trastuzumab deruxtecan efficacy in advanced breast cancer: A multicenter retrospective real-world analysis.

e13078 Background: Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC), has improved outcomes in HER2-positive and HER2-low advanced breast cancer, yet clinical responses remain variable. Body mass index (BMI), a surrogate of systemic metabolic status, may influence therapeutic efficacy, but its prognostic relevance in patients treated with T-DXd remains unclear. Methods: This multicenter, retrospective, real-world study included 199 patients aged ≥ 18 years with advanced HER2-positive or HER2-low breast cancer treated with T-DXd between January 2020 and September 2025 at two centers in China. Patients were stratified according to BMI ( &lt; 24 vs. ≥24 kg/m²) based on guideline-recommended cutoffs for the Chinese population. Propensity score matching (PSM) with a 1:2 ratio was applied to balance baseline characteristics. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: After PSM, 119 patients were analyzed (BMI &lt; 24 kg/m², n = 76; BMI ≥24 kg/m², n = 43), with well-balanced baseline characteristics between groups. At a median follow-up of 10.97 months, median PFS for the overall cohort was 6.40 months (95% CI: 4.60–8.21). On multivariable Cox analysis, BMI ≥24 kg/m² was independently associated with prolonged PFS (HR 0.52, 95% CI: 0.31–0.86, P = 0.011), with median PFS of 8.73 vs. 5.18 months compared with BMI &lt; 24 kg/m². Although differences did not reach statistical significance, patients with BMI ≥24 kg/m² demonstrated numerically higher ORR (37.2% vs. 27.6%, P = 0.278) and DCR (93.0% vs. 85.5%, P = 0.223) than those with BMI &lt; 24 kg/m². Notably, in the subgroup of patients with brain metastases (n = 35), a statistically significant improvement in ORR was observed in the higher BMI group (57.1% vs. 23.8%, P = 0.046), while DCR remained similar between BMI categories (92.9% vs. 90.5%, P = 0.805). Subgroup analyses further indicated that the association between higher BMI and improved PFS was most evident among patients without prior exposure to ADC (HR 0.32, 95% CI: 0.16-0.65, P = 0.002), and a consistent association between higher BMI and longer PFS was also observed in the HER2-low subgroup (HR 0.34, 95% CI: 0.16-0.73, P = 0.006). TRAEs were generally manageable, and no clinically meaningful differences in safety profiles or incidence of grade ≥3 adverse events were observed between BMI groups. Conclusions: This study indicated that a higher BMI (≥24 kg/m²) was independently associated with inproved efficacy in patients with advanced breast cancer treated with T-DXd, particularly among ADC-naïve patients, HER2-low patients, and patients with brain metastases. These findings suggest that BMI could be a valuable factor for prognostic stratification in patients receiving T-DXd.

The impact of environmental factors and social determinants of health on molecular alterations in a single-center endometrial cancer cohort.

e17634 Background: Molecular classification has become increasingly important in endometrial cancer (EC) management. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifies four EC subgroups: POLE mutated, mismatch repair (MMR) deficient, p53 abnormal (p53abn), and No Specific Molecular Profile (NSMP), each with prognostic and treatment implications. While environmental exposures are known to influence tumor epigenetics, their relationship with molecular alterations in EC remains unclear. This study evaluated associations between air quality measured by fine particulate matter (PM2.5), social vulnerability (SV), environmental justice (EJ), and EC molecular alterations. Methods: Newly diagnosed EC patients at a single academic institution from 1/1/2018-12/31/2021 were identified retrospectively. Demographic and clinicopathologic data were obtained through electronic medical records. Annual census tract level median PM2.5 was derived from the Environmental Protection Agency (EPA). SV and EJ index variables were obtained from the Centers for Disease Control and Prevention (CDC). The relationship between MMR, microsatellite instability (MSI), and p53 status and SV, EJ, and PM2.5 were evaluated using t-tests and Pearson’s chi-square tests. Results: Among 330 identified patients, the mean age was 62.3. Most were obese (72.7%), non-smokers (55.7%), and had stage I disease (56.7%). Black patients comprised 43% of the cohort. Low-grade histology comprised 47% of tumors. When MMR status was known, the majority were MMR proficient (68.2%), while 31.8% were MMR deficient. When MSI status was known, 70.7% were microsatellite stable and 29.3% demonstrated microsatellite instability. P53 status was known in only 42% of patients, of which 53.2% were p53abn. POLE status was not routinely tested. MMR, MSI, and p53 status were associated with histology and tumor grade (p &lt; 0.001). P53 status was associated with EC stage (p=0.001). PM2.5 was associated with tumor grade (χ², p=0.013) and p53 status (χ², p=0.014), but not MMR or MSI status in this cohort. These molecular alterations were not associated with SV, EJ, population density, or other patient-level factors. Conclusions: Census tract level PM2.5 was associated with tumor grade and p53 status in EC, but not MMR or MSI status. A better understanding of the relationship between air quality and epigenetic changes associated with EC is warranted.

Characterization of antibody-drug conjugate target antigen expression in patients with biliary tract cancer.

e15042 Background: Data on antibody–drug conjugates (ADC)s target expression prevalence, intertumoral heterogeneity, concordance with gene drivers, and effect on clinical outcome remain limited for patients (pts) biliary tract cancers (BTC). Methods: Under IRB approved retrospective biospecimens protocols, resected primary specimens and matched metastatic sites from pts with BTC were assembled into tissue microarrays and tested for CLDN18.2, c-MET, Nectin-4, TROP2, and HER2 expression by immunohistochemistry (IHC). A subset of cases underwent targeted next-generation sequencing for genomic characterization using MSK-IMPACT (NCT01775072). Protein positivity was determined using predefined thresholds (IHC 1+ ≥10% for CLDN18.2, c-MET, Nectin-4, TROP2; and HER2 by ASCO-GEA scoring criteria), and H-scores (except for HER2). Fisher exact test was used to examine associations between ADC target expression and anatomic site and between, genomic alterations. Univariate Cox regression method was used to correlate target expression with overall (OS) and recurrence-free (RFS) survivals. Cohen’s kappa(κ) was used to determine concordance on target expression (positive vs negative) between paired samples. Results: Sixty-five pts with resected biliary tract cancer with 18 paired metastatic sites were identified—median age 72 years, 55% male, 43% extrahepatic cholangiocarcinoma (eCCA), 40% intrahepatic cholangiocarcinoma (iCCA), and 17% gallbladder cancer (GBC). All evaluated target antigens were overly expressed; percent positivity and H-score &gt; = 200 in descending order of frequency were: TROP2 (83%, 26%), c-MET (75%, 26%), Nectin-4 (66% ;35%), and CLDN18.2 (46%; 7.7%). HER2 overexpression occurred in 3.1% of tumors. Fifty-four (83%) pts had more than 1 target antigen expressed, 19 (29%) had at least 2 antigens expressed. Target percent positivity in TROP2, c-MET, and CLDN18.2 had higher expression in GBC and/or eCCA anatomic sites. Agreement among paired primary and metastatic samples ranged from 43% to 75% with the highest observed for TROP2 (71%; κ not available due to near-uniform positivity) and HER2 (75%; κ = 0.29). Overall concordance was low for c-MET, CLDN18.2, and Nectin-4. In 33 pts with genomics, frequently altered genes included TP53 (36%), SMAD4 (27%), ELF3 (21%). ERRB2 amplification was observed in 1 (3%) pt and 2 pts were HER2 positive; MET amplification was not observed, and 7 pts were c-MET H-score ≥ 200. Target antigen expression did not associate with underlying genomics, RFS, or OS. Conclusions: Acknowledging limitations of this retrospective analysis, BTC displays frequent but heterogeneous expression of multiple ADC targets. These findings suggest inherent complexity of target protein quantification, target threshold determination, and target sampling discordance while providing a biologic rationale for ongoing biomarker-driven ADC trials for pts with BTC.

Impact of erythrocytosis on overall survival, thrombotic events, and risk of transformation to AML in patients with myelofibrosis.

e18637 Background: Erythrocytosis is an uncommon phenotype in myelofibrosis (MF), and its association with long-term survival and thrombotic risk remains poorly defined. We evaluated the longitudinal outcomes associated with erythrocytosis in a large real-world MF cohort. Methods: We performed a retrospective cohort study using a federated electronic health record network. Adult patients with MF were classified by the presence or absence of erythrocytosis. Patients with prior allogeneic hematopoietic stem cell transplantation were excluded. Propensity score matching (1:1) was conducted using demographics, cardiovascular comorbidities, and baseline laboratory variables. Outcomes included all-cause mortality, pulmonary embolism (PE), and venous thromboembolism (VTE), evaluated at 1, 3, and 5 years. Time-to-event analyses were performed using Kaplan–Meier methods with log-rank testing; hazard ratios (HRs) are reported with log-rank p values. Binary outcomes are summarized using odds ratios (ORs). Results: After matching, 4,357 patients were included in each cohort. Erythrocytosis was associated with significantly lower all-cause mortality at 1 year (4.9% vs 6.6%; HR 95% CI 0.61–0.87; log-rank p&lt;0.001), with this survival advantage persisting at 3 years (10.0% vs 12.4%; HR 0.69–0.89; p&lt;0.001) and 5 years (14.1% vs 16.4%; HR 0.75–0.93; p=0.001). In contrast, erythrocytosis was associated with higher thrombotic risk. PE incidence was increased at 1 year (1.1% vs 0.7%; HR 1.02–2.57; log-rank p=0.040), 3 years (2.1% vs 1.1%; HR 1.35–2.76; p&lt;0.001), and 5 years (2.8% vs 1.4%; HR 1.42–2.66; p&lt;0.001). Similarly, VTE rates were higher at 1 year (2.0% vs 1.3%; HR 1.07–2.12; p=0.020), 3 years (3.7% vs 2.6%; HR 1.10–1.81; p=0.007), and 5 years (5.3% vs 3.4%; HR 1.21–1.86; p&lt;0.001). Conclusions: In a large propensity-matched real-world cohort, erythrocytosis in MF was associated with a durable survival advantage across 5 years of follow-up, despite a progressively increased risk of thromboembolic events. These findings suggest a biologically distinct MF phenotype and highlight the importance of individualized thrombotic risk assessment in patients with erythrocytosis.

FGFR2 and favorable survival outcomes in resected poorly cohesive cell gastric cancer: Analysis from FGFR2 protein overexpression and genetic variation

Purpose Poorly cohesive cell gastric cancer has aggressive and heterogeneous characteristics. This study investigated the clinical significance of fibroblast growth factor receptor 2 expression and genetic variations in patients with PCC-GC. Materials and Methods We retrospectively collected 209 surgically resected stage II and III PCC-GC cases. After FGFR2 immunostaining, we analyzed clinical data and performed targeted sequencing to assess their impact on patient survival. Results Among 209 patients, 89 (42.6%) were classified as stage II and 120 (57.4%) as stage III. FGFR2 overexpression varied by stage, with FGFR2 positivity observed in 61.5% of stage II cases, while FGFR2-negative cases were predominant in stage III patients (60.1%) (P = 0.037). Moreover, lymph node involvement was associated with FGFR2 expression (P = 0.009). FGFR2 positivity significantly correlated with improved disease-free survival (DFS) and overall survival and remained an independent favorable prognostic factor for DFS in multivariate analysis (P = 0.022). Targeted next-generation sequencing was performed in five selected cases, FGFR2 amplification or pathogenic alterations were not found. Conclusion This study shows that FGFR2 expression was independently associated with improved DFS in PCC-GC. These findings suggest that FGFR2 may serve as a prognostic biomarker in patients with PCC-GC.

Azide‐to‐Diazo Transformation Facilitated by Michael Addition via Phosphazide Formation

ABSTRACT A new type of Michael addition of thiols and amines to 2‐azidoacrylic acid esters through azide‐to‐diazo conversion is disclosed. This unusual transformation proceeds via 1,4‐addition accompanied by N─N bond cleavage of phosphazide intermediates generated in situ from 2‐azidoacrylic acid esters and (4‐dimethylaminophenyl)di( tert ‐butyl)phosphine (Amphos) under practical conditions. The high versatility of the resulting Michael adducts enables the synthesis of a wide variety of organonitrogen compounds.

Green synthesis of bismuth oxide nanoparticles using neem leaf: Enhanced photocatalytic degradation of congo red, 4-nitrophenol reduction and antibacterial activity