Browse Articles
Discover research articles across all indexed journals
Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) to stratify recurrence risk and adjuvant treatment benefit in a real-world colorectal cancer (CRC) cohort.
3616 Background: ctDNA detection following curative surgery is known to predict recurrence in patients (pts) with stage II-III CRC. We investigate ctDNA dynamics in relation to clinical outcomes and their real-world impact on treatment decisions among pts with resected CRC. Methods: Based in a large community hospital system, we conducted a retrospective analysis of a prospectively maintained database inclusive of 407 pts with resected stage II-IV CRC. ctDNA was longitudinally quantified at MRD (2-12 weeks post-op) and surveillance timepoints (tp) using a clinically validated, personalized, tumor-informed 16-plex mPCR-NGS assay. Primary endpoint was the correlation between ctDNA status and disease-free survival (DFS) and overall survival (OS). Secondary objective was to evaluate its impact on treatment decisions. Survival distribution was analyzed by Kaplan-Meier Method. Multivariable Cox proportional hazards models were applied to adjust for clinicopathological covariates: age, gender, T, N, high risk features, obstruction, perforation, KRAS, BRAF, MMR. Results: Of 407 pts, 303 had complete evaluable data for analysis at cutoff 12/5/2025. After median follow-up of 29.6 months (mo), N=2342 ctDNA plasma levels were analyzed: 2 stage I, 119 stage II, 170 stage III, 12 stage IV. ctDNA at MRD tp was available for 259 pts (86%): 99 stage II, 144 stage III. ctDNA was negative at MRD tp in 211/259 (MRD-), positive in 48/259 (MRD+). Of 303 pts,180 (60%) received adjuvant chemotherapy (ACT): 38 MRD+, 118 MRD-. 123 (40%) were observed: 9MRD+, 93 MRD-. MRD positivity was significantly associated with inferior DFS in all stages combined (HR = 13.4, 95% CI: 7.64–23.64, p<0.0001) and in all stage-stratified subgroups. Multivariate analysis confirmed ctDNA-positivity to be the most significant prognostic factor associated with DFS when compared with clinicopathologic factors. In MRD+ subgroup, pts with transient ctDNA clearance had significantly worse DFS than those with sustained clearance (HR = 5.27, 95% CI: 2.49–11.14, p<0.0001). Among MRD- pts, ACT conferred no significant DFS benefit vs observation (HR=1.52, p<0.05). Among MRD+ pts, ACT did not reach statistical significance. ctDNA positivity predicted recurrence with a lead time up to 23.9 mo (median 3.8 mo) before imaging, including in low ctDNA shedding sites. 7% had metastatic disease diagnosed earlier because of a positive test, prompting timely therapy. ctDNA testing was associated with higher than historical rates of oligometastasis-directed therapy (17%). Conclusions: Our results highlight the value of post-surgical ctDNA monitoring as a prognostic biomarker in CRC and its potential value for treatment decision making. Clinical utility of ctDNA-guided AC will further be established by ongoing trials (CIRCULATE-NA).
Restrictive eligibility criteria in FDA-approved oncology trials following ASCO Guideline updates.
11020 Background: Despite significant advancements in new targeted and immunotherapies, enrollment in oncology clinical trials remains unrepresentative of real-world patient populations. Overly restrictive eligibility criteria – particularly related to Eastern Cooperative Oncology Group (ECOG) performance, cardiovascular status, HIV status, and prior malignancy – have been identified as key barriers to trial participation and generalizability. In response, the American Society of Clinical Oncology (ASCO) published new guidelines in 2017 lowering thresholds for enrollment. We examined whether these ASCO recommendations translated into measurable changes in eligibility criteria among FDA-approved trials for the five most common solid tumors. Methods: Clinical trial data was obtained from ClinicalTrials.gov, FDA Approved Drug Notification Database, and journal manuscripts. The study evaluated clinical trials that led to FDA-approved therapies for NSCLC, breast, melanoma, prostate, and colon cancer between 2006-2025. Eligibility criteria based on Eastern Cooperative Oncology Group (ECOG) performance, cardiovascular status, HIV status, and prior malignancy were extracted. Clinical trials were categorized as pre- or post-ASCO 2017 guideline publication, and t-tests (R v4.3.1) were used to compare exclusion rates between groups and assess alignment with ASCO recommendations. Results: Between 2006-2025, there were 167 FDA-approved clinical trials for NSCLC (59), breast (44), melanoma (25), prostate (23), and colon (16) malignancies. The proportion of trials initiated after the 2017 ASCO guidelines was 19 (32.2%) of NSCLC, 12 (27.3%) of Breast, 6 (37.5%) of Colon, 5 (21.7%) of Prostate, and 5 (20.0%) of Melanoma. There was no statistically significant reduction in the usage of restrictive exclusion criteria when comparing trials started before and after the 2017 ASCO recommendations among Colon (p = 0.953), Prostate (p = 0.896), Melanoma (p = 0.775), NSCLC (p = 0.301), and Breast (p = 0.117) cancer groups regarding ECOG performance, cardiovascular status, HIV status, and prior malignancy. Conclusions: Despite the publication of ASCO’s 2017 eligibility guideline updates, restrictive exclusion criteria remain prevalent in FDA-approved oncology trials across major solid tumors. These findings suggest that guideline dissemination alone has been insufficient to change trial design practices. More proactive regulatory, sponsor-level, and implementation-focused interventions may be required to ensure broader trial access and improve the generalizability of oncology clinical research.
Trends in lung resection and inpatient mortality among U.S. lung cancer patients (2010–2022).
e23106 Background: Despite declining lung cancer incidence and mortality in the United States, disparities in treatment utilization and outcomes persist across demographic and socioeconomic groups. We examined national trends and disparities in surgical treatment and inpatient mortality among hospitalized lung cancer patients. Methods: We analyzed National Inpatient Sample from 2010 to 2022. Adult admissions with a primary diagnosis of lung cancer were identified using ICD codes. Lung resection was defined by having a procedure during the same admission. Hospitalizations, lung resection utilization and inpatient mortality were examined overall and stratified by age, sex, race utilizing survey-weighted analyses. Multivariate logistic regression adjusted for age, sex, ethnicity, household income, comorbidities, hospital characteristics, and insurance type. Results: A total of 7,069,033 hospitalizations with a primary diagnosis of lung cancer were identified over 13 years. A decreasing trend of hospitalization numbers was seen over the period (736,075 in 2010 vs 381,080 in 2022). Females accounted for 49.1% of admissions with an increasing trend with odds ratio (OR) 1.015 (95% CI 1.013 - 1.017, P < .001).Lung resection utilization increased overtime with OR 1.042 (95% CI 1.033 - 1.050, P < .001). Compared with Whites, surgical utilization was lower among Blacks and Hispanics (aOR 0.594 and 0.880, all P < .001). Resection rates were higher among females than males (aOR 1.096, P < .001), lowest in the lowest income quartile, and higher in the 2nd, 3rd, and 4th income quartiles (all P < .001). Surgical utilization was also lower among Medicaid and self-pay patients compared with Medicare beneficiaries (all P < .001).A decreasing trend of inpatient mortality was noted (aOR 0.934; 95% CI 0.930–0.938; p < 0.001) and was seen in examined ethnic groups, when stratified into White (aOR 0.938), Black (aOR 0.939) and Hispanic (aOR 0.938) (all P < .001) with no difference in mortality trends. However, overall mortality remained higher among Blacks (aOR 1.069) and Asian/Native Americans (aOR 1.141), patients with Medicaid, private insurance, or self-pay compared to those with Medicare (all P < .001). Conclusions: Lung cancer hospitalizations and inpatient mortality declined from 2010 to 2022, while lung resection utilization increased. However, disparities in surgical treatment utilization and mortality remain across racial and insurance groups. Targeted efforts are needed to reduce these disparities and improve equity.
Real-world treatment patterns and toxicity of durvalumab after chemoradiation in stage III non-small cell lung cancer.
e20109 Background: Durvalumab following concurrent chemoradiation is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC), based on the results of the PACIFIC trial. However, real-world populations often differ from clinical trial cohorts in terms of patient characteristics, treatment delivery, and toxicity. We aimed to describe real-world treatment patterns and safety of durvalumab in patients with stage III NSCLC treated at our institution. Methods: We conducted a retrospective, single-center cohort study including all patients with stage II–III NSCLC treated with concurrent chemoradiation followed by durvalumab between March 2018 and June 2024. Data collected included baseline clinical and tumor characteristics, chemotherapy and radiotherapy regimens, durvalumab treatment duration and discontinuation, and treatment-related adverse events. Results: A total of 102 patients were included, with a median age of 68 years; 55% were male and 95% had stage III disease. The predominant histologies were adenocarcinoma (71%) and squamous cell carcinoma (27%). A smoking history was present in 79% of patients. Most patients received platinum-based doublet chemotherapy concurrent with radiotherapy, most commonly cisplatin–etoposide (29%). Durvalumab was administered every 2 or 4 weeks according to institutional protocols. Overall, 47% of patients completed all planned durvalumab cycles. The most common reasons for treatment discontinuation were disease progression (53%) and treatment-related toxicity, with pneumonitis being the most frequent adverse event leading to discontinuation (38%). Durvalumab-related adverse events occurred in 45% of patients, with pneumonitis in 24% (25/102) and hypothyroidism in 12% (13/102) being the most frequent immune-related toxicities. Recurrence was predominantly intrathoracic (49%), with isolated brain recurrence in 23% and other extrathoracic recurrence in 6%. Hospitalization occurred in 33% of patients, with 75% due to non–treatment-related causes. Home care services were required in 20%. Median overall survival was 56 months (CI: 46-57.6) and median progression-free survival was 23 months (CI: 31.5-44.6). Conclusions: In this real-world cohort of patients with stage III NSCLC treated with chemoradiation followed by durvalumab, treatment completion rates were lower and toxicity rates higher than those reported in the PACIFIC trial. Immune-related adverse events—particularly pneumonitis—were common and frequently led to treatment discontinuation. These findings highlight the challenges of translating clinical trial results into routine practice and underscore the need for optimized toxicity monitoring and careful patient selection in real-world settings.
Pathologic complete response in gastric and gastroesophageal adenocarcinoma: Context-dependent survival and CNS-enriched recurrence.
e16141 Background: Although pathologic complete response (pCR) after neoadjuvant therapy is associated with improved outcomes in gastric and gastroesophageal junction (GEJ) adenocarcinoma, whether its prognostic significance varies by tumor location, radiotherapy exposure, or systemic regimen remains unclear. In addition, recurrence patterns among complete responders have not been reassessed in contemporary cohorts. In this single-institution cohort, we investigate the prognostic significance of pCR across key disease and treatment contexts and evaluate recurrence patterns, including central nervous system (CNS) involvement. Methods: Patients receiving neoadjuvant therapy followed by R0 resection for gastric and GEJ adenocarcinoma between 1990 and 2024 were identified from a single-institution database. Final pathology classified patients as pCR (ypT0N0) or non-pCR (residual tumor with or without nodal disease, including ypT0N+). Analysis of overall survival (OS) was performed and stratified by tumor location and radiotherapy (RT) exposure and by systemic treatment (CRT, MAGIC-era chemotherapy, FLOT, IO±chemo). Results: Among 1783 patients receiving preoperative therapy, 1498 underwent R0 resection. The overall rate of pCR was 12.5% [n=187/1498], but differed across tumor location and RT exposure (gastric: 6.6% [n=44/670], GEJ+RT: 19.6% [n=123/629], GEJ-noRT: 10.1% [n=20/199]) and systemic regimen (CRT: 19.6%, MAGIC-era: 6%, FLOT-era: 9.1%, IO±chemo: 15.9%). pCR was associated with improved OS in gastric (HR: 0.36, p=0.001) and GEJ+RT (HR: 0.48, p<0.001), but not among GEJ-noRT (HR: 0.54, p=0.18). Notably, among gastric cancer patients achieving pCR, no disease-related deaths were reported. The survival benefit of pCR was strongest with CRT (HR: 0.48, p<0.001) and MAGIC-era regimens (HR: 0.45, p=0.01), while not statistically significant in FLOT (HR: 0.26, p=0.18). Complete responders experienced a significantly higher rate of CNS-involved failures relative to non-pCR (35% vs. 4.5% of recurrences, p<0.001), with enrichment primarily observed among GEJ+RT tumors. Other recurrence patterns (hematogenous, locoregional, peritoneal) and median time to relapse did not differ between groups. Conclusions: The prognostic value of pCR was not uniform across gastric and GEJ adenocarcinoma. Survival gains were greatest among gastric and radiated GEJ tumors, attenuated in non-radiated GEJ tumors and in FLOT, and accompanied by persistent enrichment of CNS-involved relapse among complete responders. Survival benefit of pCR by tumor location, radiation exposure, and treatment regimen. Stratum Subgroup HR CI p-value Site and Radiation Gastric 0.36 0.16–0.69 0.001 GEJ+RT 0.48 0.35–0.65 <0.001 GEJ-noRT 0.54 0.22–1.33 0.183 Treatment Regimen CRT 0.48 0.35–0.65 <0.001 MAGIC-era 0.45 0.25–0.83 0.01 FLOT-era 0.26 0.04–1.89 0.183 IO±chemo 0.52 0.40–0.67 <0.001
Frailty matters: Association of mFI-5 Index with odds of mortality, hospitalization, and toxicities with ADCs, BiTE, and CAR T-cell therapies in real-world data.
11002 Background: Targeted-delivery biopharmaceuticals such as antibody–drug conjugates (ADCs) or BiTE cell therapy are increasingly used in oncology. Recent meta-analyses demonstrate similar survival benefits of ADCs in younger and older patients across tumor types; however, baseline frailty predicts increased mortality, toxicity and hospitalization among patients receiving systemic anticancer therapy. While NCCN guidelines recommend frailty assessment for older adults prior to surgery, no such guidance exists for systemic treatments. Methods: We conducted a retrospective cohort study using TriNetX, a federated real-world data network with anonymized EHRs from hundreds of healthcare organizations. We included 46,674 patients with solid tumors, breast and bladder (solid ca) and 15,213 patients with hematologic cancers such as lymphoma, leukemia (heme ca) who initiated ADCs, BiTE-cell therapy, or CAR T-cell therapy. Cohort entry was defined as the first use of the drug class (index date). Toxicities, i.e. cardiotoxicity or cytopenia were outcomes if occurred within 30 days of index; patients without these events or with other outcomes served as comparators. Baseline frailty was measured using the modified Frailty Index-5 (mFI-5), derived from ICD-10 codes for hypertension (I10), care dependency (Z74), diabetes (E08–E13), COPD (J44), and heart failure (I50). Logistic regression estimated associations between frailty and each outcome, with p-values adjusted using the Benjamini–Hochberg false discovery rate. Mortality at pre-specified time points and hospitalization were fitted with a Cox proportional hazards model with frailty category as the primary exposure, controlling for age, and stratifying by cancer group and treatment. Results: In heme ca and solid ca, higher mFI-5 relative to mFI=0 was associated with significantly increased odds of toxicities with ADCs, including nausea, thrombocytopenia, anemia, cardiotoxicity, diarrhea, lung disease, and neutropenia (all p<0.001). In heme ca, higher mFI-5 was associated with significantly higher odds of toxicities, including anemia and cardiotoxicity (all p<0.001) with BiTE therapy and CAR T-cell. Results indicate a strong relationship between frailty severity and mortality risk (Table 1) and hospitalization after controlling for age and accounting for differences in baseline hazard across cancer groups and treatment strata. Conclusions: Assessing frailty severity through mFI-5 before initiating targeted systemic therapy in hematologic and solid tumors may help identify patients at increased risk of poor survival odds, adverse effects and facilitate shared treatment decision-making. Hazard ratio of mortality relative to mFI=0. mFI-5 score Hazard ratio of mortality with 95% CI 1 1.41 [1.34-1.47] 2 1.79 [ 1.69-1.9] 3 2.45 [2.24-2.69] 4+ 2.51 [2.11-2.97]
Cancer-associated type 2 versus type 1 myocardial infarction: A physiology-driven framework for inpatient risk stratification.
e23234 Background: Myocardial injury during cancer hospitalizations is frequently labeled as myocardial infarction, although many events reflect supply demand mismatch rather than plaque rupture. Distinguishing Type 2 from Type 1 myocardial infarction may better inform inpatient triage and prognosis. This study compared the burden and outcomes of Type 2 and Type 1 myocardial infarction in hospitalized oncology populations. Methods: A serial cross-sectional analysis was performed using adult hospitalizations with a principal diagnosis of malignancy in the 2018 to 2022 National Inpatient Sample with discharge-level survey weighting. Type 2 myocardial infarction was identified using ICD-10-CM I24.8 and Type 1 myocardial infarction using I21 to I22. Outcomes included in-hospital mortality, shock, all types (R57*), mechanical ventilation, intensive care unit utilization proxy, length of stay, hospitalization cost, and All Patient Refined Diagnosis Related Group (APR-DRG) severity. Survey-weighted multivariable regression compared Type 2 myocardial infarction only with Type 1 myocardial infarction only, adjusting for demographics, payer, ZIP-code income quartile, admission type, cancer subtype, hospital characteristics, and year. Results: Among 961,848 unweighted cancer hospitalizations representing 4,809,239 admissions nationally, Type 2 myocardial infarction occurred in 0.70% and Type 1 myocardial infarction in 1.03%. Mean APR-DRG severity was lower with Type 2 than with Type 1 myocardial infarction (3.38 vs 3.75). Mortality was 14.2% with Type 2 versus 19.1% with Type 1 myocardial infarction. Type 2 myocardial infarction was associated with lower shock (5.5% vs 9.2%), mechanical ventilation (8.3% vs 13.9%), intensive care unit utilization (11.9% vs 18.7%), and extreme severity (7.4% vs 12.8%), as well as shorter length of stay and lower costs. After weight adjustment, Type 2 myocardial infarction remained associated with lower mortality (adjusted odds ratio 0.68, 95% CI 0.62 to 0.75), shock (adjusted odds ratio 0.60, 95% CI 0.52 to 0.68), intensive care unit utilization (adjusted odds ratio 0.61, 95% CI 0.56 to 0.68), mechanical ventilation (adjusted odds ratio 0.58, 95% CI 0.52 to 0.65), extreme severity (adjusted odds ratio 0.28, 95% CI 0.23 to 0.34), shorter length of stay (β −1.16 days), lower costs (β −$5,601), and lower APR-DRG severity (β −0.37) compared with Type 1 myocardial infarction. Conclusions: Among cancer hospitalizations, Type 2 myocardial infarction represents a meaningful national burden with high morbidity but consistently lower severity, resource utilization, and mortality than Type 1 myocardial infarction. These findings support early identification of Type 2 myocardial infarction among cancer hospitalizations to appropriately guide prognosis and treatment rather than uniform escalation for myocardial injury.
Clinical outcomes following CAR T-cell therapy in relapsed or refractory multiple myeloma patients with baseline renal dysfunction: A TriNetX analysis.
7539 Background: Renal dysfunction is common in relapsed or refractory multiple myeloma (RRMM) and has historically limited eligibility for chimeric antigen receptor T-cell (CAR-T) therapy. However, real world data evaluating early complications and long-term outcomes in this population remains limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adult RRMM patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel. Patients with baseline renal dysfunction (creatinine ≥ 2.0 mg/dl, not on dialysis) were compared with those with preserved renal function (creatinine ≤ 1.0 mg/dl) after propensity matching. Early post-CAR-T complications: cytokine release syndrome (CRS) and disseminated intravascular coagulation (DIC) were assessed from day 0 to 15 post CAR-T therapy. Mortality was evaluated at 6 months, 1 year and 3 years. A secondary exploratory analysis assessed renal recovery at 90 days in patients with renal dysfunction following CART-cell infusion using creatinine based (≤ 1.9 mg/dl) and eGFR based (≥50 mL/min/1.73 m²) definitions. Results: 84/777 (10.8%) RRMM patients who received CAR T-cell therapy had baseline renal dysfunction. After propensity matching, 79 patients were included in each cohort, demographics in Table 1. 0-15 day CRS incidence was similar in patients with and without renal dysfunction (36.5% vs 33.3%), and no patients developed DIC or required dialysis at any point of time. Mortality was significantly higher in patients with renal dysfunction at 6 months (40% vs 13.2%), 1 year (45.3% vs 15.8%), and 3 years (52% vs 21.1%). Among patients with baseline renal dysfunction and available 90 day follow-up (61/79); renal recovery occurred in 48/61 (78.7%) by creatinine and in 38/61 (62.3%) by eGFR criteria. Conclusions: Baseline renal dysfunction was not associated with increased CRS incidence or progression of renal disease needing dialysis but was associated with higher long-term mortality, likely reflecting greater myeloma burden. Most patients with baseline renal dysfunction demonstrated renal recovery within 90 days, though they remain underrepresented among CAR-T recipients, highlighting a potential treatment gap. Baseline characteristics of both cohorts. Demographic parameter Baseline renal dysfunction cohort, N=79(n, %) Preserved renal dysfunction cohort, N=79, (n, %) Race White 54 (68.4%) 58 (73.4%) Black or African American 14 (17.7%) 15 (19%) Sex Female 26 (32.9%) 26 (32.9%) Male 53 (67.1%) 53 (67.1%) Lab Parameters Baseline renal dysfunction cohort, Mean ± SD Preserved renal dysfunction cohort, Mean ± SD Hemoglobin 9.5 ± 1.7 10.3 ± 2.2 Hematocrit 28.4 ± 5.0 31.0 ± 6.4 Urea Nitrogen 27.2 ± 13.1 14.6 ± 5.5 Bicarbonate 21.8 ± 3.7 24.6 ± 3.1 Ferritin 1587.7 ± 3073.6 628.8 ± 1099.9
Epidemiology, survival disparities, and future incidence projections of small intestine neuroendocrine carcinoma in the United States: A population-based SEER analysis.
e16322 Background: Small intestine neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy comprising less than 0.1% of gastrointestinal cancers. Population-level data remain limited, restricting understanding of long-term survival patterns, demographic disparities, and evolving disease burden. We evaluated survival outcomes, demographic predictors, and incidence trends of small intestine NEC in the United States. Methods: We conducted a retrospective population-based cohort study using SEER Research Data (17 registries, November 2024 submission). Patients diagnosed with malignant small intestine NEC (ICD-O-3 morphology code 9.3.3.1.2) between 2000 and 2022 were identified using SEER*Stat (v9.0.4.2). Variables including age group, sex, race, year of diagnosis, survival time, and vital status were analyzed in R (v4.5.1). Overall survival (OS) was estimated using Kaplan–Meier methods and compared using log-rank testing. Cox proportional hazards models identified independent predictors of OS. Annual case counts were modeled using time-series forecasting to project future incidence. Results: A total of 506 patients were included. Estimated OS was 94.4% (95% CI 92.4–96.4) at 1 year, 88.1% (85.3–91.0) at 3 years, and 82.4% (79.0–85.9) at 5 years, with a subset demonstrating survival beyond 15 years. Increasing age was associated with worse survival (log-rank p = 0.058). Significant racial differences in OS were observed (log-rank p < 0.0001). In multivariable analysis, race remained independently associated with OS. Incidence forecasting projected a modest increase in annual case burden over the next decade. Conclusions: Small intestine NEC demonstrates heterogeneous survival outcomes, significant demographic disparities, and projected growth in disease burden. These findings highlight the need for improved risk stratification, equitable access to care, and integration of molecular and treatment-level data to optimize management of this rare malignancy
Distinct late recurrence patterns and immune landscape of HER2-positive invasive lobular carcinoma (ILC): Analysis of NCCTG N9831 (Alliance) trial and real-world cohort.
564 Background: HER2+ ILC is rare (~5% of ILC), with limited data on long-term adjuvant trastuzumab outcomes. We investigated late recurrence and immune landscapes of HER2+ ILC vs invasive ductal carcinoma (IDC) in the phase III NCCTG N9831 trial (NCT00005970) and a real-world cohort. Methods: We evaluated 3304 early-stage HER2+ breast cancer patients (pts) enrolled in N9831 (122 ILC, 3182 IDC). Recurrence-free survival (RFS) and overall survival (OS) were estimated (Kaplan-Meier) and compared using multivariable Cox regression adjusting for age, tumor size, grade, hormone receptor (HR), and nodal status. Findings were validated in a real-world cohort of HER2+ pts (Caris Life Sciences CODEai platform). Immune microenvironments were profiled by WTS deconvolution (Quantiseq). Real-world overall survival was calculated from trastuzumab start to last contact. Results: In N9831, ILC pts were older (median 54 vs 49 y), more ER+ (74.6% vs 51.4%), and had more N3 disease (25.4% vs 12.7%) compared to IDC. ILC pts derived a comparable magnitude of benefit from adjuvant trastuzumab compared to the overall population (HR 0.58 vs 0.67). However, long-term outcomes diverged: while the 5-year RFS was similar (77.1% vs 82.7%), ILC pts experienced a steep decline between years 5-15 (77.1% to 57.7%; ~20% decline) vs IDC (82.7% to 72.7%; ~10% decline) after multivariable Cox analysis (Table). In the real-world early/advanced cohort (n=1328; 26 ILC vs 1302 non-ILC [subset IDC n=595]) treated with trastuzumab-based therapy, ILC pts had worse mOS (33.7 vs 68.6 m, HR 2.01, 95%CI 1.00-4.07, p=0.04) compared to non-ILC. However, there was no statistically significant difference when compared specifically to IDC (HR 1.77, 95% CI 0.87-3.61, p=0.11). ILC had: i) numerically lower tumor mutation burden (TMB)-high (4.2% vs 9.5%, p=0.38); ii) higher infiltration of B cells, Tregs, and M2 macrophages (p<0.05); iii) upregulated MHC class II expression (HLA-DOA, p<0.05); and iv) downregulated proliferative and DNA repair pathways (E2F, G2M, MYC; FDR <0.25) compared to non-ILC. Conclusions: HER2+ ILC carries late recurrence risk despite initial trastuzumab benefit. The unique immune landscape (Treg/M2 macrophage enrichment and lower proliferative signatures) distinguishes HER2+ ILC from IDC, highlighting the need for tailored strategies. Long-term RFS and OS in HER2-positive ILC vs IDC (N9831 trial). Population N 5-year% (95% CI) 10-year% (95% CI) 15-year% (95% CI) ILC 122 RFS 77.13% (69.9, 85.1) OS 84.04% (77.7, 90.9) RFS 70.57% (62.7, 79.4) OS 76.0% (68.7, 84.2) RFS 57.67% (44.2, 75.1) OS 65.22% (56.6, 75.2) IDC 3182 RFS 82.71% (81.4, 84.1) OS 90.18% (89.1, 91.2) RFS 77.45% (75.9, 78.9) OS 81.81% (80.4, 83.2) RFS 72.68% (70.77, 74.6) OS 76.68% (75, 78.4)
Evaluating the impact of treatment timing with recombinant human thrombopoietin for cancer treatment–induced thrombocytopenia: A retrospective cohort study.
12127 Background: Recombinant human thrombopoietin (rhTPO) is utilized for cancer treatment-induced thrombocytopenia (CTIT) to ensure timely and full-dose chemotherapy delivery. This study investigated the differential clinical benefits of platelet-guided intervention timing strategies to provide evidence-based support for early initiation protocols. Methods: This single-center retrospective cohort study enrolled CTIT patients receiving rhTPO therapy. Participants were stratified into three groups based on platelet count at rhTPO initiation: early intervention group 1 (platelets 75-<100×10⁹/L), early intervention group 2 (50-<75×10⁹/L), and salvage therapy group (<50×10⁹/L). Comparative analyses among the three groups encompassed time to platelet recovery and recovery rates, severe CTIT incidence, platelet transfusion requirements, bleeding event rates, chemotherapy continuity parameters (dose reduction, delay, or discontinuation), and safety profiles. Results: Among 456 solid tumor patients with CTIT, 159 (34.9%) were in early intervention group 1, 172 (37.7%) in early intervention group 2, and 125 (27.4%) in the salvage therapy group. Median time to platelet threshold achievement was significantly shorter in group 1 (7.0 d) versus group 2 and salvage therapy (both 11.0 d; P <0.001), with concomitantly shorter rhTPO treatment duration (5.0 d vs. 7.0 d vs. 7.0 d; P <0.001). Severe CTIT incidence was significantly reduced in early intervention groups (12.6% in group 1 and 19.2% in group 2 vs. 56.0% in salvage therapy; both P <0.001). Platelet recovery rates were superior in early intervention groups (81.1% in group 1 and 75.0% in group 2 vs. 59.2% in salvage therapy; P <0.001 and P =0.004, respectively). Platelet transfusion requirements were significantly lower (0.6% in group 1 and 1.2% in group 2 vs. 12.0% in salvage therapy; both P <0.001). Chemotherapy continuity was significantly improved, with lower rates of delay/discontinuation (18.9% in group 1 and 33.1% in group 2 vs. 46.4% in salvage therapy; all P <0.05). No significant inter-group differences in bleeding incidence were observed, and no rhTPO-related serious adverse events or thromboembolic events occurred. Conclusions: rhTPO therapy for CTIT exhibits a pronounced threshold effect, with early intervention (platelet count ≥50×10⁹/L) conferring substantially greater clinical benefit than salvage therapy. Initiation at 50-<75×10⁹/L effectively preserves chemotherapy continuity and reduces transfusion burden, while initiation at 75-<100×10⁹/L optimizes platelet recovery kinetics and cost-effectiveness.
Malignant ameloblastoma: Real world outcomes of a rare odontogenic malignancy using the SEER database.
e18148 Background: Ameloblastomas are rare odontogenic tumors and represent the second most common neoplasm of odontogenic origin. They predominantly arise in the jaw, most commonly the mandible, and occurrence outside the gnathic region is exceedingly rare. Although most ameloblastomas are benign, they are locally aggressive and, in rare instances, may undergo malignant transformation . Given the extreme rarity of this entity, population-level data describing its epidemiology and survival outcomes remain limited. This study evaluates incidence patterns, demographics, anatomic distribution, and overall survival of malignant ameloblastoma using the Surveillance, Epidemiology, and End Results (SEER) database. The goal of this study is to assist better in understanding of this lesser known and rare malignancy. Methods: A retrospective analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) 17 registries from 2000 to 2022. We extracted histologically confirmed malignant ameloblastoma cases diagnosed between 0–90 years using the ICD code 9310/3. Variables analyzed included age, sex, race, primary site labelled. Overall survival was assessed using Kaplan–Meier estimates with log-rank testing using GraphPad Prism. Results: Among 171 patients, the median age at diagnosis was 48 years. The cohort included 111 males (64.9%) and 60 females (35.1%). Most patients were White (41.5%), followed by Black (28.6%), Hispanic (16.9%), Asian/Pacific Islander (11.7%), and American Indian/Alaska Native (0.5%); race was unknown in 0.5% of cases. Survival curves were compared based on gender, race and primary site of origin. The average months of survival based on gender and race showed no statistical significance. Mean overall survival (MoS) was calculated based on the involved organ system and compared across tumors originating in the mandible, bones of the skull, face and associated joints, retromolar area, gums, vertebral column, lung, overlapping bones, joints and articular cartilage, other bone sites, and unknown primary origin. The highest survival (270M) was seen with mandibular tumours and lowest survival with tumours originating in the bone (65M) (p value < 0.04). Conclusions: Malignant ameloblastoma is an exceptionally rare malignancy, accounting for a small fraction of odontogenic tumors. In this population-based analysis spanning over two decades only 171 cases were found. No significant differences in survival were observed based on sex or race. However, survival outcomes varied by anatomic site, with mandibular tumors demonstrating more favorable outcomes compared with non-gnathic bone involvement. Given the extremely low incidence of malignant ameloblastomas, larger studies are warranted to understand this rare malignancy. Acknowledgements: Editorial support and guidance were provided by Dr. Thirumaran.
Molecular response and outcomes in patients with myeloproliferative neoplasms treated with interferon in the real-world setting.
6586 Background: Myeloproliferative neoplasms are clonal stem cell disorders driven by constitutive JAK-STAT signaling, classically via acquisition of the JAK2 V617F mutation. JAK2 variant allele frequency (VAF) correlates with disease phenotype and clinical risk. Interferon (IFN) therapies are immunomodulatory agents with disease-modifying potential, demonstrating reductions in JAK2 allele burden in limited prospective trials. However, IFN therapies are underutilized in clinical practice, and molecular responses are poorly defined. Therefore, we evaluated clinical outcomes and molecular response to IFN therapy in real-world practice, emphasizing long-term JAK2 VAF kinetics. Methods: We conducted a single-center, retrospective study of consecutive patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV), or pre-fibrotic myelofibrosis (pre-MF) treated with peginterferon alfa-2a or ropegintereron alfa-2b, regardless of prior therapy. Serial JAK2 V617F was measured in peripheral blood using allele-specific PCR. Clinical outcomes, treatment persistence, and longitudinal molecular responses were evaluated. Results: Eighty-two patients were included (median age 50.5 years, 73% female), with diagnosis of PV (76.8%), ET (17.1%), or pre-MF (6.1%); 44 patients (53.7%) were treatment naïve. Median follow-up was 92 mos. from diagnosis and 59 mos. from IFN initiation. At 48 mos., 82% of patients remained on treatment; 12 patients (14.6%) discontinued due to intolerance. Disease progression occurred in one patient. Complete hematologic remission (CHR) was achieved in 80.5% of patients. Median baseline JAK2 VAF was 28%, declining to a median nadir of 4.2% at 41.5 months. Median absolute and relative percent reductions were -18.7 and -81.6%, respectively. VAF reduction ≥50% was achieved by 79% of patients, 19.5% achieved a nadir <1%, and 53.2% achieved nadir <5%. VAF declined progressively until 48 mos. and then remained stable through 72 mos., with later increases mostly attributable to treatment discontinuation. No baseline clinical, molecular, or treatment-related variables predicted depth of molecular response. Treatment-free remission (TFR) was attempted in seven patients after a median of 45 mos. of therapy (mean VAF 0.52%), and median TFR duration was 39 mos. Conclusions: This real-world analysis demonstrates that interferon therapy is feasible and effective in real-world practice. Most patients achieved durable CHR with low rates of treatment discontinuation. Disease progression was exceedingly rare. IFN was associated with substantial and sustained reductions in JAK2 allele burden, supporting its disease-modifying activity outside of the trial setting. These findings reinforce the clinical relevance of serial molecular monitoring and inform emerging approaches to treatment de-escalation in select patients.
Escape to learn: A team-based gamified educational experience for hematology/oncology fellows.
9021 Background: An escape room is a team-based activity in which participants collaborate to solve puzzles within a fixed time limit and escape. Prior studies demonstrate high learner satisfaction and improved teamwork and communication with medical education escape rooms. To date, no published reports describe an escape room designed specifically for hematology/oncology (hem/onc) fellows. As part of Hem/Onc Curriculum, we designed and implemented a hem/onc-focused escape room and evaluated learner satisfaction and perceived learning impact. Methods: The escape room was designed using evidence-based learning science principles (Table 1). Teams worked to solve sequential puzzles, centered on a patient case, addressing key hem/onc concepts, including transfusion medicine, peripheral blood smears, lymphoma classification, and coagulation disorders. Each solved puzzle revealed additional patient laboratory and pathology data. Successful completion required teams to diagnose the patient and select appropriate treatment. Following the activity, teams participated in a facilitator-led debrief focused on team dynamics, communication, and problem solving. Teams observed each other and shared feedback. A larger group debrief co-led by chief fellows and faculty reviewed learning objectives and key takeaways. Learner outcomes were assessed using a post-activity survey evaluating satisfaction, engagement, and impact on learning. Results: Eighteen learners participated, including 14 hem/onc fellows, 1 APP hem/onc fellow, and 3 internal medicine residents. Three of four teams escaped within 1 hour (mean completion time, 52 minutes). All participants provided positive verbal feedback. Fifteen learners completed the post-activity survey, and all respondents reported satisfaction with the activity and would recommend it for future fellows. One-word descriptors included “engaging,” “fun,” and “challenging.” Most respondents (93.3%) agreed that the activity reinforced key hem/onc concepts and improved confidence in clinical problem-solving. All learners felt the activity supported learning, and 93.3% reported that collaboration enhanced the learning experience. Participants identified team-based problem solving, clinical application, and interactive puzzles as the most effective components. Conclusions: A hem/onc escape room resulted in high learner satisfaction and reinforced hem/onc knowledge and clinical problem-solving. This feasible, fun, and innovative activity complements traditional fellowship education by leveraging adult learning principles through gamified, team-based learning and should be incorporated into training programs’ curriculum. Learning science principles applied in a hem/onc escape room. Active Learning Belonging Contrasting Cases Debriefing Deliberate Practice Elaboration Generation Listening and Sharing Reward Worked Examples
An open-label phase Ib/II study of trastuzumab deruxtecan combined with nivolumab and CAPOX in patients with HER2-low gastroesophageal adenocarcinoma (EPOC2203).
4024 Background: Trastuzumab deruxtecan (T-DXd) is standard of care for previously treated patients with HER2-positive metastatic gastroesophageal adenocarcinoma (mGEA) with exploratory analyses of the DESTINY-Gastric01 trial suggested activity in HER2-low (IHC 1+/2+ ISH-negative) disease and preclinical synergy with anti-PD-1 therapy. Methods: EPOC2203 (jRCT2031230477) is a prospective, multicenter, phase Ib/II study evaluating first-line T-DXd combined with nivolumab and CAPOX in HER2-low mGEA. Patients received T-DXd (5.4 or 4.4 mg/kg, day1) in combination with nivolumab (360mg/body, day1) and CAPOX (capecitabine 750 mg/m² twice daily on days 1–14; oxaliplatin 70 mg/m² on day 1) every 3 weeks. The primary endpoints were DLT rate to determine RP2D in phase Ib and ORR in phase II. Assuming a threshold ORR of 58% and an expected ORR of 80%, 28 patients in the full analysis set (FAS) treated at the RP2D were planned (one-sided α = 0.10; power = 80%). Results: A total of 30 patients were enrolled. The median age was 59 years; 83.3% had HER2 IHC 1+ disease, 63.3% had gastric primary, and 96.7% had PD-L1 CPS ≥1. Two DLTs, both febrile neutropenia, occurred at T-DXd 5.4 mg/kg, while none were observed at 4.4 mg/kg in phase Ib part, which was selected as the RP2D. Among patients in the FAS (n = 28), the investigator-assessed ORR was 89.3% (80% CI, 77.7–96.0; P < 0.001), exceeding the prespecified threshold. At median follow-up of 10.1 months, median PFS was 8.1 months (95% CI, 5.6–not estimable). The 6-month OS was 89.3% (95% CI, 70.4–96.4). Six patients underwent conversion surgery, including three with pathological complete response. Grade ≥3 treatment-emergent adverse events occurred in 46.4% of patients who were treated at the recommended dose (n = 28). The most common grade ≥3 adverse events were neutropenia (25.0%), anemia (14.3%), febrile neutropenia (3.6%), and diarrhea (3.6%). Interstitial lung disease was observed in 3 patients (10.7%), with no grade ≥3 events. No treatment-related deaths were observed. Conclusions: T-DXd (4.4 mg/kg) combined with nivolumab and CAPOX demonstrated encouraging antitumor activity with a manageable safety profile as first-line treatment for HER2-low mGEA, supporting further evaluation. Clinical trial information: jRCT2031230477.
Access to care and survival outcomes in older adults with chronic lymphocytic leukemia/small lymphocytic lymphoma: A National Cancer Database study.
e19035 Background: Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) predominantly affect older adults and are managed in both academic and community cancer settings. Outcomes in elderly patients are influenced by comorbidity burden and treatment tolerance, but the impact of treatment facility type in patients aged ≥75 years remains incompletely defined. We examined institutional differences in patient characteristics, management strategies, and overall survival (OS) in elderly patients with CLL/SLL treated at Academic Cancer Programs (ACP) versus Community Cancer Programs (CCP). Methods: We conducted a retrospective cohort study using the National Cancer Database, identifying patients aged ≥75 years diagnosed with CLL/SLL between 2004 and 2022. Patients were stratified by facility type (ACP vs CCP). Demographic, socioeconomic, clinical, and treatment characteristics were compared. Time to systemic therapy, early mortality, and OS were assessed. OS was estimated using Kaplan–Meier methods, with associations evaluated using multivariable Cox proportional hazards models adjusting for race and ethnicity, insurance status, Charlson–Deyo comorbidity score, and distance to the treating facility. Results: Among 69,328 patients aged ≥75 years with CLL/SLL (ACP 32,752; CCP 36,576), median age was similar (81 years). ACP treated a more racially and ethnically diverse population, including higher proportions of Black (7% vs 5%) and Hispanic (3% vs 2%) patients, and more patients with Medicaid, private insurance, or no insurance, while CCP treated more Medicare beneficiaries and patients from lower-income and lower-education regions (all p<0.001). Comorbidity burden was slightly higher at CCP (Charlson–Deyo score ≥2: 13% vs 12%; p<0.001). Management differed modestly, with active surveillance more common at ACP (34% vs 30%), while treatment initiation rates, median time to systemic therapy (29 days), and 30- and 90-day mortality were similar. OS differed modestly by facility type. Median OS was longer at ACPs (4.7 vs 4.5 years). Two, five, and ten-year OS was numerically higher at ACP (72% vs 71%, 48% vs 46%, and 20% vs 19%, respectively), with statistical significance driven by cohort size. Conclusions: In patients aged ≥75 years with CLL/SLL, treatment facility type was associated with modest but statistically significant differences in OS amid sociodemographic variation and similar treatment timing. Although absolute survival differences were small, the population size highlights the cumulative impact of health system factors. These findings support strengthening partnerships between CCP and ACP to expand access to clinical trials, geriatric-informed supportive care, and evolving targeted therapies, promoting more equitable, high-quality care for older adults with CLL/SLL.
Prevalence of the TCF7L2 rs7903146 T allele in young Hispanic adults: Implications for colorectal cancer prevention.
e22650 Background: Colorectal cancer (CRC) incidence has increased in recent years, particularly among young adults, raising concern about underlying genetic susceptibility factors. The rs7903146 single-nucleotide polymorphism (SNP) in the Transcription Factor 7-Like 2 ( TCF7L2 ) gene, widely studied for its role in type 2 diabetes risk, has also been associated with increased CRC susceptibility. Homozygosity for the T allele has been proposed to contribute to approximately 17% of CRC cases in certain populations. Methods: Undergraduate students from a South Florida college campus were recruited under an approved Institutional Review Board protocol. Participants provided informed consent and completed a demographic questionnaire. Saliva samples were collected for genomic DNA extraction using the InstaGene Matrix method. Genotyping of the TCF7L2 rs7903146 (C/T) variant was performed using real-time polymerase chain reaction. Genotype counts (CC, CT, TT) were obtained by direct count, and allele frequencies were calculated from these counts. The population was tested for Hardy–Weinberg equilibrium. Results: A total of 100 students were genotyped, all of whom self-identified as Hispanic or Latino. Genotype frequencies were consistent with the Hardy–Weinberg equilibrium. The frequency of the rs7903146 T allele was 0.310, and 8% of participants were homozygous for the TT genotype. Conclusions: Eight percent of the sampled population was homozygous for the TCF7L2 rs7903146 T risk allele. Because genetic screening can be performed at any age and before the development of clinically detectable physiological alterations, knowledge of genotype may support population-level risk stratification and inform preventive public health strategies. Although clinical outcomes were not assessed, these findings highlight the potential value of incorporating genetic information into future screening frameworks and longitudinal studies examining CRC risk in young adults.
Evaluating AI decision support in a rapidly evolving therapeutic landscape: <i>EGFR</i> -mutant metastatic NSCLC.
1630 Background: Large language models (LLM) are increasingly used in oncology, yet may deviate from evidence-based care due to outdated knowledge, hallucinations, and inconsistent confidence calibration. EGFR-mutant metastatic Non small Cell Lung Cancer (NSCLC) treatment sequencing is rapidly evolving following 1L OS benefits from MARIPOSA and FLAURA2 and an expanding 2L landscape. In this study, we evaluate concordance, variability, and expert alignment across artificial intelligence (AI) systems. Methods: Twelve expert-curated EGFR-mutant metastatic NSCLC vignettes (6 per 1L and 2L) were evaluated across 4 general-purpose LLMs (ChatGPT, Gemini, Claude, Grok) with deep-research enabled and 2 evidence-based platforms [ASCO AI, OpenEvidence (OpenE)]. Each system simulated percentage-based treatment selections simulating how 100 U.S. med-oncologists might distribute choices across predefined therapies. 5 thoracic oncologists from 3 academic centers established a human reference standard, with unanimous agreement in all but 1 vignette where probability-weighting was applied. Inter-system and expert concordance was assessed using Kendall’s τ, while divergence was quantified using Jensen–Shannon (JS) divergence. Results: Guideline-based platforms showed strong agreement (ASCO AI–OpenE τ=0.73). Among LLMs, ChatGPT aligned the most with ASCO AI (τ=0.72), while Claude showed the highest divergence (JS=0.30); the highest inter-LLM concordance was observed between ChatGPT and Gemini (τ=0.64). Although ASCO AI is built on Gemini, agreement was only moderate (τ=0.55), suggesting added guideline constraints enhance consistency. In 1L, all systems demonstrated moderate-to-strong concordance with experts (τ>0.50), with ChatGPT and ASCO AI the highest (τ=0.80). ASCO AI appropriately emphasized guideline-endorsed options, including Osimertinib monotherapy and combination strategies, without preferential commitment. In 2L, concordance declined substantially with ChatGPT demonstrating inverse correlation with experts (τ=−0.06). Conclusions: AI systems align with expert decision-making in 1L EGFR-mutant metastatic NSCLC but diverge substantially in 2L, where evidence is evolving. Guideline-constrained platforms show greater consistency than general-purpose LLMs; despite ASCO AI using Gemini as its base model, agreement was only moderate, highlighting the value of guideline constraints. These findings highlight the need for rigorous validation and clinical safeguards when integrating AI into oncology decision-making. AI–expert concordance. System 1L - Experts (τ, JS) 2L – Experts (τ, JS) Max Inter-System (τ) ASCO AI 0.80, 0.14 0.25, 0.39 OpenE (0.73) ChatGPT 0.80, 0.15 -0.06, 0.36 ASCO AI (0.72) OpenE 0.67, 0.25 0.27, 0.24 ASCO AI (0.73) Gemini 0.61, 0.21 0.49, 0.19 ChatGPT (0.64) Claude 0.59, 0.32 0.27, 0.22 ChatGPT (0.60) Grok 0.54, 0.26 0.27, 0.25 OpenE (0.64)
Real-world outcomes and tumor gene expression analysis of sacituzumab govitecan (SG)- and trastuzumab deruxtecan (T-DXd)-treated metastatic breast cancer (MBC).
1034 Background: While the antibody-drug conjugates (ADCs) SG and T-DXd have transformed MBC care, predictive biomarkers of ADC response are lacking. This retrospective study evaluates real-world outcomes of MBC patients treated with SG or T-DXd and explores potential genomic and transcriptomic correlates of response. Methods: MBC patients treated with SG or T-DXd at BC Cancer who underwent tumor whole genome and transcriptome sequencing (WGTS) between January 2020 - May 2025 were included. Biopsy for WGTS was obtained either before (ADC-naïve) or after ADC exposure (ADC-exposed). Progression free survival (PFS) was clinically evaluated and assessed using Kaplan-Meier analysis. Treatment response was classified into 2 groups using PFS benchmarks from ASCENT (Bardia et al 2021, SG: expected ≤6 months (mo), favorable >6 mo) and DESTINY-Breast04 (Modi et al 2022, T-DXd: expected ≤12 mo, favorable >12 mo). RNA-seq data were assessed with DESeq2 differential expression and gene pathway enrichment analyses. Immune cell deconvolution was performed using CIBERSORT, with group comparisons by Wilcoxon rank-sum tests. Results: Forty-three patients met eligibility for inclusion (17 SG, 24 T-DXd, 2 treated with both agents). Median PFS was 4.0 mo (95% CI 2.0-6.0) for those treated with SG and 7.4 mo (95% CI 4.6-10.7) for those treated with T-DXd. Among T-DXd-naïve patients, ESR1 expression was higher in those with poor ADC response (69.8 vs 7.8 transcripts per million, p = 0.049). Oxidative phosphorylation gene cluster expression was reduced in T-DXd-exposed vs T-DXd-naïve patients (normalized enrichment score -1.9, p = 0.005). ADC target expression did not differ by response in either treatment cohort ( TACSTD2 p = 0.86, ERBB2 p = 0.67). Whole genome sequencing identified 12 tumors with FGFR1 amplifications, all with poor ADC response, and demonstrated homologous recombination deficiency in half of those with favorable SG response. While not statistically significant, the post-ADC tumor microenvironment of favorable responders trended toward enrichment with naïve B-cells and T-cell infiltrate in T-DXd-treated patients (p = 0.28, 0.33) and both monocytes and NK cells in SG-treated patients (p = 0.1, 0.27). Conclusions: This study highlights the heterogeneity of outcomes among SG- and T-DXd-treated MBC patients and identifies potential predictive and prognostic biomarkers warranting exploration in prospective trials of first-line ADC (NCT07299409) and ADC sequencing (NCT06665178). SG-treated patients (n=19) T-DXd-treated patients (n=26) HR status:PositiveNegative 118 224 HER2 status:Negative/UltralowLowPositive 8101 11114 Timing of biopsy for WGTS:Pre-ADCPost-ADC 127 1511 Favorable ADC response 4 3 Median lines of therapy for MBC pre-ADC (range) 2 (0-6) 4 (0-8) Median lines of endocrine therapy for HR + MBC pre-ADC (range) 0 (N/A) 1 (0-5)
Challenges in identifying HER2-low metastatic breast cancer: Real-world perspectives from a nationwide pathologist survey.
e13138 Background: HER2-low/ultralow metastatic breast cancer (mBC) is now clinically actionable with HER2-directed antibody–drug conjugates, but expanding HER2 classification beyond a binary model has increased diagnostic complexity and variability in practice. A prior quality improvement (QI) initiative identified diagnostic and therapeutic gaps among community oncologists, including ambiguous results, inconsistent HER2 testing and reporting, limited multidisciplinary communication, and uncertainty in applying HER2 results to treatment decisions. Building on these findings, we surveyed pathologists nationwide to characterize real-world HER2 testing and reporting practices and identify diagnostic and care coordination barriers between specialties. Methods: From May–June 2025, 100 pathologists completed surveys assessing HER2 testing workflows, interpretation, and classification challenges, including barriers to coordinating with oncologists, with key items tethered to the prior oncology survey. Results: The majority of respondents reported practicing in community-based hospitals and clinics (58%). Sixty-three percent of pathologists identified risk of HER2 misclassification as the greatest challenge in identifying HER2-low/ultralow mBC, compared with 21% of oncologists surveyed in the prior QI initiative, whose top challenge was interpreting ambiguous or borderline results. Similar proportions of pathologists and oncologists reported difficulty interpreting ambiguous or borderline results (53% vs 51%) and limited familiarity with the clinical relevance of lower HER2 expression (28% vs 24%), while inconsistencies in testing and reporting were cited by 55% and 24%, respectively. Pre-analytic and analytic barriers included tumor heterogeneity (52%), suboptimal sample conditions (43%), and inadequate clinical information (39%). Evolving HER2 classification was the most common reporting challenge (76%), and only 47% of pathologists felt comfortable distinguishing HER2 IHC 0 from IHC 1+. Fewer than half of pathologists and oncologists reported that HER2-low status was routinely specified in pathology reports 41% and 37%, respectively. Collaboration with oncologists is hindered by understanding of HER2 testing guidelines (58%), pressure to alter or expedite reporting (28%), and communication through intermediaries (26%). To improve identification, nearly two-thirds of pathologists favored workflows to better differentiate IHC 0 versus 1+, and 58% supported standardizing definitions and documentation. Conclusions: Persistent diagnostic variability and inconsistent reporting limit accurate identification of HER2-low and HER2-ultralow mBC, underscoring the need for standardized workflows, clearer reporting, and improved multidisciplinary coordination between pathologists and oncologists.