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Early ovarian cancer detection with a multiomic liquid biopsy.
e17563 Background: Ovarian cancer is associated with one of the highest mortality rates among gynecologic malignancies. However, detecting ovarian cancer early can significantly improve patient prognosis; early-stage disease is associated with five-year survival rates exceeding 90%, compared to approximately 30% for advanced-stage disease. Despite this marked survival benefit, fewer than 25% of ovarian cancers are diagnosed at an early stage, reflecting the limitations of current detection strategies. Methods: This study explores the ability of a multiomic liquid biopsy as an alternative strategy for ovarian cancer detection. This approach utilizes infrared (IR) spectroscopy to interrogate blood samples, producing disease-specific spectral signatures that capture cancer-associated biochemical alterations. 201 patients were included in this proof-of-concept study, 50 with ovarian cancer and 151 with a non-cancer diagnosis. Blood plasma samples were analyzed by the Dxcover Liquid Biopsy Platform and classified with machine learning algorithms. Levels of CA-125 and HE4 were obtained for each patient, enabling a comparison and combination of biomarker and spectral data. Results: The receiver operating characteristic (ROC) curve reported an area under the curve (AUC) value of 0.85. The sensitivity-tuned algorithm reported 90% sensitivity with 62% specificity, and the specificity-tuned model reported 62% sensitivity with 90% specificity. Significantly, the diagnostic performance was unaffected by cancer stage showing enhanced utility as an early detection test. The addition of spectral data to biomarker-only models improved the diagnostic performance overall. Conclusions: Earlier detection of ovarian cancer is associated with improved prognosis and survival. The blood-based test described here offers a low barrier to clinical integration, as it is simple to operate, requires only minimal sample volumes, and delivers rapid results.
Wearable-derived physical activity monitoring with AI-based detection of treatment-related adverse events during neoadjuvant chemotherapy for early breast cancer: TRACK-BC.
1631 Background: Neoadjuvant chemotherapy (NAC) for early breast cancer (EBC) is commonly delivered in the outpatient setting, yet within-cycle changes in adverse events reduce physical activity (PA). Wearable devices may capture these short-term changes. However, prospective data describing activity patterns during modern regimens, including pembrolizumab (PEMB)-based therapy, are limited. This study evaluated changes in PA using Fitbit-derived digital biomarkers (dBM) and explored associations with patient-reported outcomes (PROs). Methods: We conducted a multicenter, prospective observational study in patients (pts) with stage I–IIIA EBC initiating NAC. Eligible pts were ≥18 years old, smartphone users, and able to wear a Fitbit daily. Chemotherapy regimens were grouped into weekly, q2w, or q3w cohorts. Fitbits were worn from ≥7 days before treatment initiation through four cycles. Total PA (TPA), moderate-to-vigorous PA (MVPA), heart rate, sleep, and other metrics were collected. PRO-CTCAE and HADS were completed weekly electronically (ePROs). The primary outcome was change in TPA and MVPA from baseline to the week following cycle 2. As a secondary endpoint, machine learning approaches extending conventional multivariable regression incorporated multiple wearable-derived parameters to individually predict the worst change in ePRO scores from baseline. Model performance was evaluated by cross-validation, and feature contributions were examined using SHapley Additive exPlanations (SHAP) to enhance clinical interpretability. Results: A total of 101 pts were enrolled across the three predefined chemotherapy cohorts. Fitbit use was feasible with high adherence. The primary outcome indicated a consistent decline in PA during NAC. From baseline to the week following cycle 2, mean TPA decreased by 141.4 METS-min/day and MVPA by 33.7 min/day. ePROs revealed worsening symptoms including fatigue, insomnia, appetite loss, and neuropathy. Symptoms varied according to the chemotherapy schedule and generally aligned with changes in PA levels and dBM. The secondary outcomes identified multiple vital signals showing absolute correlations >0.3 with all PRO and HADS metrics. For fatigue, the best model (ridge regression) yielded mean R² 0.33±0.20 and RMSE 1.86±0.26; SHAP analysis highlighted contributions from nocturnal heart-rate-variability minima and overall variability. Conclusions: Continuous wearable monitoring during NAC for EBC was feasible. Objective declines in PA occurred early and paralleled symptom worsening captured by ePROs. AI-based models explained a modest but clinically meaningful proportion of symptom deterioration with acceptable error. These findings support the potential utility of wearable-derived dBM for real-time surveillance of treatment-related toxicities during NAC. Clinical trial information: UMIN000053991.
High acceptance of trained scent detection dogs for postoperative surveillance among cancer survivors: A prospective survey on willingness, motivators, and barriers.
e23184 Background: Canine olfaction can detect cancer-specific volatile organic compounds (VOCs) with high accuracy, yet its integration into patient-centered surveillance has not been explored. Conventional post-operative monitoring relies on repeated imaging and blood tests, imposing physical, financial, and psychosocial burdens. We evaluated patient acceptance of a novel home-based surveillance model using trained scent detection dogs for cancer recurrence monitoring and psychosocial support. Methods: We conducted a prospective single-center survey of 320 adults with stage I–III lung (n = 160) or colorectal cancer (n = 160) within 3–24 months after curative surgery. All participants received a standardized 60-minute educational intervention delivered by a research nurse and oncologist, including evidence on canine VOC detection, training demonstrations, and Q&A. Surveys were completed the following day and assessed willingness to adopt a trained dog, perceived benefits, barriers, and psychosocial impact. Validated HADS subscales and demographic and clinical variables were collected. Multivariable logistic regression identified predictors of willingness. Results: Overall, 89.4% (286/320) of patients expressed willingness to consider a trained detection dog for home-based surveillance. Key motivators included reduced hospital visits (92%), avoidance of radiation exposure (87%), avoidance of blood draws (85%), and companionship to reduce anxiety (78%). Willingness was higher among patients ≥65 years (96% vs. 82%; p < 0.01) and those living alone (94% vs. 86%; p < 0.05). Willingness was not associated with sex, education level, income, or prior pet ownership (all p > 0.05). Among unwilling patients (10.6%), barriers included fear of dogs (41%), allergies (29%), and caregiving concerns (21%). After education, 91% of participants believed trained dogs could detect cancer recurrence. Conclusions: This first patient-centered evaluation demonstrates high and demographically broad acceptance of scent detection dogs as a novel home-based cancer surveillance strategy. Acceptance was strongest among older and socially isolated patients and was driven by both practical and psychosocial benefits. These findings support pilot studies assessing feasibility, clinical performance, and survivorship impact of this integrative bio-detection model.
Event-free survival from the randomized phase 2 neoHIP trial evaluating neoadjuvant taxane, HER2-targeted therapy, +/- pembrolizumab in early-stage HER2-positive breast cancer.
623 Background: In early-stage HER2–positive breast cancer, achieving a pathological complete response (pCR) after neoadjuvant therapy is strongly associated with improved event-free survival (EFS); however, a substantial proportion patients (pts) fail to achieve pCR, requiring subsequent adjuvant systemic therapy and remaining at higher risk for recurrence. Pembrolizumab (pembro) is well-tolerated, invigorates anti-tumor immunity, and may enhance response of chemotherapy and/or anti-HER2. We previously reported the positive primary outcome of the randomized phase 2 neoHIP trial, showing an improvement in pCR with the addition of pembro to neoadjuvant paclitaxel, trastuzumab, and pertuzumab (4 cycles, THP–pembro, pCR: 67% v. THP: 48%, p=.026). With long-term follow-up now mature, we now report EFS outcomes. Methods: Pts aged ≥ 18 years with stage II–III HER2–positive breast cancer were randomized, stratified by hormone receptor status and nodal status, to receive neoadjuvant THP or THP–pembro. EFS was defined as the time from randomization to progression of disease precluding surgery, local or distant recurrence, or death from any cause. EFS was estimated using the Kaplan–Meier (KM) method and compared between arms using a two-sided stratified log-rank test. Data were analyzed with a cutoff date of January 23, 2026. Results: Among 116 pts (58 per arm) randomized to THP +/- pembro, median follow-up was 37 months (range, 33–43). The 36-month EFS rate was 95% (95% CI, 89–100) for THP and 100% (95% CI, 100–100) for THP-pembro, with a trend towards significance (p=.099). Three EFS events were observed, all occurring in the THP arm, with one death related to recurrence and n=2/3 events occurring in patients with non-pCR. Conclusions: THP + pembro was associated with 100% EFS after a median follow-up of 37 months, whereas recurrences were observed in the THP arm, consistent with historical EFS expectations for neoadjuvant chemotherapy + dual HER2-targeted therapy. Although not powered for EFS, these findings support definitive evaluation of THP +/- pembro in a phase III trial. Clinical trial information: NCT03747120 .
Preliminary efficacy of GFH375 in patients with advanced cholangiocarcinoma or colorectal cancer harboring KRAS G12D mutation.
3008 Background: Kirsten rat sarcoma (KRAS) G12D is the most prevalent RAS mutation in human cancers, accounting for 10.6-19.2% and 5.8-10.8% of cases in colorectal cancer (CRC) and cholangiocarcinoma (CCA), respectively. Currently, the later-line therapies for metastatic CCA and CRC remain very limited. The KRAS G12D mutation is associated with poor prognosis and confers resistance to conventional chemotherapy. GFH375, a potent, selective, orally bioavailable KRAS G12D inhibitor, has demonstrated antitumor efficacy in pancreatic cancer and non-small cell lung cancer. Here we report the preliminary efficacy results of GFH375 in patients (pts) with advanced KRAS G12D mutant CCA and CRC. Methods: This is a phase I/II study (NCT06500676) evaluating the safety, tolerability, pharmacokinetics and efficacy of GFH375 in pts with advanced solid tumors harboring KRAS G12D mutations. Pts with locally advanced or metastatic CCA and CRC who had failed prior therapies were also enrolled. Tumor assessments were performed every 6 weeks during the first 48 weeks, and every 12 weeks thereafter. All efficacy endpoints, including objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were evaluated according to RECIST v1.1. Circulating tumor DNA (ctDNA) samples were collected at baseline and at the end of treatment for exploratory analyses. Results: As of 31 Oct 2025, twenty CCA and 41 CRC pts were treated with GFH375 once daily (400, 600 or 750 mg). Among the CCA pts (median age: 59.5 yrs; 80.0% male), 17 (85.0%) had metastatic disease at baseline, and the median prior lines of therapy were 2 (range: 1-6). ORR was 35.0% (7/20), and DCR was 95.0% (19/20). Nine out of 12 pts with stable disease (SD) had tumor shrinkage. Median PFS was 6.3 months, and median overall survival (OS) was not reached. Among those CRC pts (median age: 56 yrs; 61.0% male), all had metastatic disease at baseline, and the median prior lines of therapy were 3 (range: 1-6). Among 35 pts who had at least one post-treatment tumor assessment, ORR was 11.4% (4/35), and DCR was 77.1% (27/35). Median PFS was 4.1 months and median OS was not reached. Baseline ctDNA results were available in 19 CCA pts and 36 CRC pts. KRAS G12D mutations were detected in 14 (73.7%) CCA pts and 31 (86.1%) CRC pts. The common co-mutated genes (≥15%) in CCA were TP53, BCL2L11 and APC, while in CRC were TP53, APC, RUNX1, SMAD4 and PIK3CA. The safety profile in the 61 pts was similar to that of the whole population as previously reported. The most common treatment-related adverse events (TRAEs) (≥30%) included diarrhea, nausea, vomiting, aspartate aminotransferase increased, anemia and decreased appetite. Conclusions: GFH375 monotherapy has demonstrated promising antitumor activities in heavily treated pts with CCA and CRC. GFH375 monotherapy in CCA and in combination with other anti-tumor therapies for CRC is under development. Clinical trial information: NCT06500676 .
PRiMAL (precision randomized clinical trial comparing MTB assisted care to usual care): Quality of life analysis in patients with newly diagnosed non-small cell lung cancer (NSCLC).
1574 Background: Precision medicine—tailoring cancer treatment to a tumor’s genomic profile—is more effective and less toxic than traditional chemotherapy. However, its use in community oncology remains limited. Molecular Tumor Boards (MTBs), interdisciplinary teams that interpret genomic data and guide treatment, have improved precision medicine adoption and clinical outcomes, especially in academic centers. However, MTBs are less accessible in community practices, where most cancer care is delivered. Methods: The PRiMAL trial is a prospective, parallel-group, cluster randomized trial, comparing MTB assisted care (MTB-AC) to usual care in 10 community medical oncology practices aligned with the Markey Cancer Network. MTB-AC included nurse navigator assistance with next generation sequencing (NGS) ordering, MTB referral, and communication with treating oncologists. Usual care allowed access to the MTB at the discretion of treating oncologist. Eligible patients had untreated stage IIb-IV NSCLC. The co-primary endpoints were 1-year overall survival and health related quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy (FACT) Trial Outcome Index-Lung Cancer (FACT-L TOI), FACT-G, and FACT-L Cancer (FACT-L) administered at baseline, 8 weeks and 12 weeks after treatment initiation. A multilevel linear mixed-effects model was used to estimate the intervention effects for the QOL outcomes while controlling for demographic, clinical, and socioeconomic covariates. Results: At the data cut-off of 1/12/26, 405 pts were included for assessment of QOL at baseline (MTB, n=250; usual, n=155). Baseline demographics and disease characteristics were similar for sex, age, race, ethnicity, histology, stage and performance status. QOL assessments were completed by 292 patients at 8 weeks and 245 patients at 12 weeks; MTB-AC patients experienced numerically greater declines at 8 weeks compared to usual care (FACT-L TOI: -2.7 vs -0.5; FACT-G: -1.9 vs 0.50; FACT-L: -1.4 vs 1.1), but these differences were not significant. Between weeks 8 and 12, QOL was estimated to have declined in usual care patients while MTB-assisted care patients improved, FACT-L TOI (3.28, 95% CI: 0.10 to 6.46); FACT-G (between-group difference: 3.97, 95% CI: 0.56 to 7.38); and FACT-L (4.70, 95% CI: 0.58 to 8.81). Survival is immature. Conclusions: The preliminary analysis showed that MTB-AC demonstrated significant, and in some cases clinically meaningful, improvement in QOL between weeks 8 and 12 after treatment across all three FACT measures compared to usual care, suggesting a delayed but meaningful benefit of MTB-AC. Clinical trial information: NCT05254795 .
Analyzing trends in multimorbidity-related mortality among patients with lung cancer and hypertensive diseases: A 25-year nationwide analysis.
e20694 Background: Multimorbidity, defined as the coexistence of two or more chronic conditions, poses major challenges to healthcare systems globally. Hypertension is a critical comorbidity in lung cancer patients contributing to cardiovascular complications through shared risk factors and treatment-related cardiotoxicity. Despite its clinical significance, temporal trends and demographic disparities in multimorbidity-related mortality among this population remain inadequately characterized. This study aims to identify patterns and correlations to guide healthcare interventions and policies and investigates trends in multimorbidity-related mortality among US patients with lung cancer and hypertensive diseases over two decades. Methods: We conducted a retrospective analysis using CDC WONDER database (1999-2023), including adults ≥25 years with hypertensive diseases (ICD-10: I10-I15) and lung cancer (C34) as causes of death. Age-adjusted mortality rates (AAMR) per 100,000 were calculated. Joinpoint regression identified trends via annual percentage change (APC) and average annual percentage change (AAPC). Results were stratified by sex, age, race/ethnicity, region, and urbanization. Results: From 1999-2023, 274,959 hypertension diseases-related deaths occurred among lung cancer patients. AAMR increased from 2.60 (95% CI: 2.52-2.67) to 6.03 (95% CI: 5.94-6.12), a 131.9% increase, with overall AAPC of 3.31% (95% CI: 2.26-4.37, p < 0.001). Joinpoint analysis identified: acceleration 1999-2001 (APC: 19.53%), increase 2001-2008 (APC: 3.74%), stabilization 2008-2018 (APC: -0.85%), resurgence 2018-2021 (APC: 9.20%), and plateau 2021-2023 (APC: -0.53%). Males had higher AAMRs (5.97 vs 3.92), but females showed steeper increases (AAPC: 3.52% vs 3.02%). Adults ≥65 years had highest AAPC (3.47%). White individuals had highest AAPC (3.91%), followed by Hispanic (3.75%), Black (1.29%), and Asian/PI (1.28%). The South exhibited highest regional AAPC (4.99%), followed by Midwest (2.65%) and Northeast (2.29%). Non-metropolitan areas exceeded metropolitan (AAPC: 4.76% vs 3.10%). Oklahoma (AAMR: 24.55), Mississippi (20.69), South Carolina (16.42) had highest state rates and Utah (1.40) has the lowest. Conclusions: This analysis demonstrates a nearly three-fold increase in multimorbidity-related mortality among lung cancer and hypertensive diseases patients over 25 years, with females, White populations, Southern states, and non-metropolitan areas showing pronounced increases. These findings emphasize the need for integrated cardio-oncology protocols and targeted interventions addressing geographic and demographic disparities.Targeted healthcare strategies are essential to address the specific needs of high-risk populations and ensure equitable access to healthcare resources.
Survival implications of context-dependent oncogenic <i>PIK3CA</i> mutations in HNSCC.
6114 Background: Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease that generally lacks clinically useful stratification methods beyond anatomy and HPV status. PIK3CA is the most frequently mutated oncogene in HNSCC, and previous studies have linked PIK3CA mutations to survival in HNSCC. Thus, we aimed to investigate overall survival (OS) in a large multi-center cohort of HNSCC as a function of specific PIK3CA mutation hotspots to better understand the molecular drivers of risk and prognosis in HNSCC. Methods: A subset of oral cavity (OC, n=606) and oropharyngeal (OP, n=480) tumors from the VOYAGER consortium underwent exon sequencing in 1,109 cancer related genes and whole HPV16/18 genomes. Mutations in PIK3CA were analyzed using a somatic variant calling and filtering pipeline, and driver alterations were annotated based on gain-of-function variants at recurrent hotspots in specific functional protein domains. HPV status was defined using serology, p16 IHC, RNA ISH, and viral genomics. Multivariable Cox proportional hazards models were used to assess the relationship between PIK3CA mutations and five-year OS adjusted for age, sex, HPV status, tumor type, and TNM staging. Results: In OP tumors, 289 were HPV(+) and 174 were HPV(-), while only 13 of OC tumors were HPV(+). The overall PIK3CA mutation rate was 18% (13% of OC vs 24% of OPs), and among OP cases, PIK3CA mutations occurred in 28% of HPV(+) vs 18% of HPV(-) tumors. Of the nine recurrent hotspots in PIK3CA, the most common were the APOBEC-associated ones in the helical domain, p.E545K (3% OC vs 12% OP) and p.E542K (2% OC vs 5% OP), as well as smoking-associated kinase domain mutations at p.H1047R (3% OC vs 2% OP). In OC and OP cases combined, tumors harboring PIK3CA driver alterations in one of the nine hotspots showed a statistically significant improvement in OS that was independent of age, sex, staging, tumor type, and HPV status (HR 0.72, P=0.048). Among all HPV(+) tumors, driver mutations in PIK3CA conferred significantly better OS in the adjusted model (HR 0.42, P=0.02). Likewise, in all OP tumors, PIK3CA driver mutations were significantly associated with improved OS in the multivariate models (HR 0.60, P=0.04) and when stratified by HPV status this effect was particularly strong for HPV(+) OP tumors only (HR 0.45, P=0.04). Among the hotspots, p.E545K was the only one with improved survival in a univariable analysis of the full cohort (Log-rank P=0.01), but this was not significant in the adjusted model (HR 0.62, P=0.07). Conclusions: Our findings validate previously described associations between PIK3CA mutation and OS in HNSCC that are dependent on anatomic site and HPV status. Moreover, we provide a new perspective by analyzing OS as a function of recurrent mutation hotspots in PIK3CA , which may signify distinct pathologic processes among HNSCCs and thus may be clinically useful for patient stratification with prognostic or therapeutic intent.
Evaluating tumor genomics and FES-PET in estrogen receptor–positive (ER+) breast cancer (BC).
e15072 Background: 18 F-fluoroestradiol positron emission tomography (FES-PET) is a highly specific imaging modality for detecting estrogen receptor-positive (ER+) breast cancer (BC), particularly when biopsy is not feasible or conventional staging is equivocal. Endocrine therapy (ET) resistance often develops during ER+ BC treatment and arises from genomic alterations that promote estrogen-independent signaling and, for some alterations, reduced ER expression. As clinical use of FES-PET expands, understanding the potential impact of these alterations on FES-PET avidity is important. Therefore, we assessed the relationship between tumor genomic profiles and FES-PET positivity in ER+ BC. Methods: We conducted a single-center retrospective study of patients with histologically confirmed ER+ BC at diagnosis who underwent FES-PET/CT or PET/MR between 12/2023-8/2025 and had blood- or tissue-based genomic testing within 6 months of imaging. Human epidermal growth factor receptor 2-positive (HER2+) and negative (HER2-) tumors were included. FES-PET positivity was defined as SUVmax >1.5 in the most avid lesion, assessed by a board-certified nuclear radiologist. Results: Forty-three patients were included (4 local recurrences, 39 metastatic). FES-PET was positive in 22 patients, was non-avid in 9, had mixed ER+ and ER- disease in 2, was indeterminate in 2, and showed no evidence of disease in 8. Of the 9 non-avid FES-PET cases, 3 had ER+ disease on biopsy at metastatic recurrence, 4 had ER- disease, and 2 had mixed ER+ and ER- disease. Genomic profiling was performed via liquid biopsy (n = 33), tissue-based testing (n = 9), or both (n = 1). PIK3CA and TP53 mutations were the most frequent alterations seen in 15 and 11 patients, respectively; 9 patients with PIK3CA mutations and 6 with TP53 alterations had a positive FES-PET. ESR1 mutations were identified in 5 patients, 4 with a positive FES-PET. FGFR1 amplification was seen in 3 patients; one had a strongly positive FES-PET, one had mixed ER+ and ER- lesions, and one had a negative FES-PET despite ER+ disease. KRAS mutations were present in 3 patients; two had a positive FES-PET. The other had ER- disease at recurrence and negative FES-PET. RB1 loss was seen in 2 patients; one had a negative FES-PET in the setting of ER- disease at recurrence, the other had mixed ER+ and ER- lesions. ERBB2 mutations were identified in 2 patients; one had a positive FES-PET, the other had lesions too small to characterize. Conclusions: FES-PET is a valuable imaging tool, though false-negative results can occur and may limit its suitability for initial staging in advanced ER+ BC. In this cohort of ER+ BC patients undergoing FES-PET with concurrent genomic profiling, heterogeneity in FES avidity was seen across multiple genomic alterations associated with resistance to antiestrogen therapies. Further evaluation in a larger cohort is ongoing; updated findings will be presented at the meeting.
Firmonertinib combined with cisplatin/carboplatin plus pemetrexed as neoadjuvant therapy in resectable stage II-IIIb <i>EGFR</i> -mutated non–small cell lung cancer: A single-arm, single-center, open-label phase II study.
8058 Background: For patients with resectable, locally advanced EGFR-mutated NSCLC, traditional neoadjuvant chemotherapy yields suboptimal efficacy. While EGFR-TKIs are standard in the adjuvant therapy, their role in neoadjuvant therapy is under active investigation. Methods: This single-arm, phase II study evaluated neoadjuvant firmonertinib plus platinum-based chemotherapy in patients with stage II-IIIB EGFR-mutated NSCLC. The primary endpoint was major pathological response (MPR), the major second endpoint were pathological complete response (pCR), objective response rate (ORR), R0 resection rate and rate of downstaging. Results: Among the 13 patients currently enrolled, 11 completed 4 cycles of neoadjuvant therapy, and 9 underwent radical surgery. The MPR rate and the pCR rate are both currently at 0. The ORR is 77.8%, and the radical resection rate reaches 100%. The TNM tumor stage reduction rate is 66.7%. The incidence of grade 3/4 adverse events is 11.1%, and there are no 5-grade adverse events. Conclusions: Firmonertinib with chemotherapy as neoadjuvant in II-IIIB EGFR-mutated NSCLC demonstrated a promising surgical conversion rate and a manageable safety profile, supporting its feasibility for further study. Clinical trial information: NCT06890182 .
Natural language processing chatbot and continuous activity monitoring in a phase II randomized trial: Impact on hospitalizations and quality of life.
12132 Background: Toxicities associated with concurrent chemoradiotherapy (CRT) can lead to hospitalizations and impaired quality of life (QoL). This study reports on secondary endpoints investigating whether combining continuous activity monitoring (CAM) with an AI-driven chatbot can support symptom identification, triage, reduce hospitalizations, and improve QoL. Methods: Patients receiving CRT for head and neck (H&N), gastrointestinal (GI) or thoracic cancers were recruited from radiation oncology clinics at a single, urban institution. Subjects were randomized to: (1) CAM with nursing triage or (2) CAM with chatbot triage with as needed symptom assessments. A Fitbit device monitored the step count and heart rate (HR) relative to baseline. Triage was triggered when the daily average HR was >100 or 20% above their resting average or if there was a decrease of >1000 steps from baseline. In the control arm, triage prompted a nursing assessment within 1 business day. In the intervention arm, triage visits were triggered based on a low-, intermediate-, or high-risk symptom algorithm determined by the chatbot (next OTV, next business day, within 24 hrs, respectively). Hospitalizations during CRT and one month post treatment were counted. Logistic regression controlled for ECOG and sex. EORTC C30 QoL instruments were administered at baseline, during OTVs, and during follow-up. A mixed method for repeated measures model assessed global health status/QoL, fatigue, and physical, role, emotional, cognitive, and social functioning scales adjusting for ECOG, race, and stage. All statistical tests were completed on SAS 9.4. Results: From June 2023 to January 2025, 77 patients undergoing CRT for their H&N (n=30, 39%), GI (n=29, 38%), or thoracic cancers (n=18, 23%) were enrolled. The median age at consent was 59 years (range 28-81 years). Subjects were randomized to either nursing (N = 36, 50%) or chatbot triage (N = 36, 50%). There were no statistically significant demographic or clinical differences between arms. Subjects in the chatbot arm had significantly fewer hospitalizations (11%, n=4 chatbot; 39%, n=14 nursing triage, p=0.01). On logistic regression, subjects on the chatbot arm (p=0.0125) and those who had ECOG 0 (p=0.0131) were less likely to be hospitalized. In both arms, global QoL/health, fatigue, and physical, social, cognitive, and emotional functioning declined during CRT. Chatbot subjects had significantly inferior global QoL/Health status (p=0.049), cognitive functioning (p=0.005), and physical functioning (p=0.02) vs nursing triage. Conclusions: Patients undergoing CRT experience functional decline. While AI-driven chatbots may reduce hospitalizations, they are not a perfect substitute for a compassionate healthcare team. An analysis of alerts and triage visits will be reported with our primary endpoint.
Reply to: Interpreting Circulating Tumor DNA-Guided Risk Stratification After First-Line Therapy
Vitiligo and alopecia areata as complementary human models of immune-mediated melanoma protection: A systematic review and meta-analysis.
e21547 Background: Durable immune-mediated tumor surveillance is central to cancer prevention and long-term disease control, yet naturally occurring human models of sustained antitumor immunity remain poorly defined. Although autoimmune diseases are traditionally conceptualized as states of immune dysregulation, select autoimmune phenotypes may paradoxically confer protection against malignancy. Vitiligo and alopecia areata (AA) represent distinct autoimmune conditions characterized by targeted immune responses within separate compartments of the integumentary system, providing a unique opportunity to evaluate whether convergent immune phenotypes are associated with reduced melanoma incidence at the population level. Methods: Two independent PRISMA-compliant systematic reviews and meta-analyses were conducted to evaluate melanoma incidence in individuals with vitiligo and AA, respectively. Searches were performed across PubMed, Embase, Scopus, and ClinicalTrials.gov through July 2025. Studies comparing melanoma incidence in affected individuals versus non-disease control populations were included. Random-effects meta-analyses with Hartung-Knapp adjustment were used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for each condition separately. Between-study heterogeneity, sensitivity analyses, and publication bias assessments were performed. Results: Across nine population-based cohort studies comprising 454,307 individuals with vitiligo and 3,583,147 controls, vitiligo was associated with a reduced incidence of melanoma (OR 0.43; 95% CI, 0.16-1.13), reaching statistical significance in sensitivity analyses following exclusion of a heterogeneous outlier (OR 0.33; 95% CI, 0.13-0.84; p = 0.021). In parallel, five retrospective cohort studies including 29,886 individuals with AA and 275,902 matched controls demonstrated a significantly reduced melanoma risk in AA (OR 0.58; 95% CI, 0.36-0.94; p = 0.028), with moderate heterogeneity (I 2 = 58%) and consistent effect directionality across sensitivity analyses. Conclusions: Despite affecting distinct aspects of the integumentary system, vitiligo and AA demonstrate convergent reductions in melanoma incidence, supporting their role as complementary, naturally occurring human models of immune-mediated cancer protection. This convergence across independent autoimmune phenotypes highlights the potential importance of sustained antigen-specific immune surveillance in melanoma prevention and may inform future strategies in cancer immunoprevention and the development of durable immune-based therapies.
Can functional tumor profiling lead to superior care within standard of care?: A meta-analysis of randomized controlled trials.
e23092 Background: The adoption of novel drugs or therapies is generally dependent on randomized controlled trials (RCTs), as they provide the highest level of evidence. In contrast, the adoption of diagnostic tests, which do not have a therapeutic effect on their own, is typically based on whether they can meaningfully inform treatment decisions. However, while dozens of studies have repeatedly shown functional tumor profiling predicting a patient’s tumor response with 80% sensitivities and specificities or more, functional profiling has been held to a higher standard, with professional organizations and insurers often opposing its use due to the lack of RCT-level evidence for improved outcomes. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing functional profiling–guided therapy with physician-directed standard care in patients with solid tumors. The primary outcome was defined as 1-year overall survival (OS); with secondary outcomes as 1-year progression-free survival (PFS) and objective response rates (ORR). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and pooled estimates were obtained using inverse-variance weighting. Results: We identified four RCTs enrolling 472 heavily pretreated cancer patients with analyzable clinical outcomes. One RCT in recurrent glioblastoma (n = 78) reported 1-year overall survival, with 49% (21/43) of patients alive in the assay-guided group versus 23% (8/35) in the clinician’s choice group (OR 3.37; 95% CI 1.16–9.82, p = 0.026). Two RCTs (n = 159) reported 1-year progression-free survival, with 18% (15/83) of patients being progression-free in the assay-guided arms compared with 1% (1/76) in the clinician’s choice arms (OR 11.16; 95% CI 2.02–61.81, p = 0.006). Three RCTs (n = 394) reported objective response rates of 26.7% (54/202) in the assay-guided arms versus 13.5% (26/192) in control arms; however, substantial between-study heterogeneity was observed (I² = 81%), so the random-effects pooled estimate failed statistical significance (OR 4.25; 95% CI 0.66–27.38, p = 0.128). Of note, earlier studies reported no difference in median survival but did not report 12-month survival outcomes and therefore could not be included in landmark survival analyses. Conclusions: Earlier RCTs of assay-guided therapies did not demonstrate increased survivals, supporting the official position of guidelines that such tests should not override standard-of-care recommendations. However, more recent RCTs of more advanced tests, in which assay-guided therapy was used to choose among guideline-recommended options, have shown unprecedented improvements in patient outcomes and suggesting that assay-guided therapy might help clinicians to provide “superior care within standard of care.”
Efficacy and safety of larotrectinib in patients with <i>TRK</i> fusion lung cancer: An updated analysis.
8618 Background: NTRK gene fusions are oncogenic drivers in various tumor types, including lung cancer. Larotrectinib is the first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer based on a robust and durable objective response rate in patients with various cancers. Here, we report updated long-term efficacy and safety data in the subset of patients with TRK fusion lung cancer treated with larotrectinib after 1 additional year of follow-up. Methods: Patients with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02122913, NCT02576431 [NAVIGATE]) were included. Larotrectinib was administered at 100 mg twice daily. In NCT02122913, primary endpoints were safety and the minimum tolerated and recommended dose; secondary endpoints included pharmacokinetics, overall response rate (ORR), and duration of response (DoR). In NCT02576431, the primary endpoint was best overall response; secondary endpoints included DoR, survival, and safety. Responses were independent review committee-assessed per Response Evaluation Criteria in Solid Tumors version 1.1. The data cutoff was July 20, 2025. Results: A total of 32 patients with measurable disease were treated, including 12 with known CNS metastases at baseline. Median age was 56 years (range 25–81). One patient (3%) was systemic treatment-naïve in the metastatic/unresectable setting; 19 (59%) had received ≥2 prior therapies. All NTRK gene fusions were identified by next-generation sequencing (NGS). The ORR was 69% (95% confidence interval [CI] 50–84): 4 (13%) complete responses, 18 (56%) partial responses, 6 (19%) stable disease, 2 (6%) progressive disease, and 2 (6%) not evaluable or undefined. Median duration of treatment was 20 months (range 2–81); at data cutoff, no patients remained on treatment. Median time to response was 1.8 months (range 1.5–7.3). Median DoR, progression-free survival (PFS), and overall survival (OS) were 20 months (95% CI 13–67), 19 months (95% CI 10–36), and 41 months (95% CI 17−not estimable), respectively, with median follow-ups of 53, 49, and 58 months. The 4-year rates for DoR, PFS, and OS were 34% (95% CI 12–57), 26% (95% CI 8–44), and 49% (95% CI 30–69), respectively. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs were reported in 10 (31%) patients. One patient (3%) discontinued treatment due to TRAEs (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase increased). Conclusions: Larotrectinib continues to demonstrate rapid and durable responses, extended clinical benefit, and a favorable safety profile in patients with advanced TRK fusion lung cancer. These results support the wider adoption of NGS panels that include NTRK gene fusions in patients with lung cancer to identify those who may benefit from TRK inhibitor therapy. Clinical trial information: NCT02122913 , NCT02576431 .
Comparative effectiveness of first-line FOLFIRINOX versus gemcitabine plus nab-paclitaxel in patients aged ≧ 75 years with metastatic pancreatic cancer: A multinational real-world study.
e16385 Background: Randomized trials supporting first-line chemotherapy for metastatic pancreatic cancer have systematically underrepresented very old adults. As a result, the comparative effectiveness of intensive chemotherapy in patients aged ≧75 years remains uncertain in routine clinical practice. Methods: We conducted a retrospective cohort study using the TriNetX multinational electronic health record database. Patients aged ≧75 years with metastatic pancreatic cancer receiving first-line FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) were identified. 1:1 propensity score matching (PSM) was performed to balance demographics, comorbidities, metastatic site, and baseline laboratory markers including albumin, total bilirubin and CA19-9. The primary outcome was overall survival (OS). Secondary outcomes included time to next treatment or death (TTNT-D), 6-month OS rate, and acute healthcare utilization (ER and acute inpatient visits). Results: After matching, 274 patients were included in each group. First-line FOLFIRINOX was associated with significantly longer OS compared with GnP (median OS: 11.4 vs 9.7 months; HR 0.82, 95% CI 0.666–0.999, log-rank P = 0.048). The 6-month OS rate was notably higher with FOLFIRINOX (70.3% vs. 59.2%; HR 0.68, 95% CI 0.49-0.93). TTNT-D showed a consistent trend (median: 6.94 vs. 6.28 months; HR 0.857, 95% CI 0.709-1.036). Importantly, acute healthcare utilization did not differ significantly between FOLFIRINOX and GnP groups (35.6% vs 27.1%, p = 0.224). Conclusions: In this large-scale real-world cohort of patients aged ≧75 years with metastatic pancreatic cancer, first-line FOLFIRINOX demonstrated a significant survival advantage over GnP and improved early survival outcomes without a statistically significant increase in acute healthcare utilization. This study provides evidence to support FOLFIRINOX as a viable front-line option for fit older adults.
Stiffness Reinforcement in Polymer Networks Through Supramolecular Topological Linking
ABSTRACT Polymer networks possess numerous elastically defective and isolated loops, which do not contribute to mechanical stiffness. In this report, we introduce a strategy of supramolecular topological linking to access stiffer‐yet‐ductile polymeric materials through incorporation of supramolecular tetravalent crosslinkers. Dynamic dissociation/re‐association between these high‐functionality crosslinks enables the formation of topologically‐linked loops that serve as elastic springs to stiffen the networks. An exceptional scaling exponent of 2.05 for Young's modulus versus crosslinker concentration is obtained, exceeding most reported randomly‐crosslinked polymeric systems. Compared to conventional analogs, the mechanical properties of the resultant materials are enhanced: Young's modulus (2‐fold), elongation at break (8‐fold), and work of fracture (100‐fold). Uplifting modulus scalings through supramolecular topological linking paves a new path to the design of stiffness‐reinforced soft materials, holding substantial promise in load‐bearing application scenarios such as tissue implants, bioelectronic interfaces, and soft robotics.