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Clinical impact of <i>MSH3</i> loss-of-function alterations in patients treated with immune checkpoint blockade across cancer types.
10516 Background: MSH3 is an alternate mismatch repair protein specialized in the recognition of larger indels through its interaction with MSH2 within the MutSβ complex. While monoallelic germline MSH3 variants are not associated with cancer susceptibility, the impact of MSH3 loss-of-function (LOF) alteration has not been systematically assessed for immune checkpoint blockade (ICB) sensitivity. Methods: Tumors with MSH3 loss-of-function alterations were identified by next-generation sequencing in the MSKCC IMPACT cohort (discovery cohort). Overall survival (OS) from diagnosis and from ICB initiation was compared between MSH3-altered and wild-type (WT) tumors using 2:1 propensity score matching, adjusting for age, sex, disease stage, and tumor type. Tumors harboring pathogenic POLE or POLD1 mutations were excluded. An independent pan-cancer cohort (Caris) was used for validation. Results: Among 65,570 profiled tumors, 767 patients (1.2%) carried MSH3 LOF alterations, including 46 (6.0%) germline variants. MSH3 LOF tumors were MMR-deficient (MMRd) in 71.2% of cases, MMR-proficient (MMRp)/microsatellite instable (MSI) in 2.6% and MMRp/ microsatellite stable (MSS) in 26.2%. In MMRd tumors, MSH3 -LOF occurred mainly in colorectal (64%), endometrial (20%), and esophagogastric cancers (12%), whereas in MMRp tumors it was most frequent in lung (17.4%), colorectal (12.5%), breast (10.3%), and esophagogastric cancers (4.9%). In MMRd tumors, patients with MSH3 LOF tumors experienced significantly prolonged OS compared with MSH3 WT tumors after ICB (mOS NR vs 85.2 months (mo), p = 0.008), attributed to the fact that they were all MSI while discordant cases (MMRd/MSS) were observed only in the absence of MSH3 LOF. To further assess the impact of MSH3 LOF on immunogenicity independent of classical MSI, we performed specific analysis in MMRp/MSS tumors. While these tumors remained mostly TMB low (median TMB 7 Mut/Mb vs 5 Mut/Mb, p = 0.14) with a modest but significant increase in MSI score (1.01 vs 0.42, p = 0.013), MSH3 LOF patients had significantly improved OS following ICB compared with propensity matched WT controls (median OS 33.7 [95% CI 18.4–NR] vs 20.4 mo [95% CI 12.5–24.5]; p = 0.015). In particular, germline and somatic MSH3 altered tumors were associated with similar benefit (median OS 33.7 [95% CI 14.4–NR] and 31.1 mo [95% CI 17.3–NR], respectively). No survival difference was observed among patients who did not receive ICB (p = 0.91). Predictive value of MSH3 LOF for improved OS after ICB was independently validated in the Caris cohort. Conclusions: Somatic and germline MSH3 LOF alterations define a unique subset of cancers with enhanced sensitivity to ICB, in particular in MMRp/MSS tumors, where MSH3 deficiency may drive immunogenicity through mechanisms distinct from classic MSI. These data support MSH3 LOF as a potential predictive biomarker for immunotherapy benefit.
Long-term safety outcomes of pregnancy among young breast cancer survivors: Results from a prospective, multicenter cohort study.
632 Background: Prospective data on the risk of breast cancer (BC) recurrence among young BC survivors who have a subsequent pregnancy are limited. We sought to evaluate the long-term impact of pregnancy and live birth on BC outcomes in the Young Women’s Breast Cancer Study (NCT01468246), a prospective multicenter study of women aged ≤40 years at BC diagnosis. Methods: Women with stage 0-III BC without prior hysterectomy were included. The primary endpoint was breast cancer-free interval (BCFI) between patients with and without a (a) pregnancy and (b) live birth after BC. Secondary endpoints were distant recurrence-free interval (DRFI) and overall survival (OS). A time-varying Cox proportional hazards model was performed by estrogen receptor (ER) status, controlling for age at diagnosis, tumor stage, HER2 status, tumor grade, parity at diagnosis, and germline pathogenic variant status. Results: Among 1,016 BC survivors at a median follow-up of 12 (range, 0.5-18.5) years, 198 reported ≥1 pregnancy and 165 reported ≥1 live birth post-diagnosis. Among survivors who reported a post-diagnosis pregnancy, median age at diagnosis was 32 (range, 17-40) years; most had stage I (35%) or II (40%) BC, with 72% hormone receptor (HR)-positive and 25% HER2+; 42% were nulligravid and 60% were nulliparous at diagnosis. Among BC survivors who did not become pregnant post-diagnosis, median age at diagnosis was 37 (range, 21-40) years; most had stage I (35%) or II (43%) BC, with 75% HR-positive and 28% HER2+; 25% were nulligravid and 29% were nulliparous at diagnosis. Among BC survivors with ER-positive tumors (n = 737), pregnancy after BC was not associated with a difference in BCFI (adjusted hazard ratio [HR] 0.60, 95% CI 0.31-1.16, P = 0.130), DRFI (HR 0.73, 95% CI 0.35-1.55, P = 0.416), or OS (HR 0.58, 95% CI 0.24-1.40, P = 0.227). Similarly, live birth after BC did not impact BCFI (HR 0.83, 95% CI 0.45-1.55, P = 0.560), DRFI (HR 1.04, 95% CI 0.52-2.06, P = 0.923), or OS (HR 0.77, 95% CI 0.34-1.76, P = 0.541). Outcomes among BC survivors with ER-negative tumors (n = 278) were also not affected by post-diagnosis pregnancy (BCFI [HR 1.48, 95% CI 0.70-3.14, P = 0.304], DRFI [HR 1.59, 95% CI 0.68-3.75, P = 0.287], OS [HR 0.99, 95% CI 0.39-2.49, P = 0.975]) or live birth (BCFI [HR 1.02, 95% CI 0.41-2.53, P = 0.974], DRFI [HR 0.80, 95% CI 0.24-2.69, P = 0.722], OS [HR 0.39, 95% CI 0.09-1.69, P = 0.208]). Conclusions: In this multicenter, prospective study with 12 years of median follow-up, pregnancy and live birth after BC did not impact BC events or overall survival, irrespective of ER status. These long-term data from a modern cohort provide reassurance for young BC patients interested in future fertility. Clinical trial information: NCT01468246 .
Efficacy and patient-reported outcome of trophoblast cell surface antigen-2 antibody-drug conjugate in advanced non–small cell lung cancer: An individual patient data survival analysis and meta-analysis.
e20511 Background: Trop-2 ADCs have emerged as a novel therapeutic approach in NSCLC that is refractory to chemotherapy and immune checkpoint inhibitors. Comparative interpretation of the efficacy of multiple Trop-2 ADCs, including Sacituzumab tirumotecan (Sac-TMT), Datopotamab deruxtecan (Dato-DXd), and Sacituzumab govitecan (SG), is limited. We therefore conducted a systematic review, IPD survival analysis, and meta-analysis to evaluate the efficacy and PROs of Trop-2 ADCs compared with chemotherapy in NSCLC. Methods: A systematic search was conducted from inception to October 31, 2025, across PubMed, Scopus, Cochrane, and CT.gov. Clinical trials evaluating Overall Survival (OS) and Progression-free survival (PFS) in patients treated with Trop-2 ADC alone or compared with Chemotherapy were included. IPD were extracted from the Kaplan-Meier curves of clinical trials for reconstruction using the KMfromIPD website by MD Anderson, which stratified the data by treatment group. Outcomes included OS, PFS, and time to deterioration (TTD). The cumulative data were analyzed using R 4.5.1 and RStudio. RevMan version 5.4.1 was used for the meta-analysis of subgroups. Heterogeneity was assessed using the I 2 statistic. Results: Of 513 articles, 7 phase 1/2 single-arm and 4 randomized control trials were included, comprising 2,619 patients.Trop-2 ADCs were associated with improved OS (Median 15.6 vs 12.5 months; HR 0.78, 95% CI 0.69-0.88; p < 0.0001) and PFS (Median 5.5 vs 4.1 months; HR 0.66, 95% CI 0.59-0.74; p < 0.0001). Sac-TMT demonstrated the greatest OS benefit (OS 23.3 months; HR 0.40). Further drug classes are depicted in Table 1. PROs assessment showed TROP-2 ADCs were associated with longer time to deterioration in global quality of life and dyspnea-free survival compared to chemotherapy (HR 0.8 and 0.69), (p = 0.04 and p < 0.0001, respectively). Exploratory subgroup analysis showed improved OS among patients with actionable gene alteration (AGA) treated with Trop-2 ADCs (HR 0.58, p < 0.00001). However, no significant difference was observed in either treatment arm among patients without AGA (HR 0.89, p = 0.15). Conclusions: Trop-2 ADCs were associated with improved survival and PROs compared with chemotherapy in NSCLC, with variability across agents. Sac-TMT has shown higher OS and PFS. Dato Dxd had a favorable PFS; however, the OS was not superior to chemo. Furthermore, SG showed no favorable clinical outcomes compared with the chemo group. These findings support the continued development of Trop-2-directed therapies and highlight the need for prospective comparative trials and biomarker-driven patient selection. Drug N mOS (months) HR p- value mPFS (months) HR p- value Sac-TMT 386 23.32 0.4 <0.000001 7.5 0.5 <0.000001 Dato-DXd 486 13.2 0.95 0.55 5.02 0.71 <0.000001 SG 347 12.61 1.02 0.82 4.18 0.87 0.05
Robot-assisted versus laparoscopic radical nephrectomy for renal tumors in adults: A systematic review and meta-analysis.
e16503 Background: Minimally invasive radical nephrectomy is the standard treatment for renal tumor resection. While laparoscopic radical nephrectomy (LRN) is well established, robot-assisted radical nephrectomy (RARN) has gained popularity, yet its comparative clinical benefits remain debated. This systematic review and meta-analysis compared perioperative and oncologic outcomes between RARN and LRN. Methods: A comprehensive literature search of major databases was performed to identify comparative studies evaluating RARN versus LRN for renal cancers. Outcomes analyzed included operative time, estimated blood loss, length of hospital stay, perioperative complications, blood transfusion, mortality, readmission, infection, conversion to open surgery, and cancer recurrence. Pooled effect estimates were calculated using random-effects models and reported as mean differences (MD) or odds ratios (OR) with 95% confidence intervals (CI). Results: Thirteen studies encompassing 136,766 patients were included (RARN: 51,667; LRN: 85,099).Compared with LRN, RARN was associated with significantly longer operative time (MD 30.80 minutes; 95% CI 13.14 to 48.46). No significant differences were observed in estimated blood loss (MD 27.21 mL; 95% CI -9.67 to 64.09), length of hospital stay (MD -0.41 days; 95% CI -1.17 to 0.34), overall complications (OR 0.93; 95% CI 0.78–1.11), infection (OR 0.89; 95% CI 0.53–1.48), or conversion to open surgery (OR 0.97; 95% CI 0.23–4.05). RARN was associated with higher odds of blood transfusion (OR 1.15; 95% CI 1.04–1.27) but lower odds of mortality (OR 0.59; 95% CI 0.40–0.87) and readmission (OR 0.44; 95% CI 0.22–0.87). Recurrence was more frequent following RARN (OR 1.92; 95% CI 1.09–3.36). Conclusions: Robot-assisted radical nephrectomy yields outcomes largely comparable to laparoscopy. While associated with lower mortality and readmission, these benefits are offset by longer operative time, higher transfusion rates, and increased recurrence. Laparoscopic radical nephrectomy therefore remains a reliable standard, with robotic use best reserved for selected patients until stronger prospective evidence is available. The role of robotic surgery should be individualized, and future well-designed prospective studies are essential to clarify which patients get meaningful oncologic benefit from a robotic approach.
Comparison by immunotherapy agent of real-world outcomes with chemoimmunotherapy in first-line extensive-stage small cell lung cancer.
8103 Background: Chemoimmunotherapy became the standard of care for extensive-stage small cell lung cancer (ES-SCLC) after two Phase III trials (IMpower133, CASPIAN) demonstrated significant improvement in overall survival (OS) over platinum-based chemotherapy. While both anti-PD-L1 agents provide durable responses in a subset (~10%), the magnitude of benefit with immunotherapy (IO) is similar, suggestive of therapeutic interchangeability. Real-world data (RWD) suggests durvalumab confers superior outcomes in ES-SCLC, compared to atezolizumab. Recently, durvalumab received regulatory approval for limited-stage SCLC, whereas atezolizumab failed to demonstrate benefit after chemoradiation. Here, we investigate whether IO choice impacts outcomes for first-line ES-SCLC. Methods: We retrospectively reviewed the charts of patients diagnosed with ES-SCLC in the Indiana University (IU) Health System from 2018 to 2024. Patients were stratified by receipt of either atezolizumab or durvalumab for first-line chemoIO for comparison of demographics and outcomes. Kaplan-Meier, univariate Cox regression, and Fishers exact test was applied. Results: We identified 158 patients diagnosed with ES-SCLC who received chemoIO (Table 1). Platinum-sensitivity and objective response rates were similar between groups ( P = 0.14 and P >0.9, respectively). The median number of IO cycles received (induction and maintenance) was significant higher with atezolizumab (9), compared to durvalumab (7, P <0.001). Similarly, median progression-free survival (PFS) trended in favor of atezolizumab over durvalumab (6.3 vs 5.2 months, P = 0.08). Subsequent therapy post-progression was comparable between groups, including lurbinectedin (31% vs 23%, P = 0.5) and tarlatamab (17% vs 23%, P = 0.4). The unadjusted median OS for atezolizumab was 16.5 months (95% CI, 13.2-19.5), compared to durvalumab 12.4 months (95% CI, 9.9-17.3) ( P = 0.11). To account for group imbalances, overlap-weighted multivariable Cox regression was performed, in which ECOG performance status (PS) of 0-1 (HR 0.53, 95% CI, 0.30-0.92, P = 0.03) and receipt of atezolizumab (HR 0.56, 95% CI, 0.34-0.93, P = 0.02) were independently associated with improved OS. Conclusions: In our study, atezolizumab demonstrated improved OS and trended to improve PFS in first-line ES-SCLC, compared to durvalumab. Potential confounders when evaluating the impact of IO agents across RWD studies include ECOG PS, variable use of thoracic radiotherapy, geographical differences, and ethnic distributions. Characteristic Atezolizumab (n = 127) Durvalumab (n = 31) Overall (n = 158) P value Age (Q1, Q3) 66 (61, 73) 68 (63, 73) 67 (61, 73) >0.9 Sex (female) 79 (62%) 17 (55%) 96 (61%) 0.5 ECOG PS (0-1) 87 (74%) 20 (69%) 107 (73%) 0.6
Prevalence of high-risk human papillomavirus infection in allogeneic stem cell transplant recipients.
e18565 Background: Persistent infection with high-risk human papillomavirus (HR-HPV) is an important cause of malignancy, and patients receiving allogeneic hematopoietic stem cell transplant (SCT) for hematologic malignancies are at heightened risk of HPV-related secondary malignancies due to immunosuppressive therapies and graft versus host disease. However, the prevalence of HR-HPV among SCT recipients has not been well established. We aimed to describe the prevalence of HR-HPV in this population. Methods: This prospective observational study enrolled patients at MD Anderson Cancer Center planning to undergo allogeneic SCT for hematologic malignancies from March 2017 to January 2019. Patients completed a self-administered survey providing demographic information and HPV-related risk factors. Specimens were collected at 3 anatomical sites (oral, anal, and either cervical [female] or penile [male]) before and at 6-12 months after SCT. Cervical specimens were tested with Cervista. Oral, anal, and penile specimens underwent HPV PCR-based testing. Specimens that had a positive HPV result were then genotyped using the Roche Linear Array HPV test, which detects 37 HPV types including 14 HR-HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Results: A total of 48 eligible patients were identified, and of these, 40 (27 males, 13 females) were enrolled in the study. Median age at enrollment was 54 years (range 22-69). All 40 patients received baseline HPV testing, and 12 patients received 6-12-month follow-up testing. At baseline 9 patients had positive HR-HPV test results (22.5%, 95% CI 10.8-38.5%). In females, prevalence of HR-HPV was highest in the cervical (2/13, 15%) and anal (2/13, 15%) specimens; none tested positive for HR-HPV in oral specimens. In males, prevalence of HR-HPV was highest in the penile (4/27, 15%) and oral (3/27, 11%) specimens; none tested positive for HR-HPV in anal specimens. Of the 12 patients who had baseline and follow up testing, 2 tested positive for HR-HPV before SCT. Among these, 1 patient's testing remained positive for HR-HPV after SCT. Conclusions: The prevalence of HR-HPV infection was high in our population of SCT recipients. In females, HR-HPV positivity was most frequently seen in cervical and anal specimens, while in males HR-HPV positivity was most frequently seen in penile and oral specimens. Larger studies with longer follow up are warranted to evaluate the long-term effects of HR-HPV positivity on development of HPV-related secondary malignancies in this population.
Survival outcomes in melanoma of unknown versus known primary receiving immunotherapy: A systemic review and meta-analysis.
e21500 Background: Historically, patients with melanoma of unknown primary (MUP) had better survival than those with melanoma of known primary (MKP). However, it remains unclear whether this difference persists among patients treated with immune checkpoint inhibitors (ICIs). Methods: We searched MEDLINE and Embase databases from inception to December 15, 2025, for studies that reported survival outcomes (overall survival, progression-free survival, and/or hazard ratio [HR] with 95% confidence interval [CI]) in patients with MUP and MKP treated with ICIs (anti-CTLA-4 and/or anti-PD-1). When survival outcomes were not reported, we reconstructed individual patient survival data from published Kaplan–Meier curves to derive estimates. We then pooled survival outcomes using a random-effects model based on the generic inverse variance method. Results: A total of seventeen studies published between 2015 and 2025 were included. Among 905 patients with MUP, pooled overall survival rates were 80% at 6 months, 64% at 1 year, 54% at 2 years, and 48% at 3 years. ICI–treated MUP and MKP demonstrated comparable overall survival (672 vs 3,886 patients; HR, 0.99; 95% CI, 0.83–1.18) and progression-free survival (305 vs 1,596 patients; HR, 0.98; 95% CI, 0.54–1.80). Subgroup analyses similarly showed no significant survival differences between MUP and MKP among patients receiving either anti-CTLA-4 or anti-PD-1. Conclusions: Survival outcomes in MUP have improved substantially over the past decade. In contrast to findings from the pre-immunotherapy era, no significant survival differences were observed between MUP and MKP among patients treated with ICIs.
Lymphoma histology as independent predictor of ICU mortality after adjustment for illness severity: A retrospective cohort study of 1,268 patients.
e19106 Background: Lymphomas comprise biologically heterogeneous malignancies ranging from aggressive to indolent subtypes. Whether histologic classification independently predicts intensive care unit (ICU) mortality after accounting for severity of critical illness remains unknown. Methods: We conducted a retrospective cohort study using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (2008-2022). Adult lymphoma patients requiring ICU admission were classified into histology groups: aggressive non-Hodgkin lymphoma (NHL), indolent NHL, Hodgkin lymphoma, and plasma cell neoplasms. The primary outcome was hospital mortality. Multivariable logistic regression assessed whether histology independently predicted mortality after adjusting for demographics, illness severity, and admission characteristics. Results: Among 1,268 lymphoma patients requiring ICU admission, overall hospital mortality was 19.3%. Unadjusted mortality rates did not differ across histology groups (15.8-20.8%, p=0.79). After multivariable adjustment, histology did not independently predict mortality: Hodgkin lymphoma (adjusted OR 0.86, 95% CI 0.44-1.68, p=0.66), indolent NHL (OR 0.77, 95% CI 0.37-1.59, p=0.48), plasma cell neoplasms (OR 0.99, 95% CI 0.63-1.55, p=0.97), and other lymphomas (OR 1.04, 95% CI 0.69-1.56, p=0.86) versus aggressive NHL. Independent mortality predictors were ICU length of stay (OR 1.53, p<0.001) and emergency admission (OR 3.18, p=0.001). Conclusions: Lymphoma histology does not independently predict ICU mortality after adjustment for critical illness severity. ICU triage decisions and prognostic discussions should focus on acute illness reversibility rather than lymphoma subtype, supporting evidence-based admission policies and equitable resource allocation.
A randomized phase II study of capmatinib plus osimertinib with or without ramucirumab in patients with <i>EGFR</i> -mutant, <i>MET</i> -amplified stage IV or recurrent no–small cell lung cancer (Lung-MAP Sub-Study S1900G).
TPS8677 Background: Patients (pts) with advanced EGFR -mutant non-small cell lung cancer (NSCLC) typically respond well to first-line tyrosine kinase inhibitor (TKI) therapy, however disease progression is inevitable. A common mechanism of resistance to third-generation EGFR TKIs is MET amplification in up to 15% of patients. Prior trials have demonstrated efficacy of combined EGFR and MET TKI for patients with acquired MET amplification, however treatment can be limited by toxicity due to peripheral edema. Preclinical evidence demonstrates the benefit of VEGF inhibition combined with an EGFR TKI and MET TKI, both in efficacy and reduced edema. Lung MAP S1900G is a randomized phase II trial of osimertinib and capmatinib plus or minus the VEGFR2 inhibitor ramucirumab in patients with EGFR -mutant NSCLC and MET amplification after progression on osimertinib. Methods: Pts have stage IV or recurrent NSCLC with a sensitizing EGFR mutation and have disease progression on osimertinib alone or in combination with other agents. Documentation of MET amplification must be determined by tissue- or blood-based assay; testing for MET amplification can be done locally or centrally through the LUNGMAP screening process and any level of amplification is allowed. Measurable disease is not required. Patients with asymptomatic treated or untreated brain metastases are eligible. Prior VEGF inhibitor or MET antibody (such as amivantamab) are allowed. Pts are randomly assigned to receive osimertinib 80mg by mouth daily, capmatinib 400mg by mouth twice daily, and ramucirumab 10m/kg intravenously on days 1 and 15 of a 28 day cycle, or osimertinib plus capmatinib alone. Treatment continues until disease progression, symptomatic deterioration, unacceptable toxicity or treatment delay greater than 28 days. Disease assessment per RECIST 1.1 is performed every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint is investigator-assessed progression-free survival (PFS) and secondary endpoints include toxicity, ORR, duration of response, overall survival, rates of edema, and change in weight. A safety run-in of the first 10 pts in each arm evaluable for dose-limiting toxicity is included due to limited safety data on both the doublet and triplet combinations. The target sample size is 40 eligible pts (20 per arm) which will provide 85% power to rule out no difference at a 1-sided 15% level if the true hazard ratio is 0.5. A hazard ratio of 0.71 or less, equivalent to a 2.4 month difference in median PFS, will be consistent with rejecting the null hypothesis. Accrual is ongoing, with 24 of 40 patients enrolled. S1900G is the first Lung-MAP sub-study that focuses on EGFR -mutant lung cancer, representing a new era for this platform trial. Clinical trial information: NCT05642572 .
A phase III placebo controlled randomized controlled trial using combination therapy for treatment-related fatigue in patients with prostate cancer.
12005 Background: To determine if the combination of exercise (EX) plus methylphenidate (MP) is superior to EX plus placebo (PL) for 12 weeks in the treatment of cancer-related-fatigue (CRF) in patients with prostate cancer receiving androgen deprivation therapy (ADT) and/or radiation therapy (RT). Methods: Using a phase III randomized double-blind placebo-controlled design, we assessed treatments combining either EX or its stretching (ST) control with either MP (5mg twice a day, with dose titrated up to 20mg a day) or placebo. Patients were eligible if they had prostate cancer patients who are receiving androgen deprivation therapy and/or radiation therapy and had CRF; Eligible patients were randomized into one of four arms, EX + MP, EX + PL, ST + MP, ST + PL (2:1:1:1). Primary outcome was assessed using linear mixed-effects model comparing the differences in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores at Weeks 1, 2, 4, 8 and 12. Results: 161 eligible patients were randomly assigned to 4 arms EX+MP (n = 65), EX+PL(n = 34), ST+MP (n = 30), and ST+PL (n = 32). Demographics, including mean age (65-67 years) were similarly distributed between arms (all p > 0.05). Bone metastases (~25%), and treatment modality distributions (ADT alone, ADT + RT, or RT alone) were comparable among the arms. The baseline FACIT-F scores [mean (SD) were 28.5(11.0), 28.7(8.9), 28.5(9.3), and 30.3(11.0)] respectively in arms EX+MP, EX+PL, ST+MP, and ST+PL arms. All 4 arms showed CRF improvement over time. There was a nonsignificant improvement in CRF in the EX+MP intervention arm, compared with EX+PL arm [FACIT-F coefficient, 2.73(95% CI, –0.49 to 5.96); P = 0.097]. Methylphenidate-containing arms (EX+MP and ST+MP) significantly improved CRF compared with their placebo counterparts (EX+PL and ST+PL), [FACIT-F coefficient, 3.23 (95% CI 0.84 to 5.63), P = 0.008]. There were no significant differences in CTCAE v.5 grade ≥3 adverse events by arms (P > 0.99). Conclusions: EX+MP arm was not superior to EX+PL arm in improvement of CRF. Methylphenidate-containing arms significantly improved CRF compared with their placebo arms. All four treatment arms showed improvement of CRF overtime suggesting strong placebo response. Further methylphenidate-containing multimodal CRF studies are needed. Clinical trial information: NCT03772834 .
Epidemiology and survival of melanoma in Jordan, 2013-2022: A registry-based study of trends and histologic patterns.
e21542 Background: Melanoma is an aggressive skin malignancy with increasing global incidence and wide geographic variation in survival outcomes. Data describing melanoma epidemiology and survival in Middle Eastern populations remain limited, despite potential differences in ethnic background, skin phototype distribution, ultraviolet exposure patterns, and healthcare access. This study provides updated national registry-based data on malignant melanoma in Jordan, describing demographic characteristics, histologic patterns, temporal trends, and overall survival from 2013 to 2022. Methods: We conducted a retrospective registry-based study including all malignant melanoma cases recorded in Jordan between January 1, 2013, and December 31, 2022, identified using ICD-10 code C43. Tumors were classified according to ICD-O-3 morphology codes (8720–8790). Extracted variables included age at diagnosis, sex, nationality, governorate of residence, year of diagnosis, histologic subtype, topography, laterality, grade, and summary stage. Descriptive statistics were summarized as frequencies and percentages, annual case counts were used to assess temporal trends, and overall survival was estimated using the Kaplan–Meier method. Results: A total of 322 malignant melanoma cases were identified. Females accounted for 55.9% of cases (n = 180) and males for 44.1% (n = 142). The mean age at diagnosis was 54.9 ± 18.3 years (median 57; IQR 44.3–66.0). The most common histologic subtype was malignant melanoma, not otherwise specified (NOS; ICD-O-3 8720) (72.0%), followed by nodular melanoma (16.8%). Less frequent subtypes included spindle/epithelioid or mixed melanoma (2.8%), acral lentiginous melanoma (1.9%), superficial spreading melanoma (1.6%), lentigo maligna melanoma (0.9%), and desmoplastic melanoma (0.3%). Most cases had valid skin subsite topography codes (93.5%), while 6.5% were coded outside the standard skin subsite range. Annual case counts demonstrated an overall increasing trend, with a peak in 2021. Five-year overall survival was lower than that reported in many high-income countries worldwide. Conclusions: This national registry-based analysis demonstrates an increasing burden of melanoma in Jordan over the past decade, frequently characterized by aggressive histologic subtypes, diagnosis at older ages, and lower survival compared with global benchmarks, suggesting delayed diagnosis. These findings highlight the need for greater public awareness, earlier clinical recognition, improved access to dermatologic care, and strengthened cancer registry documentation to support prevention and early detection efforts in Jordan and similar Middle Eastern settings.
Evaluating nuclear lamina-associated alterations as predictors of prostate cancer recurrence.
e17119 Background: Prostate cancer exhibits marked disparities, and despite definitive treatment, some men with clinically localized disease develop biochemical recurrence (BCR). Nuclear architecture alterations are implicated in progression, but prognostic value of nuclear lamina-associated components remains unclear. We evaluated lamin A/C protein expression in a racially diverse cohort and leveraged a publicly available transcriptomic dataset to evaluate the prognostic relevance of nuclear envelope-associated biomarkers. Methods: Lamin A/C was measured by multiplex immunofluorescence on tissue microarrays representing multiple tumor cores per case from archival prostatectomy specimens (N=185, ~50% Black) at Boston Medical Center. Primary endpoint was BCR (2 consecutive post-operative PSA values ≥0.2 ng/mL). Lamin A/C was categorized into four groups by qualitative assessment and confirmed by quantitative digital image analysis in a subset to compute a continuous intensity ratio. Associations were tested using Fisher’s exact and chi-squared tests, with odds ratios estimated by logistic regression. Kaplan-Meier survival analyses and univariate and multivariate Cox proportional hazards models assessed associations between lamin A/C protein expression, clinicopathologic variables, and BCR. At the transcriptomic level, RNA-seq data with clinical outcomes from the TCGA prostate adenocarcinoma (PRAD) cohort (N=497) were analyzed, focusing on LMNA and other nuclear envelope-associated genes (e.g. LBR , EMD ). Results: Median follow up was 4.71 years; 53 BCR events (28.6%) occurred. Tumor lamin A/C protein expression was heterogeneous. Logistic regression revealed that Grade Group 2 had significantly higher odds of elevated lamin A/C protein expression vs Grade Group 1. Lamin A/C protein expression was not associated with pathologic features, race, or BCR, and lacked independent prognostic value in univariable and multivariable Cox analyses. Concordantly, LMNA mRNA expression in the TCGA-PRAD cohort showed no association with pathologic features or BCR. In contrast, transcriptomic analyses of additional nuclear lamina-associated genes demonstrated gene-specific prognostic signatures. Lamin B receptor ( LBR ) expression significantly increased with higher grade, while emerin ( EMD ) expression was independently associated with BCR in multivariate Cox models (HR=2.31, 95% CI 1.05-5.07; p=0.039). Conclusions: While lamin A/C reflects tumor differentiation, it does not independently predict BCR at either the protein or transcript level. In contrast, among nuclear lamina-associated components, only EMD demonstrates independent prognostic significance, supporting a functional distinction between relatively static nuclear lamin architecture and emerin-associated nuclear envelope dynamics, with potential utility for refining risk stratification.
Chronotherapy in metastatic non–small cell lung cancer: Clinical outcomes according to immune checkpoint inhibitor administration time during the day in patients treated with first-line chemoimmunotherapy.
8575 Background: Although circadian rhythms are known to modulate immune cell function, the effect of immune checkpoint inhibitor (ICI) infusion timing during the day on oncologic outcomes in metastatic non–small cell lung cancer (NSCLC) patients treated with first-line chemoimmunotherapy has not been fully elucidated. Methods: We retrospectively analyzed patients with de novo metastatic NSCLC without actionable oncogenic driver alterations who received first-line chemotherapy plus ICI between January 1, 2018, and October 31, 2025, at two centers. Patients receiving platinum-based doublet chemotherapy plus pembrolizumab and/or nivolumab were included, whereas those treated with dual ICIs (nivolumab plus ipilimumab with platinum-based chemotherapy) were excluded. Infusion times for the first four cycles were recorded, and patients were categorized as the early group if they received ≥2 of the first four ICI cycles before 11:00 a.m., and as the late group if they received ≤1 of the first four ICI cycles before 11:00 a.m. Endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: We identified 101 eligible patients who met the inclusion criteria, comprising 34 patients in the early group and 67 patients in the late group. Median follow-up was 18.4 months (95% CI 12.4 – 24.4). There were no differences between the early group and the late group in terms of age, gender, body mass index, smoking status, ECOG performance status, stage (IVA vs. IVB), histologic subtype (squamous vs. non-squamous), PD-L1 tumor proportion score ( < 1% vs. 1-49% vs. ≥50%), central nervous system metastases, liver metastases, number of metastatic sites (≤2 vs. ≥3 organ systems), and ICI agent (pembrolizumab vs. nivolumab). The early group demonstrated significantly longer median PFS (14.6 vs. 7.1 months; HR = 0.54 [95% CI 0.31 – 0.93]; p = 0.027) and median OS (not reached vs. 27.3 months; HR = 0.28 [95% CI 0.11 – 0.71]; p = 0.008). Both the ORR (97.1% vs. 56.7%; p < 0.001) and the disease control rate (97.1% vs. 64.2%; p < 0.001) were significantly higher in the early group. The majority of patients who experienced primary progression after the first four cycles were in the late group (24 of 25 patients; 96%). In multivariate analysis, only disease stage (IVB vs. IVA; HR = 2.35 [95% CI 1.05 – 5.26]; p = 0.039) and timing-based group assignment according to the number of the first four ICI infusions administered before 11:00 a.m. (late vs. early; HR = 2.97 [95% CI 1.14 – 7.76]; p = 0.026) were independently associated with OS. Conclusions: Our findings demonstrated that receiving majority (≥2) of the first four ICI infusions before 11:00 a.m. might be associated with better response rates, improved PFS and OS in patients with de novo metastatic NSCLC treated with first-line chemotherapy plus ICI.
An NCDB analysis on the demographic, treatment, and survival of small cell carcinoma with fusiform cells of the lungs.
e20137 Background: Small cell carcinoma with fusiform cells (SCC-FC), commonly originating in the lungs, is clinically characterized by spindle-shaped tumor cells and represents a highly aggressive morphological variant of the general small cell carcinoma. Though survival statistics for SCC-FC are limited due to its rarity, the 98% five-year mortality rate of general small cell carcinoma suggests possible similarity aggressive behavior. Given the rarity of this disease, we aim to provide insights into its epidemiology by analyzing the National Cancer Database (NCDB) to characterize sociodemographic factors of patients diagnosed with SCC-FC. Methods: A retrospective cohort study using the 2004–2020 NCDB included patients with histologically confirmed cases of SCC-FC (N = 304), ICD-O-3 code - 8043. Demographic and clinical variables—age, sex, race, Hispanic ethnicity, mortality rate, treatment methods, and Charlson/Deyo comorbidity score—were analyzed using descriptive statistics, and incidence trends were evaluated using regression analysis. Survival analysis was conducted using Kaplan-Meier estimates. Results: A total of 304 patients with SCC-FC were identified in the NCDB between 2004 and 2020 with a decreasing incidence (R² = 0.6). Most patients were female (54.3%), White (91.1%), and non-Hispanic (93.1%), with the mean age at diagnosis being 67.5 years old (SD = 0.59). The primary payor at diagnosis was Medicare (60.5%), followed by private insurance/ managed care (26.3%). The median household income quartiles and distribution are as follow, 21.0% within Q1 ( < $46,277), 36.9% in Q2 ($46,227 - $57,856), 24.1% in Q3 ($57,857 - $74,062), and 17.9% in Q4 ($74,063 or more). The upper lobes of the lungs are the most common primary site location with most cases being diagnosed at Stage IV (52.0%) and Stage III (22.4%); most of the patients (57.2%) had a Charlson-Deyo Score of 0. The mean tumor size is 47mm (SD = 5.09). The vast majority (95.7%) of patients received no surgical procedure at the primary site, instead 51.6%, 61.8%, and 0.7% of patients received radiation, chemotherapy, and immunotherapy as their primary treatment, respectively. The 2, 5, and 10 year survival rates are 13.5%, 5.9%, and 3.7% respectively, with the mean survival time being 18.231 months (SD = 2.26). Conclusions: To the best of our knowledge this is the first NCDB analysis on SCC-FC. The upper lobes were the most common primary site, differing slightly from prior reports that emphasize central lung involvement. According to previously published papers chemotherapy does present itself as the primary treatment option the vast majority of patients use for small cell lung cancer, which aligns with the data we have for the variant with fusiform cells. This analysis is the first to suggest that most SCC-FC patients do not receive surgery at the primary site and instead, are primarily treated using radiation and chemotherapy.
Clinicopathology-based machine learning model for prediction of pathologic complete response to neoadjuvant chemotherapy in breast cancer.
e12567 Background: Pathologic Complete Response (pCR) following neoadjuvant chemotherapy (NAC) is a surrogate for long-term survival in breast cancer. While pCR status informs surgical and therapeutic decisions, accurate patient-level prediction is hindered by tumor heterogeneity and skewed outcomes. Standard parameters (T/N stage, molecular subtype, HER2 status, Ki-67) are routinely documented but rarely integrated into robust decision-support tools. We developed an interpretable machine learning (ML) framework to provide calibrated, data-driven predictions of pCR using routine clinicopathological data. Methods: This retrospective study analyzed a Turkish cohort of 298 breast cancer cases (n = 84 pCR vs. n = 214 non-pCR) using 20 expert-curated variables. To ensure a leakage-proof methodology, the dataset was partitioned into training and independent hold-out test sets, with all preprocessing and feature selection parameters were fitted strictly on training data. Model performance was evaluated using nested cross-validation. We screened 12 ML algorithms, comprising linear models (Logistic Regression, SVM), distance-based (KNN) and tree-based ensembles (XGBoost, CatBoost, Random Forest), along with meta-ensemble architectures (Voting and Stacking). Optimal model selection was guided by a composite score integrating MCC, PR-AUC, F1-score and Brier score. Models were benchmarked against a 100-iteration Monte Carlo simulation. Class imbalance was addressed through balanced weighting, and outputs were calibrated using Platt scaling. Decision thresholds were tailored using a weighted Youden’s index to prioritize sensitivity. Interpretability was established through permutation importance and SHAP analysis. Results: Calibrated Logistic Regression (LR) emerged as the optimal model, achieving a ROC-AUC of 0.803. In the test set (n = 60), LR correctly identifies 15 out of 17 pCR cases, yielding 88% sensitivity and 93.1% NPV (63% specificity, 48.4% PPV). These outcomes significantly outperformed random baseline estimates (NPV:71%, PPV:26.9%), confirming a substantial predictive gain. Feature analysis identified HER2 expression (0.60) as the primary positive predictor of pCR, whereas ER status (-0.56) and AJCC stage (-0.31) were the strongest negative predictors. Other contributors included nodal status (0.11) and Ki-67 (0.11). Conclusions: We present the first clinicopathology-based ML framework for a Turkish breast cancer cohort. This calibrated LR model provides clinically meaningful pCR discrimination, potentially aiding clinical decision-making in the neoadjuvant settings.
Implementation of a cancer-oriented geriatric assessment (COGA) clinic to promote age-friendly cancer care: A type III hybrid implementation–effectiveness method in community practice.
TPS1681 Background: Cancer incidence increases with age, and adults aged ≥65 years account for the majority of new cancer diagnoses. Standard oncology assessments often fail to identify age-related vulnerabilities such as frailty, cognitive impairment, and functional decline (Hurria et al., JCO 2011). The American Society of Clinical Oncology (ASCO) recommends routine geriatric assessment–guided management for older adults receiving systemic cancer therapy to inform treatment decisions and reduce treatment-related toxicity (Mohile et al., JCO 2018). In alignment with these goals, we established a Cancer-Oriented Geriatric Assessment (COGA) clinic within an academic cancer center. Methods: We implemented a Type III hybrid implementation–effectiveness design to integrate Cancer-Oriented Geriatric Assessment (COGA) into routine oncology practice using the 5M framework (Mind, Mobility, Medications, Matters Most, and Multicomplexity). The Eleanor N. Dana Cancer Center is part of a large academic health system in Northwest Ohio, serving a predominantly rural and suburban population across Ohio and Southeast Michigan. Eligibility included oncology patients aged ≥65 years with a positive G8 screen (≤14), consistent with ASCO and European Society for Medical Oncology (ESMO) recommendations for comprehensive geriatric assessment. A tiered workflow was implemented on January 15, 2026, in which medical assistants obtained vital signs, performed medication reconciliation, and completed standardized screenings for cognition, mood, and nutrition, followed by a geriatrician-led assessment of frailty, fall risk, mobility, and functional status. The medication domain emphasized deprescribing of potentially inappropriate medications, while the Matters Most domain addressed goals of care, advance directives, and social support. Additional geriatric syndromes—including sensory impairment, sleep disturbances, incontinence, and fatigue—were systematically assessed and managed. Risk stratification was guided by validated tools, including the Cancer and Aging Research Group (CARG) toxicity tool and the Schonberg Index, to estimate non-cancer mortality. Primary implementation outcomes included reach (the proportion of eligible patients receiving COGA), adoption (use of COGA by oncology teams), and fidelity (completion of the core 5M domains as intended). Secondary effectiveness outcomes included patient-centered outcomes and unplanned hospitalizations. This scalable, real-world implementation model enables systematic integration of geriatric assessment into oncology practice, with the potential to improve outcomes for older adults with cancer and support broad dissemination across diverse cancer care settings.
Evaluation of atezolizumab, durvalumab, lurbinectedin, and tarlatamab in high-grade extrapulmonary neuroendocrine carcinoma: A multicenter retrospective comparative analysis.
e20115 Background: Small cell lung cancer (SCLC) is the most common high-grade neuroendocrine neoplasm (NEN). SCLC is associated with poor survival due to treatment resistance, though in the past decade new therapies such as atezolizumab, durvalumab, lurbinectedin, and tarlatamab have shown improved outcomes. While SCLC has seen an influx of new therapies, other rarer high-grade NENs have not been studied prospectively. Treatment is still routinely extrapolated from SCLC, though limited data remains for these patients. This study aimed to evaluate atezolizumab, durvalumab, lurbinectedin, and tarlatamab regimens in patients with high-grade NENs. Methods: This retrospective study evaluated patients treated with durvalumab, atezolizumab, and lurbinectedin from 2018–2025 at the University of Kansas, and patients treated with tarlatamab from 9 cancer centers in the DLL3 PanTUMOR database. Any high-grade NEN other than SCLC was included. Key endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: A total of 54 patients were included: 24 received platinum-based therapy plus atezolizumab, 7 received platinum-based therapy plus durvalumab, 19 received lurbinectedin, and 25 received tarlatamab. Median OS with platinum-based chemotherapy and durvalumab or atezolizumab was 14.29 and 13.57 months, respectively. The ORR of tarlatamab and lurbinectedin were 47.6% and 52.6%. In 15 patients with DLL3-positive testing, the ORR to tarlatamab was 66.7% with a median of 70% of cells positive. Conclusions: This retrospective analysis supports the use of durvalumab, atezolizumab, lurbinectedin, and tarlatamab regimens in rare NENs other than SCLC. Larger observational trials should identify sequencing data and differences in OS between these regimens and among other commonly used treatments. Endpoint Total Number of Patients Outcome Median OS of platinum + etoposide + PD-L1 inhibitor (atezolizumab and durvalumab) Atezolizumab: 24Durvalumab: 7 Atezolizumab: 13.57 moDurvalumab: 14.29 mo ORR of tarlatamab 25 47.6%,95% CI: 41.7-84.8% ORR of tarlatamab if DLL3+ 15 (median DLL3 expression via IHC of 70%) 66.7%,95% CI: 41.7-84.8% ORR of lurbinectedin 19 52.6%,95% CI: 36-78.4% Median PFS of tarlatamab 25 3.29 mo,95% CI: 1.91-7.69 Median PFS of lurbinectedin 19 3.35 months,95% CI: 2.53-8.44 Median OS from first line systemic therapy of patients who received subsequent line tarlatamab versus any other subsequent line therapy Tarlatamab: n=25 Other therapy: n=29 Taralatamab: 14.88 mo,Other therapy: 12.55 mo,HR=0.79, p=0.42 Median OS from first line therapy of patients who received subsequent line lurbinectedin versus those who received any other subsequent line therapy Lurbinectedin: 19Other therapy: 14 Lurbinectedin: 12.88 mo,Other therapy: 12.87 mo,HR=0.98, p=0.97
Progress of phase II study of MVR-T3011, an IL-12/anti-PD-1 armed oncolytic HSV-1, in high-risk BCG-unresponsive CIS and papillary NMIBC.
4608 Background: MVR-T3011 is a novel Phase II oncolytic immunotherapy candidate based on herpes simplex virus type 1 (HSV-1). It combines potent tumor lysis with co-expression of anti-PD-1 antibody and IL-12. MVR-T3011 is being evaluated as monotherapy in patients with non-muscle invasive bladder cancer (NMIBC), including both BCG-unresponsive and BCG-naïve populations. Herein, we report the latest Phase II results of MVR-T3011 in BCG-unresponsive carcinoma in situ (CIS) and papillary NMIBC. Methods: In this ongoing trial, MVR-T3011 is administered intravesically in 50 mL without prewash. This simplified procedure utilizes the virus’s natural ability to bind to glycosaminoglycans (GAGs) on the urothelial surface as attachment receptors. Patients were assigned to two groups: 1) 2 × 10⁹ PFU, administered weekly for 12 weeks during the induction phase, followed by maintenance treatment every 2 weeks; 2) 1 × 10¹⁰ PFU, administered weekly for 6 weeks for induction, then every 3 weeks of treatment for maintenance. Both continued for up to 2 years. Efficacy was assessed every 3 months via cystoscopy, cytology, biopsy, and imaging. Primary endpoints were complete response rate (CRR) for CIS and recurrence-free survival (RFS) for papillary disease. The safety was fully evaluated. Results: As of Dec 31, 2025, a total of 43 patients were enrolled, 14 with CIS and 29 with Papillary. Among 13 evaluable CIS patients, 7 were treated at 2 × 10⁹ PFU dose level, achieving 6-month CRR of 71.4% (5/7), 3 patients maintained CR for 12 months, and 1 patient remained in CR for 18 months. 6 patients treated at 1 × 10¹⁰ PFU dose level, all achieved complete responses, with 100% CRR at 3 months (6/6), 6 months (5/5), and 9 months (3/3). Among 26 evaluable papillary patients, 16 were treated at the 2 × 10⁹ PFU dose level. The RFS rate was 80.8% (95% CI: 51.4–93.4) at 6 months, 74.0% (95% CI: 44.6–89.4) at both 12 and 15 months, and 64.8% (95% CI: 34.0–84.0) at both 18 and 21 months. 10 patients treated at 1 × 10¹⁰ PFU dose level, the 3-month and 6-month RFS rates were both 88.9%% (95% CI: 43.3–98.4). Assessment of the safety data revealed that most treatment-related adverse events (TRAEs) were grade 1. Common events included hematuria (25.0%), urinary tract infection (11.4%), proteinuria (9.1%), pollakiuria (6.8%), and rash (6.8%; immune-related). Only two grade 3 TRAEs were reported, both of which were urinary tract infections. No higher-grade TRAE or SAE occurred. Conclusions: MVR-T3011 is being evaluated as mono or combination therapy across multiple solid tumors. In this study, MVR-T3011 demonstrates suitability for intravesical administration, plus promising efficacy and a favorable safety profile. Durable complete responses were observed in CIS patients and encouraging 12-month RFS rates in papillary disease. These findings support its potential as a bladder-sparing option for BCG-unresponsive NMIBC. Clinical trial information: NCT06427291 .
Real-world efficacy and safety of neoadjuvant pembrolizumab in early-stage triple-negative breast cancer: A systematic review and meta-analysis.
e12638 Background: Neoadjuvant chemotherapy (NACT) has become the standard treatment for early-stage triple-negative breast cancer (TNBC), an aggressive form of cancer with poor prognosis. Although addition of the immune checkpoint inhibitor pembrolizumab to NACT regimens has improved response rates in clinical trials, its effectiveness in real-world practice has not been systematically explored. This systematic review and meta-analysis aimed to synthesize evidence regarding the efficacy and safety of adding neoadjuvant pembrolizumab in early-TNBC across real-world settings. Methods: We searched PubMed, Embase, Scopus, and Cochrane from inception to August 14, 2025 for prospective and retrospective cohorts comparing pembrolizumab plus NACT versus NACT alone in early-TNBC. RevMan version 5.4.1 was used to pool outcomes with a random-effects model. Results: Six studies were included (N = 1580, mean ages 34.3-57.8 years). Pembrolizumab significantly improved pathologic complete response (OR 2.30 [1.70–3.12], p < 0.00001) and event-free survival (OR 2.08 [1.24–3.50], p = 0.006), while reducing the odds of axillary lymph node dissection (OR 0.57 [0.42–0.79], p = 0.0008). No significant difference was observed in time to adjuvant therapy (MD -8.36 [-30.08, 13.36], p = 0.45) or overall post-operative complications (OR 0.86 [0.57–1.29], p = 0.47). Similarly, no significant differences were found in specific adverse events, including infection (OR 0.52 [0.17–1.55]), wound dehiscence (OR 0.86 [0.18–4.08]), seroma (OR 1.02 [0.59–1.78]), flap necrosis (OR 1.08 [0.46–2.52]), and bleeding (OR 0.37 [0.04–3.64]). Conclusions: Neoadjuvant pembrolizumab combined with chemotherapy significantly increases pCR rates and reduces axillary lymph-node dissections in early-stage TNBC, without introducing excess perioperative complications. These benefits suggest its potential for real-world use, though careful monitoring for side effects is essential.
Evaluation of ultrasensitive ddPCR and NGS for circulating tumor HPV DNA in minimal residual disease monitoring and lymph-node metastasis in cervical cancer: A prospective study.
e17511 Background: Circulating tumor HPV DNA (ctHPV) is emerging as a promising biomarker for minimal residual disease (MRD) in cervical cancer. Prospective studies investigating the association of ctHPV at diagnosis with primary tumor size and lymph node metastasis (LNM), as well as its potential for longitudinal MRD monitoring, are limited. Establishing a rapid and clinically feasible method for ctHPV quantification could improve early risk stratification and guide precision management strategies. Methods: Newly diagnosed HPV16/18-positive cervical cancer patients are being prospectively enrolled, with a planned cohort of 83 patients. 76 patients have been analyzed to date. ctHPV levels at diagnosis were quantified using droplet digital PCR (ddPCR) and next-generation sequencing (NGS). The concordance between ddPCR and NGS was evaluated using correlation analysis and Bland–Altman plots. Associations of ctHPV with LNM status and trends according to primary tumor size were analyzed. Post-treatment ctHPV measurements are ongoing, and patients will continue longitudinal follow-up to evaluate ctHPV dynamics and their potential association with treatment response and prognosis. Results: Analyses presented here include 76 patients from the ongoing prospective cohort. ctHPV was detectable at diagnosis in all patients. ddPCR showed high concordance with NGS, with Bland–Altman analysis demonstrating minimal bias, supporting its use as a rapid and clinically feasible quantification method. Patients with LNM exhibited higher ctHPV levels at diagnosis compared with those without LNM, and ctHPV levels increased with greater primary tumor size. These findings highlight the potential of ctHPV to reflect tumor burden and LNM status at diagnosis. Conclusions: ctHPV at diagnosis is associated with primary tumor size and lymph node metastasis in cervical cancer. ddPCR provides a rapid and reliable method for ctHPV quantification. Ongoing and future longitudinal analyses will explore ctHPV dynamics during treatment and follow-up as a marker for MRD and prognosis, supporting its potential clinical utility in prospective patient management. Circulating tumor HPV DNA (ctHPV) levels measured by ddPCR and NGS in the prospective cohort, showing stratified by lymph node metastasis and primary tumor size. Analysis/cohort N ddPCR log10 (ctHPV + 1) (copies/ml) NGS log10 (ctHPV + 1) (copies/ml) Mean difference (95% LoA) P Value (ddPCR) P Value (NGS) ddPCR/NGS concordance 76 2.091 ± 1.19 2.27 ± 1.29 -0.18 (-0.72 – 0.36) # - - LNM positive 37 2.58 ± 1.24 2.80 ± 1.41 - 0.0003 0.0003 LNM negative 39 1.63 ± 0.94 1.77 ± 0.93 - Tumor <= 2 cm 9 1.25 ± 0.91 1.46 ± 0.89 - 0.0002 * 0.0005 * Tumor 2 – 4 cm 21 1.57 ± 0.86 1.71 ± 0.79 - Tumor >= 4 cm 46 2.49 ± 1.20 2.69 ± 1.38 - #: Bland–Altman analysis; *: Linear trend was evaluated by polynomial contrasts in one-way ANOVA.