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Significance of marrow complete remission (mCR) in higher-risk MDS: A meta-regressive assessment of surrogate endpoint validity.
e18580 Background: mCR is frequently used in trials evaluating therapies for higher-risk MDS (HR MDS) as an indicator of treatment efficacy and is often incorporated into composite response endpoints. Although mCR increases response rates, evidence suggests that patients achieving mCR derive inconsistent benefit, and its association with improved overall survival (OS) remains unclear. If mCR lacks prognostic value, its inclusion in composite endpoints may overestimate treatment efficacy and misguide clinical interpretation, trial design, and regulatory decisions. We therefore evaluated the association between mCR and median OS (mOS) in prospective trials of hypomethylating agents (HMA) for HR MDS. Methods: PubMed and Embase were systematically searched from July 2006 through August 2025. We identified prospective phase I–III trials of HMA enrolling adults with HR MDS per IPSS/IPSS-R that reported mCR (IWG 2006) and survival outcomes. Retrospective studies, case series, conference abstracts, duplicate datasets, and post-transplant trials were excluded. Five reviewers independently screened 2,273 records in Covidence, with inclusion determined by consensus of ≥2. Data were abstracted in accordance with PRISMA guidelines. For studies lacking 95% CIs for mOS (n=2), individual patient data were reconstructed from Kaplan–Meier curves using the Guyot algorithm. Quantitative synthesis included random-effects meta-analysis (REma) of mOS and a primary mixed-effects meta-regression with random intercepts for study and treatment arm, evaluating the association between arm-level mCR proportion and mOS. An unadjusted random-effects meta-regression was performed as sensitivity. Results: Twelve trials (16 arms; 859 pts) were included (1,562 unique records; 105 full texts assessed). Across arms, mean mCR was 23.5% (SD, 12.5%). REma of 11 arms estimated a log-transformed pooled mOS of 12.8 months (I²=95.0%). Knapp–Hartung–adjusted, disease-setting estimates were 16.1 (frontline), 12.1 (mixed), and 8.9 months (relapsed/refractory, R/R). In the primary mixed-effects meta-regression (MR, final analytic dataset: 9 arms with complete mCR/mOS data), each 10% increase in mCR was associated with an estimated +1.02 months in mOS (95% CI, 0.30–2.16; P=.60; I²=97.7%), a non-significant association. In unadjusted MR, the estimate was +0.22 months per 10% mCR (95% CI, −0.49 to 0.93; P=.55; I²=98.2%). Covariate adjustments (R/R status, TP53 mt) attenuated effects and did not yield significance. Conclusions: Across trials, mCR did not demonstrate a robust association with longer mOS at the study-arm level. Apparent correlations were attenuated after adjustment for adverse biology and R/R status, suggesting that the relationship may reflect confounding rather than true surrogacy. Reliance on mCR risks overstating therapeutic benefit and misdirecting late-phase testing.
Early palliative care and symptom-directed care utilization in pancreatic cancer: A national Epic Cosmos analysis.
e24089 Background: Pancreatic cancer is associated with high symptom burden and frequent acute care utilization. Although early palliative care improves quality of life in advanced malignancies, real-world data describing its timing and downstream impact in pancreatic cancer remain limited. Methods: We conducted a retrospective cohort study using Epic Cosmos (2015–2025). Adults (≥18 years) with pancreatic cancer were identified using ICD-10 code C25.*. Early palliative care was defined as a documented palliative care encounter (ICD-10 Z51.5) within 0–2 months of cancer diagnosis. Patients were categorized as early palliative care versus not-early palliative care (late or no palliative care). A landmark approach was applied, with outcomes assessed beginning 2 months after diagnosis to mitigate immortal time bias. Outcomes included opioid use, antiemetic use, occupational/physical therapy (OT/PT) utilization, emergency department (ED) encounters resulting in inpatient admission, and inpatient length of stay. Results: Among 4,641 patients with pancreatic cancer, 464 (10.0%) received early palliative care, 365 (7.9%) received palliative care later, and 3,812 (82.1%) had no documented palliative care encounter. Compared with patients without early palliative care, early palliative care recipients demonstrated higher utilization of symptom-directed interventions, including opioids (40.6% vs 22.5%), antiemetics (37.2% vs 20.3%), and occupational/physical therapy services (6.2% vs 3.2%). Early palliative care was associated with a higher proportion of emergency department encounters resulting in inpatient admission (52.5% vs 23.6%), consistent with earlier consolidation of symptom-driven care. Mean inpatient length of stay was similar between groups (6.0 vs 6.2 days). Overall survival appeared comparable between groups; however, survival estimates in EHR-based analyses are limited by residual confounding and timing constraints. Conclusions: In a large national EHR cohort, early palliative care within two months of pancreatic cancer diagnosis was infrequently used but was associated with greater engagement in symptom-directed medications and supportive services, as well as a distinct downstream pattern of acute care utilization. These findings suggest that earlier integration of palliative care may improve coordination of symptom-focused care and represent an actionable quality-of-care target in pancreatic cancer.
Ocular toxicity of belantamab mafodotin-based combination regimens in multiple myeloma: A systematic review of phase I-III clinical trials.
e19578 Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate approved for relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone. However, ocular toxicity, manifesting as keratopathy and visual acuity decline, frequently leads to dose delays and treatment discontinuation. We conducted a systematic review to summarize the incidence, severity, reversibility, and clinical impact of ocular toxicity associated with belamaf-based combination regimens in multiple myeloma. Methods: PubMed, Embase, Cochrane, and major conference proceedings (ASCO, ASH) were searched through January 2026 to identify interventional trials evaluating belamaf-based combination regimens in multiple myeloma. Eligible phase I–III trials reporting ocular adverse events (OAEs) using trial-defined grading systems, such as the Keratopathy and Visual Acuity (KVA) scale, were included. Monotherapy trials were excluded. Given heterogeneity in regimens, dosing schedules, and outcome definitions, results were summarized descriptively. Results: Six belamaf-based combination trials (n = 689) met the inclusion criteria, including four RRMM studies (DREAMM-7, DREAMM-8, DREAMM-6, ALGONQUIN) and two newly diagnosed multiple myeloma (NDMM) studies (DREAMM-9, BelaRd). In the phase III RRMM trials DREAMM-7 and DREAMM-8, which used standard every-3-week dosing, KVA-assessed OAEs occurred in 84–87% of patients, with grade ≥3 OAEs in 70–74%. Approximately one-third of patients experienced a decline in vision to 20/50 or worse, though severe vision loss (20/200 or worse) was rare, affecting 1–2% of participants. Ocular toxicity was largely reversible, with improvement in 92–98% of patients and median resolution within 9–12 weeks. Treatment discontinuation due to ocular toxicity occurred in 9–10% of patients. Phase I/II RRMM combination studies demonstrated similar toxicity patterns with standard dosing. In contrast, NDMM phase I/II trials explored alternative dosing strategies. In the DREAMM-9 trial, grade ≥3 OAEs occurred in 53% of patients, with dose delays in 52% and dose reductions in 12%. In the BelaRd study, extended-interval dosing (every 8–12 weeks at 1.9 mg/kg) was associated with lower ocular toxicity, with grade 3–4 OAEs in 13.5% of ophthalmologic assessments, grade 3–4 keratopathy in 0.4%, and median resolution within 1–2 months. Conclusions: Ocular toxicity with belamaf-based combination regimens is common in RRMM but is largely reversible and infrequently leads to permanent treatment discontinuation. Early NDMM studies suggest that extended-interval and lower-intensity dosing may reduce ocular toxicity while maintaining clinical benefit. Further prospective research is needed to evaluate the ocular safety of belamaf in earlier-line myeloma settings.
SARC045: A phase 2 trial of tebentafusp in HLA-A*02:01–positive patients with advanced clear cell sarcoma.
TPS11591 Background: Tebentafusp (Kimmtrak) is a first-in-class bispecific T-cell engager, specifically a T-cell receptor (TCR)-anti-CD3 fusion protein, approved for HLA-A*02:01+ metastatic or unresectable uveal melanoma. Tebentafusp binds to the HLA-A02:01/gp100 peptide complexes on the tumour cell surface, recruiting polyclonal T cells, via CD3, to release cytokines and cytolytic mediators against the tumour. Clear cell sarcoma (CCS) is an ultra-rare soft-tissue sarcoma subtype with poor prognosis and limited therapeutic options. On histopathology, CCS is characterised by the expression of melanocytic antigens, including gp100. Methods: This Phase 2 trial evaluates the efficacy of Tebentafusp in HLA-A*02:01 positive patients with advanced CCS. Twenty-three patients will be treated with weekly I.V. infusion of Tebentafusp at the recommended dose until evidence of clinical benefit or patient withdrawal from study. Baseline and on-treatment biopsies, as well as longitudinal peripheral blood samples will be collected for translational analyses. Prospective data will also be collected from an observational non-comparative cohort of up to 24 patients with advanced CCS not eligible for the study due to incompatible HLA. Enrolment to the study has commenced in October 2025 in the US, with two currently active sites (Memorial Sloan Kettering Cancer Center and University of Southern California). One additional US site (Northwestern University) and one UK site (The Royal Marsden Hospital) are due to open. At the time of submission, 1 HLA-A*02:01 advanced CCS patient had started treatment with Tebentafusp. Clinical trial information: NCT06942442 .
Biology-informed predictive modeling and resistance monitoring in trastuzumab deruxtecan–treated metastatic breast cancer.
1023 Background: The antibody-drug conjugate (ADC), trastuzumab deruxtecan (T-DXd), produces meaningful responses in metastatic breast cancer (mBC), yet current biomarkers inadequately identify likely responders or elucidate resistance mechanisms. We developed a biology-informed survival model to predict T-DXd benefit in real-world data, assess treatment specificity, and characterize resistance evolution at time of progression. Methods: We analyzed RNA-seq and clinical outcomes from 150 de-identified T-DXd–treated mBC patients in the Tempus real-world multimodal database. Baseline expression profiles were embedded into biology-structured biomodules using a large molecular foundation model trained on over 1-million transcriptomes, capturing processes relevant to ADC activity: DNA damage response (DDR), intracellular trafficking, cellular stress adaptation, and tumor microenvironment signaling. These biomodules informed a survival model trained to predict T-DXd–specific clinical benefit. Predictive specificity was evaluated in a matched cohort of T-DXd–eligible mBC patients treated with taxane-based chemotherapy and HER2-targeting therapy. Longitudinal tumor profiling from 15 patients with progressive disease were analyzed to monitor resistance evolution. Results: The survival model predicted and identified biologically distinct benefit groups within the T-DXd cohort, with minimal separation observed in a control standard-of-care cohort, confirming treatment-specific predictive value (HR 2.22 [95% CI 1.14–4.35], p = 0.017). Predicted-benefit patients had longer rwTTNT (median=345 vs 245 days), and no prognostic signal appeared in control cohorts (C-index = 0.51), suggesting predictive specificity. Longitudinal analysis of progressed patients revealed reproducible biological shifts at progression, including attenuation of programs associated with effective ADC engagement and upregulation of adaptive stress-response pathways. These molecular transitions correlated with clinical deterioration and earlier transition to subsequent therapy. Conclusions: This study delineates the biology associated with durable T-DXd benefit and captures resistance evolution at progression in real-world patients. These findings highlight opportunities to refine patient selection and identify therapeutically actionable biology driving acquired resistance to T-DXd in the mBC setting.
Clinical validation of red blood cell DNA for early detection of advanced colorectal neoplasia: A single-center prospective observational case-control clinical trial.
3568 Background: Early detection of colorectal cancer (CRC) improves survival, but current screening is limited by poor colonoscopy compliance and low cfDNA sensitivity for early-stage lesions and advanced adenomas (AA). Beyond tumor shedding, solid tumors remotely disrupt bone marrow hematopoiesis, inducing systemic genomic instability in hematopoietic lineages. Leveraging this mechanism, we developed a noninvasive detection strategy using genome-wide profiling of DNA remnants in mature red blood cells (rbcDNA). We previously showed that tumor-induced IL-18/NR4A1 signaling drives locus-specific DNA damage in hematopoietic progenitors, generating rbcDNA signatures distinct from shedding-dependent cfDNA and enabling improved detection of early-stage cancer. Here, we report the first multicenter and prospective clinical validation of this rbcDNA-based assay for the detection of early colorectal neoplasia (NCT05875584). Methods: We enrolled 1,251 colonoscopy-confirmed participants (561 non-advanced neoplasia controls (non-AN), 330 AA, 360 CRC). Peripheral blood (1–2 mL) was collected from each participant, and rbcDNA was isolated and sequenced by low-coverage whole-genome sequencing (~2×), as previously described (PMID: 40341742). Participants were randomly assigned (8:2) to discovery and test cohorts. The discovery cohort was used for CRC- and AA-associated rbcDNA features identification and model development, while the test cohort was used for cutoff optimization. This locked model was externally validated in two independent cohorts. A prospective, observational case-control study was also conducted, in which blood and stool samples were collected simultaneously to compare the rbcDNA classifier with quantitative FIT (qFIT). Among 598 enrolled participants, 585 were included in the final analysis (299 non-AN, 206 AA, and 80 CRC). Results: At a predefined 90% specificity, the rbcDNA classifier achieved sensitivities of 85% for AA and 95% for CRC in the test cohort. Across two external cohorts, the assay consistently achieved 80% and 78% sensitivity for advanced colorectal neoplasia, 91% sensitivity for CRC in both cohorts, and 92% and 91% specificity. In the prospective study, rbcDNA yielded 90% sensitivity for CRC and 60% for AA at 90% specificity, with specificity remaining comparable in participants with non-neoplastic findings and non-advanced adenomas. Compared with qFIT, rbcDNA matched overall CRC sensitivity (90% vs. 88%) but outperformed it for stage I CRC (89% vs. 58%) and advanced adenomas (60% vs. 18%), including >50% of large sessile serrated lesions and tubular adenomas (≥1 cm) versus <15% by qFIT. Conclusions: This first prospective clinical study demonstrates that rbcDNA provides a highly sensitive, non-invasive approach for early colorectal neoplasia detection. Clinical trial information: NCT05875584 .
Patient-perceived caregiver burden after intense oncology treatment.
11104 Background: Although oncology caregiver burden is well-known (e.g. Alam, JCO , 2020), less is understood about how patients themselves perceive their caregivers’ quality of life (QOL) after intensive cancer treatment such as hematopoietic cell transplantation (HCT). Methods: Patients undergoing allogeneic HCT at Dana-Farber Cancer Institute (12/2017 to 12/2021) were surveyed approximately 100 and 180 days post-HCT. We utilized a questionnaire adapted from the Caregiver Quality of Life Index–Cancer Scale (Weitzner, Qual Life Res, 1999), redesigned to be administered to patients themselves. Caregiver stress was assessed with the question “My caregiver seems more stressed than before my transplant” (0: not at all to 4: very much), dichotomized into lower (0–2) versus higher (3–4) stress. Familial financial burden was measured with the question “How satisfied are you with your family’s present financial situation?” (1: not satisfied at all to 5: completely satisfied), dichotomized into higher (1-3) versus lower (4-5) burden. Paired McNemar tests assessed changes in caregiver stress between Day 100 and Day 180, and multivariable logistic regression modeled the relationship between financial burden and caregiver stress, adjusting for age and gender. Results: At Day 100 and Day 180, 165 and 142 patient surveys were analyzed (overall response rates were 60.5% and 70.0% among patients alive at each time); 89 patients completed surveys at both times. The mean age was 61.5, 38.2% were female, and 61.8% received reduced-intensity HCT conditioning. Most respondents (86.1%) identified their caregiver as a family member (as compared to a friend or paid professional). Approximately half reported their caregiver was working at both Day 100 (51.2%) and Day 180 (53.2%). The majority felt that the HCT process had not negatively impacted their relationship with their caregiver (93.3% at Day 100; 96.5% at Day 180). At Day 100, 30.9% of respondents perceived their caregiver as being more stressed than prior to HCT, compared with 33.3% at Day 180 (comparing the two time point proportions: χ 2 = 0.80, p = 0.37). Lower financial burden was significantly associated with lower odds of reporting increased caregiver stress at both Day 100 (OR = 0.49, 95% CI: 0.24-0.99) and at Day 180 (OR = 0.17, 95% CI: 0.07–0.39). Conclusions: In this cohort of patients undergoing intense oncology treatment, most had caregivers who were working family members. A minority perceived increased caregiver stress due to their treatment, with similar perceptions at both Day 100 and Day 180. This relatively modest perception of stress potentially reflects caregivers’ successful efforts to lower patients’ self-perceived burden. Moreover, lower familial financial burden was strongly protective against patient-perceived caregiver stress, particularly at Day 180, suggesting that financial circumstances meaningfully influence how patients interpret and perceive caregiver burden.
An RNA sequencing approach for isoform detection of DPEP1 in colorectal cancer and in vitro characterization of a novel isoform.
e15734 Background: Microsatellite stable colorectal cancer (CRC) is historically poorly responsive to immunotherapy, due in part to low neoantigen burden, an immunosuppressive tumor microenvironment, and poor T-cell infiltration. Dipeptidase-1 (DPEP1) is a GPI-anchored protein involved in glutathione and leukotriene metabolism and was identified as a part of a 4-gene immune cell exclusion signature associated with worse overall and progression free survival. Here we investigated the incidence and distribution of DPEP1 isoforms in data from The Cancer Genome Atlas (TCGA) and the in vitro properties of both isoforms. Methods: To determine the prevalence of DPEP1 Isoform B in human CRCs, we aligned TCGA Colon Adenocarcinoma (COAD) and Rectal Adenocarcinoma (READ) sample transcripts to the RefSeq (NCBI) genome database which has annotation of both DPEP1 isoforms. Murine CRC MC38 cells overexpressing human DPEP1 isoform A or isoform B were generated via lentiviral infection. The resulting cells underwent RNA sequencing followed by genome ontology and KEGG pathway over-representation analysis using the WebGestalt R package with FDR q-values ≤ 0.05. These DPEP1-expressing cells were injected into the tail veins of host mice to determine the effect of each isoform on metastasis, differences in means determined via Welch’s T-test. Results: Bulk RNA sequencing of 640 samples from 615 patients revealed DPEP1 A was found in 61% of CRC samples, while DPEP1 B was found in 91% of CRC samples, making DPEP1 B the predominant isoform. Furthermore, samples expressing high levels of DPEP1 B as compared to low or no expression, were associated with left-sided primary tumor location, MSS status, younger age at diagnosis, and no prior history of colon polyps. Transcriptional profiling revealed three distinct gene expression clusters that were correlated with DPEP1 isoform expression. Cluster one was associated with low to no DPEP1 A but high DPEP1 B. This cluster was enriched for non-coding RNAs and alternative spicing genes including RUNX1T1 and the small nuclear spliceosome RNAs. Cluster two was associated with high levels of both DPEP1 A and B expression. This was enriched for multiple G2/M cell cycle and Myc-associated genes. RNA sequencing revealed an upregulation in Myc-targets, EMT, and TNFα pathways in MC38 cells expressing isoform B. This expression of isoform B led to an increased metastatic burden in a mouse model compared to isoform A (p < 0.05). Conclusions: This marks the discovery of a novel isoform of DPEP1 that is upregulated in colorectal cancer patients. These data support the continued exploration of DPEP1 as a predictive biomarker for response to immune checkpoint inhibitors in MSS CRC as well as an emerging therapeutic target given its association with Myc and increased metastatic burden in preclinical models.
Lung cancer burden in AYAs: Global and U.S. trends.
8603 Background: Lung cancer remains a leading cause of cancer-related mortality and is increasingly observed among adolescents and young adults (AYA), with shifting tobacco use and rising air pollution implicated as potential risk factors. This study examines global and U.S. epidemiological and risk factor trends of tracheal, bronchial, and lung cancer (TBLC) in AYA population (20-54 years). Methods: We utilized Global Burden of Disease database (1990-2023) for TBLC, to extract Age Specific incidence (ASIR) and mortality rates (ASMR), as well as proportional and absolute ASMRs associated with all risk factors, tobacco use and ambient particulate matter (PM2.5). Joinpoint analysis assessed changes in trends and calculated EAPC (Estimated Annual Percentage Changes). All rates are reported per 100,000 population. Results: In 2023, the global ASIR of TBLC among AYAs was 8.69 (n = 167,524) in males and 4.70 (n = 88,569) in females, with absolute incidence increasing by 13% in males and 50% in females. Absolute mortality similarly increased by 9% in males and 39% in females, with ASMRs of 6.99 and 3.52, respectively in 2023. In US, while overall incidence and mortality declined, ASIR in 2023 for females (0.62) was found to be almost similar to males (0.64), whereas ASMR remained higher in males (0.49) than females (0.43). At global level, tobacco remained the leading ASMR contributor in 2023, with higher burden in males (males 4.8, 68.2%; females 1.1, 31%), followed by PM2.5 (males 1.1, 20.5%, females 0.5, 20.8%). No TBLC-related mortality was attributed to household air pollution in 2023. The most significant decline in tobacco- and PM2.5–associated TBLC mortality in males occurred from 2003 to 2020 (tobacco: EAPC −2.66; PM2.5: 2006-2017: EAPC −0.76), and in females between 2008 to 2021 (tobacco: EAPC −3.5, PM2.5: 2017-2020: EAPC -4.8). By 2023, 18.8% of male and 43.1% of female TBLC deaths had no identified risk factors. In the US, ASMR declined continuously across all risk factors in both sexes, and by 2023, 25.4% of male and 32.0% of female TBLC deaths had no identified associated risk factors. Despite overall reductions in ASIR and ASMR globally and in USA, Mortality to Incidence ratio remained largely stable, with only minimal decreases observed globally (males −3.6%, females −7.5%) and in the US (males −2.3%, females −5.8%). Conclusions: Our analysis demonstrated an absolute increase in TBLC incidence and mortality globally in both sexes, with males continuing to experience higher mortality. In the USA, the sex-based gap in ASIR has nearly disappeared. Although tobacco-related mortality declined, it remained the leading risk factor. By 2023, 20–25% of AYA males and 30–43% of AYA females TBLC deaths were attributable to non-modifiable risk factors, highlighting the need for screening guidelines that better address AYAs, particularly those without traditional risk factors.
Clinical impact of genomic co-mutation profiles including TP53 in resected early-stage <i>EGFR</i> -mutated NSCLC: LC-SCRUM-Advantage.
8035 Background: Adjuvant osimertinib is the standard of care for resected stage IB–IIIA EGFR-mutated non-small cell lung cancer (NSCLC), and its benefit in stage IA2–IA3 disease is being evaluated in ADAURA2. However, the prognostic impact of genomic co-alterations, particularly TP53, in early-stage EGFR-mutated NSCLC remains unclear. This study characterized genomic co-alterations and their association with clinicopathologic features in resected early-stage EGFR-mutated NSCLC. Methods: LC-SCRUM-Advantage is a prospective genomic screening program for resected NSCLC. Postoperative tumor specimens were analyzed using the Oncomine Precision Assay to identify co-alterations, including TP53 and other recurrent genes, across major EGFR mutation subtypes. PD-L1 expression was assessed by immunohistochemistry. Clinico-genomic characteristics and survival outcomes were evaluated. Results: Among 1052 enrolled patients, 327 had EGFR-mutated adenocarcinoma (19del 42%, L858R 47%, others 11%). Among tumors with common EGFR mutations, single EGFR alterations accounted for 59%, while co-alterations were detected in 41%. Frequent co-alterations included TP53 (19%), CTNNB1 (4%), PIK3CA (4%), additional EGFR mutations (5%), and EGFR amplification (12%). Co-alteration prevalence increased with pathological stage (IA1 25%, IA2–IA3 41%, IB 53%, II 47%, III 46%), with TP53 showing a similar pattern (IA1 8%, IA2–IA3 18%, IB 19%, II 28%, III 27%). PD-L1 positivity also increased progressively with disease stage (I 37%, II 52%, III 73%; p = 0.0002). TP53-mutated tumors showed a significantly higher PD-L1 positivity rate than TP53 wild-type tumors (60% vs. 39%; p = 0.007). Co-alteration frequencies were comparable across EGFR subtypes. With limited follow-up, five recurrences were observed (IB 1, IIA 1, IIIA 2, IVA 1); three involved co-alterations (TP53, EGFR amplification, EGFR E709V). Conclusions: Genomic co-alterations, including TP53, were common and increased with pathological stage in early-stage EGFR-mutated NSCLC. Co-altered tumors exhibited features associated with aggressive biology, including higher PD-L1 expression. Early recurrences were frequently observed in patients with co-alterations, underscoring their potential prognostic relevance. These findings highlight substantial molecular heterogeneity within early-stage EGFR-mutated NSCLC and support incorporating co-alteration status into risk stratification and adjuvant treatment planning. Ongoing follow-up from this study will further clarify the prognostic and predictive significance of co-alterations, particularly regarding their implications for adjuvant targeted therapy.
STARS (NCT 07265661): Surgical timing after preoperative hypofractionated radiotherapy for patients with primary localized soft tissue sarcoma of the extremity and trunk—A randomized phase 2 clinical trial.
TPS11597 Background: Local management paradigm for localised soft tissue sarcoma of the extremities and trunk (ESTS) has remained relatively stable, due to the excellent outcomes associated with preoperative radiotherapy combined with limb-sparing surgery. Conventional regimens (50 Gy in 25 fractions) are effective but time-intensive and resource-demanding. Ultra-hypofractionated radiotherapy (HFRT) has emerged as a promising strategy, with comparable oncological outcomes, in preliminary retrospective analyses, prospective cohorts, and Phase II non-randomised trials. However, the optimal interval between HFRT and surgery remains undefined. Methods: STARS is a national, multicenter, phase II, randomized, non-inferiority trial promoted by a co-sponsorship between the Italian Sarcoma Group and the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (NCT07265661). Patients with localised, resectable ESTS scheduled for combined radiotherapy and surgery are randomized 1:1 to receive preoperative HFRT (30 Gy in 5 fractions) followed by surgery at either 1–2 weeks (Arm A) or 4–6 weeks (Arm B). Randomization is stratified by tumor size, depth, site, and comorbidities. The primary endpoint is the incidence of postoperative complications (Clavien–Dindo, any grade) within 90 days. Secondary endpoints include quality of life and patient satisfaction, oncologic outcomes (local recurrence, distant metastasis, disease-free and overall survival), pathological and radiological response, treatment-related toxicity, nutritional status, and economic impact. A concurrent observational cohort will capture outcomes of patients treated with standard approaches (surgery with/without standard radiotherapy). Statistical Design: A total of 142 patients (71 per arm) will be enrolled to test non-inferiority, assuming a 35% postoperative complication rate and a non-inferiority margin of 15% (one-sided α=0.05; power 80%). Approximately 30 additional patients are expected in the observational cohort. Significance: STARS is the first randomized trial specifically designed to address surgical timing following HFRT in ESTS. The study is conducted within a novel co-sponsorship framework involving a national academic tertiary cancer center (Fondazione IRCCS Istituto Nazionale dei Tumori) and the leading non-profit cooperative group for rare cancers in Italy (Italian Sarcoma Group), establishing a sustainable platform for high-quality clinical research in rare diseases. By defining the safest and most effective interval between HFRT and surgery, this trial aims to optimize perioperative outcomes while enabling a shorter, patient-centered, and resource-efficient treatment pathway, informing future standards of care and guideline recommendations for localised ESTS. Clinical trial information: NCT 07265661 .
Clinical-genomic discordance and chemotherapy (CT) outcomes in early-stage HR+/HER2– invasive lobular carcinoma.
e12531 Background: Invasive lobular cancer (ILC) is biologically and clinically distinct from invasive ductal carcinoma (IDC). Prior studies evaluating CT benefit across these histologic subtypes yielded conflicting results, highlighting a knowledge gap. We studied the impact of adjuvant CT on overall survival (OS) and identified factors associated with CT receipt in patients (pts) with early-stage HR+/HER2– ILC and IDC. Methods: Data was obtained from the National Cancer Database for pts who had surgical resection of ILC or IDC of the breast between 2010 and 2021. Subgroup analyses were conducted by CT receipt, Oncotype DX Recurrence Score (RS) (low (L) 0–15, intermediate (I)16–25, high (H) ≥26) and menopausal status, with age (< 50 vs ≥50 years) used as a proxy. Overlap propensity score weighting (OPSW) balanced confounding factors (race, ethnicity, T and N stage, grade (G), and use of radiation and hormone therapies), and OPSW Cox proportional hazard models assessed the association between ILC vs IDC and OS. Results: Of the total 954,934 pts, 15% had ILC. ILC cohort had more G2 tumors (63.5 vs 49.1%), postmenopausal pts (88.4 vs 84.5%), higher clinical T stage (T2: 25.3 vs 18.7%, T3: 5.7 vs 1.2%), and node-positive disease (N1-3: 6.9 vs 6.1%). RS testing was available in 38% of pts: ILC had higher rates of L (19.4 vs 19.2) and I (16.3 vs 13.0) RS, whereas IDC had more H RS (6.0 vs 2.9), all p < 0.001. Among pts who received CT (n = 196,829), 14.2% had ILC. In this cohort, ILC pts had more G1 (23.1 vs 14.2%) and G2 (68.2 vs 47.7%) tumors, higher T stage (T2: 39.4 vs 36.3%; T3: 14.9 vs 3.0%), and nodal involvement (N1-3: 21.9 vs 18.0%) and more were postmenopausal pts (78.2 vs 69.5%). ILC pts who received CT had higher rates of L (4.3 vs 2.9), I (11.1 vs 10.3), and unknown (75.4 vs 65.6) RS, while IDC pts had higher rates of H RS (21.2 vs 9.2), all p < 0.001. ILC pts who received CT had higher mortality compared to IDC (aHR 1.20, 1.16–1.25). Univariate 10-year OS was higher for ILC (Table 1). However, ILC pts with I (aHR 1.23, 1.06–1.43) and unknown RS (aHR 1.22, 1.17–1.27) had higher mortality compared to IDC. No OS difference was observed in low (p = 0.76) or high (p = 0.92) RS groups. Among postmenopausal pts, OS differences were observed in I (aHR 1.21, 1.03–1.42) and unknown RS (aHR 1.22, 1.17–1.27). Among premenopausal pts, the difference was observed only in unknown RS (aHR 1.28, 1.15–1.43). Conclusions: We observed a discordance between clinical and genomic risk in ILC, with ILC pts presenting with higher clinical risk but low or unknown RS. CT decisions appeared driven more by clinicopathologic factors than RS suggesting that existing recurrence prediction models may not reliably predict outcomes in ILC, highlighting the need for new individualized treatment strategies. 10-year OS of ILC vs IDC pts who received adjuvant CT. RS groups ILC OS (%) IDC OS (%) p-value Overall cohort 76.2 81.8 <0.01 L 88.3 88.8 0.76 I 87.0 89.3 0.01 H 80.8 80.6 0.92
Pemivibart for prevention of COVID-19: Subset analysis of CANOPY participants with solid tumor or hematologic malignancies.
2522 Background: Due to the chronic immunosuppression associated with both their condition and treatments, patients with solid tumors or hematologic malignancies experience reduced vaccine protection and are at high risk of infections, including COVID-19. This post hoc analysis of the phase 3 CANOPY study assesses the safety and outcomes of pemivibart in the oncology subset from the open-label, single-arm, immunocompromised Cohort A. Methods: Cohort A dosing: 4500 mg of pemivibart (intravenous) on day 1; 2 nd dose at month 3. Primary objectives: 1) Evaluation of pemivibart safety and tolerability via study drug-related treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment interruption/discontinuation, 2) Evaluation of protection against symptomatic COVID-19 based on sVNA titers against SARS-CoV-2 after receiving pemivibart. Exploratory endpoint: composite incidence of RT-PCR-confirmed symptomatic COVID-19, including COVID-19-related hospitalization and all-cause mortality. Data were analyzed through Month 6. Results: Enrollment began in Sep 2023. The oncology subset included 55 (18.0%) Cohort A participants; median age [range] 65 [35-83] years; 25 (45.5%) female. Eight participants (14.5%) were receiving immunosuppressants, including 6 (10.9%) receiving corticosteroids. Prior to enrollment, 89.1% received ≥1 COVID-19 vaccine; seropositivity: N antigens (43.6%), S antigens (98.2%). Month 6 TEAEs were reported in 32 (58.2%) participants; 5 (9.1%) were considered study drug-related with 1 (1.8%) requiring treatment interruption due to infusion site extravasation and tachycardia (Table). SAEs occurred in 5 (9.1%) participants; none were considered drug-related. Following pemivibart dosing, sVNA titers in the oncology subset were elevated to levels associated with protection against COVID-19 and comparable with Cohort A. No anaphylaxis was reported in the oncology subset; 4 cases among 306 participants in Cohort A. Through Month 6, there was no RT-PCR-confirmed symptomatic COVID-19 in the oncology subset; with 9/298 (3.0%) in Cohort A. Conclusions: Pemivibart was well tolerated in the CANOPY Cohort A oncology subset. These data showed limited events overall and no development of symptomatic COVID-19 in the oncology subset through Month 6. Clinical trial information: NCT06039449 . Select outcomes through month 6. Parameter Immunocompromised Cohort A Cohort A Oncology Subset a Study drug-related TEAE, n (%) - Leading to death - Leading to interruption - Leading to discontinuation 34/306 (11.1)0/306 (0)14/306 (4.6)7/306 (2.3) 5/55 (9.1)0/55 (0)1/55 (1.8)0/55 (0) COVID-19 composite event, n (%)PCR-confirmed COVID-19, n (%)All-cause mortality, n (%) 11/298 (3.7)9/298 (3.0)2/298 (0.7) 1/55 (1.8)0/55(0)1/55 (1.8) b a 20 (36%) were being actively treated for solid tumor or hematologic malignancy; 40 (73%) had a hematologic malignancy. b Unrelated to study drug.
Temporal trends in metabolic syndrome–associated mortality among patients with upper gastrointestinal cancers, 1999–2020: A CDC WONDER analysis.
e16062 Background: Upper gastrointestinal (UGI) cancers remain a major cause of cancer mortality in the United States. Metabolic disorders, including diabetes, obesity, dyslipidemia, and hypertension, may worsen prognosis and contribute to disparities in outcomes. However, national mortality trends assessing UGI cancer deaths in the context of metabolic comorbidities are not wellcharacterized. Methods: A retrospective population-based analysis was conducted using the CDC WONDER Multiple Cause of Death database (1999–2020). Deaths with oesophageal or gastric cancer as the underlying cause and metabolic disorders as contributing causes were included. Age-adjusted mortality rates (AAMRs) per 100,000 population and annual percent change (APC) were calculated. Joinpoint regression was done and analyses were stratified by age, sex, race/ethnicity, urbanisation, and state. Results: From 1999 to 2020, 45,086 deaths occurred among adults with UGI cancers and metabolic comorbidities. Overall AAMRs increased from 2.0 to 4.2 per 100,000, with a significant rise from 1999 to 2009 (APC 4.30%; 95% CI, 2.97–5.56; p < 0.01), a modest decline from 2009 to 2014 (APC −3.50%; 95% CI, −7.45 to 0.61; p = 0.08), and a sharp increase from 2014 to 2020 (APC 6.44%; 95% CI, 4.35–8.57; p < 0.01). Age-stratified analysis demonstrated the highest crude mortality among adults aged ≥85 years (5.2 to 9.3; APC 0.55%; 95% CI, 0.03–1.08; p = 0.03) and the lowest among those aged 45–54 years (0.1 to 0.3; APC 3.53%; 95% CI, 2.06–5.02; p < 0.01). Males consistently exhibited higher mortality than females (overall AAMR 1.7 vs. 1.0), with significant increases among males from 1999–2006 (APC 5.95%; 95% CI, 3.60–8.35; p < 0.01) and 2017–2020 (APC 7.46%; 95% CI, 2.19–13.00; p < 0.01). Racial disparities were observed, with the highest AAMR among Non-Hispanic (NH) Black individuals (3.0), followed by Hispanics (2.2; APC 1.36%; 95% CI, 0.71–2.01; p < 0.01), NH Asian or Pacific Islanders (2.0; APC −0.47%; 95% CI, −1.39 to 0.45; p = 0.29), and NH Whites (1.6; APC 5.43%; 95% CI, 3.11–7.81; p < 0.01). By urbanisation, micropolitan areas demonstrated the highest AAMR (2.0; APC 2.46%; 95% CI, 1.81–3.11; p < 0.01), followed by large metropolitan and non-core areas (1.9 each), while large fringe metropolitan areas had the lowest AAMR (1.5). The District of Columbia (2.7), Mississippi (2.6), California (2.5), Hawaii (2.5), Nebraska (2.5), and Ohio (2.5) had state-level AAMRs above the 90th percentile (≥2.49 per 100,000). Conclusions: UGI cancer mortality associated with metabolic comorbidities increased substantially from 1999 to 2020, with pronounced disparities by age, sex, race, urbanization, and state. These findings underscore the need for targeted prevention strategies addressing metabolic health and geographic inequities to reduce UGI cancer mortality.
Mechanical ventilation timing categories and inpatient outcomes in adult cancer hospitalizations: A 2018–2022 National Inpatient Sample analysis.
e23095 Background: Mechanical ventilation (MV) during cancer hospitalizations is commonly evaluated as a binary event, potentially obscuring heterogeneity in escalation trajectories. The association between length-of-stay–based MV timing categories and distinct inpatient patterns of severity and resource intensity among hospitalized adults with malignancy was examined. Methods: We performed a serial cross-sectional analysis of adult hospitalizations with a principal diagnosis of malignancy in the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample. MV was identified using ICD-10-PCS procedure codes and categorized as no MV, early MV (LOS ≤3 days), intermediate MV (LOS 4–9 days), or late MV (LOS ≥10 days) as an administrative timing proxy. Outcomes included in-hospital mortality (primary), shock and dialysis-requiring acute kidney injury as escalation-associated endpoints, LOS, hospitalization cost derived using cost-to-charge ratios, and APR-DRG severity of illness subclass. National estimates were generated using survey-weighted analyses incorporating discharge weights with hospital-level clustering and stratification. Results: Among an estimated 4,809,239 cancer hospitalizations nationally, MV occurred in 2.6% of admissions, distributed as 0.31% early MV, 0.70% intermediate MV, and 1.58% late MV. Mortality differed markedly by MV timing: 3.40% among non-ventilated admissions versus 66.65% for early MV, 42.80% for intermediate MV, and 35.47% for late MV. Early MV corresponded to a rapid escalation trajectory with very short LOS (1.84 days), high APR-DRG severity (3.74), and high shock prevalence (25.36%). Intermediate MV admissions had LOS similar to non-ventilated admissions (6.53 vs 6.52 days) but substantially higher mortality (42.80% vs 3.40%), higher shock prevalence (17.82%), and higher mean costs ($42,394 vs $28,448). Late MV corresponded to prolonged critical illness with extreme resource utilization, including LOS of 25.89 days and mean cost of $132,530; late MV admissions had the highest dialysis-requiring acute kidney injury prevalence (10.25%) and the highest APR-DRG severity (3.89). Conclusions: LOS-defined MV timing categories group adult cancer hospitalizations into distinct escalation-associated trajectories with large differences in mortality, severity, and resource intensity. Timing-based MV gives an insight into cancer patients’ hospital course and will aid in future research into prognosis of hospitalized cancer patients.
The efficacy of polatuzumab vedotin targeting CD79B in the treatment of non-Hodgkin lymphoma: A systematic review and meta-analysis.
e19085 Background: Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of lymphoid malignancies with a substantial proportion of patients developing relapsed or refractory disease despite standard immunochemotherapy. Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, has emerged as a novel therapeutic option aimed at improving response and survival outcomes in this high-risk population. However, variability in reported efficacy and safety across studies necessitates a comprehensive synthesis of available evidence. This systematic review and meta-analysis evaluates the effectiveness and safety of Polatuzumab based regimens in patients with NHL. Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. A systematic search of PubMed, EMBASE, and Web of Science identified studies published up to January 2026 comparing Polatuzumab-based therapy with control regimens in NHL. Fifteen eligible studies were included. Outcomes assessed were complete response (CR) rates, progression-free survival (PFS), overall survival (OS), and adverse events including neutropenia, fatigue, and diarrhea. Meta-analysis was performed using common-and random-effects models, with pooled risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes. Results: Fifteen studies encompassing a total of 2553 patients (1298 Polatuzumab; 1255 control) were included. Polatuzumab based therapy significantly improved complete response rates compared with control (RR 1.29; 95% CI 1.01–1.64). Progression-free survival was significantly prolonged (MD 4.16 months; 95% CI 1.22–7.10). Overall survival showed no statistically significant difference between groups (RR 1.27; 95% CI 0.69–2.32). Among adverse events, neutropenia rates were comparable (RR 1.08; 95% CI 0.79–1.46), while fatigue showed no significant increase (RR 3.73; 95% CI 0.22–62.12). Diarrhea occurred more frequently with Polatuzumab-based therapy (RR 2.31; 95% CI 0.85–6.31). Conclusions: Polatuzumab vedotin-based therapy significantly improves complete response rates and progression-free survival in patients with Non-Hodgkin lymphoma without a corresponding increase in overall mortality. While gastrointestinal toxicity warrants attention, the overall safety profile remains acceptable. These findings support Polatuzumab vedotin as an effective targeted therapeutic strategy in the management of relapsed or refractory NHL.
Clinical outcomes of febrile neutropenia with colony stimulating factors: A multicenter retrospective analysis.
e24141 Background: Patients with solid and hematologic malignancies receiving cytotoxic chemotherapy are vulnerable to febrile neutropenia (FN), a high-risk complication that often necessitates hospitalization and can lead to treatment delays, morbidity, or death. Granulocyte colony-stimulating factor (G-CSF) is often used for prevention of FN, however its benefits in treatment of hospitalized patients with FN are not well understood. Methods: We performed a retrospective cohort analysis using de-identified patient data from the HCA healthcare national database from 2016 to 2022. Adult patients hospitalized with FN and diagnosis of a hematologic or solid malignancy were included. Patients were stratified by inpatient G-CSF use, and propensity matched using the Van Walraven score. Primary outcomes include hospital length of stay and time to neutrophil recovery. Secondary outcomes include inpatient mortality. Results: Among 2,065 patients, 90 (4.4%) received inpatient G-CSF. G-CSF use was associated with a shorter median hospital length of stay (8 versus 12 days, p-value: <0.01 [95% CI:0.66-0.91]) and faster neutrophil recovery (4 versus 5 days, p-value: <0.01 [95% CI: 0.97-0.98]). There was no significant difference in inpatient mortality. Conclusions: The aim of this retrospective study was to evaluate the clinical outcomes of G-CSF administration to hospitalized patients with FN. G-CSF use in hospitalized patients with FN significantly reduced neutrophil count recovery time (4 versus 5 days) and decreased length of hospitalization (8 versus 12 days), suggesting a benefit of G-CSF in select hospitalized populations with FN. Our findings complement previous research study findings by underlining that there is a significant decrease in length of hospitalization when using G-CSF compared to the control group. Such findings can help inform current guidelines regarding the use of G-CSF as secondary prophylaxis in hospitalized patients with febrile neutropenia. Negative binomial regression for days to recovery and hospital length of stay. Days to Recovery 1 IRR 95% Confidence Interval p-value G-CSF 0.98 0.97 0.98 <0.01 Hospital Length of Stay 2 IRR 95% Confidence Interval p-value G-CSF 0.87 0.66 0.91 <0.01 1: The incidence rate ratio (IRR) of patients receiving G-CSF was 0.98 (CI: 0.97-0.98, p-value: <0.01), indicating a statistically significant difference in days to recovery between the group that received G-CSF and the non-G-CSF group. 2: The incidence rate ratio (IRR) of patients receiving G-CSF was 0.78 (CI: 0.66-0.91, p-value of <0.01), indicating a statistically significant difference in length of hospital stay between the groups that received G-CSF and the non-G-CSF group.
The presentation of brain metastases by breast cancer subtype and potential implications for surveillance brain MRIs.
e13101 Background: As systemic therapy improves, the prevalence of breast cancer brain metastases(BCBM) is increasing. Current National Comprehensive Cancer Network(NCCN) guidelines do not recommend breast cancer brain MRI surveillance unless suspicious central nervous system(CNS) symptoms are present. We sought to understand the presentation and outcomes of BCBM by subtype. Methods: Breast cancer patients who developed brain metastases(BM) at our institution between 2015 and 2025 were identified. Details of initial presentation, treatments delivered and overall survival(OS) were assessed. Kruskal-Wallis and Pearsons's chi-square tests were used to test differences between subtypes. OS was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis (MVA) to identify variables prognostic for OS. Results: A total of 426 patients were identified including 176(41%) hormone receptor (HR)+/HER2-, 133(31%) HER2+, and 117(27%) triple negative (TN). HER2+ patients were younger at initial presentation (HER2+ median age: 55, TN: 56, HR+/HER2-: 57, p = 0.03). TN patients had the shortest interval from stage IV diagnosis to BM diagnosis (TN median: 10.4 months, HER2+:12.6 months, and HR+/HER2-: 16 months, p = 0.0005) and cancer diagnosis to BM diagnosis (TN median: 26.8 months, HER2+: 27.8 months, and HR+/HER2-: 54.7 months, p < 0.0001). The median lines of therapy in the stage IV setting at BM diagnosis were HER2+:1, TN:2, and HR+/HER2-:3, p < 0.0001. TN patients were most likely to present without evidence of systemic metastases (TN:25.6%, HER2+:19.6% and HR+/HER2-:13.1%, p = 0.02). TN patients were less likely to have liver metastases at the time of their diagnosis (TN:19%, HER2+:44% and HR+/HER2-:44%, p < 0.0001). TN patients were more likely to undergo surgical resection at the time of their BM diagnosis(TN: 28%, HER2+:22%, HR+/HER2-:16%, p = 0.05) while HER2+ patients were more likely to present with > 20 BM at diagnosis (HER2+:21%, TN:11%, HR+/HER2-:10%, p = 0.04). Median OS following BM diagnosis was 38.1, 11.6 and 9.1 months, p < 0.0001, for HER2+, HR+/HER2- and TN subtypes. On MVA, TN subtype(p < 0.0001), presence of leptomeningeal disease(p = 0.0007), presence of > 20 BM(p = 0.0013), > 2 lines of systemic therapy (p < 0.0001), and symptomatic intracranial presentation(p = 0.004) were significant for worse OS following BM diagnosis. Conclusions: Our institutional analysis found significant differences in presentation of brain metastases by breast cancer subtypes, with TN patients presenting earlier in their diagnosis and undergoing surgical resection more commonly. On MVA, > 20 brain metastases, leptomeningeal disease, and symptomatic presentation predicted for worse OS. These findings potentially support early brain MRI surveillance to facilitate detection.
Venous thromboembolism in gynecologic malignancies as a chronic vascular disease: A systematic review and meta-analysis of extended risk during first-line therapy in advanced epithelial ovarian cancer.
e17609 Background: Venous thromboembolism (VTE) is a frequent and clinically significant complication of gynecologic malignancies, particularly epithelial ovarian cancer (EOC). Current clinical practice largely conceptualizes cancer-associated VTE as an acute perioperative or treatment-related event, with preventive strategies focused on short-term postoperative prophylaxis. However, emerging cohort-level evidence suggests that thrombotic risk in EOC may persist across the entire first-line treatment continuum, including diagnosis, systemic therapy, surgery, and early surveillance. This pattern supports reframing VTE as a chronic vascular disease process rather than a discrete acute complication. Methods: A targeted systematic search identified cohort studies reporting VTE incidence during first-line therapy in advanced EOC, including fallopian tube and primary peritoneal cancers. Eligible studies captured events anchored to diagnosis and/or surgery with follow-up extending to ≥6 months. Cumulative incidence and event counts were extracted where available. Random-effects meta-analysis of VTE incidence was performed using logit transformation. Results: Three advanced EOC cohorts provided extractable data. Postoperative cumulative VTE incidence was 13.8% by 6 months following primary debulking surgery (N=860). Another cohort reported a cumulative VTE incidence of 6.1% within 6 months of diagnosis (N=230), with events occurring across diagnosis, neoadjuvant chemotherapy, and postoperative phases, and additional VTE events beyond 6 months (3.9%). A third cohort observed a 12.5% VTE incidence during frontline adjuvant chemotherapy (16/128). The pooled random-effects VTE incidence across cohorts was 10.3% (95% CI 5.9–17.2), with substantial heterogeneity (I² ≈ 88%), reflecting differences in prophylaxis strategies and time anchoring. Conclusions: In advanced epithelial ovarian cancer, VTE risk is substantial throughout first-line therapy and is not limited to the perioperative period. The occurrence of thrombotic events beyond 6 months in at least one cohort supports conceptualizing cancer-associated VTE as a chronic vascular disease. These findings underscore the need for extended risk stratification and longitudinal surveillance strategies and motivate prospective studies evaluating prevention beyond standard postoperative prophylaxis windows.
Diverging trends in head and neck cancer incidence: SEER 17 analysis of HPV-related and non–HPV-related sites, 2000–2019.
e22584 Background: Population-based evidence suggests divergent incidence patterns for head and neck squamous cell carcinoma (HNSCC) at HPV-related versus non–HPV-related sites, but contemporary estimates spanning both groups are limited. Methods: We analyzed SEER Research Plus 17 registries (November 2024 submission), diagnosis years 2000–2019. HNSCC was restricted to squamous histology (ICD-O-3 8050–8084). HPV-related HNC was defined by oropharyngeal subsites (base of tongue, tonsil, soft palate, oropharynx, Waldeyer’s ring) as a site-based proxy; non–HPV-related HNC comprised oral cavity, hypopharyngeal, and laryngeal subsites. Age-adjusted incidence rates (per 100,000; 2000 U.S. standard) were calculated overall and by sex and age group. Average annual percent change (AAPC) with 95% CIs summarized 2000–2019 trends. Results: Overall HNC incidence declined modestly from 11.5 (8,011 cases) in 2000 to 10.5 (11,074 cases) in 2019 (AAPC −0.6; 95% CI −0.7 to −0.4). HPV-related HNC increased from 3.3 (2,323 cases) to 4.4 (4,694 cases) (AAPC 1.5; 95% CI 1.1 to 1.8), while non–HPV-related HNC decreased from 9.3 to 7.7 (AAPC −1.1; 95% CI −1.2 to −0.9). Among men, HPV-related HNC rose from 5.4 (1,766 cases) to 7.7 (3,933 cases) (AAPC 1.7; 95% CI 1.1 to 2.2), with the steepest increases at ages 60–69 (AAPC 2.6) and ≥70 (AAPC 3.0). The proportion of all HNCs that were HPV-related increased from ~29% (2000) to 42% (2019). Conclusions: From 2000–2019, overall HNC incidence decreased slightly in SEER 17, but HPV-related (oropharyngeal-proxy) HNC increased, most notably among older men, while non–HPV-related sites declined. Because HPV-related disease was defined by anatomic proxy rather than tumor HPV status, findings should be interpreted as site-based trend divergence. Results support sustaining tobacco/alcohol control while maintaining high HPV vaccination coverage and monitoring HPV-related HNC burden over time. Overall incidence trends in head and neck cancer, HPV-related (oropharyngeal-proxy), and non–HPV-related sites in SEER 17, 2000–2019. Outcome group Incidence rate, 2000 (cases) Incidence rate, 2019 (cases) AAPC, 2000–2019 (95% CI) All HNC 11.5 (8,011) 10.5 (11,074) −0.6 (−0.7 to −0.4) HPV-related HNC (oropharyngeal proxy) 3.3 (2,323) 4.4 (4,694) 1.5 (1.1 to 1.8) Non–HPV-related HNC 9.3 7.7 −1.1 (−1.2 to −0.9) Incidence rates are per 100,000 persons and age-adjusted to the 2000 U.S. standard population. HPV-related HNC was defined using anatomic oropharyngeal subsites as a site-based proxy (not tumor HPV status). AAPC indicates average annual percent change; CI, confidence interval; HNC, head and neck cancer.