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Impact of pre-treatment antibiotic exposure on immunotherapy outcomes in gastrointestinal malignancies: A multicenter propensity-matched real-world cohort study.
e15598 Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of gastrointestinal (GI) malignancies. Emerging evidence suggests that gut microbiome composition plays a critical role in modulating the efficacy of immunotherapy. Antibiotics, by disrupting intestinal microbial diversity, may attenuate antitumor immune responses and compromise ICI outcomes. We evaluated time-dependent clinical outcomes associated with antibiotic exposure using real-world data. Methods: We conducted a retrospective cohort study using a large federated real-world database (2015-2025). Adults (18–89 years) with gastrointestinal or hepatobiliary malignancies (including colorectal, gastric, esophageal, and liver cancers) treated with ICI, receiving systemic antibiotics, were compared with matched controls without antibiotic exposure. Cohorts were balanced using 1:1 Propensity score matching for demographics, comorbidities, and treatment variables. The primary outcome was all-cause mortality at 30 days of ICI initiation; the secondary outcomes were hospitalization secondary to infectious and organ-related complications, overall survival at 1 and 3 years. Pre-specified subgroup analyses were performed in older adults ( > / = 65 years). Effect estimates were reported as risk ratios( RR), hazard ratios (HR), and absolute risk differences. Survival was analyzed using Kaplan–Meier curves and Cox proportional hazards models. Results: Within 30 days, antibiotic exposure was associated with significantly increased risks of Clostridioides difficile infection (RR 2.39), pneumonia (RR 2.93), acute kidney injury (RR 1.40), acute respiratory failure (RR 2.11), and neutropenia (RR 1.18) (all p < 0.05). Absolute risk differences translated to a number needed to harm (NNH) of approximately 38 for pneumonia, 143 for acute kidney injury, and ~140 for C. difficile infection. One-month mortality was modestly higher in the antibiotic group (5.4% vs 4.5%; HR 1.22; p = 0.014). However, no significant differences in mortality were observed at 6 months, 1 year, or 3 years, and survival curves converged over time. In the subgroup analysis of adults ≥65 years, early adverse event patterns were preserved, while long-term mortality remained unchanged. One-year hospital admission rates did not differ significantly between groups. Conclusions: Antibiotic exposure is associated with substantial early infectious and organ-related harm and a small increase in short-term mortality, without improvement in long-term survival, including among older adults. These findings highlight a critical opportunity for risk-adapted antibiotic stewardship and careful reassessment of empiric antibiotic use. Key words: ICI- Immune checkpoint inhibitors, RR- Risk ratio, HR- Hazard Ratio, NNH- Number Needed to Harm.
Randomized phase 2 study to evaluate the efficacy and safety of silevertinib in combination with temozolomide in newly diagnosed patients with EGFRvIII-positive IDHwt MGMT unmethylated glioblastoma.
TPS2098 Background: Targeted therapy for patients with newly diagnosed glioblastoma (ND-GBM) has made little progress. First-line therapy remains surgery, adjuvant radiotherapy with temozolomide (TMZ), and maintenance TMZ. This treatment paradigm is even less effective for the ~60% of patients with MGMT unmethylated status. Oncogenic epidermal growth factor receptor (EGFR) alterations are identified in ~ 50% of ND-GBM tumors irrespective of MGMT status. EGFRvIII is present in ~30% of ND-GBM and is nearly always expressed with other EGFR mutations and/or EGFR amplification. Prior clinical trials of EGFR targeting drugs have shown limited benefit primarily due to poor CNS penetrance and/or lack of potency across EGFR variants and EGFR amplification. Silevertinib (BDTX-1535) is a 4th generation covalent EGFR tyrosine kinase inhibitor (TKI) with high CNS penetrance targeting the full spectrum of oncogenic EGFR alterations in GBM, including variants (EGFRvIII, vII, vVI), mutations, and amplification. Silevertinib has shown additive antitumor effects with TMZ in an intracranial GBM tumor model expressing EGFRvIII with EGFR amplification. A phase 0/1 window-of-opportunity study in patients with recurrent GBM showed that silevertinib reached therapeutic levels in infiltrative GBM tissue with associated biomarker suppression (NCT06072586). Silevertinib was well tolerated and demonstrated promising clinical activity in a phase 1 study in patients with recurrent GBM (ASCO 2024). This randomized phase 2 study will evaluate efficacy and safety of silevertinib in combination with TMZ in adults with EGFRvIII-positive (EGFRvIII) unmethylated MGMT ND-GBM. Methods: This multicenter study (NCT05256290) will be conducted in the US and consists of 2 sequential parts. Part 1 (Safety Run-in) will enroll up to 12 patients to evaluate the safety of two doses of silevertinib (150mg QD, 200mg QD) in combination with TMZ and will inform the selected dose for Part 2. In Part 2 (Efficacy Evaluation), patients will be randomized 1:1 to receive adjuvant silevertinib in combination with TMZ or TMZ alone. Patients with EGFRvIII ND-GBM who have completed surgery and adjuvant chemoradiation are eligible (Table). The primary endpoint for Part 2 is progression free survival by blinded independent central review using Response Assessment in Neuro-Oncology (RANO2.0) criteria. Clinical trial information: NCT05256290 . Key inclusion criteria. Surgically resected and histologically proven ND-GBM Tumor EGFR status by local test using commercially available or CLIA certified assay Part 1: any pathogenic EGFR alteration Part 2: EGFRvIII-positive by NGS Unmethylated MGMT tumor status (Part 2 only) No treatment for ND-GBM other than surgery followed by chemoradiation ≥4 weeks after chemoradiation therapy with post-radiation MRI showing no progression
Mortality trend from multiple myeloma with hypertensive diseases as a contributing cause in the United States, 1999–2024: A CDC WONDER analysis across age, sex, and geographic variables.
e19530 Background: Multiple myeloma (MM) is a malignancy frequently accompanied by comorbid conditions such as hypertensive diseases (HTN), which contribute to end-organ damage and increase mortality risk. However, national trends in MM mortality involving HTN as a contributing cause remain underexplored. This study aims to assess the mortality trends among U.S. adults aged ≥ 55 years from 1999 to 2024, stratified by age, sex, region, and urbanization. Methods: Using CDC WONDER Multiple Cause of Death data, we identified deaths with ICD-10 code C90 (MM) and HTN (I10–I15). Age-adjusted mortality rates (AAMRs) per 100,000 population were computed. Joinpoint regression estimated annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results: A total of 33,341 MM-related deaths with HTN were identified. AAMR increased from 7.5 in 1999 to 26.3 in 2024 (AAPC: 4.64%, 95% CI: 2.63–6.68). Males had higher mortality than females (AAMRs in 2024: 35.3 vs. 19.5; AAPCs: 5.95% vs. 3.60%). Individuals aged 75–85+ exhibited the greatest burden (AAMR: 69.6; AAPC: 5.56%), compared to those aged 55–74 (AAMR: 9.3; AAPC: 3.47%). The South and Midwest experienced the highest AAMRs in 2024 (32.3 and 25.5), with AAPCs of 4.18% and 5.06%, respectively. Urban-rural disparities were noted: non-metropolitan areas had higher AAMRs (26.3) but a lower AAPC (3.65%) compared to metropolitan areas (AAMR: 23.7, AAPC: 5.35%). Oklahoma experienced the largest increase in AAMR, rising from 21.0 (1999–2020) to 67.7 (2021–2024), while Hawaii showed a decline from 17.3 to 13.8 during 2021–2024, Mississippi had one of the highest AAMRs (52.2), whereas Utah reported one of the lowest (10.6). Conclusions: MM mortality involving HTN has increased substantially, with disparities by sex, age, region, and rurality. Recent trends suggest stabilization, yet high-burden populations remain. These findings highlight the need for integrated hypertension management in MM care and targeted public health interventions.
Efficacy and safety of camrelizumab combined with docetaxel and carboplatin as neoadjuvant therapy for triple-negative breast cancer: The HELEN-Trio 011 randomized clinical trial.
1009 Background: The KEYNOTE-522 trial demonstrated that adding a PD-1 inhibitor to neoadjuvant chemotherapy significantly improves pathological complete response (pCR) rates, albeit with notable toxicity. The phase III Camrelief trial further confirmed that camrelizumab combined with sequential neoadjuvant chemotherapy significantly improved pCR compared with placebo in early-stage triple-negative breast cancer (TNBC). This study aimed to evaluate the efficacy and safety of camrelizumab plus neoadjuvant docetaxel and carboplatin in previously untreated stage II–III TNBC. Methods: This multicenter, randomized, open-label, phase III trial (ClinicalTrials.gov identifier: NCT05475678) enrolled eligible female patients aged 18-70 years with previously untreated stage II-III TNBC. Patients were randomized (2:1) to receive six 21-day cycles of docetaxel (75 mg/m²) and carboplatin (area under the curve=6) on day 1, with or without camrelizumab (200 mg intravenously on day 3). The primary endpoint was pCR (ypT0/Tis ypN0), assessed in the modified intention-to-treat (mITT) population, which included all patients who received at least one dose of the trial treatment. Results: Between December 2022 and June 2025, 369 patients from fourteen hospitals in China were enrolled and randomized to the camrelizumab-chemotherapy group (n=245) or the chemotherapy-alone group (n=124), of whom 352 comprised the mITT population. The pCR rate was 57.5% (134 of 233) in the camrelizumab-chemotherapy group versus 45.4% (54 of 119) in the chemotherapy-alone group (absolute difference, 12.2 percentage points; 95% CI, 1.4-22.9; one-sided P= 0.014). In the prespecified exploratory subgroup (CPS ≥1), pCR rates were 69.8% (97/139; 95% CI, 62.2%-77.4%) with camrelizumab-chemotherapy and 51.9% (41/79; 95% CI, 40.9%- 62.94%) with chemotherapy-alone (absolute difference, 17.9%; 95% CI, 5.3%-30.5%; one-sided P = 0.004). In the PD-L1-negative subgroup (CPS <1), pCR rates were 37.8% (31/82; 95% CI, 27.4%-48.2%) and 28.1% (9/32; 95% CI, 12.5%-43.7%), respectively (absolute difference, 9.7%; 95% CI, -10.5%-29.9%; one-sided P = 0.165). Grade 3 or higher treatment-related adverse events occurred in 24.8% (58/233) of patients in the camrelizumab-chemotherapy group, and 21.8% (26/119) in the chemotherapy-alone group. No treatment related deaths were reported. Conclusions: The addition of camrelizumab to neoadjuvant docetaxel and carboplatin significantly improved pCR rates in patients with stage II–III TNBC with a manageable safety profile. This anthracycline-free regimen represents a promising neoadjuvant treatment option for early TNBC. Clinical trial information: NCT05475678 .
Current real-world treatments in patients with metastatic colorectal cancer (mCRC) in US clinical practice.
e15604 Background: As the landscape of mCRC treatment continues to evolve, it is important to understand real-world treatment patterns with newer agents. This study characterized current US treatment patterns for mCRC focusing on third line (3L) and fourth line (4L), including novel agents like fruquintinib (F) and trifluridine/tipiracil (TAS-102) combined with bevacizumab (TB). Methods: In this retrospective cohort study, patients ≥18 years of age at mCRC diagnosis who received ≥3 lines of treatment from January 1, 2015, to June 30, 2025, were identified using the nationwide de-identified Flatiron Health electronic health record derived database. The index date was defined as the 3L start date, and 3 months of follow-up (FU) from index was required unless the patient died. Treatments included regorafenib monotherapy (R), TAS-102 monotherapy (T), TB, F and other therapies. Overall 3L treatments by agent and most common regimens were described as well as the proportion of patients continuing to 4L. For 3L→4L sequential treatments with R→TB, R→F, TB→F, TB→R, sample size, baseline characteristics, time to treatment discontinuation (TTD), and number of subsequent lines were reported. All analyses were descriptive, and TTD was estimated by the Kaplan–Meier method. Results: Out of a total of 46,033 mCRC patients, 6,640 received ≥3 lines of treatment during the study period. Median age was 61 years, 58% were male, 64% had Stage IV at initial diagnosis, 72% had ECOG PS 0 or 1 at index date, and 89% were treated in community practice. Median FU was 9.0 months (IQR 4.6, 17.3). Of the patients treated in the 3L setting, 29% received R, T, TB, and F, and 71% received other therapies (Table). A total of 3,377 (50.9%) went on to receive 4L treatments. Median TTD of sequential treatments with R, TB, and F ranged from 7.4 to 12.9 months. Conclusions: In this real-world cohort from predominantly community oncology practices in the US, R, T, TB, and F accounted for approximately 29% of 3L treatments. Use of newer agents indicated heterogeneous adoption in current clinical practice. Patients treated in 3L N= 6,640. Regorafenib monotherapy 720 10.8% TAS-102 monotherapy 717 10.8% TAS-102, bevacizumab 403 6.1% Fruquintinib monotherapy 79 1.2% Other therapies* 4,721 71.1% FOLFIRI + bevacizumab; FOLFIRI; FOLFIRI + panitumumab 1,302 19.6% FOLFOX + bevacizumab 487 7.3% Irinotecan + cetuximab 213 3.2% *Therapies listed below are the most common other therapies for patients treated in 3L.
Puxitatug samrotecan (AZD8205) vs chemotherapy in patients with B7-H4–selected advanced/metastatic endometrial cancer: The phase 3 randomized Bluestar-Endometrial01 (BE01)/GOG-3110/ENGOT-EN28 trial.
TPS5647 Background: The transmembrane glycoprotein B7-H4 is highly expressed in endometrial cancer (EC), with limited expression in normal tissue; therefore, B7-H4 is an attractive antibody–drug conjugate (ADC) target in the treatment of advanced/recurrent EC. Puxitatug samrotecan (Puxi-Sam), a novel B7-H4-directed topoisomerase I inhibitor ADC, was assessed as monotherapy in the first-in-human, Phase 1/2a BLUESTAR trial in several B7-H4-expressing tumors, and showed manageable toxicity and promising efficacy during dose escalation in heavily pre-treated patients (pts). 1 In pts with advanced/recurrent EC, who progressed after available standard of care therapy (including chemotherapy and/or a programmed death [PD]-ligand [L] 1 inhibitor), objective response rates (ORRs) were 34.6% and 38.5% with 2.0 and 2.4 mg/kg Puxi-Sam, respectively, after ≥13 weeks of follow-up. 2 The safety profile of Puxi-Sam was favorable, with manageable hematologic and gastrointestinal toxicities, no adverse events (AEs) leading to discontinuation, and low dose reduction rates due to treatment-related AEs. 2 Following these encouraging results, Bluestar Endometrial01, a global Phase 3 trial, will investigate Puxi-Sam monotherapy versus physician’s choice of chemotherapy in pts with B7-H4-selected EC whose disease has progressed following prior platinum-based chemotherapy and immunotherapy. Methods: This Phase 3, randomized, open-label, multicenter study includes pts with B7-H4-selected advanced/metastatic EC that progressed following platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapy. Approximately 700 pts will be randomized 1:1 to either Arm A: Puxi-Sam (2.4 mg/kg; intravenous [IV] on Day 1 every 3 weeks [q3w]) or Arm B: either doxorubicin (60 mg/m 2 IV on Day 1 q3w) or paclitaxel (80 mg/m 2 IV on Days 1, 8, and 15 in 28-day cycles). The primary outcomes are progression-free survival (PFS) and overall survival (OS). Secondary outcomes include ORR, duration of response (DoR), second PFS, time until first subsequent anticancer therapy (TFST) and second subsequent anticancer therapy (TSST) after discontinuation of the randomized treatment, or death, and time until discontinuation of treatment (TDT) for any reason, or death. All outcomes are to be assessed for Arm A versus Arm B. Safety will be assessed throughout. Clinical trial information: NCT07044336. First Patient In date: Aug 1, 2025. 1. Meric-Bernstam F, et al. Ann Oncol. 2024;35:S485–S486. 2. Gaillard S, et al. Gynecol Oncol. 2025;200:347–348. Editorial acknowledgment: Medical writing assistance was provided by Lewis C Rodgers, PhD, of Omnicom Health Medical Communications, and was funded by AstraZeneca. Clinical trial information: NCT07044336 .
A phase II trial of binimetinib in combination with encorafenib in patients with pancreatic malignancies and a somatic <i>BRAF</i> <sup>V600E</sup> mutation.
4219 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a notoriously difficult-to-treat malignancy, with limited therapy options for patients with advanced disease. While KRAS mutations are the dominant oncogenic driver in PDAC, next-generation sequencing has enabled the identification of rare, targetable alterations such as the BRAF V600E mutation, which occurs in approximately 2-3% of cases. BRAF mutant cell lines are responsive to MEK and RAF inhibitors. This study evaluates the efficacy of the combination of encorafenib and binimetinib as ≥ 2nd line therapy in this specific molecular subgroup of pancreatic cancer patients. Methods: This study used a planned two-stage design. Seven patients were pre-registered; one did not meet eligibility criteria and was excluded. Six patients were enrolled in Stage 1, which required an objective response (OR) in 40% of patients to proceed to Stage 2. Stage 2 was planned to enroll an additional 16 patients, contingent on meeting this efficacy threshold. Enrolled patients received treatment in 28-day cycles until disease progression or for a maximum of 36 cycles. Patients self-administered encorafenib (450 mg orally once daily) and binimetinib (45 mg orally twice daily) starting on Day 1 of each cycle. Objective responses were assessed using RECIST version 1.1 over 24 weeks. Results: The median number of cycles was 8. The objective response rate at 24 weeks was 33.33%. The overall objective response rate was 50%. The median time to response for progression-free survival, overall survival, duration of response, and time to response was 7.1, 15.0, 9.9, and 3.9 months respectively, with 95% CI in all categories. 50% of patients experienced at least one Grade ≥3 adverse event, including anemia, thromboembolic events, and acute kidney injury. Conclusions: The six BRAF-V600E-mutated PDAC patients in our cohort demonstrated meaningful antitumor activity with a manageable safety profile after treatment with encorafenib and binimetinib. Although the study was prematurely terminated due to limited accrual, observed objective responses and survival outcomes suggest that dual RAF/MEK inhibition may represent a feasible therapeutic strategy in this rare molecular subgroup. Larger studies are warranted to further define the efficacy and safety of this treatment combination in BRAF-V600E-mutated pancreatic cancer. Clinical trial information: NCI-2020-02972 .
Improving patient self-management in hepatocellular carcinoma using care sequence plans: A comparative survey study.
e23327 Background: Care Sequence plans, a 4R Oncology model tool (Right Information and Right Care for the Right Person at the Right Time), have demonstrated benefits in care delivery and patient self-management. Prior studies have shown their usefulness in supporting patient engagement and understanding of care. This study evaluated the impact of Care Sequence plans on patient-reported self-management outcomes among people with hepatocellular carcinoma (HCC) at a Houston-based institution. Methods: Care Sequence plans were provided to people with HCC from May to October 2025 (Care Seq cohort). Patient surveys were administered to them and to a baseline cohort of patients with HCC who did not receive plans. Survey responses were compared across 15 patient-reported metrics. Fisher’s exact test was used. Results: Survey response rates were 78% (25/32) in the baseline cohort and 73% (16/22) in the Care Sequence cohort. Directional improvement observed in all 15 self-management metrics among patients who received Care Sequence plans. Five metrics demonstrated statistically significant improvement. The most significant improvement was in patient-reported knowledge of responsibility for different components of cancer care (100% vs 72%, p = 0.02). Other significant improvements were understanding provider instructions, participation in treatment decisions, clarity of the cancer care plan, and perception that providers had a detailed plan to manage care. Conclusions: Implementation of Care Sequence plans for patients with HCC was associated with consistent directional improvement across patient self-management domains, with statistically significant gains in care clarity and patient engagement. These findings support the value of Care Sequence plans as a scalable tool to enhance patient understanding, coordination, and self-management in complex cancer care. Metric Care Seq % Baseline % pvalue n=16 n=25 Told and remembered goal of care 81 64 0.2 I was confident in my ability to understand my doctor’s instructions 100 80 0.07~ It was easy for me to actively participate in decisions about my treatment 100 80 0.07~ My providers had a detailed plan to manage my cancer care 100 80 0.07~ I wanted to be in control of my cancer care 81 68 0.29 I knew who was responsible for different parts of my cancer care 100 72 0.02^ I knew my own responsibilities, like scheduling and going to appointments 100 84 0.12 My care providers spent enough time with me during my appointments 100 84 0.12 I wanted to know details about my cancer care plan 100 84 0.12 My cancer care plan for the next 3-6 months was clear to me 88 64 0.09~ I was able to manage and organize my care 88 80 0.43 I was able to explain my care plan to my family or friends 94 80 0.23 I knew how long different steps in my care will take 73 64 0.40 I knew what care steps should finish before other steps or care begins 88 67 0.13 I felt in control of my care 75 72 0.56 ^significant at < 0.05, ~ at < 0.1
Long-term impacts of stomatitis and related lesions on clinical outcomes in lung cancer patients receiving chemotherapy and immunotherapy: Insights from a propensity-matched cohort study.
e24205 Background: Stomatitis and related oral lesions are common adverse effects of antineoplastic therapies in lung cancer patients, but their long-term implications remain understudied. This study compares long-term outcomes between lung cancer patients with and without stomatitis who underwent chemotherapy and/or immunotherapy. Methods: Using data from the TriNetX federated health research network (88 healthcare organizations), we conducted a propensity score-matched comparative outcomes analysis. Cohort 1 included 8,350 adult patients with lung cancer (ICD-10: C34), stomatitis (ICD-10: K12), and antineoplastic therapy (ICD-10: Z51.1). Cohort 2 comprised 8,350 matched patients without stomatitis. Outcomes assessed post-index event (starting 1 day after therapy initiation, with no end date) included mortality, severe sepsis, malaise/fatigue, respiratory diseases, cardiac arrhythmias, pneumonia, dysphagia, and skin diseases. Analyses encompassed risk measures, Kaplan-Meier survival, and instance counts, excluding prior outcomes where specified. Results: After matching for demographics, comorbidities, and performance status, the stomatitis cohort exhibited a significantly higher hazard for mortality (HR 1.078, 95% CI 1.032-1.126, p < 0.001; median survival 807 vs. 899 days) and severe sepsis (HR 1.118, 95% CI 1.010-1.238, p = 0.032). Risks were elevated for dysphagia (RR 1.186, 95% CI 1.088-1.293, p < 0.001; HR 1.270, 95% CI 1.157-1.394, p < 0.001) and skin diseases (RR 1.119, 95% CI 1.046-1.196, p = 0.001; HR 1.235, 95% CI 1.139-1.338, p < 0.001). Stomatitis in lung cancer patients showed no significant effects on malaise/fatigue (RR 0.974, 95% CI 0.923-1.029, p = 0.346; HR 1.025, p = 0.167), respiratory diseases (RR 1.028, p = 0.394; HR 1.100, p = 0.522), cardiac arrhythmias (RR 0.967, p = 0.468; HR 1.021, p = 0.927), or pneumonia (RR 0.990, p = 0.731; HR 1.032, p = 0.666). Conclusions: Stomatitis in lung cancer patients on chemotherapy/immunotherapy is associated with increased long-term risks of mortality, severe sepsis, dysphagia, and skin diseases, highlighting the need for proactive oral care and monitoring to mitigate these effects and improve quality of life. Further prospective studies are warranted to explore causal mechanisms and interventions.
Insurance and racial disparities in palliative care utilization and end-of-life outcomes in metastatic pancreatic cancer: A national analysis.
e16439 Background: Disparities in palliative care access and end-of-life (EOL) care intensity by insurance and race in metastatic pancreatic cancer remain poorly characterized nationally. Methods: Using the National Inpatient Sample (2019-2022), we identified hospitalizations for metastatic pancreatic cancer (ICD-10: C25.x with C77-C79). Outcomes included palliative care consultation (Z51.5), aggressive EOL care (mechanical ventilation, CPR, vasopressors, dialysis), and in-hospital mortality. Multivariable logistic regression estimated adjusted odds ratios (aOR) by insurance and race. Mediation analysis assessed whether palliative care explained insurance-mortality associations. Results: Among 236,160 hospitalizations (mean age 67.6 years), mortality was 9.6%, palliative care occurred in 27.0%, and aggressive EOL care in 8.0%. Uninsured patients had higher palliative care (aOR 1.43, p < 0.001) yet higher mortality (aOR 1.46, p < 0.001) versus privately insured; palliative care mediated ~40% of this disparity. Medicare patients had lower palliative care (aOR 0.88) and lower mortality (aOR 0.77). Black patients had 70% higher aggressive EOL care odds (aOR 1.70, p < 0.001) despite higher palliative care rates (aOR 1.13). Hispanic and Asian patients showed 44% and 61% higher aggressive EOL care odds, respectively. Conclusions: Uninsured patients receive more palliative consultations yet have higher mortality, suggesting reactive rather than proactive engagement. Black patients experience 70% higher aggressive EOL interventions despite similar palliative exposure. Findings support early palliative integration and culturally-concordant goals-of-care conversations for equitable EOL care. Palliative care disparities. Outcome/Subgroup N Private (%) Medicare (%) Medicaid (%) Uninsured (%) aOR vs Private 95% CI P-value Key Finding Overall Cohort 236,160 — — — — — — — Mean age 67.6y; 65.8% liver mets PALLIATIVE CARE CONSULTATION By Insurance 236,160 23.7 26.8 28.4 32.0 1.43 (Unins) 1.33-1.53 <0.001 Uninsured 43% higher IN-HOSPITAL MORTALITY By Insurance 236,160 10.3 8.5 11.0 14.5 1.46 (Unins) 1.32-1.61 <0.001 Uninsured 46% higher After Palliative Adjustment — — — — — 1.26 (Unins) 1.14-1.40 <0.001 ~40% mediated AGGRESSIVE EOL CARE (Race) Black vs White 236,160 6.7 (W) — — 11.3 (B) 1.70 1.63-1.77 <0.001 70% higher in Black pts Hispanic/Asian vs White — 6.7 (W) — — 10.1/11.7 1.44/1.61 1.37-1.52/1.50-1.72 <0.001 44-61% higher
Association between smoking, tumor genetics, and outcomes in men with metastatic prostate cancer.
5052 Background: Smoking has been associated with increased metastatic prostate cancer (mPC) mortality, but the mechanisms behind this association are largely unknown. We hypothesized that smoking promotes genetic alterations associated with aggressive disease and/or the transformation to neuroendocrine prostate cancer (NEPC). Methods: We utilized the Prostate Cancer Precision Medicine Multi-institutional Collaborative Effort (PROMISE) clinical genomic database for this retrospective analysis. We examined associations between patient characteristics and tumor genetic data with smoking exposure at diagnosis (current, former, never and pack years) and with clinical outcomes, including overall survival (OS) from diagnosis, OS from metastasis, and NEPC status. Patients with unknown smoking status or incomplete/empty/insufficient NGS entries were excluded from analysis. Results: We identified 2353 men with mPC and next generation somatic tumor sequencing available for analysis in PROMISE, including 8.1% current, 39.5% former, and 52.4% never smokers. Current smokers were more likely to be younger, present with metastatic (M1 or N1) disease at diagnosis, and were less likely to have prior local therapy (all p<0.001). Current smoking was associated with worse OS from diagnosis (99.9 mo in current vs 137 mo in former, and 139.4 mo in never smokers; p=0.008), which remained significant after adjusting for disease characteristics (HR 1.27 95% CI 1.01-1.59). No differences in OS from metastasis were observed for amongst the three groups (current 68.1mo, former 60.3 mo, and never 64.2 mo; p=0.86) We also found no difference in the percentage of NEPC at initial diagnosis or at any time between current, former, and never smokers (p=0.8). However, positive associations were observed between smoking status and genetic alterations in SPOP (current: 15%, former 6.7%, never 3.8%; p= 0.018), FGFR1 (current 10%, former 0.4%, never 1.1% p=0.001), and ARID1A (current 5.1%, former 2.2%, never 0.4%; p=0.035) in mHSPC. No other associations between smoking status and genes of interest were identified. Conclusions: Active smoking is associated with worse overall and prostate cancer specific survival as compared to never/former smoking and was associated with specific tumor genetic alterations but not small cell/NEPC transformation. Association of tumor genetics with smoking status; alterations detected in hormone sensitive tissue only. Characteristic Current N = 39 1 Former N = 224 1 Never N = 264 1 p-value TP53 17 (44%) 79 (35%) 100 (38%) 0.58 RB1 3 (7.7%) 11 (4.9%) 17 (6.4%) 0.59 PTEN 8 (21%) 55 (25%) 60 (23%) 0.81 BRCA2 8 (21%) 20 (8.9%) 35 (13%) 0.07 MYC 3 (7.7%) 18 (8.0%) 11 (4.2%) 0.15 SPOP 6 (15%) 15 (6.7%) 10 (3.8%) 0.02 FGFR1 4 (10%) 1 (0.4%) 3 (1.1%) 0.001 ARID1A 2 (5.1%) 5 (2.2%) 1 (0.4%) 0.04 PIK3CA 2 (5.1%) 9 (4.0%) 13 (4.9%) 0.80 1 n (%).
Evolution of treatment and survival in primary tracheal cancer: Insights from a global real-world dataset.
e18141 Background: Primary tracheal cancer is a rare malignancy associated with poor survival and highly heterogeneous treatment patterns. Studies have demonstrated that only a small proportion of patients receive definitive therapies. Our aim was to evaluate the differences in treatment patterns between two diagnostic eras and to assess the impact of evolving practices on outcomes in primary tracheal cancer. Methods: We conducted a multi-center retrospective study of patients ≥18 years old with primary tracheal cancer using TriNetX, a global database of de-identified electronic health records.Two diagnostic eras were defined: pre-2010 (2000-2009) and post-2015 (2015-2024). Propensity score matching controlled for confounding variables including age, sex, race, ethnicity, histology (squamous cell vs adenoid cystic carcinomas) and metastases. Treatment patterns, Kaplan-Meier overall survival (OS) and mortality risk were compared between the two cohorts. Results: A total of 7315 patients were included (1919 pre-2010 and 5396 post-2015). The annual number of new tracheal cancer diagnoses increased significantly over time. Surgical resection was recorded as 10% in the pre-2010 cohort compared to 27% in the post-2015 cohort, suggesting increased use of definitive surgical resection. Radiation +- chemotherapy was 25% in the pre-2010 cohort and 29% in the post-2015 cohort. Immunotherapy was <1% in the pre-2010 cohort vs 10% in the post-2015 cohort. A substantial proportion of patients: 63% in the pre-2010 cohort and 43% in the post-2015 cohort had no recorded curative-intent therapy. After propensity score matching, 513 patients were included in each cohort. Kaplan–Meier analysis showed a better 3 year OS (58% vs 50%; log rank test p=0.0072) and 5 year OS (52% vs 43%, log rank test p=0.0063) in the post-2015 cohort compared to the pre-2010 cohort. Median survival was significantly better in the post-2015 cohort (2026 days, 39% in the post-2015 group vs 1083 days, 16% in the pre-2010 group; log rank test p=0.0078). Mortality risk was higher in the pre-2010 cohort (65% for pre-2010 vs. 43% for post-2015; risk difference is 22%; 95% CI (16.25%-28.25%);p<0.0001). Conclusions: Overall survival for primary tracheal cancer has improved, coinciding with increases in surgical resection. This likely reflects better diagnosis of this rare disease and enhancements in surgical techniques, facilitating the feasibility of definitive resection. Nonetheless, persistently high rates with nearly half of the patients with non-curative intent therapies highlight ongoing barriers to improve survival outcomes in primary tracheal cancer.
HRD as a predictor of response to platinum-based chemotherapy and PARP inhibitors in a Chinese ovarian cancer population.
e17571 Background: Homologous Recombination Deficiency (HRD) predicts response to platinum-based chemotherapy and PARP inhibitors (PARPi) in ovarian cancer. This real-world study aimed to evaluate the value of HRD status, accessed via a genomic scar analysis (GSA) algorithm, and platinum sensitivity, PARPi efficacy in Chinese epithelial ovarian cancer (EOC) patients. Methods: We retrospectively analyzed 209 non-mucinous EOC patients treated at our hospital between Jan 2016, and Jun 2021. The HRD score was calculated by GSA algorithm (BGI Genomics). HRD positivity was defined as pathogenic BRCA1/2 mutations and/or an HRD score≥30; other patients were seemed as homologous recombination proficient (HRP). Associations with platinum response, progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan-Meier and Cox regression. Results: Of 209 patients, 62.2% were HRD and 37.8% were HRP, with a median follow-up of 67.9 months (range: 3.6-99.9). The median PFS for the entire cohort was 22.3 months, which was longer in the HRD group than in the HRP group (30.0 vs. 15.4 months; P=0.003). At the final follow-up, 36.8% of patients had died. The median OS was longer in the HRD group (not reached vs. 47.4 months; P=0.001). In multivariate analysis, HRD was an independent predictor of both longer PFS (HR=0.64, 95% CI: 0.45-0.90; P=0.010) and OS (HR=0.46, 95% CI: 0.29-0.73; P=0.001). Platinum-sensitive relapse rate was higher in the HRD group (79.8% vs. 66.7%; P=0.034). Among HRD patients, those with BRCA mutations (BRCAmt) had superior PFS (HR=0.62, 95% CI: 0.40-0.95; P=0.028) and OS (HR=0.52, 95% CI: 0.28-0.98; P=0.042) versus BRCA wild-type (BRCAwt). In the subset receiving first-line platinum-based chemotherapy without PARPi maintenance (n=147), the median PFS and OS were 16.7 and 80.3 months, respectively. HRD remained associated with improved PFS (22.2 vs. 13.7 months; P=0.007) and OS (not reached vs. 44.2 months; P=0.002). Multivariate analysis confirmed HRD as an independent predictor for longer PFS (HR=0.64, 95% CI: 0.44-0.94; P=0.022) and OS (HR=0.45, 95% CI: 0.27-0.76; P=0.003). Within this HRD subgroup, BRCAmt patients had longer OS (HR=0.46, 95% CI: 0.22-0.95; P=0.037) and a trend toward longer PFS (HR=0.66, 95% CI: 0.41-1.07; P=0.091) versus BRCAwt patients. Among patients receiving first-line PARPi maintenance therapy (n=60), the median PFS was 76.3 months. OS data were not yet mature. HRD patients had longer PFS than HRP patients (not reached vs. 22.5 months; P=0.034), with HRD status independently predicts prolonged PFS in multivariate analysis (HR=0.41, 95% CI: 0.18-0.95; P=0.037). Conclusions: HRD status by GSA is a valid predictor of response to platinum-based chemotherapy and PARPi therapy in Chinese patients with EOC and is associated with improved survival. Within the HRD group, BRCAmt patients have a more favorable prognosis.
Impact of substance use disorder on pneumonia hospital outcomes in chronic lymphocytic leukemia: An inpatient nationwide analysis.
e19034 Background: CLL is associated with immune dysfunction and severe infections, particularly pneumonia (PNA). Substance use disorders (SUD) increase respiratory infection risk and impair healthcare engagement. The impact of SUD on pneumonia outcomes in CLL is unknown. Methods: Retrospective National Inpatient Sample analysis 2016 to 2023 of CLL hospitalizations for infectious non-COVID PNA with or without documented SUD. Primary outcome was in hospital mortality. Secondary outcomes included mechanical ventilation, complications, and discharge disposition. Multivariable logistic regression models adjusted for demographics, hospital factors, income, insurance, and comorbidities were developed. Chi-squared tests for independence were performed. Propensity matching (PSM) was performed for age, sex, race, income, insurance, hospital factors, and comorbidities. Results: Our cohort included 127,915 hospitalized patients with CLL and PNA, of whom 1,990 (1.56%) had documented SUD. SUD was more prevalent among patients aged 50 to 69 years (54.77% vs 24.71%, p<0.001), those with median household income below USD 57,488 (37.44% vs 25.44%, p<0.001), and Medicaid insurance (22.36% vs 3.39%, p<0.001). Patients with CLL/PNA and SUD were more likely to smoke (55.03% vs 39.17%, p<0.001), have chronic pulmonary disease (52.26% vs 39.81%, p<0.001), and depression (22.11% vs 12.03%, p<0.001), whereas those without SUD more frequently had hypertension (70.04% vs 63.88%, p<0.001), diabetes (30.54% vs 23.87%, p<0.001), and dementia (9.01% vs 3.27%, p<0.001). After PSM, discharge against medical advice remained higher in the CLL/PNA with SUD group (7.29% vs 1.26%, p<0.001). In hospital mortality was lower in the CLL/PNA with SUD group (7.29% vs 9.20%), but this difference was not statistically significant after multivariable adjustment (aOR 1.05, 95% CI 0.70 to 1.58, p=0.816) or after PSM (aOR 0.84, 95% CI 0.50 to 1.40, p=0.497). SUD was associated with higher odds of invasive mechanical ventilation (15.83% vs 8.94%, aOR 1.42, 95% CI 1.05 to 1.93, p=0.024), pneumothorax (2.26% vs 0.73%, aOR 2.70, 95% CI 1.35 to 5.41, p=0.005), and vasopressor use (5.03% vs 2.59%, aOR 1.80, 95% CI 1.06 to 3.05, p=0.029). Conclusions: In hospitalized patients with CLL and PNA, concomitant SUD was associated with higher odds of in hospital respiratory complications and discharge against medical advice. No statistically significant difference in in hospital mortality was observed after multivariable adjustment and propensity score matching. These results suggest an association between SUD and increased inpatient clinical complexity, without evidence of a difference in short term mortality in this cohort.
Sequential therapy in BRAF-mutant melanoma: Comparison of combination immunotherapy anti-CTLA4 and anti–PD-1 versus anti–PD-1 monotherapy after targeted treatment failure.
e21527 Background: The optimal immunotherapy strategy for patients with BRAF-mutant advanced melanoma who progress on first-line BRAF/MEK inhibitors remains undefined. While anti–PD-1 monotherapy is commonly used, combination ipilimumab/nivolumab (Ipi/Nivo) offers potentially superior efficacy but with a higher toxicity burden. This study directly compares these two standard approaches in this patient population in routine practice. Methods: A retrospective, multicenter observational analysis of adult patients with BRAF V600–mutant advanced melanoma who progressed on BRAF/MEK inhibitors and were managed at two Russian centers (N.N. Blokhin NMRCO and Moscow Oncology City Hospital No. 62) from 2019 to 2023. This retrospective analysis included 63 patients with advanced melanoma who received first-line (1L) combined targeted therapy (e.g., BRAF/MEK inhibitors) and, upon progression, initiated second-line (2L) immunotherapy. Patients received either ipilimumab plus nivolumab (Ipi/Nivo) (n = 46) or anti–PD-1 monotherapy (n = 17). Results: Treatment assignment information was available for all 63 patients (Ipi/Nivo combination, n = 46; anti-PD-1 monotherapy, n = 17). The median age of all included patients was 50.4 years; 54.3% were male. Metastatic stage at treatment initiation differed between groups (M1d: 50.0% vs 35.3%; M1c: 28.3% vs 35.3%), respectively. The median duration of follow-up after second-line treatment initiation was 26.9 months. The objective response rate (ORR; complete and partial responses) to second-line immunotherapy was 19.0%. Combination immunotherapy did not increase ORR compared with monotherapy (19.6% with ipilimumab/nivolumab vs 17.0% with anti–PD-1 therapy). The majority of patients (85.7%) had documented disease progression on 2L therapy, confirming an aggressive, treatment-resistant population The median progression-free survival (mPFS) was 5.5 months (95% CI, 3.00–13.6) in the ipilimumab/nivolumab group and 4.7 months (95% CI, 3.33–23.8) in the anti–PD-1 therapy group. The median overall survival (OS) was 28.7 months (95% CI, 12.03–45.4) in the ipilimumab/nivolumab group and 35.8 months (95% CI, 25.1–46.5) in the anti–PD-1 therapy group, with a hazard ratio (HR) of 0.98 (95% CI, 0.49–1.95; p = 0.956). Conclusions: Second-line immunotherapy provided modest disease control with a high primary progression rate. No significant efficacy difference was observed between anti–PD-1 monotherapy and ipilimumab/nivolumab combination as a 2L strategy, suggesting limited benefit from intensification to combination immunotherapy after targeted therapy failure in this setting. These results need to be interpreted with caution given the retrospective nature of the analysis and the small number of patients in the treatment groups.
Geographic migration patterns of practicing medical oncologists in the United States, 2020-2025.
1527 Background: The regional provision of cancer care in the United States (US) remains plagued by disparities along the continuum of screening, diagnosis, and treatment. The geospatial accessibility and migration patterns of medical oncologists may contribute to these disparities. We aimed to assess urban-rural and state-level migration patterns of practicing medical oncologists in the US using national datasets. Methods: The Doctors and Clinicians national downloadable file was used as the primary dataset for these analyses. Physician data from August 2020 and August 2025 was used to identify changes in geographic location. The specialties “Hematology/Oncology” and “Medical Oncology” were used to identify oncologists. We utilized Rural-Urban Continuum Codes (RUCC) to classify counties as urban (RUCC 1-3) or rural (RUCC 4-9). If oncologists practiced in multiple states, they were included in all relevant states for these analyses. For categorical variables, the chi-squared test was used for statistical significance. For continuous variables, the two-sample t-test was used for statistical significance. Results: There were 12,222 oncologists in 2020 and 13,420 oncologists in 2025. Our final cohort for analysis comprised 10,172 oncologists present in both datasets. 1,233 oncologists (12.1%) began practicing in a new state during this time period. The five states with the largest percentage of oncologists gained from net migration were: Hawaii (10.8%), Montana (6.7%), Vermont (5.5%), Idaho (5.0%), and Nebraska (4.1%). The five states with the largest percentage of oncologists lost from net migration were: Wyoming (-8.7%), West Virginia (-6.2%), Delaware (-6.2%), Alaska (-4.2%), and Arkansas (-4.1%). Female oncologists were more likely to migrate to a new state (12.6%) than male oncologists (11.8%); however, the difference was not statistically significant (p-value = 0.25). The mean number of years since medical school graduation was 25.1 years for oncologists who began practicing in a new state and 28.4 years for oncologists who did not (p-value <0.001). Oncologists in rural areas were more likely to migrate to urban areas (N = 492; 48.7%) than oncologists in urban areas were to migrate to rural areas (N = 380; 4.1%; p-value <0.001). Conclusions: Oncologists in the US exhibit distinct regional and urban-rural migration patterns. Targeted interventions to ensure adequate geospatial supply of physicians should focus on rural areas and states such as Wyoming and West Virginia. Improving understanding of the underlying factors driving oncologist migration patterns is crucial to ensuring a distributed oncology workforce.
Prognostic effect of neoadjuvant chemotherapy in gBRCA-mutated compared to gBRCA wild-type patients with advanced HGSOC treated with first-line PARP inhibitor maintenance: A large series propensity score–matching analysis.
5602 Background: Recent results from the TRUST trial (ENGOTov33/AGO-OVAR OP.7) have renewed interest in the prognostic role of primary debulking surgery (PDS) versus interval debulking surgery (IDS) in advanced high-grade serous ovarian cancer (HGSOC). This study evaluated the prognostic impact of neoadjuvant chemotherapy (NACT) according to germline BRCA (gBRCA) status in advanced HGSOC patients receiving first-line PARP inhibitor (PARPi) maintenance, and its influence on outcomes at recurrence. Methods: We retrospectively identified patients with advanced HGSOC, treated between 2019 and 2024 at our gynecologic oncology referral center, who underwent upfront surgery and platinum-based chemotherapy followed by PARPi monotherapy. gBRCA status, surgical approach(PDS vs NACT+IDS), and survival outcomes, were collected. Patients were stratified by gBRCA status (gBRCAmut vs gBRCAwt). Propensity score matching (PSM) was performed based on age, ECOG-PS, FIGO stage, tumor histotype, surgical approach, and residual disease after first cytoreduction. Progression-free survival (PFS), overall survival(OS), post-recurrence PFS(PFS2), and post-recurrence OS(OS2) were analyzed. Results: After PSM, 406 patients were included (203 gBRCAmut and 203 gBRCAwt). In the gBRCAmut cohort, 58.6% underwent PDS and 41.4% received NACT+IDS, while 42.9% and 57.1% of gBRCAwt underwent PDS and NACT+IDS, respectively. All gBRCAmut patients received olaparib maintenance; among gBRCAwt, those with somatic BRCA mutations received olaparib (45/203) and the remainder niraparib (158/203). Complete cytoreduction was achieved in 92.1% of cases, with no differences between groups. Among gBRCAwt patients, median PFS was 43 months with PDS versus 19 months with NACT+IDS (p=0.008). Among gBRCAmut, median PFS was not reached with PDS and was 28 months with NACT+IDS (p<0.001). Median OS was not reached in either surgical group for gBRCAwt patients, whereas in gBRCAmut patients median OS was not reached with PDS and was 60 months following NACT+IDS (p<0.001). At recurrence, PFS2 did not differ by upfront treatment. However, NACT+IDS was associated with inferior OS2 in both gBRCAwt (p=0.019) and gBRCAmut (p=0.048) patients, with shorter median OS2 observed in gBRCAmut (15 vs 18 months). Conclusions: NACT was associated with inferior survival outcomes in advanced HGSOC patients receiving first-line PARPi, with a more pronounced detrimental effect observed in gBRCAmut patients. This suggests that BRCA-mutated tumors, despite their intrinsic sensitivity to PARP inhibition, may be particularly vulnerable to the negative consequences of delayed cytoreduction, with potential implications for treatment sequencing and surgical decision-making.
Global insights into survival outcomes and unmet therapeutic needs in <i>KRAS</i> -mutant gallbladder cancer: A comprehensive federated network analysis.
4141 Background: Gallbladder cancer (GBC) is an aggressive malignancy with limited systemic options and poor survival. KRAS targeted therapeutic are emerging across solid tumors, yet their prognostic relevance in GBC remains poorly defined. We evaluated the real-world impact of KRAS mutations on survival in patient with advanced gallbladder cancer utilizing a large, federated health data network. Methods: A retrospective cohort study was performed using the TriNetX Global Collaborative Network. Adults (≥18y) with GBC were grouped by genomic testing into KRAS-mutant (KRAS MT ) or KRAS-wild type (KRAS WT ). Propensity-score matching (PSM) was performed 1:1 adjusting for demographics and comorbidities, yielding 604 patients per cohort. Outcomes were assessed from 1 to 1825 days after index diagnosis. The primary endpoint was overall survival (OS). Kaplan-Meier (KM) estimates, log-rank testing, and hazard ratios (HR) were generated. Results: After PSM, median follow-up was 358.5 (11,7 months) vs 491 (16.1 months) days for KRAS WT and KRAS MT cohorts, respectively. Death occurred in 214 (35.4%) KRAS WT vs 305 (50.5%) KRAS MT patients (risk difference −15.1%, 95% CI −20.6 to −9.5; p < 0.001). Median OS was 1326 days (43.5 months) for KRAS WT vs 694 days (22.8 months) for KRAS MT patients, with survival probability at end of time window of 48.74% vs 32.49%. Kaplan-Meier survival analysis demonstrated significantly worse OS in the KRAS MT cohort (log-rank χ² = 10.76; p = 0.001). Hazard ratio favored KRAS WT (HR 0.747; 95% CI 0.627–0.890; p = 0.011), indicating 34% higher mortality in KRAS MT patients. Conclusions: In this large real-world PSM analysis, KRAS mutations conferred poor prognosis in GBC patients with significantly higher mortality and shorter survival. These differences highlight pivotal clinical implications amid the growing role of KRAS-targeted therapeutics. Ensuring expanded trial access, including early-line KRAS-targeted therapies, is necessary to reach this rare and clinically fragile patient population.
De-escalation of neoadjuvant chemotherapy for HER2-positive breast cancer: A systematic review and meta-analysis.
616 Background: The addition of carboplatin to taxane-based dual HER2 blockade (TCbHP) is a standard neoadjuvant regimen for high-risk, HER2-positive breast cancer. However, this combination incurs significant hematological toxicities. Whether omitting carboplatin (THP) preserves efficacy while enabling de-escalation of toxicity remains a critical unanswered question. Methods: A comprehensive search of PubMed, Embase, Cochrane CENTRAL, and major oncology conference abstracts was conducted through June 15, 2025, for studies comparing THP with TCbHP. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included grade ≥3 hematological toxicities. A non-inferiority margin for pCR was pre-specified at a risk ratio (RR) of 0.85. Data were pooled using a DerSimonian-Laird random-effects model. The study was registered on PROSPERO (CRD420251084035). Results: Seven studies (2 RCTs, 5 observational) comprising 2,061 patients (989 THP; 1,072 TCbHP) were included. The pooled pCR rate was 61.9% for THP versus 63.9% for TCbHP (RR 0.92, 95% CI 0.79–1.07). Statistical non-inferiority was not met, as the lower bound of the 95% CI crossed the pre-specified margin. The absolute pCR difference was a modest -2.0%. Although pCR showed substantial heterogeneity (I² = 69%), this was largely driven by study design differences (RCTs: RR 1.06 vs. observational: RR 0.80). In stark contrast, the THP regimen demonstrated a profound and remarkably consistent safety advantage, with an 82% reduction in grade ≥3 thrombocytopenia (RR 0.18, 95% CI 0.09–0.39), a 69% reduction in anemia (RR 0.31, 95% CI 0.17–0.57), and a 56% reduction in neutropenia (RR 0.44, 95% CI 0.33–0.58). Crucially, all three major hematological toxicity endpoints showed a complete absence of statistical heterogeneity (I² = 0% for all), indicating a robust and generalizable safety benefit. Conclusions: While the carboplatin-free THP regimen did not meet the strict criteria for statistical non-inferiority in pCR, the small absolute efficacy decrement is substantially offset by a large, clinically meaningful, and highly consistent reduction in severe hematological toxicities. These findings provide strong evidence to support THP as a reasonable and safer de-escalation strategy for selected patients with HER2-positive breast cancer, particularly those where toxicity is a major concern.
Adjuvant radiotherapy versus observation following curative surgery for early-stage oral squamous cell carcinoma (AREST; CTRI/2017/07/009114).
6000 Background: The role of adjuvant radiotherapy (RT) in early-stage, node-negative oral squamous cell carcinoma (OSCC) with one or more intermediate risk factors - such as depth of invasion (DOI) ≥5 to ≤10mm, perineural invasion (PNI), lymphovascular emboli (LVE), or poor differentiation - remains debatable and is largely based on retrospective data. This multicenter, open-label, phase III randomized controlled trial was designed to assess the impact of post-operative adjuvant RT in this setting. Methods: Patients with early-stage (pT1-T2), node-negative (pN0) OSCC undergoing adequate surgery (defined as clear margins ≥5mm and at least ipsilateral level I-III neck dissection with ≥16 nodes) with presence of one or more intermediate risk factors were screened. Eligible patients underwent stratified randomization (oral cavity subsite, PNI/LVE, and differentiation) in 1:1 ratio to either observation or adjuvant RT (60Gy in 30 fractions over 6-weeks) to the resected tumor-bed and at-risk neck nodal region after written informed consent. Primary endpoint was loco-regional recurrence-free survival (LRFS) measured from randomization to first documented event of local and/or regional recurrence from index cancer. All time-to-event outcomes were computed using Kaplan-Meier (KM) method with log-rank test for comparison and expressed as 3-year point estimates with 95% confidence intervals (CI). The planned sample size (N=392) provided 80% power at an α of 0.05 to detect a Hazard Ratio (HR) of 0.6256, assuming 3-year LRFS of 70% in the observation arm. Results: Following curative surgery, a total of 392 patients were randomized (191 to adjuvant RT; 201 to observation). Baseline characteristics were balanced between the two arms. At a median follow-up of 47.2 months (inter-quartile range=30-59.4 months), 3-year KM estimate of LRFS was 89.2% in adjuvant RT arm vs 80.9% in observation arm (HR=0.52, 95%CI=0.30-0.91; p=0.02) in the intention-to-treat (ITT) population and 91.1% vs 80.9% (HR=0.43, 95%CI=0.23-0.80; p=0.01) on per-protocol (PP) analyses. Cumulative incidence of loco-regional failure with death as competing event was 10.6% (95%CI=6.1%-15.1%) with adjuvant RT and 18.9% (95%CI=13.3%-24.6%) with observation (HR=0.52, 95%CI=0.30-0.91; p=0.021) in the ITT population and 8.7% (95%CI=4.3%-13.1%) vs 18.9% (95%CI=13.3%-24.6%) (HR=0.43, 95%CI=0.23-0.79; p=0.007) on PP analyses. Disease-free and overall survival were not significantly different between the two arms. Subgroup analysis identified oral tongue deriving higher benefit of adjuvant RT compared to buccal mucosa. Conclusions: Adjuvant RT significantly reduces risk of loco-regional recurrence for early-stage, node-negative adequately resected OSCC, particularly oral tongue. However, such reduction in loco-regional failure does not translate into significant survival benefit. Clinical trial information: CTRI/2017/07/009114.