Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (m 6 A) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent m 6 A regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with m 6 A regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 m 6 A regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/ AKT/mTOR signaling were remarkably enriched in the clus-ter1. A prognostic risk score was constructed using seven m 6 A regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, m 6 A regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that m 6 A regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of m 6 A methylation in TIME of HNSCC. The proposed m 6 A regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.

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Departmental sources Background:This retrospective study aimed to evaluate the prognostic roles of distant metastatic patterns in de novo metastatic triple-negative breast cancer to explore the roles of surgery on the primary tumor and to characterize the prognostic factors of organ-specific metastasis. Material/Methods:Data were obtained from the Surveillance, Epidemiology, and End Results program. Kaplan-Meier analyses and log-rank tests were employed to compare survival outcomes among variables. The Cox proportional hazards model was used to assess risk factors for survival. The key endpoints were overall survival and breast cancerspecific survival. Results:A total of 1888 patients were eligible. Distant metastatic site displayed a significant prognostic impact on survival. Using liver metastasis as the reference, overall survival was higher for bone (hazard ratio [HR] 0.770, 95% confidence interval [CI] 0.634-0.935, P=0.008) and lung (HR 0.747, 95% CI 0.612-0.911, P=0.004) metastases. Using patients with brain metastasis as the reference, patients with bone (HR 0.516, 95% CI 0.392-0.680, P<0.001), lung (HR 0.500, 95% CI 0.379-0.661, P<0.001) or liver (HR 0.670, 95% CI 0.496-0.905, P=0.009) metastases exhibited better overall survival. Single-site metastatic patients who received surgery for the primary tumor had more favorable overall survival (P<0.001) and breast cancer-specific survival (P<0.001) than those who did not. Additionally, age, insurance status, chemotherapy, and surgery affected overall survival for patients with isolated bone metastasis; chemotherapy, and surgery affected overall survival for patients with isolated lung metastasis; and insurance status, chemotherapy, and surgery affected overall survival for patients with isolated liver metastasis. Conclusions:Our study verified the specific prognostic significance of distant metastatic site for metastatic triple-negative breast cancer at diagnosis. Surgery on the primary tumor significantly improved survival for patients with single distant metastasis. The identified prognostic factors contributed to evaluating the prognoses for distant metastatic triple-negative breast cancer patients.

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ImportanceUse of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)–mutated non–small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear.ObjectiveTo investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases.Design, Setting, and ParticipantsThis open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled.InterventionsThe eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone.Main Outcomes and MeasuresThe primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed.ResultsA total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P &amp;lt; .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P &amp;lt; .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable.Conclusions and RelevanceIn this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients.Trial RegistrationClinicalTrials.gov Identifier: NCT01951469

Background: Hepatitis B virus (HBV) reactivation may occur with chemotherapy and/or immunotherapy. Antiviral prophylaxis is recommended for all patients who are hepatitis B surface antigen (HBsAg)-positive during chemotherapy and/or immunosuppressive therapy. However, the optimal timing of antiviral therapy before chemotherapy and/or immunosuppressive therapy is not fully elucidated. Patients and methods: We retrospectively evaluated 446 HBsAg-positive patients who underwent chemotherapy and/or immunosuppressive therapy. The cumulative rates of HBV reactivation were evaluated using the Kaplan-Meier method and were compared using the log-rank test. The risk factors of HBV reactivation were examined via univariate and multivariate analyses using the Cox proportional hazards model. Results: The cumulative HBV reactivation rates of patients who received antiviral therapy before chemotherapy and/or immunosuppressive therapy were significantly lower than those of patients who received antiviral therapy after chemotherapy and/or immunosuppressive therapy (P = 0.002). The incidence of HBV reactivation was significantly different between patients who received antiviral therapy at least 1 day before chemotherapy and/or immunosuppressive therapy and those who did not (P = 0.006). No significant difference was observed in the HBV reactivation rates between patients who received antiviral therapy at least 2 days (P = 0.310), 3 days (P = 0.494), and 1 week (P = 0.655) before chemotherapy and/or immunosuppressive therapy and those who did not. The multivariate Cox proportional hazards model showed that women had a lower risk of developing HBV reactivation than men (P = 0.025). The use of the prophylactic antiviral agent entecavir, compared with lamivudine and telbivudine, was associated with the decreased risk of developing HBV reactivation (P = 0.002). Conclusion: HBsAg-positive patients who received preemptive antiviral therapy after chemotherapy and/or immunosuppressive therapy had a high risk of developing HBV reactivation. However, it is not necessary for patients to receive antiviral therapy at least 1 week before chemotherapy and/or immunosuppressive therapy.

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P < 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P < 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

BackgroundThe prevalence of patients newly diagnosed with early-stage lung adenocarcinoma (LUAD) is growing alongside significant advances in screening approaches. This study aimed to construct ferroptosis-related gene score (FRGscore) for predicting recurrence, explore immune-molecular characteristics, and determine the benefit of immunotherapy in distinct ferroptosis-based patterns and FRGscore-defined subgroups.MethodsA total of 1,085 early-stage LUAD patients from four independent cohorts were included. Consensus clustering analysis was performed using 217 co-expressed FRGs to explore different ferroptosis-mediated patterns. An FRG scoring system was established to predict relapse, quantify ferroptosis-mediated patterns, and evaluate the response to immunotherapy in individual patients based on Lasso-penalized and stepwise Cox regression analyses. Immune landscape involving multiple parameters was further evaluated, stratified by cluster subtypes and FRGscore subgroups.ResultsTwo ferroptosis-mediated patterns were identified and verified, which were characterized by significantly distinct prognosis and immune profiles. Analyses of immune characteristics showed that identified ferroptosis patterns were characterized as immune-inflamed phenotype and immune-exhausted phenotype. The FRG scoring model based on 11 FRG-derived signatures panel classified patients into the FRGscore-high and FRGscore-low subgroups. Significantly longer recurrence-free survival (RFS) and overall survival (OS) were observed in the FRGscore-low subgroup. FRGscore-low patients were characterized by higher tumor mutational burden (TMB), immunoscore, immunophenoscore, and PD-L1 expression level and were associated with lower Tumor Immune Dysfunction and Exclusion (TIDE) score, whereas the opposite was observed in FRGscore-high patients. Immune-active pathways were remarkably enriched in the FRGscore-low subgroup. This scoring model remained highly predictive of prognosis across different clinical, molecular, and immune subgroups. Further analysis indicated that FRGscore-low patients exhibited higher response to anti-PD-1/PD-L1 immunotherapy and better clinical benefits based on two independent immunotherapy cohorts.ConclusionThe proposed FRGscore could highly distinguish the recurrence patterns and molecular and immune characteristics and could predict immunotherapy prognosis, potentially representing a powerful prognostic tool for further optimization of individuated treatment and management strategies in early-stage LUAD.