Cancer Research and Treatment最新文献

Purpose: Relapsed or refractory (R/R) primary central nervous system lymphoma (PCNSL) is an aggressive malignancy for which salvage chemotherapy has limited efficacy. We conducted an investigator-initiated, single-arm, multicenter phase II trial to evaluate the efficacy and safety of a chemotherapy-free salvage regimen comprising rituximab, lenalidomide, and poseltinib (R2P) in patients with R/R PCNSL.

Materials and methods: The R2P regimen consisted of two phases: six cycles of induction with rituximab, lenalidomide, and poseltinib, followed by three cycles of consolidation with lenalidomide and poseltinib. The primary endpoints were complete response rate (CRR) and overall response rate (ORR). Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).

Results: A total of 10 patients were enrolled (one withdrew before cycle 1; nine were evaluable for efficacy). The median age was 70 years (range, 53-75), and all had received methotrexate-based first-line chemotherapy. The ORR was 55.6%, and the CRR was 33.3%. The median PFS was 5.6 months, and the median OS was not reached. Next-generation sequencing was performed in four patients (three responders and one non-responder). CD79B missense mutations were identified in all three responders. A total of 11 adverse events (AEs) were observed in six patients. The most common AE was neutropenia (30.0%). The only grade ≥3 AE was a single case of grade 3 neutropenia. No dose modifications were required due to toxicity.

Conclusion: Poseltinib in combination with lenalidomide and rituximab showed activity in patients with R/R PCNSL, warranting further investigation in larger studies.

Purpose: Acute promyelocytic leukemia (APL) is curable, but relapse remains a concern, particularly in patients treated with all-trans retinoic acid (ATRA) and chemotherapy-based regimens. The identification of prognostic factors for relapse is important for enhanced survival outcomes.

Materials and methods: This retrospective multicenter study analyzed the clinical outcomes and prognostic factors for relapse in 286 Korean patients treated with ATRA and idarubicin-based chemotherapy protocols between 2002 and 2024.

Results: Propensity score-matched analysis revealed key prognostic factors, such as post-consolidation measurable residual disease (MRD) (hazard ratio [HR]: 20.16, p<0.001) and male sex (HR: 5.96; p=0.016). No significant benefit of ATRA-based maintenance therapy was observed in relapse-free survival, compared with observation alone. We also found that FLT3-internal tandem duplication (ITD) mutations were associated with an increased risk of relapse.

Conclusion: These findings highlight prognostic factors for relapse and the importance of individualized therapeutic strategies for high-risk patients. Moreover, our findings indicate that post-consolidation MRD is the most significant predictor of relapse, emphasizing the need for molecular profiling and longitudinal monitoring. Future prospective studies should validate these prognostic markers and refine personalized therapeutic approaches for APL.

Purpose: Low-dose computed tomography (LDCT) is effective in reducing lung cancer mortality among high-risk smokers. The Korean National Lung Cancer Screening Program (KNLCS), the world's first nationwide lung cancer screening initiative using LDCT, was launched in 2019. This study aimed to evaluate the KNLCS uptake rates in relation to participants' economic status and changes in positive screening rates across screening rounds.

Materials and methods: Data from the National Health Insurance Service (NHIS) and National Cancer Screening Information System for 2019-2023 were analyzed. Eligible participants in the KNLCS were current smokers aged 54-74 years with a smoking history of at least 30 pack-years. The KNLCS provides counseling by physicians on screening results and smoking cessation. Screening uptake rates, counseling rates, and Lung CT Screening Reporting and Data System (Lung-RADS) distributions were assessed.

Results: Screening uptake rates increased from 24.7% in 2019 to 51.2% in 2023 (p < 0.001). Economic disparities were observed, with higher-income groups showing consistently higher uptake rates than lower-income group. Screening positive rates has been decreased from 9.1% in 2019 to 7.0% in 2023 according to increasing the proportion of subsequent screening participants. The inter-institutional variance in Lung-RADS category 4 decreased significantly over the years (p < 0.001).

Conclusion: The KNLCS rapidly increased screening uptake rates by systematically inviting eligible participants. Positive screening rates decreased primarily due to a reduction in Lung-RADS category 3 findings in subsequent rounds.

Purpose: Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare entity with a distinct relapse pattern involving the central nervous system (CNS). However, data regarding predictors of CNS relapse in this population remain limited.

Materials and methods: CNS relapse was retrospectively analyzed in two multicenter cohorts comprising 53 patients with newly diagnosed primary breast DLBCL, including a prospective trial and real-world cohort, all treated with rituximab-based immunochemotherapy. The impact of baseline clinical parameters, cell-of-origin, and MYC/BCL2 dual expression (DE) status on CNS relapse was assessed using a multivariate Cox regression model, separately conducted for the overall study set (n=53) and the immunohistochemical study set (n=36).

Results: By the CNS-International Prognostic Index (CNS-IPI), most patients were classified as low or intermediate risk; no patients were classified as high risk. With a median follow-up of 58.8 months, the 4-year risk of CNS relapse was 15.6% in the overall study set and 14.2% in the immunohistochemical set. MYC/BCL2 DE was identified in 14 patients (38.9%) and was significantly associated with increased risk of CNS relapse (4-year risk, 30.7% vs. 0%, p=0.001). Patients with non-germinal center B-cell-like subtype had a numerically higher risk of CNS relapse. However, in multivariate analysis, only MYC/BCL2 DE status was associated with CNS relapse. Synchronous bilateral involvement was also an independent predictor of CNS relapse in both study sets. CNS-IPI was not discriminatory for CNS relapse.

Conclusion: MYC/BCL2 DE and synchronous bilateral breast involvement may help identify patients at higher risk for CNS relapse. Further studies are warranted.

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with poor outcomes. IMpower133 and CASPIAN established platinum-etoposide plus anti-PD-L1 antibody as standard first-line therapy for extensive-stage SCLC (ES-SCLC). Real-world data in Korean patients are scarce. We evaluated the effectiveness and safety of first-line chemo-immunotherapy in ES-SCLC and compared outcomes with pivotal trials.

Materials and methods: We retrospectively reviewed patients diagnosed with ES-SCLC between 2018 and 2021. Overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT) were analyzed using Kaplan-Meier methods. Multivariate Cox regression identified prognostic factors. Objective response rate (ORR) was assessed by RECIST v1.1, and histological subtypes evaluated.

Results: Among 177 patients, median age was 66 years (range, 42-91), with 63.8% aged ≥65; most were male (92.7%) and ECOG 0-1 (91.5%). Smoking history was present in 80.8%. Baseline brain and liver metastases occurred in 27.7% and 26%. Median follow-up was 27.2 months (range, 3.9-43.2). ORR was 74.5% (95% CI, 67.1-81.1). Median OS, PFS, and TTNT were 12.4 (95% CI, 11.6-14.9), 5.3 (95% CI, 5.1-5.87), and 5.6 months (95% CI, 1.43-38.27). In 49 patients with brain metastases, ORR was 63.2%, with no difference in efficacy. Local therapy for brain metastases improved OS (HR 0.42; p=0.012), while PFS was not different. Treatment-related adverse events occurred in 90%, primarily grade ≥2 cytopenias; the most common immune-related event was grade 1 rash.

Conclusion: In this real-world Korean cohort, first-line chemo-immunotherapy achieved outcomes comparable to pivotal trials, supporting its role as standard care for ES-SCLC in clinical practice.

Purpose: The objective of this study was to analyze the impact of post-mastectomy radiotherapy (PMRT) in male breast cancer (MBC) patients and develop an artificial neural network (ANN) model to identify a potential PMRT benefit population.

Materials and methods: Data from a total of 2,247 MBC patients with T1-2N0-1M0 who underwent total mastectomy between 1998 and 2016 were enrolled from the SEER database. Propensity score matching was used to reduce covariate imbalances. Cox regression analysis was conducted to compare overall survival (OS) between the PMRT and no-PMRT groups. The hypothesis was that patients who had undergone PMRT and lived longer than the median OS of the no-PMRT group could benefit from PMRT. An ANN model was then developed to predict PMRT benefit population.

Results: Multivariate Cox regression analysis demonstrated better OS in the PMRT group compared to the no-PMRT group of matched patients. This survival benefit was particularly significant in patients with grade III or T2N0 and T2N1 disease, while no significant difference was observed in patients with grade I/II or T1N0 and T1N1 disease. An ANN model was established to predict PMRT benefit population based on patients with T2N0/T2N1. The optimal cut-off value for the model predicted probability was 0.51. Survival curves indicated that a score of 0.51 could accurately distinguish potential PMRT benefit population.

Conclusion: For MBC patients with T2N0, T2N1, and grade III, PMRT would improve survival. The ANN model would be used to identify patients who are likely to benefit from PMRT and aid in clinical decision-making.

Purpose: IMC-002 is a fully human cluster of differentiation 47-targeted immunoglobulin G4 monoclonal antibody, designed to minimize off-target effects. This study (NCT05276310) assessed its safety/tolerability and preliminary anti-tumor activity in patients with advanced solid tumors who were not eligible for or had progressed on standard treatment.

Materials and methods: Here we report results from the initial 3 + 3 design dose-escalation part of a two-part Phase 1, open-label, dose-escalation/expansion study. IMC-002 was administered intravenously every 2 weeks at four doses (5, 10, 20, and 30 mg/kg). The primary objective was to assess safety/tolerability, including maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary objectives included pharmacokinetics and clinical activity, including best overall response (BOR), disease control rate (DCR), and clinical benefit rate (CBR).

Results: Twelve patients were included in total, with three per dose level. Most patients (11/12) had stage IV disease; 7/12 had received three prior systemic therapies. No dose-limiting toxicities were observed and MTD was not reached. The most common treatment-related adverse events (TRAEs) were rash (9/12), vitreous floaters (8/12), and (hemolytic) anemia (5/12). There was no treatment-related thrombocytopenia, neutropenia, or infection. IMC-002 had dose-proportional pharmacokinetics, achieving steady state levels from Cycle 2. BOR was stable disease in six patients (DCR 50.0%). CBR was 33% (four patients maintaining disease control for ≥6 months).

Conclusion: IMC-002 demonstrated favorable safety/tolerability at doses of 5-30 mg/kg every 2 weeks. RP2D was defined as 20 mg/kg every 3 weeks. Preliminary anti-tumor activity was observed, with a CBR of 33%.

Purpose: Immune checkpoint inhibitors (ICIs) are the standard treatment for platinum-refractory head and neck squamous cell carcinoma (HNSCC). This study aimed to characterize genomic alterations, monitor dynamic changes in circulating tumor DNA (ctDNA) associated with treatment response, and identify novel alterations linked to resistance through serial ctDNA profiling.

Materials and methods: Patients with platinum-refractory HNSCC receiving nivolumab were enrolled. ctDNA was analyzed using FoundationOne Liquid CDx at baseline, 6 weeks after treatment, and at disease progression.

Results: A total of 36 patients were enrolled, and 33 were evaluable for ctDNA. The most frequent baseline alterations were TP53 (75.8%), followed by TERT (27.3%), NOTCH1 (24.2%), CDKN2A (12.1%), and CCND1 (12.1%). Of 27 patients with measurable lesions, 5 achieved a partial response with a response rate of 18.5%. Dynamic ctDNA profiling revealed all responders had marked reductions in both the sum of variant allele frequencies (sumVAF) and the maximum variant allele frequencies (maxVAF) across detected mutations. A decrease in sumVAF or maxVAF correlated with longer treatment durations, and patients with a >50% decrease in either sumVAF or maxVAF showed significantly longer progression-free survival. Additionally, serial profiling identified de novo mutations in 17 patients, detected during stable disease or progression.

Conclusion: Serial ctDNA analysis provides a noninvasive tool for monitoring treatment response and detecting emerging resistance in HNSCC treated with ICIs. A significant reduction in ctDNA at 6 weeks was associated with improved clinical outcomes and warrants validation in larger, prospective studies to define its role as a predictive biomarker in HNSCC.

Purpose: Keap1 mutations mainly caused NRF2-dependent anti-oxidative stress responses, yet whether there are other downstream substrates and pathways remains unknown. This study aimed to uncover the role of Keap1 mutations in regulating PHF10-NRF2 axis in NSCLC and ferroptosis evasion.

Materials and methods: Tandem affinity purification with mass spectrometry was used to screen peptides. Co-IP and ubiquitination assays were used to confirm the Keap1-PHF10 axis. A series of analyses in cell lines, patient samples, and xenograft models were conducted to uncover the functional dependency between Keap1 and NRF2. Transmission electron microscope was used to detect mitochondrion swelling under ferroptosis.

Results: Here, we reported that Keap1 binds and promotes polyubiquitination and degradation of PHF10, a subunit of the PBAF complex. NSCLC-associated Keap1 mutations are incapable of degrading PHF10, and thus induces PHF10 proteins stability. PHF10 ablation shows synthetic lethality in Keap1-deficient NSCLC cells. Mechanistically, PHF10 interacts with NRF2 to activate its downstream targets and enhance the NRF2-dependent anti-oxidative stress capacity in NSCLC. PHF10 recruits SMARCA2, one core cBAF subunit, to increase chromatin accessibility in NRF2-binding transcriptional regions. Cancer-associated Keap1 mutants confer resistance to ROS-induced cell death via accumulating PHF10-SMARCA2 complex. Increased PHF10 further induced ferroptosis resistance in Keap1-deficient NSCLC. Lastly, we utilized one small molecule inhibitor, SMARCA2-IN-8, to inhibit progression of Keap1-deficient NSCLC murine models.

Conclusion: Together, our study highlight the synthetic lethal relationship between Keap1 and PHF10, and provide targeting PHF10-SMARCA2 complex as an effective option to hit Keap1-deficient NSCLC.

Purpose: Oligometastatic soft tissue sarcoma (STS) may offer the possibility of cure compared with polymetastatic disease, with progression patterns and treatment responses varying across histologic subtypes. This study investigated the clinical characteristics, oncologic outcomes, and histologic subtype-specific features of oligometastatic STS.

Materials and methods: We reviewed records of 1,243 patients with extremity/trunk STS who underwent curative surgery between 2000 and 2023. Oligometastatic recurrence occurred in 170 (13.6%), 149 of whom received local ablative therapy (LAT). Disease-specific survival (DSS) and progression-free survival (PFS) were analyzed, along with prognostic factors and subtype-specific characteristics.

Results: The median follow-up was 52.5 months. Surgery alone was the most common LAT (71.2%), followed by surgery with radiotherapy, radiotherapy alone and radiofrequency ablation. The median DSS was 50.0 months (95% confidence interval [CI], 31.5-68.5), with a 5-year DSS rate of 45.2%. The median PFS was 12.0 months (95% CI, 7.6-16.4), with a 5-year PFS of 28.1%. On multivariate analysis, LAT was independently associated with longer DSS (hazard ratio [HR], 9.629; p<0.001). Smaller oligometastatic lesion size and adequate local control of the primary tumor were also independently associated with longer DSS. Metastasis-free interval > 6 months independently predicted longer PFS. Histologic subtypes demonstrated distinct clinical behaviors; for example, myxofibrosarcoma had a lower metastatic rate but poorer DSS, whereas synovial sarcoma showed relatively favorable long-term survival.

Conclusion: Oligometastatic STS represents an intermediate disease state in which LAT can provide meaningful survival benefit. Subtype-specific differences in metastatic behavior and survival outcomes would support individualized, multimodal, and potentially curative treatment strategies.