Therapeutic Advances in Medical Oncology最新文献

Background: Dysregulated pathways in cancer may be hub addicted. Identifying these dysregulated networks for targeting might lead to novel therapeutic options.

Objective: Considering the hypothesis that central hubs are associated with increased lethality, identifying key hub targets within central networks could lead to the development of novel drugs with improved efficacy in advanced metastatic solid tumors.

Design: Exploring transcriptomic data (22,000 gene products) from the WINTHER trial (N = 101 patients with various metastatic cancers), in which both tumor and normal organ-matched tissue were available.

Methods: A retrospective in silico analysis of all genes in the transcriptome was conducted to identify genes different in expression between tumor and normal tissues (paired t-test) and to determine their association with survival outcomes using survival analysis (Cox proportional hazard regression algorithm). Based on the biological relevance of the identified genes, hub targets of interest within central networks were then pinpointed. Patients were grouped based on the expression level of these genes (K-mean clustering), and the association of these groups with survival was examined (Cox proportional hazard regression algorithm, Forest plot, and Kaplan-Meier plot).

Results: We identified four key central hub genes-PLOD3, ARHGAP11A, RNF216, and CDCA8, for which high expression in tumor tissue compared to analogous normal tissue had the most significant correlation with worse outcomes. The correlation was independent of tumor or treatment type. The combination of the four genes showed the highest significance and correlation with the poorer outcome: overall survival (hazard ratio (95% confidence interval (CI)) = 10.5 (3.43-31.9) p = 9.12E-07 log-rank test in a Cox proportional hazard regression model). Findings were validated in independent cohorts.

Conclusion: The expression of PLOD3, ARHGAP11A, RNF216, and CDCA8 constitute, when combined, a prognostic tool, agnostic of tumor type and previous treatments. These genes represent potential targets for intercepting central hub networks in various cancers, offering avenues for novel therapeutic interventions.

Background: Locally advanced rectal cancer (LARC) presents significant treatment challenges, particularly as patient age may influence disease progression and treatment response. Understanding the differences in progression patterns and treatment outcomes between older patient (OP) and non-older patient (NOP) is essential for tailoring effective management strategies.

Objectives: We aimed to explore the differences of progression pattern, postoperative treatment, and survival outcome between OP and NOP groups in LARC.

Design/methods: The random survival forest model was used to determine the probability of time-to-event occurrence every 3 months. Patients in the NOP and OP group were both categorized into three risk groups based on progression-free survival nomogram scores. We employed inverse probability of treatment weighting (IPTW) analysis and the Surveillance, Epidemiology, and End Results (SEER) database to verify our findings.

Results: Our results revealed that Groups 1, 2, and 3 experienced peaks in progression within the first 24 months in NOP group. As for OP group, Group 4 reached a progression peak at the 18th month, Group 5 at the 12th month, and Group 6 at the 9th month. In NOP group, high-risk patients who underwent postoperative chemotherapy had significantly improved overall survival compared to those who did not. Additionally, postoperative chemotherapy did not significantly improve prognosis for patients in low-, moderate-, or high-risk groups of OP group. Finally, the validation results of IPTW analysis and SEER database showed compliance with our findings.

Conclusion: For NOP group, we recommended close follow-up during the first 2 years. As for OP group, it was suggested to conduct close follow-up at the 18th, 12th, and 9th month for low-, moderate-, and high-risk groups, respectively. Furthermore, postoperative chemotherapy can provide survival benefits for patients in high-risk group of NOP group. However, OP group patients should be informed that the potential benefits of postoperative chemotherapy may be minimal.

Background: Bevacizumab is extensively used in the treatment of advanced non-small-cell lung cancer (NSCLC). Numerous clinical trials have proven the clinical efficacies of bevacizumab biosimilars (BB).

Objective: Our study aimed to compare the clinical outcomes between bevacizumab reference product (RP) and BB among advanced NSCLC patients in a real-world setting.

Design: We retrospectively analyzed stage IV metastatic NSCLC patients who were treated with bevacizumab as part of a combination therapy. Patients were categorized into chemotherapy (CT) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) groups. We compared the patients' characteristics, treatment efficacy, and adverse events between RP and BB in the two treatment groups.

Methods: From January 2020 to July 2022, a total of 171 patients who underwent combination therapy with bevacizumab were screened. Seventy-nine of these patients met the study's inclusion criteria and were enrolled in the final analysis. We utilized the Kaplan-Meier method to estimate progression-free survival (PFS) and the log-rank test to compare PFS between groups. The Cox proportional hazards model was used to identify predictors of PFS.

Results: Within the CT cohort, 34 patients were treated with RP in combination with platinum and pemetrexed, and 25 patients received a combination regimen with BB. The median PFS was 6.9 months in the RP group and 8.9 months in the BB group (p = 0.255). Within the EGFR-TKI cohort, 20 patients with EGFR-mutant NSCLC received first-line treatment with EGFR-TKI plus bevacizumab. Of these patients, 9 were treated with a combination regimen that included RP, and 11 patients received EGFR-TKI in combination with BB. The median PFS was 18.4 months for the RP group and 13.6 months for the BB group (p = 0.363).

Conclusion: In our advanced NSCLC patients, we found no difference in clinical outcomes when receiving treatment with RP or BB. Given a combination regimen, BB was as effective as RP together with either CT or EGFR-TKIs.

Non-small cell lung cancer (NSCLC) represents the most prevalent histological subtype of lung cancer. Within this disease, the MET gene emerges as a critical therapeutic target, exhibiting various forms of dysregulation. Although MET tyrosine kinase inhibitors, HGF/c-MET targeting antibodies, and antibody-drug conjugates constitute the primary treatment modalities for patients with MET-altered NSCLC, numerous questions remain regarding their optimal application. The advent of immunotherapy holds promise for enhancing therapeutic outcomes in patients with MET-altered NSCLC. MET mutations can reshape the tumor immune microenvironment of NSCLC by reducing tumor immunogenicity, inducing exhaustion in immune-activated cells, and promoting immune evasion, which are crucial for modulating treatment responses. Furthermore, we emphasize the promising synergy of immunotherapy with emerging treatments and the challenges and opportunities in refining these approaches to improve patient outcomes.

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have emerged as the mainstay of treatment for advanced EGFR-mutant advanced non-small cell lung cancer (NSCLC), effectively overcoming the problems of acquired threonine-to-methionine (T790M) mutations associated with the first- or second-generation TKIs. Evidence from several studies suggests that these agents, including osimertinib and aumolertinib, also show potential benefits in T790M-negative or unknown populations, particularly those with brain metastases, where the high permeability of the blood-brain barrier allows effective control of intracranial lesions. Despite the encouraging results, further high-quality research, including prospective trials, is warranted to fully elucidate the efficacy profiles of these third-generation TKIs in T790M-negative or unknown NSCLC patients after first- or second-line TKI failure. The present expert consensus highlights the evolving role of third-generation EGFR-TKIs in overcoming therapeutic resistance and optimizing patient outcomes.

Background: Given that only a small subset of patients with advanced non-small-cell lung cancer (aNSCLC) benefit from immune checkpoint inhibitors (ICIs), the effectiveness of ICIs is often compromised by the complex interplay within the tumor microenvironment (TME).

Objectives: To identify predictive biomarkers associated with ICI resistance at a multi-omics spatial level.

Design: A total of eight aNSCLC patients who received first-line anti-programmed cell death protein-1 (PD-1) monoclonal antibody camrelizumab at Shandong Cancer Hospital and Institute between 2021 and 2022 were included in the discovery cohort. An additional validation cohort of 45 samples from camrelizumab-treated aNSCLC patients was also enrolled.

Methods: NanoString GeoMx^® digital spatial profiling was conducted at the transcriptomic and proteomic level within pan-cytokeratin (panCK⁺), CD45⁺, and CD68⁺ compartments. For validation, multiplex immunofluorescence (mIF) staining was performed.

Results: Distinct spatial expression patterns and levels of immune infiltration were observed between tumor and leukocyte compartments. Higher CD34 expression in the macrophage compartment correlated with poorer prognosis and response to camrelizumab (p < 0.05). mIF validation confirmed the association of elevated CD34 expression level with reduced progression-free survival (PFS; hazard ratio (HR) = 5.011, 95% confidence interval: 1.057-23.752, p = 0.042), outperforming traditional tumor markers in predictive accuracy.

Conclusion: Our findings identify CD34 as a novel spatial biomarker for anti-PD-1 therapy efficacy, potentially guiding the selection of aNSCLC patients who are more likely to benefit from ICI treatment.

Trial registration: ChiCTR2000040416.

Brain metastases (BM) are the most common intracranial malignancies. They are responsible for death as well as impairment of quality of life and cognitive function. In some cases, BMs can cause intracranial hemorrhage, which is not only responsible for the acute onset of either a new focal neurological deficit or worsening of a preexisting focal deficit but also poses a new challenge in treatment planning and clinical management. The aim of this study was to evaluate the available treatment modalities and their efficacy in hemorrhagic brain metastases (HBMs) with special attention to radiotherapy. In this review, we searched PubMed, BMJ, NCBI, Springer, BMC Cancer, Cochrane, and Google Scholar for articles containing data on the diagnosis and treatment of patients with HBMs, excluding the pediatric population. Treatment strategies consist of neurosurgery, whole brain radiotherapy, and stereotactic techniques (fractionated stereotactic radiosurgery (fSRS)/stereotactic radiosurgery (SRS)). Although the optimal treatment strategy for HBMs has not been established, we found no convincing evidence that radiotherapy, especially fSRS/SRS, is contraindicated in HBMs. We concluded that fSRS/SRS is a promising option for patients with HBM, particularly when surgical intervention poses risks.

Background: Immunotherapy blocking programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) has revolutionized the treatment of extensive-stage small-cell lung cancer (SCLC), but only with limited real-world efficacy data; evidence from immunotherapy for other pulmonary neuroendocrine carcinoma (PNEC) is scarce.

Objective: The purpose of this study is to evaluate the efficacy of receiving PD-1/PD-L1 inhibitors in patients with advanced PNEC and explore factors related to survival prognosis, providing clues for treatment for patients with advanced PNEC.

Methods: In all, 203 patients with advanced PNEC who received PD-1/PD-L1 inhibitors between January 2019 and December 2021 were retrospectively analyzed. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS).

Results: For the 203 patients, the objective response rate (ORR) was 48.3%, the disease control rate (DCR) was 83.3%, the median PFS (mPFS) was 6.0 months, and the median OS (mOS) was 13.1 months. Among them, the histology was 166 SCLC, 13 large-cell neuroendocrine carcinoma, and 24 other unspecified PNEC. Histologically, no significant difference was observed in PFS (p = 0.240) or OS (p = 0.845). In first-line (1L) treatment (N = 125), patients received chemoimmunotherapy and had an ORR of 64.8%, DCR of 92.0%, mPFS of 6.6 months, and mOS of 14.9 months. In second-line (2L) or later-line setting, the ORR, DCR, mPFS, and mOS were 21.8%, 69.2%, 4.4, and 9.4 months; immunotherapy plus small-molecule antiangiogenic agents showed significantly greater PFS than immunotherapy monotherapy or chemoimmunotherapy (6.4 vs 1.4 vs 3.7 months, p = 0.041). Patients without liver metastasis had superior PFS (7.0 vs 5.1 months, p < 0.001) and OS (19.2 vs 9.6 months, p < 0.001) than those with liver metastasis.

Conclusion: In clinical practice, PD-1/PD-L1 inhibitors are effective in patients with advanced PNEC, regardless of the pathological histology. The efficacy of 1L immunochemotherapy is worthy of recognition, and the addition of small-molecule antiangiogenic agents to immunotherapy in 2L or later-line treatment provides a better survival trend.

Design: Retrospective study.

Background: Plasma Epstein-Barr virus (EBV) DNA has been identified as a significant prognostic marker for nasopharyngeal carcinoma (NPC), yet there is limited research on the prognosis of NPC patients with negative EBV DNA.

Objectives: We explore the prognostic value of comprehensive immune-inflammatory and nutritional indicators to offer personalized treatment recommendations and prognosis predictions for non-metastatic NPC patients with negative EBV DNA.

Design: This was a retrospective study.

Methods: This study retrospectively analyzed 257 non-metastatic NPC patients with negative EBV DNA between January 2015 and December 2019. The Kaplan-Meier survival curves evaluated survival endpoints, and group discrepancies were assessed with log-rank tests. Principal component analysis (PCA) reduced data dimensionality. Univariate and multivariate Cox regression analyses identified significant prognostic variables. Risk stratification was performed based on recursive partitioning analysis (RPA). A robust prognostic model was constructed by nomogram and evaluated by calibration curves, decision curves, and the time-dependent area under the curve analysis.

Results: PCA was employed to compute the immune-inflammation index (III) and nutrition index (NI). Multivariate Cox regression analysis revealed lactate dehydrogenase, III, and NI as significant prognostic variables for overall survival (OS). Utilizing RPA, we stratified the risk into three categories: low-risk group (low III + high NI), middle-risk group (low III + low NI), and high-risk group (high III). Both the middle- (p = 0.025) and high-risk groups (p < 0.001) exhibited poorer OS compared with the low-risk group. The nomogram model exhibited superior predictive accuracy compared to tumor lymph node metastasis stage alone (C-index: 0.774 vs 0.679).

Conclusion: Our study validated the prognostic significance of III and NI in non-metastatic NPC patients with negative EBV DNA. Additionally, a clinical risk stratification was constructed to offer valuable insights into the individualized treatment of these patients.

Background: Programmed cell death protein 1 ligand 1 (PD-L1) expression alone may not be the optimal predictor of immunotherapy (IO) efficacy in advanced non-small cell lung cancer (NSCLC). Evaluation of circulating immune signatures using mass cytometry is a promising technique for predicting IO response and prognosis. The utility of circulating immune signatures for efficacy prediction after IO in advanced NSCLC remains to be elucidated.

Objectives: To assess the feasibility of circulating immune cells and cytokines in predicting tumor response to IO in advanced NSCLC.

Design: A prospective observational study.

Methods: To investigate dynamic changes in immune signatures, blood specimens were prospectively collected from patients with NSCLC at baseline and following chemotherapy (C/T) and/or IO. Mass cytometry and enzyme-linked immunosorbent assay were used to characterize immune signatures and cytokine patterns to identify correlations between immune profiles and treatment efficacy.

Results: The study enrolled 45 patients. The proportion of circulating natural killer (NK) cells and CD8⁺ T cells significantly increased after IO alone treatment. Cell levels of PD-1⁺CD8⁺ T cells, PD-1⁺CD4⁺ T cells, TIM-3⁺CD8⁺ T cells, LAG-3⁺ NK cells, and LAG-3⁺CD8⁺ T cells significantly decreased in patients with treatment response to IO alone. Tumor necrosis factor-alpha (TNF-α) levels significantly increased after IO alone treatment. Patients with high PD-1⁺CD8⁺ T cells before IO alone treatment had lower overall survival (OS) compared to those with low levels. Patients with high LAG-3⁺CD8⁺ T cells before chemotherapy plus immunotherapy treatment had lower OS compared to those with low levels.

Conclusion: Responses to IO in NSCLC were correlated with declines in specific exhausted T cells, suggesting that IO may exert therapeutical efficacy by decreasing circulating exhausted T cells, which were associated with poorer survival, while also increasing TNF-α. These results highlight the prognostic value of monitoring changes in circulating exhausted T cells to predict IO response and survival outcomes in advanced lung cancer.