Therapeutic Advances in Medical Oncology最新文献

Background: The treatment response to radiotherapy of hepatocellular carcinoma (HCC) primary tumors and different types of tumor thrombus under identical radiation doses remains uncertain.

Objectives: This multicenter study aimed to evaluate and compare the radiotherapy responses of primary tumors (PT), portal vein tumor thrombus (PVTT), and hepatic vein tumor thrombus (HVTT) in HCC patients and to establish a prediction model for treatment response.

Design: This multicenter retrospective cohort study analyzed the treatment response of 242 HCC patients with macrovascular tumor thrombus who received radiotherapy combined with systemic therapy from five hospitals.

Methods: The objective response rate (ORR) was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 and modified RECIST (mRECIST) criteria. Independent factors of treatment response were identified by logistic regression analysis and used to create a nomogram. Model performance was evaluated through the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis (DCA).

Results: Among the entire cohort, the ORRs evaluated by RECIST were 51.65% for PT, 56.32% for PVTT, and 81.93% for HVTT; the ORRs evaluated by mRECIST were 55.79% for PT, 62.63% for PVTT, and 87.95% for HVTT. Both criteria demonstrated that HVTT exhibited significantly higher response rates than PT and PVTT (p < 0.001). Multivariate logistic regression analysis identified irradiated primary tumor size, biologically effective dose, and tumor thrombus type as independent predictors of response in the radiation-field lesions. The developed nomogram showed good discriminative ability with an AUC of 0.788 in the training cohort and 0.736 in the external validation cohort. Calibration and DCA indicated that the model provided reliable predictions and substantial clinical benefit.

Conclusion: Under identical radiation doses, macrovascular tumor thrombus, especially HVTT, is associated with a higher response rate to radiotherapy compared to HCC primary tumors. The nomogram demonstrated good predictive performance, but prospective validation in larger cohorts is still warranted.

Background: Immune checkpoint inhibitors (ICIs) offer significant benefits for advanced non-small cell lung cancer (NSCLC) but yield objective response rates of only 10%-30% in unselected patients. Circular RNAs (circRNAs), implicated in cancer RNA dysregulation, may serve as biomarkers for ICI response.

Objectives: Identify circRNA signature to predict atezolizumab efficacy of NSCLC.

Design: This study analyzed circRNA expression profiles from 891 advanced NSCLC patients in the OAK and POPLAR clinical studies.

Methods: Based on The Cancer CircRNA Immunome Atlas database, we identified circRNAs associated with the efficacy of immunotherapy in NSCLC patients. Then, we establish predictive models for immunotherapy efficacy using multiple methods and conduct performance verification. Finally, we performed Gene Set Enrichment Analysis and Gene Set Variation Analysis to explore potential mechanisms.

Results: We identified an 11-circRNA signature, named circRNA-Sig, which predicted atezolizumab efficacy with an area under the curve of 0.71 in OAK and 0.67 in POPLAR. Survival analysis in OAK showed patients with low circRNA-Sig scores benefited more from ICI than chemotherapy (hazard ratio (HR) = 1.347; 95% confidence interval (CI): 1.049-1.730; p = 0.019), whereas those with high scores showed no significant difference (HR = 1.020; 95% CI: 0.796-1.307; p = 0.876). Enrichment analysis revealed that low-scoring patients exhibit an activated tumor immune microenvironment, with upregulated pathways in interferon-γ and IL-2/STAT5, which can activate immune cells such as CD8 + T cells and natural killer cells, suggesting mechanistic links to ICI sensitivity.

Conclusion: This circRNA-Sig model, validated across two large cohorts, offers a novel, clinically actionable tool for stratifying NSCLC patients for atezolizumab therapy, potentially enhancing personalized treatment strategies.

Uterine malignancies represent a broad and heterogeneous group of neoplasms, which collectively account for the majority of gynaecological malignancies in developed countries. For a significant proportion of these, mortality rates and clinical outcomes are of major concern, owing to complex molecular profiles and aggressive phenotypes that are largely refractory to conventional therapeutic approaches. Recent advancements in precision medicine and the development of targeted therapies have been transformative for several common cancer types; however, the same benefits are yet to be realised for many uterine cancers. This review comprehensively details the diverse molecular features characterising the various subtypes of uterine malignancies. Furthermore, we have examined the therapeutic approaches actively investigated to target these unique molecular features, identifying pathways and treatments that offer the greatest potential patient benefit. Among increasingly personalised strategies, particular promise is shown by HER2-targeted therapies for HER2-positive malignancies (e.g. trastuzumab deruxtecan). Additionally, targeting TP53 wild-type tumours with selinexor, as well as addressing AKT and DNA repair pathways in both uterine carcinomas and sarcomas (i.e. AKT inhibitor and poly(ADP-ribose) polymerase inhibitor combinations), represents key advancements. Furthermore, anti-angiogenic and immune checkpoint inhibitor combinations hold significant promise for future therapeutic strategies.

Background: Platinum-based chemotherapy has demonstrated superior efficacy as a first-line treatment for metastatic triple-negative breast cancer (mTNBC), at a cost of higher toxicity. Reliable prognostic tools are needed to refine risk stratification and facilitate individualized treatment discussions.

Objectives: To develop and validate prognostic nomograms for overall survival (OS) and progression-free survival (PFS) in patients with mTNBC receiving first-line platinum-based chemotherapy.

Design: Patient-level pooled analysis of prospective trial data, with internal and external validation.

Methods: Individual patient-level data of 777 mTNBC patients from 5 prospective clinical trials were collected. In total, 445 patients who received first-line platinum-based chemotherapy at our center were included as the PFP-TNBC cohort, which was randomly divided (7:3) into training and validation sets. An independent real-world cohort of 216 mTNBC patients was used for external validation. Multivariable Cox regression was used to construct OS and PFS models based on clinical characteristics, laboratory biomarkers, and regimen choice. Model performance was evaluated using concordance index (C-index), time-dependent area under the curve (AUC), calibration, and decision curve analysis.

Results: Both nomograms included the number of metastatic sites and the choice of platinum combination agent. The OS model additionally incorporated baseline cancer antigen 125 and lactate dehydrogenase; the PFS model included liver metastasis, baseline pain, and CA153 and carcinoembryonic antigen. For OS, the C-indexes were 0.67, 0.66, and 0.65 in the training, internal validation, and external cohorts, with AUCs of 0.71-0.74, 0.71-0.75, and 0.69-0.71 for 1-, 2-, and 3-year OS. For PFS, the C-indexes were 0.66, 0.62, and 0.61 in the training, internal validation, and external cohorts, with AUCs of 0.69-0.80, 0.66-0.74, and 0.63-0.72 for 6-, 12-, and 24-month PFS, respectively. Both models demonstrated good calibration and risk stratification identified groups with significantly different survival outcomes (log-rank p < 0.001).

Conclusion: The PFP-TNBC-OS and PFP-TNBC-PFS nomograms provide practical tools to estimate outcomes in mTNBC patients treated with first-line platinum chemotherapy. While C-index values indicated modest discrimination, time-dependent AUCs showed good accuracy at clinically relevant intervals. These models may aid risk stratification, patient counseling, and shared decision-making in chemotherapy-only settings. Future studies are warranted to evaluate their applicability in the evolving era of chemoimmunotherapy.

Background: Circulating tumor DNA (ctDNA) analysis that is tumor-informed and personalized requires high-quality tissue specimens, which are unavailable in certain clinical contexts and pathology practice in Southeast Asia.

Objectives: We aimed to develop and clinically validate an alternative tumor-naïve ctDNA assay.

Design: A retrospective observational study.

Methods: Our tumor-naïve multimodal profiling integrated mutation detection, using both amplicon and hybridization sequencing, with analysis of copy number alteration (CNA) and fragmentomics of cfDNA. We analyzed blood samples of 948 cancer patients and 566 non-cancer donors enrolled in previous studies to evaluate the analytical performance of ctDNA detection. Clinical performance was assessed using post-surgical samples of 97 breast cancer and 51 colorectal cancer patients to compare tumor-naïve ctDNA status with clinical recurrence. The performance was directly compared with the tumor-informed method using identical samples.

Results: For mutations, a combination of amplicon and hybridization sequencing provided higher sensitivity and broader coverage of mutation detection than single methods. Variants of clonal hematopoiesis of intermediate potential were common, mainly in the TP53 gene, and must be excluded. Besides mutations, the addition of CNA and fragment length profiles significantly improved the sensitivity of ctDNA detection in the metastatic stage, but modestly in the early stage. In breast cancer, surveillance tumor-naïve ctDNA achieved 54.5% sensitivity and 98.8% specificity for predicting recurrence (hazard ratio (HR) = 23.3, p < 0.0001). In colorectal cancer, the sensitivity and specificity of surveillance ctDNA for predicting recurrence were 80.0% and 100%, respectively (HR = 35.6, p < 0.0001). The overall accuracy of the tumor-naïve method was lower than the tumor-informed method, but the performance gap varied by cancer stage and cancer type.

Conclusion: The tumor-naïve method could be a reliable alternative to monitor ctDNA when obtaining high-quality tissue samples is challenging. The performance of this method was better in high ctDNA-shedding cancer or at the metastatic stage.

Background: Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen for patients with unresectable or recurrent pancreatic cancer (urPC) after gemcitabine-based chemotherapy. However, little is known about the clinical impact of previous chemotherapy on the effects of NFF in the real world.

Objectives: We retrospectively evaluated whether the efficacy and safety of NFF differed depending on the history of prior chemotherapy among urPC patients receiving NFF.

Design: This study was conducted using the real-world data of Japanese patients with urPC who received NFF in the multicenter NAPOLEON-2 study.

Methods: We compared the efficacy and adverse events (AEs) after NFF initiation between previous irinotecan users and non-users, fluorouracil users and non-users, and platinum users and non-users. We also investigated whether the treatment duration of gemcitabine plus nab-paclitaxel (GnP) influenced the efficacy of NFF among patients treated with NFF as a second-line therapy after GnP.

Results: Overall, 161 patients were enrolled, all of whom had previously received gemcitabine. In the efficacy analysis between irinotecan users and non-users, the median overall survival (OS) was 9.2 and 8.0 months, respectively (hazard ratio (HR) 0.88; p = 0.66). For fluorouracil, the median OS was 9.1 months for users and 7.6 months for non-users (HR 0.98; p = 0.93). For platinum, the median OS was 9.1 months for users and 8.0 months for non-users (HR 0.88; p = 0.67). There was no clinical difference in AEs between irinotecan users and non-users, which affected ⩾10% of patients in both groups. The median OS in the group with previous GnP for ⩾7.8 months was 9.5 months, while it was 4.8 months in the group with GnP for <7.8 months (HR 0.50; p < 0.01).

Conclusion: NFF may be effective and tolerable, even in patients previously treated with irinotecan-, fluorouracil-, or platinum-based chemotherapy, in the real world.

Background: Genome and transcriptome analysis has enhanced the characterisation of pancreatic ductal adenocarcinoma (PDAC), paving the way for targeted therapies. Tumours KRAS wild type (WT) represent a unique subgroup.

Objectives: Characterise the population and molecular abnormalities present in KRAS WT PDAC.

Design: Clinical and molecular data from a large retrospective cohort of KRAS WT PDAC were analysed.

Methods: Next-generation sequencing (NGS) was used to analyse DNAs and RNAs, allowing molecular and transcriptomic characterisation.

Results: We identified 93/1059 (9%) KRAS WT PDAC, among which eight had druggable fusions (n = 8/30 contributive samples), six had BRAF mutations and 19 (n = 19/47) had mutations in homologous recombination (HR) pathway genes. Potential molecular targets in this series may be underestimated due to many non-contributive results. Clinical characteristics and survival did not differ between patients with KRAS WT and KRAS-mutated tumours. Transcriptomic data were available for 350 samples. Their analysis shows a difference in phenotype between mutated and WT tumours, with a molecular profile that appears to be better prognostic for KRAS WT tumours.

Conclusion: KRAS WT tumours are enriched with molecular abnormalities of therapeutic interest. These include oncogene driver alterations (gene fusions and mutations) and mutations in genes of the HR pathway. Targeted therapy strategies for PDAC rely on molecular testing beyond RAS, but further research is needed to identify new therapeutic approaches that improve outcomes in PDAC.

Background: Malignant brain tumors, including gliomas and brain metastases, present therapeutic challenges due to their aggressive nature and high recurrence rates. Intraoperative radiotherapy (IORT) is a promising novel therapeutic approach that delivers immediate irradiation to the resection cavity. This may trigger a local and systemic immune response. However, the immunological effects of IORT remain poorly understood.

Objectives: To investigate the immunomodulatory effects of IORT by analyzing perioperative profiles of inflammatory mediators (IMs) in patients undergoing surgical resection of malignant brain tumors.

Design: A prospective observational cohort study comparing IM responses in patients undergoing brain tumor resection with and without IORT.

Methods: In total, 44 patients undergoing surgical resection of brain tumors were included, with 20 receiving IORT and 24 serving as controls without IORT. In both groups, cerebrospinal fluid/wound fluid samples were collected from the resection cavity at several predefined intraoperative and postoperative time points. A multiplex proteomic assay was used to measure 19 IM involved in inflammation and immune activation.

Results: IORT significantly increased the levels of seven IM (interleukin (IL)-1β, IL-6, IL-8, IP-10, MCP-1, MIP-1β, and VEGF) within the IORT group compared to baseline levels. When comparing to the non-IORT group, the increase in IL-1β was significantly greater for patients with metastases, while IL-10 also showed a trend toward significance.

Conclusion: IORT induces distinct changes in levels of IM, which may contribute to improved tumor control. These findings provide novel insights into the immunomodulatory effects of IORT and may have implications for optimizing multimodal treatment strategies for malignant brain tumors. As an exploratory study with a limited sample size, the findings should be interpreted as hypothesis-generating.

Background: Systemic therapy is a standard treatment option for pancreatic neuroendocrine neoplasms (Pan-NENs) with unresectable or metastatic disease. Streptozocin (STZ)-based chemotherapy is considered a standard treatment option for tumors with a high Ki-67 index or for cases refractory to molecular targeted agents. More recently, the combination of capecitabine and temozolomide (CAPTEM) therapy has emerged as a new treatment option.

Objectives: This study aimed to compare the efficacy, safety, and clinical outcomes between the STZ-based regimen and CAPTEM therapy in patients with unresectable or metastatic Pan-NENs.

Design: This was a single-center retrospective study of histologically confirmed Pan-neuroendocrine tumor (NET) patients treated with either STZ-based regimens or CAPTEM between November 2015 and June 2024.

Methods: We compared efficacy, safety, and clinical outcomes between the two regimens. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events were graded according to Common Terminology Criteria for Adverse Events version 5.0. The study was conducted in compliance with the STROBE guidelines.

Results: Of the 371 patients diagnosed with Pan-NENs, 47 received STZ-based regimen and 21 received CAPTEM therapy. In the NET-G1/G2 patients, the STZ group showed a significantly higher tumor shrinkage rate compared to CAPTEM therapy. Although no significant differences were observed in progression-free survival (PFS) or overall survival between the two groups, subgroup analysis showed that the median PFS in the STZ group was significantly longer than that in the CAPTEM group in NET G1/G2 patients. Renal dysfunction was the main adverse event in the STZ regimen group, while gastrointestinal symptoms were common in the CAPTEM therapy group; however, both were manageable.

Conclusion: Both STZ-based regimen and CAPTEM therapy are safe and effective treatment options for advanced Pan-NENs. STZ-based regimen was more beneficial in NET-G1/G2 patients, suggesting Ki-67 index and tumor grade may serve as indicators for treatment selection. Further prospective studies are warranted to validate these findings.

Radiation-induced normal tissue injuries (RITIs) are the main complications that can significantly limit the use of radiotherapy and affect clinical outcomes in patients with cancer. This article aims to review current literature on the role of proinflammatory cytokine interleukin (IL)-17A in different types of RITIs. While irradiation significantly increases IL-17A expression in normal tissues, activated IL-17A plays a dual role of both promoting and protecting against RITIs, depending on the tissue type. These novel findings have led to a strong interest in evaluating the therapeutic potential of targeting IL-17A/IL-17 receptor signals in RITIs in different normal tissues. Preliminary results from preclinical animal models have shown that blocking IL-17A/IL-17 receptor signaling after irradiation significantly reduces the pathogenesis of RITIs in the skin and lung but enhances it in the intestine and oral mucosa. However, the mechanisms underlying the tissue-dependent dual roles of IL-17A in RITIs remain elusive. Therefore, future studies focusing on the precise role and mechanism of IL-17A action in different RITIs are needed.