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In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the “Precision Pro”, “Dynamic Precision”, and “Intelligent Precision”. This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Background Tumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD‐L1 amplification (PD‐L1 AMP) may predict the efficacy of the PD‐1/PD‐L1 blockade. With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. This study aimed to characterize the distributions of these biomarkers and explore the relationships among these biomarkers for Chinese patients with cancer. Methods In this study, we examined the aforementioned biomarkers in more than 1000 Chinese patients with cancer. These biomarkers were determined based on whole‐exome sequencing (WES) of tumor/blood samples. Results Of the 953 samples from Chinese cancer patients assessed in this study, 35% exhibited high TMB (TMB‐H), 4% were positive for high MSI (MSI‐H), dMMR occurred in 0.53%, and PD‐L1 AMP was positive in 3.79%. We found higher rates of TMB‐H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas (TCGA) data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild‐type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI‐H was the highest in CRC and gastric cancer. PD‐L1 AMP occurred most frequently in lung squamous cell carcinoma and HER2‐positive breast cancer. While MSI and dMMR are associated with higher mutational loads, correlations between TMB‐H and other biomarkers, between MSI‐H and dMMR, and between PD‐L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Conclusion The results reveal the frequency of these biomarkers in different malignancies, with potential implications for PD‐1/PD‐L1 blockade use for Chinese patients with cancer. Our study showed that incidence rates among 953 Chinese cancer patients of TMB‐H, MSI‐H, dMMR, and PD‐L1 AMP were 35%, 4%, 0.53%, and 3.79%, respectively. These findings may provide important information prior to administration of PD‐1/PD‐L1 blockade treatment to Chinese patients with cancer.

AbstractObjectiveTo investigate the individual and comparative efficacy and safety of targeted therapy based strategies in advanced BRAF-mutated colorectal cancer.DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to 31 May 2025, and international conference proceedings.Eligibility criteria for selecting studiesClinical trials and multicentre, real world studies investigating the efficacy and safety of targeted therapies for advanced BRAF-mutated colorectal cancer with at least one of the clinical outcomes of interest.Data synthesisThe primary endpoint was overall survival in the first line and second or later line settings. Secondary endpoints included progression-free survival, objective response rate, disease control rate, and grade ≥3 adverse events. Single arm meta-analysis, pairwise meta-analysis, and network meta-analysis were performed to pool hazard ratios with 95% credible intervals (CrIs) for overall survival and progression-free survival, and odds ratios with 95% CrIs for objective response rate, disease control rate, and adverse events. The rankogram and surface under the cumulative ranking curve (SUCRA) evaluated the relative superiority of regimens in the network meta-analysis.Results60 studies involving 4633 patients with advanced BRAF-mutated colorectal cancer were included. Pooled estimates indicated that patients could benefit from an anti-EGFR (epidermal growth factor receptor)/BRAF based regimen. Doublet chemotherapy (DCT)-anti-EGFR/BRAF was associated with the best overall survival, providing significant benefits compared with DCT-anti-VEGF (vascular endothelial growth factor) (hazard ratio 0.49, 95% CrI 0.36 to 0.66), triplet chemotherapy-anti-VEGF (0.51, 0.33 to 0.80), and anti-EGFR/BRAF (0.70, 0.51 to 0.96) regimens in the first line setting. Chemotherapy-anti-EGFR/BRAF showed significant superiority in overall survival (SUCRA=0.94 for DCT-anti-EGFR/BRAF, 0.90 for single agent chemotherapy (SCT)-anti-EGFR/BRAF) and progression-free survival (0.93 for DCT-anti-EGFR/BRAF and 0.92 for SCT-anti-EGFR/BRAF) among all first line targeted therapy strategies. In the second or later line setting, anti-EGFR/BRAF with or without an additional inhibitor (anti-MEK (mitogen-activated protein kinase kinase) or anti-PI3K (phosphoinositide 3-kinase)), exhibited better efficacy compared with other alternative strategies, ranking highest across study endpoints based on rank probability and SUCRA.ConclusionsFor initial treatment of advanced BRAF-mutated colorectal cancer, combining doublet chemotherapy with anti-EGFR/BRAF therapy offers the best survival benefit. For patients who have had previous treatment, anti-EGFR/BRAF regimens (with or without a MEK inhibitor) are the most effective and tolerable options.Systematic review registrationPROSPERO CRD420250653959.

Background This cohort study aimed to evaluate the impact of tumor burden (TB) on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Materials and Methods Data from the POPLAR and OAK trials were extracted as the training and validation cohorts, respectively. TB was defined as the sum of the longest dimensions (blSLD) of measurable target lesions as per RECIST v1.1. The Kaplan-Meier curves and multivariate Cox regression analyses were performed to assess the association between TB with blood-tested tumor mutation burden (bTMB), PD-L1 expression, and survival outcomes. Additionally, random forest algorithms analysis was performed to evaluate the accuracy of TB in predicting 12-month mortality of NSCLC patients received atezolizumab. Results A total of 105 patients from the POPLAR trial and 322 patients from the OAK trial were recruited in the training and validation sets, respectively. Patients with TB-L have significantly better OS than those with TB-H in the training (mOS: 15.8 months vs 6.93 months) as well as the validation (mOS: 16.0 months vs 7.59 months) cohort. The multivariate Cox regression analysis indicated that TB is an independent biomarker for OS prediction, regardless of bTMB, PD-L1 expression, and number of metastasis sites. The impact of TB on 12-month mortality was expected to be stronger with the increase of TB, suggesting that patients with a high tumor burden experienced a detrimental effect on 12-month mortality. Conclusion TB may act as a prognostic biomarker for clinical benefit in NSCLC patients treated with immunotherapy alone. This may be potentially effective for predicting the efficacy of immunotherapy-based regimens. Plain language summary This study explored how the size of tumors influences the effectiveness of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). We analyzed data from two clinical trials involving NSCLC patients treated with the immunotherapy drug atezolizumab. Tumor burden (TB) was measured as the total size of all measurable tumors. The results showed that patients with smaller tumors had longer overall survival compared to those with larger tumors. This finding was consistent across both clinical trials. Even after considering other factors like tumor biomarkers (e.g., PD-L1 and blood-based tumor mutation burden) and the number of metastasis sites, tumor size remained an important predictor of survival. We also found that patients with larger tumors had a higher risk of dying within 12 months of treatment. These results suggest that tumor size can help predict which patients are more likely to benefit from immunotherapy. This information could guide doctors in tailoring treatment plans and selecting patients for immunotherapy-based treatments. In summary, measuring tumor size could provide valuable insights into how well lung cancer patients might respond to immunotherapy, making it an important tool for improving patient outcomes.

Background Colorectal cancer (CRC) is the third most common cancer and leading cause of cancer-related deaths worldwide. Aberrant cellular metabolism is a hallmark of cancer cells, and disturbed metabolism showed clinical significance in CRC. The membrane-associated RING-CH 8 (MARCH8) protein, the first MARCH E3 ligase, plays an oncogenic role and serves as a prognostic marker in multiple cancers, however, the role of MARCH8 in CRC is unclear. In the present study, we aimed to investigate the biomarkers and their underlying mechanism for CRC. Method In this study, we first examined the function of MARCH8 in CRC by analysing public database. Besides, we performing gene silencing studies and generating cellular overexpression and xenograft models. Then its protein substrate was identified and validated. In addition, the expression of MARCH8 was investigated in tissue samples from CRC patients, and the molecular basis for decreased expression was analysed. Results Systematic analysis reveals that MARCH8 is a beneficial prognostic marker in CRC. In CRC, MARCH8 exhibited tumor-suppressive activity both in vivo and in vitro. Furthermore, we found that MARCH8 is negatively correlated with hexokinase 2 (HK2) protein in CRC patients. MARCH8 regulates glycolysis and promotes ubiquitination-mediated proteasome degradation to reduces HK2 protein levels. Then HK2 inhibitor partially rescues the effect of MARCH8 knockdown in CRC . Poised chromatin and elevated miR-32 repressed MARCH8 expression. Conclusion In summary, we propose that in CRC, poised chromatin and miR-32 decrease the expression of MARCH8, further bind and add ubiquitin, induce HK2 degradation, and finally repress glycolysis to promote tumor suppressors in CRC.

BRAC1 has multiple important interactions with triple-negative breast cancer, the specific molecular characteristics of this interaction, however, have not yet been completely elucidated. By examining cell signaling pathways, important information for comprehending the potential mechanisms of this cancer may become known. The aim of the present study was to identify the effects of BRAC1 and to find the signaling pathway(s) involved in the pathogenic mechanism of triple-negative breast cancer. In this study, GSE27447 microarray data were obtained from the Gene Expression Omnibus (GEO) database of the National Center for Biotechnology Information, and differentially expressed genes (DEGs) from GSE27447 were distinguished by Significant Analysis of Microarray. Gene ontology (GO) analysis was carried out on 132 upregulated and 198 downregulated genes with DAVID. The signaling was forecast by the Kyoto Encyclopedia of Genes and Genomes (KEGG). Transcription factors were recognized by TFatS. The BRAC1 relevant protein-protein interaction networks (PPI) were fixed by STRING and visualized by CytoScape. Overall, the upregulated DEGs, which included CR2, IGHM, PRKCB, CARD11, PLCG2, CD79A, IGKC and CD27, were primarily enriched in the terms associated with immune responses, and the downregulated DEGs, which included STARD3, ALDH8A1, SRD5A3, CACNA1H, UGT2B4, SDR16C5 and MED1, were primarily enriched in the hormone metabolic process. In addition, 13 pathways, such as the B-cell receptor-signaling pathway, the hormone synthesis signaling pathway and the oxytocin-signaling pathway, were chosen. MYC, SP1 and CTNNB1 were determined to be enriched in triple-negative breast cancer. A total of 8 genes were identified to be downregulated in the BRAC1-related PPI network. The results of the present study show a fresh angle on the molecular mechanism of triple-negative breast cancer and indicate a possible target for its treatment.

Evidence-guided regimens for advanced gastric cancer (AGC) in patients with performance status 2 (PS 2) are limited. Here, we proposed a structured therapeutic framework termed “performance status-matched strategy”, and further conducted the APICAL-GC trial (NCT04278222). This open-label, single-arm phase II study evaluated the efficacy and safety of anlotinib combined with toripalimab among 24 treatment-naïve AGC patients with PS 2. The primary outcome was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety profile. This trial met its prespecified endpoints, demonstrating an ORR of 58.3% (95%CI 36.6–77.9) with a DoR of 12.1 months (range: 1.43–48.5), and a DCR of 95.8% (95%CI 78.9–99.9). Median PFS reached 7.33 months (95%CI 3.83–17.1), while median OS was 15.9 months (95%CI 7.73–23.2). Treatment-related adverse events (TRAEs) of any grade occurred in 21 patients (87.5%), with grade-3 TRAEs observed in 7 patients (29.2%). No grade-4/5 TRAEs were reported. These findings provide a rationale for anlotinib plus toripalimab as a promising chemotherapy-free option for the first-line treatment of AGC patients with PS 2 under the performance status-matched strategy, showing comparable anticancer activity and a lower occurrence rate of TRAEs. Patients with gastric cancer often present with poor performance status, limiting both quality of life but also treatment options as they are often excluded from clinical trials. Here, the authors report a phase II trial investigating anlotinib (multi-TKI) plus toripalimab (anti-PD-L1 monoclonal antibody) in treatment-naïve advanced gastric cancer patients with performance status 2.

The sustained benefit of immunotherapy-based regimens in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) failure is debatable. Neither Checkmate-722 nor Keynote-789 reached the prespecified statistical level of clinical benefit, but the ORIENT-31 and ATTLAS trials showed that the addition of a VEGF inhibitor to immunotherapy plus chemotherapy could significantly prolong survival. However, head-to-head comparisons of the efficacy of immunotherapy plus bevacizumab with chemotherapy versus that of immunotherapy with chemotherapy in this patient population are lacking. In addition, the critical question of who would benefit from an immunotherapy-based regimen remains unclear. We conducted an indirect comparative meta-analysis using chemotherapy as a common comparator to classify the relative efficacy of the two immunotherapy-based regimens. The indirect comparison showed that immunotherapy and bevacizumab plus chemotherapy had a significantly better progression-free survival (PFS) (HRIO+Bev+Chemo/IO+Chemo=0.71, 95% CI 0.55 to 0.91) than immunotherapy plus chemotherapy. The EGFR mutation type and T790M mutation were found to be significantly associated with PFS of immunotherapy-based regimens. Compared with their counterparts, patients with L858R (HR 0.52, 95%CI 0.37 to 0.72), without T790M mutation (HR 0.50, 95% CI 0.35 to 0.71) tended to benefit significantly more from immunotherapy-based regimens. In conclusion, our findings support that the addition of VEGF inhibitor to immunotherapy and chemotherapy could be the preferred option for TKI-resistant, EGFR-mutated NSCLC, and that L858R mutation and T790M negativity could be identified as efficacy-associated factors for immunotherapy-based regimens.

Background Gastric cancer patients with widespread metastasis, especially meningeal metastases, have an extremely prognosis and limited therapeutic choices. Case presentation We reported the case of a 39-year-old male patient with HER2-positive gastric cancer with bone and meningeal metastases. He presented with multiple bone metastases and received 3 cycles of docetaxel plus S1. However, he complained with headache and imaging examinations revealed leptomeningeal carcinomatosis. FISH revealed that tumor cells in the cerebrospinal fluid were HER-positive. Herceptin was added to the regimen, but the symptoms were not relieved, the patient suffered from dizziness and nausea. The chemotherapy regimen was switched d to lapatinib (orally at 1250 mg/day, every day), capecitabine (orally at 1000 mg/m2, bid for 2 weeks, followed by a 1-week rest interval, as 1 cycle) and Herceptin (390 mg/3 weeks). After 3 weeks of the new treatment, all the symptoms relieved. The clinical complete response was maintained for 3 months. Conclusions Lapatinib/Capecitabine combination therapy is an alternative treatment strategy for leptomeningeal carcinomatosis of HER2-positive gastric cancer in which trastuzumab and/or chemotherapy essentially has no effect.

In patients without tissue availability at presentation, the analysis of cell-free DNA derived from liquid biopsy samples, in particular from plasma, represents an established alternative for providing epidermal growth factor receptor (EGFR) mutational testing for treatment decision-making. Compared with quantitative polymerase chain reaction and digital polymerase chain reaction-targeted methods, next-generation sequencing can provide more information about tumor molecular alterations, especially EGFR mutations. Here, we present a case of a patient with non-small cell lung cancer (NSCLC) harboring 3 uncommon mutations of EGFR-R670W in exon 17 and H833V, and H835L in exon 21, as shown by next-generation sequencing of plasma cell-free DNA. To the best of our knowledge, this is the first case report of a patient harboring the R670W mutation. The patient responded well to second-generation tyrosine kinase inhibitors (TKIs). T790M is an acquired resistant mutation in patients with R670W, H833V, and H835L. This is also the first case of a patient harboring the H833V/H835L/T790M triple mutation; the patient had a good response to the third-generation TKI osimertinib. In this work, we also performed a literature review on the clinical characteristics of NSCLC patients with the H833V/H835L double mutation, together with a descriptive analysis about their response to EGFR TKI monotherapy as a first-line treatment, according to data from previous case reports. The results showed that the cohort of NSCLC patients with H833V/H835L responded well to EGFR TKIs; thus, before treatment in clinical practice, screening for EGFR mutations should be conducted and EGFR TKIs should be preferred in NSCLC patients with H833V/H835L mutations.