British Journal of Cancer最新文献

Background: We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraCT 2016-003099-28).

Methods: This study included patients treated with either single-agent nivolumab (Nivo monotherapy group, n = 39) or nivolumab plus ipilimumab (Ipi/Nivo group, n = 71). Trough plasma concentrations (C_min) were assayed at week 6 after treatment start. Cox proportional hazard and logistic regression models were used to investigate the E/R relationship between C_min and clinical outcomes.

Results: Low nivolumab C_min (min (<4.9 µg/mL) was independently associated with worse PFS in the Ipi/Nivo group (HR 1.77, 95% CI [1.03-3.05]; p = 0.040). In both groups, neither nivolumab C_min nor ipilimumab C_min was associated with the risk of death or grade ≥ 3 TRAEs occurrence.

Conclusions: This study suggests an E-R relationship for the efficacy of ipilimumab in m-ccRCC patients treated in combination with nivolumab. Prospective validation of our efficacy threshold in larger cohorts or phase 3 trials is essential prior to the implementation of a pharmacokinetically guided strategy.

Background: Sacituzumab govitecan (SG) was granted early access in France as third-line therapy for metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-mBC) metastatic breast cancer. This nationwide cohort study assessed its real-world use and survival outcomes.

Methods: Using the French National Health Data System, we included all patients initiating SG between July 1, 2021, and December 31, 2023, with follow-up until June 30, 2024. Patient demographics, comorbidities, and prior treatments were recorded. Overall survival (OS) and time to treatment discontinuation (TTD) were estimated by Kaplan-Meier methods, and multivariable Cox models identified OS prognostic factors.

Results: 3653 patients were included: 2527 mTNBC and 1,126 HR+/HER2- mBC, with median ages of 58 and 61.5 years. Median OS was 11.0 months (95%CI: 10.4-11.7) for mTNBC and 11.4 months (95% CI: 10.7-12.4) for HR+/HER2-mBC. One-year survival was 47% and 48% and median TTD of 4.3 and 3.5 months, respectively. Poorer OS was independently associated with inpatient SG initiation and liver/digestive metastases. In mTNBC, additional factors included brain metastases, respiratory disease, tobacco-related hospitalisation, multiple metastatic sites, and prior treatments.

Conclusion: The study highlights SG's clinical relevance and the challenge of translating trial efficacy into real-world outcomes, reinforcing the need for further investigation of tolerability in broader populations.

Background: People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in England if MCED screening were introduced.

Methods: Diagnostic demand was modelled based on (1) estimates of the volume of people aged 50-79 years who would be referred for diagnostic investigation following a 'cancer signal detected' result after MCED screening and (2) MCED test performance metrics. Predicted usage was compared with current annual usage using routine NHS datasets.

Results: In an established MCED screening programme, assuming 70% of the total eligible population is screened annually (~13 million), the relative change in diagnostic demand was greatest for colonoscopy (+2.09%; +13,730 each year); the greatest absolute change was for computed tomography (CT; +0.76%; +62,320). This equates to +1040 colonoscopies and +4720 CT scans for every million screened.

Conclusions: The predicted relative increase in diagnostic testing generated by MCED screening is small, though a large eligible population and maximum uptake could translate into a large number of procedures. Cancer diagnoses brought forward in time through screening should reduce diagnostic use for symptomatic presentations in the future.

Background: V-domain Ig-containing suppressor of T cell activation (VISTA) is an immune checkpoint molecule predominantly expressed on myeloid cells and has recently been recognised as a key mediator of immunosuppression within the tumour microenvironment (TME). However, its expression pattern in gastric cancer and the functional characteristics of the VISTA-high TME remain poorly understood.

Methods: We conducted multiplex immunohistochemistry on tumour samples from 172 patients to characterise the immune landscape of the VISTA-high tumour microenvironment. Additionally, single-cell RNA sequencing (n = 17) and spatial transcriptomics (n = 3) were employed to delineate the cellular expression patterns of VISTA and investigate the potential immunomodulatory functions of VISTA-expressing macrophages.

Results: High VISTA expression was associated with an immunosuppressive TME characterised by increased infiltration of exhausted CD8⁺ T cells, regulatory T cells (Tregs), M2-like macrophages, and cancer-associated fibroblasts (CAFs). Moreover, elevated VISTA levels in the tumour region were linked to worse immune-related progression-free survival (irPFS) in patients treated with immune checkpoint inhibitors (ICIs). Mechanistically, VISTA⁺ monocyte-macrophage (MoMac) populations promoted T cell exhaustion via the LGALS9-PTPRC signalling axis and exhibited enhanced antigen-presenting capacity.

Conclusions: Our findings establish VISTA as a central immunoregulatory checkpoint in gastric cancer, suggesting its potential as a promising therapeutic target for combination immunotherapeutic approaches.

Background: Patients undergoing gastrointestinal cancer surgery are often immunocompromised and susceptible to infectious complications. Recombinant Interleukin 2 activates effector immune cells and stimulates the expansion of regulatory T-cells, making it a promising intervention for prevention of inflammatory complications.

Objective: Our objective was to investigate effects of different preoperative rIL2 dosages on postoperative outcome parameters.

Methods: We conducted a systematic literature review and meta-analysis and included RCTs that recruited adult patients undergoing gastrointestinal cancer surgery who received preoperative subcutaneous rIL2. We performed a systematic search of MEDLINE (via PubMed), Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) from 1989 up to April 18th, 2024.

Results: Out of 2324 screened studies, we included 13 RCTs with a total of 504 patients. Lymphocyte counts [cells/mm³] at 1 week postoperative were higher in the intervention compared to the control group (MD 865 (95%CI: 26, 1705)). Surgical site infections and systemic infections were less likely to occur in the intervention group (OR 0.13 (95%CI: 0.03, 0.50); OR 0.25 (95%CI: 0.10, 0.66)). Severe side effects of rIL2 were not reported.

Conclusion: Preoperative rIL2-based immunomodulation prevents postoperative immunosuppression while the occurrence of severe side effects does not seem to be relevant.

Background: Gastric cancer (GC) is one of the most common malignant tumors with poor overall survival (OS). The mechanism underlying the progression of GC needs to be investigated in depth.

Methods: Differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) and Gene Expression Omnibus (GEO) datasets in GC. The function of INHBA in GC was investigated in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and western blot assays were performed to identify the target transcription factors. Immune cell infiltration was assessed using CIBERSORT algorithms. M2 macrophage polarization induced by INHBA was detected in vitro. The expression levels of downstream target genes of INHBA were measured at mRNA and protein levels.

Results: INHBA was upregulated in GC cells, and high expression of INHBA was associated with poor OS. INHBA was able to promote GC cell migration, invasion, and tumor metastasis and growth. INHBA expression was upregulated by the transcription factor C/EBPβ. Moreover, INHBA in GC cells mediated M2 macrophage polarization. Of note, our data showed that INHBA activated PI3K/AKT pathway and formed a PI3K/AKT/TGF-β positive feedback loop to promote tumor progression.

Conclusions: High INHBA expression predicts poor survival of GC patients. INHBA, upregulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating PI3K/AKT pathway in GC. INHBA may be a potential therapeutic target for GC.

Background: Whole Transcriptome Sequencing (WTS) is a comprehensive alternative to targeted panels for detecting gene fusions and splice variants. To integrate WTS into clinical diagnostics, we compared its performance against established fusion assays (Archer FusionPlex and TSO500 RNA).

Methods: WTS was evaluated in an initial cohort of 64 FFPE tumor samples, and quality control (QC) thresholds were defined based on missed fusions correlating with low tumor cell content (TCC < 40%). Key QC metrics included TCC ≥ 40%, RNA input ≥50 ng, ≥50 million reads, and median insert size >100 bp.

Results: WTS identified 92% of known fusions in the initial cohort. Validation in 357 samples showed 100% concordance with panel-based results when QC thresholds were met. Subsequent clinical deployment across 812 diverse tumor cases detected 121 fusions, though 423 (34%) required fallback to targeted assays due to low TCC. WTS provided added value by detecting novel fusions, pathogens, and enabling oncogenic pathway analysis.

Conclusion: WTS is a reliable and informative method for fusion and splice variant detection in clinical diagnostics, provided rigorous pre-analytical and sequencing QC metrics are strictly applied.