British Journal of Cancer最新文献

Background: Combining high-dose stereotactic body radiation therapy (SBRT) with FOLFIRINOX (FFX) is promising as neoadjuvant strategy for pancreatic ductal adenocarcinoma (PDAC). This study provides an in-depth histo-molecular characterisation of resected PDAC samples from patients treated with FFX ± SBRT.

Methods: Residual tumour tissues from 56 non-metastatic PDAC patients were analysed: seventeen underwent upfront surgery, seventeen received neoadjuvant FFX alone and twenty-two FFX followed by radiotherapy (sixteen SBRT, six radiochemotherapy [RT-CT]). Samples were assessed using RNAseq and immunohistochemistry/fluorescence, including multiplex.

Results: Addition of SBRT to FFX favourably remodelled PDAC, influencing stromal, immune, metabolic and molecular features. Unlike RT-CT, SBRT counteracted several detrimental effects induced by FFX alone. Notably, FFX + SBRT enriched tumours with 'Classical' and 'Inactive stroma' signatures-linked to better prognosis - while reducing 'Basal-like' cell enrichment. SBRT promoted COL1A1-driven stromal remodelling while globally preserving T-lymphocyte infiltration, including cytotoxic T cells, which maintained close proximity to tumour cells despite increased desmoplasia. Key transcriptional alterations induced by SBRT were identified, offering targets for future combination therapies.

Conclusions: Highlighting a more favourable stromal and molecular profile after integration of high-dose SBRT to FFX, this study supports the development, rationale and validation in prospective trials of using this treatment combination in non-metastatic PDAC.

The effect of involved margins after breast cancer surgery on distant recurrence (DR) is unknown. We determined the association between margin width or involvement, DR and cancer deaths.

Patients and methods: Greater Manchester (GM) and the National Cancer Registry (NCRAS) cohorts were analysed. Margin status after curative surgery was measured. Cox-proportional hazards investigated factors associated with LR, DR and breast cancer deaths.

Results: In GM (2010-2014), 2295 (70.2%) patients had clear margins ( > 2 mm), 302 (9.2%) close (1-2 mm) and 673 (20.6%) involved ( < 1 mm) margins. 2030 patients underwent breast conservation surgery (BCS). After multivariable adjustment in BCS patients, involved margins had an increased hazard of DR (HR 1.73, 95% CI:1.03, 2.88, p = 0.037) and LR (HR 2.16, 95% CI:1.31, 3.58, p = 0.003). NCRAS data from 2010-2013 in 16,420 BCS patients included 3,913 patients (23.9%) with final margins <1 mm. There were 642 deaths (3.9%) after 80.2 months median follow-up: 5.6% in patients with final margins <1 mm and 3.4% with margins >1 mm. After BCS, in 5246 patients who underwent chemotherapy after BCS, involved margins <1 mm had a HR of 1.33 (CI 1.10-1.60, p = 0.003) for cancer death.

Conclusions: Margins >1 mm were associated with lower DR and cancer deaths. Guidelines should recommend a minimum margin clearance of 1 mm.

Background: Individuals with Down syndrome have an elevated risk of childhood leukaemia and are suggested to have a reduced risk of solid tumours in adulthood. However, it remains unclear which cancer subtypes contribute to this pattern and the lifetime cancer risk.

Methods: This Swedish population-based matched cohort study investigated age- and subtype-specific cancer risks in Down syndrome. National healthcare registers were used to include 9742 individuals with Down syndrome, born in Sweden between 1930-2017. Each individual was matched by birth year, sex, and birth county to 50 comparisons. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazard models.

Results: Children with Down syndrome had a 20-fold increased risk of acute lymphoblastic leukaemia (ALL), and nearly a 500-fold increased risk of acute myeloid leukaemia (AML) before the age of 5. In contrast, individuals with Down syndrome had an overall lower risk of solid tumours, with significantly decreased risks for breast, prostate, lung, colorectal, gynaecological cancers, and melanoma, in adults. However, an increased risk was observed for testicular cancer and chondrosarcoma/chondroblastoma.

Conclusion: We present the most comprehensive profile of cancer risk in Down syndrome, aiming to guide clinical practices, encourage tailored surveillance recommendations, and incite research on chromosome 21's role in oncogenesis.

Background: Locally advanced penile squamous cell carcinoma (PSCC) generally has a poor prognosis. Our aim was to access the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitor tislelizumab combined with chemotherapy for locally advanced PSCC.

Methods: In this prospective, single-arm clinical study, eligible patients received Nab-Paclitaxel (175 mg/m2 D1), Cisplatin (70 mg/m² in 3 days), Bleomycin (30 mg D1, 8), and tislelizumab (200 mg D1) every 3 weeks for 4-6 cycles, followed by consolidative treatment if necessary. The primary endpoint was objective response rate (ORR) and progression-free survival (PFS).

Results: Of all 20 enrolled patients, 75.0% (15/20) had a history of previous penectomy and were recurrence cases. The median treatment cycles was 4 (range: 2-6). The ORR reached 75.0%. 35.0% (7/20) of patients underwent consolidative surgery, and 55.0% (11/20) received maintenance immunotherapy (median 7 cycles). At median follow-up of 29.3 months, the median PFS and the median overall survival (OS) were 12.5 months (95% CI 7.4-NE), 22.8 months (95% CI 13.7-NE), respectively. Grade≥3 treatment-related adverse events (TRAEs) were observed in 40% (8/20) patients. No treatment-related deaths occurred.

Conclusions: The combination of tislelizumab with chemotherapy demonstrated promising antitumor efficacy in locally advanced PSCC, with a manageable safety profile.

Background: Host immunity status and hypoxia are the hallmarks of radiosensitivity. Induction of anti-PD-1 immunotherapy demonstrates promise in locally advanced tumor radiotherapy, but whether anti-PD-1 immunotherapy improves radiosensitivity is unclear.

Methods: In vivo experiments were performed in mouse models (4T1 and LLC) treated with anti-PD-1 antibodies or X-ray irradiation. Tumor tissues were subjected to bulk-RNA sequencing. The immune cell profile was characterised by flow cytometry. The hypoxia level was detected by immunofluorescence and Hypoxyprobe and measured using the hypoxia gene score. Vessel normalization was determined by the pericyte-endothelial cell ratio. Anti-CD4 and anti-CD8 monoclonal antibodies were used to deplete CD4⁺ and CD8⁺ immune cells, respectively, in mice. The differences among anti-PD-1 immunotherapy, anti-PD-1 immunotherapy without CD4⁺ cells, and anti-PD-1 immunotherapy without CD8⁺ cells were compared using transcriptome analysis. The spatial immunophenotype was investigated using multi-marker immunofluorescence and HALO analyses.

Results: Induction immunotherapy increased radiosensitivity and maximized anti-tumor response compared with concurrent administration of immunotherapy by mitigating hypoxia. Immune cell profile analysis showed that the number of CD4⁺ IFNγ⁺ T cells, but not CD8⁺ IFNγ⁺ T cells, increased significantly after the induction of anti-PD-1 therapy combined with radiotherapy compared with concurrent radioimmunotherapy. Using antibodies to deplete CD4⁺ or CD8⁺ T cells, we confirmed that CD4⁺ T cells contribute to PD-1 inhibitor-induced vessel normalization and reduced hypoxia. Spatially, more CD4⁺ T cells infiltrate the tumor invasive margin and are located around CD31⁺ endothelial cells after anti-PD-1 immunotherapy.

Conclusions: PD-1 inhibitors improve radiosensitivity through vasculature and immune reprogramming, and vessel normalization may be a biomarker for distinguishing patients who will benefit from radiotherapy after induction immunotherapy.

Background: Deregulated pyrimidine metabolism (PyMet) contributes to various tumorigenic features of cancer, including chemoresistance and epithelial-to-mesenchymal transition. However, cancer often encompasses complex signalling and metabolic pathway cascades for its progression and understanding of these molecular regulatory processes in PyMet is quite limited.

Methods: A comprehensive pan-cancer analysis of around 10,000 gene expression profiles of 32 cancer types was employed using a pathway-based approach utilising gene-sets of signalling and metabolic pathways. The findings were validated using in vitro inhibitor treatments, genetic perturbations and mouse-derived lung tumour organoids.

Results: Pan-cancer analysis identified several top connections with PyMet, including TERT, MTOR, DAX1, HOXA1, TP53 and TNC, implying an interdependency of regulations, which in turn was linked to the chemoresistance mechanisms. Further, these PyMet-signalling interactions were validated in vitro by inhibiting thymidylate synthase (TS) activity using knockdown approach and by brequinar (BRQ), a DHODH inhibitor. Strikingly, the BRQ treatment profile showed a strong inverse association pattern with doxorubicin chemoresistance in multiple cancer types. Indeed, BRQ synergistically sensitises cells to doxorubicin in both lung cancer cell lines and mouse-derived Kras^G12D p53^Δ/Δ (KP) lung tumour organoids.

Conclusions: The study highlights the PyMet-pathway interactions and its role in chemoresistance, providing a strategy for targeting PyMet in cancer.

Background: BRCA1 and BRCA2 are tumor suppressor genes essential for DNA repair. Mutations in these genes significantly increase breast (BC) and ovarian cancer (OC) risk, with BRCA1-positive facing a 70% BC and 40% OC lifetime risk. While guidelines for BRCA-positive are well established, recommendations for BC surveillance in BRCA-patients already diagnosed with OC remain limited. This meta-analysis evaluates BC risk post-OC in BRCA-mutated women.

Methods: A systematic search of PubMed, Embase, and the Cochrane Library was performed. Single-arm outcomes were pooled using meta-analysis of proportions, and survival data were synthesized using hazard ratio (HR), both with 95% confidence intervals (CIs). Heterogeneity was assessed using the I² statistic. All analyses were conducted in R (version 4.3.2).

Results: A total of 2380 patients from 10 retrospective cohort studies were included. Among them, 181 (8%; 95% CI: 6%-11%) developed BC post-OC, with similar rates observed for BRCA1 and BRCA2-mutated (9%; 95% CI: 7%-12%). In overall survival analysis, BRCA-mutated patients who developed BC after OC had significantly improved outcomes compared to those with OC only (HR = 0.4657; P < 0.001).

Conclusion: This meta-analysis underscores the need for tailored BC surveillance and evidence-based screening guidelines in BRCA-mutated OC survivors.

Background: Chemotherapy selection traditionally relies on tumor tissue of origin. However, since genetic alterations drive tumor behavior, it remains unclear if mutations can better predict response. We hypothesized that genetic aberrations might influence chemotherapy outcomes more than tissue origin.

Methods: We retrospectively analyzed 15,474 Japanese patients with solid tumors who underwent comprehensive genomic profiling (CGP) and received cytotoxic chemotherapy. Genetic alterations and tumor origin were evaluated for objective response rate (ORR) and time to next treatment (TNT). Gene mutations were assessed across five chemotherapy classes: platinum-based, alkylating agents, antimetabolites, microtubule inhibitors, and topoisomerase inhibitors.

Results: Genomic alteration data alone did not surpass organ-based models in predicting response. For platinum-based agents, the gene-only model had an AUC of 0.575 versus 0.604 for the organ-only model. A combined gene-organ model yielded an AUC of 0.618 (P < 0.01). Certain gene-organ interactions were associated with improved outcomes. For example, APC-mutated colorectal cancer showed higher ORR and prolonged TNT (hazard ratio, 0.82; 95% CI, 0.73-0.92; P < 0.001) for platinum-based drugs.

Conclusions: While genetic alterations alone did not outperform tumor origin as a predictor, incorporating both may improve exploratory predictions of chemotherapy response. These exploratory findings require prospective validation before any clinical application.

Background: World-wide consensus is lacking regarding patient selection and timing of high-dose chemotherapy (HDCT) with autologous stem-cell support in males with germ cell cancer (GCC). However, within the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) guidelines are harmonised. Our aim was to evaluate survival and toxicity in HDCT-treated GCC-patients within SWENOTECA.

Methods: In total, 7322 GCC patients were diagnosed between 2011-2021 in Sweden and Norway, among which 80 ( ~ 1.1%) patients were treated with HDCT. Indications for HDCT were: Delayed tumour-marker decline during primary/intensified primary treatment (n = 45), progressive disease (n = 29), or relapse (n = 25). The HDCT-regimen consisted of two cycles of carboplatin/etoposide.

Results: The 5-year overall survival (5-yr OS) and progression-free survival (5-yr PFS) after HDCT was 55% and 43%, respectively. Indication delayed tumour-marker decline: 5-yr OS:75%, 5-yr PFS:53%, indication progressive disease 5-yr OS:29%, 5-yr PFS:18%, indication relapse 5-yr OS:61%, 5-yr PFS:58%. Four (5%) died due to HDCT-related complications, none within the delayed tumour-marker decline group. Grade 3-4 infections were seen in n = 69, 86%.

Conclusion: HDCT-treatment according to the SWENOTECA-programme was feasible and associated with promising OS. Early intensification to HDCT for patients with delayed tumour-marker decline during primary-treatment was safe and led to 5-yr OS of 75% with no toxic deaths.

Background: Polyploid giant cancer cells (PGCCs), characterized by enlarged or multiple nuclei, have long been considered non-proliferative and hallmarks of high malignancy. However, their functional contribution to tumor progression remains unclear.

Methods: We identified and characterized a subset of mitotically active (MA)-PGCCs in human oral squamous cell carcinoma specimens and cell lines. Mitotic activity and cell cycle was assessed using immunofluorescence, time-lapse microscopy and FUCCI. We evaluated the interactions between MA-PGCCs and cancer-associated fibroblasts (CAFs), focusing on transforming growth factor-beta (TGF-β) signaling. Chemoresistance to 5-fluorouracil (5-FU) was analyzed using cell viability assays.

Results: MA-PGCCs exhibited both bipolar and multipolar mitosis, generating heterogeneous progeny that contributed to genomic instability. These cells increased the number of CAFs with elevated TGF-β expression, promoting epithelial-mesenchymal transition (EMT) and enhancing resistance to 5-FU. Mechanistically, enhanced reactive oxygen species in MA-PGCCs upregulated urokinase-type plasminogen activator (uPA) and its receptor uPAR, promoting plasmin-mediated activation of TGF-β secreted from adjacent CAFs. Upregulation of TGF-β receptors in MA-PGCCs further amplified TGF-β signaling, accelerating EMT.

Conclusions: Our findings identify MA-PGCCs as a proliferative subpopulation that promotes EMT and chemoresistance through a TGF-β-uPA/uPAR feedback loop. Targeting this pathway may offer a novel therapeutic strategy for the treatment of aggressive tumors enriched in MA-PGCCs.