British Journal of Cancer

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ISSN / EISSN : 0007-0920 / 1532-1827
Total articles ≅ 25,664
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Roberto Moretto, Daniele Rossini, Veronica Conca, , Cosimo Rasola, Carlotta Antoniotti, Daniele Santini, Federica Marmorino, Gianluca Tomasello, Beatrice Borelli, et al.
Published: 12 July 2021
British Journal of Cancer pp 1-7; doi:10.1038/s41416-021-01483-x

Abstract:
In mCRC, CEA is used to monitor response to systemic therapy together with imaging. After the end of induction, no major improvement in tumour shrinkage is expected, and the availability of a marker able to predict progressive disease (PD) versus no-PD might allow avoiding CT scans. We pooled data from patients with baseline CEA ≥ 10 ng/mL included in TRIBE and TRIBE2 studies with the aim of identifying a threshold for percent increase of CEA from nadir able to predict PD after the end of the induction therapy. In total, 1178 paired CEA and radiological assessments from 434 patients were included. According to the optimal cut-off determined by ROC, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of CT scans. However, CEA cut-off of 120% was not able to detect radiological PD in 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as a threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected. In mCRC with baseline CEA ≥ 10 ng/mL, CEA values can accurately predict PD versus no-PD after the end of the first-line induction therapy.
Noha Gwili, Stacey J. Jones, Waleed Al Amri, Ian M. Carr, Sarah Harris, Brian V. Hogan, William E. Hughes, Baek Kim, Fiona E. Langlands, Rebecca A. Millican-Slater, et al.
Published: 12 July 2021
British Journal of Cancer pp 1-11; doi:10.1038/s41416-021-01484-w

Abstract:
Background Breast cancer stem cells (BCSCs) are drivers of therapy-resistance, therefore are responsible for poor survival. Molecular signatures of BCSCs from primary cancers remain undefined. Here, we identify the consistent transcriptome of primary BCSCs shared across breast cancer subtypes, and we examine the clinical relevance of ITGA7, one of the genes differentially expressed in BCSCs. Methods Primary BCSCs were assessed using immunohistochemistry and fluorescently labelled using Aldefluor (n = 17). Transcriptomes of fluorescently sorted BCSCs and matched non-stem cancer cells were determined using RNA-seq (n = 6). ITGA7 expression was examined in breast cancers using immunohistochemistry (n = 305), and its functional role was tested using siRNA in breast cancer cells. Results Proportions of BCSCs varied from 0 to 9.4%. 38 genes were significantly differentially expressed in BCSCs; genes were enriched for functions in vessel morphogenesis, motility, and metabolism. ITGA7 was found to be significantly downregulated in BCSCs, and low expression significantly correlated with reduced survival in patients treated with chemotherapy, and with chemoresistance in breast cancer cells in vitro. Conclusions This study is the first to define the molecular profile of BCSCs from a range of primary breast cancers. ITGA7 acts as a predictive marker for chemotherapy response, in accordance with its downregulation in BCSCs.
Sanne Ten Hoorn, Dirkje W. Sommeijer, Faye Elliott, David Fisher, Tim R. de Back, Anne Trinh, Lianne Koens, Tim Maughan, Jenny Seligmann, Matthew T. Seymour, et al.
Published: 12 July 2021
British Journal of Cancer pp 1-9; doi:10.1038/s41416-021-01477-9

Abstract:
Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.
Xinchen Wang, Qing Liu, Óskar Ö. Halfdanarson, Helga Zoega, Omid Sadr-Azodi, Lars Engstrand, Katja Fall,
Published: 12 July 2021
British Journal of Cancer pp 1-8; doi:10.1038/s41416-021-01480-0

Abstract:
Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality. We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure. Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32–1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0−I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40–1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24–1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality. PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.
Yi Sui, Wei Hu, Wei Zhang, Dejian Li, Hongbo Zhu, Qinghua You, Rujian Zhu, Qingtong Yi, Tao Tang, Lili Gao, et al.
Published: 10 July 2021
British Journal of Cancer pp 1-13; doi:10.1038/s41416-021-01482-y

Abstract:
Background Metastasis is the major cause of treatment failure and cancer-related deaths in prostate cancer (PCa) patients. Our previous study demonstrated that a CD44+ subpopulation isolated from PCa cells or tumours possesses both stem cell properties and metastatic potential, serving as metastatic prostate cancer stem cells (mPCSCs) in PCa metastasis. However, the underlying mechanisms remain unknown. Methods In this study, we established PCa models via the orthotopic and subcutaneous implantation of different human PCa cancer cell lines, and compared the metastatic efficacy, after which process function analysis of target genes was pinpointed. Results Several novel differentially expressed genes (DEGs) between orthotopic and ectopic tumours were identified. Among them, human homeobox B9 (HOXB9) transcription factor was found to be essential for PCa metastasis, as evidenced by the diminished number of lung metastatic foci derived from orthotopic implantation with HOXB9-deficient CWR22 cells, compared with the control. In addition, HOXB9 protein expression was upregulated in PCa tissues, compared with paracancer and benign prostate hyperplasia tissues. It was also positively correlated with Gleason scores. Gain- and loss-of-function assays showed that HOXB9 altered the expression of various tumour metastasis- and cancer stem cell (CSC) growth-related genes in a transforming growth factor beta (TGFβ)-dependent manner. Moreover, HOXB9 was overexpressed in an ALDH+CD44+CXCR4+CD24+ subpopulation of PCa cells that exhibited enhanced TGFβ-dependent tumorigenic and metastatic abilities, compared with other isogenic PCa cells. This suggests that HOXB9 may contribute to PCa tumorigenesis and metastasis via TGFβ signalling. Of note, ALDH+CD44+CXCR4+CD24+-PCa cells exhibited resistance to castration and antiandrogen therapy and were present in human PCa tissues. Conclusion Taken together, our study identified HOXB9 as a critical regulator of metastatic mPCSC behaviour. This occurs through altering the expression of a panel of CSC growth- and invasion/metastasis-related genes via TGFβ signalling. Thus, targeting HOXB9 is a potential novel therapeutic PCa treatment strategy.
, Fearghas Middleton, Hannah P. Cagney,
Published: 6 July 2021
British Journal of Cancer pp 1-12; doi:10.1038/s41416-021-01425-7

Abstract:
Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.
Ping Wu, Chubo Xie, Ling Yang, Yalan Liu, Junfeng Zeng, Xin Li, Xing Fang, Yuhua Fan, Suping Zhao, Ni Kuang, et al.
Published: 6 July 2021
British Journal of Cancer pp 1-11; doi:10.1038/s41416-021-01464-0

Abstract:
Head and neck squamous cell carcinoma (HNSCC) is characterised by a dismal prognosis; nonetheless, limited studies have unveiled the mechanisms underlying HNSCC relapse. Next-generation sequencing was performed to identify the somatic mutations in 188 matched samples, including primary tumours, tumour-adjacent tissues (TATs), pre- and post-operative plasma, saliva and peripheral blood lymphocytes (PBLs) from 27 patients. The evolutionary relationship between TATs and tumours were analysed. The dynamic changes of tumour- and TAT-specific mutations in liquid biopsies were monitored together with survival analysis. Alterations were detected in 27 out of 27 and 19 out of 26 tumours and TATs, respectively. TP53 was the most prevalently mutated gene in TATs. Some TATs shared mutations with primary tumours, while some other TATs were evolutionarily unrelated to tumours. Notably, TP53 mutations in TATs are stringently associated with premalignant transformation and are indicative of worse survival (hazard ratio = 14.01). TAT-specific mutations were also detected in pre- and/or post-operative liquid biopsies and were indicative of disease relapse. TATs might undergo the processes of premalignant transformation, tumorigenesis and eventually relapse by either inheriting tumorigenic mutations from ancestral clones where the tumour originated or gaining private mutations independent of primary tumours. Detection of tumour- and/or TAT-specific genetic alterations in post-operative biopsies shows profound potential in prognostic use.
, Mario Kratz, Rachel C. Malen, James Y. Dai, Sara Lindström, Yingye Zheng,
Published: 6 July 2021
British Journal of Cancer pp 1-10; doi:10.1038/s41416-021-01458-y

Abstract:
Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival. We included 306 eligible incident stage II–III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models. Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10–2.59), 2.72 (2.07–3.56), 1.97 (1.18–3.28) and 1.71 (1.14–2.58), respectively. IL-6 and adiponectin had a dose–response effect (Ptrend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2–2.56), IL-6 (HR = 5.02, 95% CI: 2.92–8.59), MCP-1 (HR = 3.78, 95% CI: 1.41–10.08), and adiponectin (HR = 3.16, 95% CI: 1.27–7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29–0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years. Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II–III CRC patients.
Correction
José J. G. Marin, Maria Giuseppina Prete, Angela Lamarca, Simona Tavolari, Ana Landa-Magdalena, Giovanni Brandi, Oreste Segatto, Arndt Vogel, Rocío I. R. Macias, Pedro M. Rodrigues, et al.
Published: 5 July 2021
British Journal of Cancer pp 1-1; doi:10.1038/s41416-020-01243-3

Published: 5 July 2021
British Journal of Cancer pp 1-3; doi:10.1038/s41416-021-01401-1

Abstract:
Metastasis is the spread of cancer cells to new areas of the body by way of the lymph system or bloodstream. Mechanism-based therapeutics have transformed its treatment. This issue of British Journal of Cancer will highlight recent advances in our understanding of metastasis, and how to block its spread.
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