British Journal of Cancer

Abbasi, Kamran; Ali, Parveen; Barbour, Virginia; Bibbins-Domingo, Kirsten; Olde Rikkert, Marcel GM; Horton, Richard; Mash, Robert; Monteiro, Carlos; Naumova, Elena N.; Rubin, Eric J.; Sahni, Peush; Tumwine, James; Yonga, Paul; Zielinski, Chris; Mitra, Arun; Ruff, Tilman; Haines, Andy; Helfand, Ira

doi: 10.1038/s41416-023-02447-zpmid: 37853166

Whitfield, Emma; White, Becky; Denaxas, Spiros; Barclay, Matthew E.; Renzi, Cristina; Lyratzopoulos, Georgios

doi: 10.1038/s41416-023-02450-4pmid: 37794179

Researchers and research funders aiming to improve diagnosis seek to identify if, when, where, and how earlier diagnosis is possible. This has led to the propagation of research studies using a wide range of methodologies and data sources to explore diagnostic processes. Many such studies use electronic health record data and focus on cancer diagnosis. Based on this literature, we propose a taxonomy to guide the design and support the synthesis of early diagnosis research, focusing on five key questions:Do healthcare use patterns suggest earlier diagnosis could be possible?How does the diagnostic process begin?How do patients progress from presentation to diagnosis?How long does the diagnostic process take?Could anything have been done differently to reach the correct diagnosis sooner?We define families of diagnostic research study designs addressing each of these questions and appraise their unique or complementary contributions and limitations. We identify three further questions on relationships between the families and their relevance for examining patient group inequalities, supported with examples from the cancer literature. Although exemplified through cancer as a disease model, we recognise the framework is also applicable to non-neoplastic disease. The proposed framework can guide future study design and research funding prioritisation.

Weston, William A.; Barr, Alexis R.

doi: 10.1038/s41416-023-02401-zpmid: 37608096

Tumour dormancy and recurrent metastatic cancer remain the greatest clinical challenge for cancer patients. Dormant tumour cells can evade treatment and detection, while retaining proliferative potential, often for years, before relapsing to tumour outgrowth. Cellular quiescence is one mechanism that promotes and maintains tumour dormancy due to its central role in reducing proliferation, elevating cyto-protective mechanisms, and retaining proliferative potential. Quiescence/proliferation decisions are dictated by intrinsic and extrinsic signals, which regulate the activity of cyclin-dependent kinases (CDKs) to modulate cell cycle gene expression. By clarifying the pathways regulating CDK activity and the signals which activate them, we can better understand how cancer cells enter, maintain, and escape from quiescence throughout the progression of dormancy and metastatic disease. Here we review how CDK activity is regulated to modulate cellular quiescence in the context of tumour dormancy and highlight the therapeutic challenges and opportunities it presents.

Valcarcel-Jimenez, Lorea; Frezza, Christian

doi: 10.1038/s41416-023-02412-wpmid: 37689804

Fumarate hydratase (FH) is an enzyme of the Tricarboxylic Acid (TCA) cycle whose mutations lead to hereditary and sporadic forms of cancer. Although more than twenty years have passed since its discovery as the leading cause of the cancer syndrome Hereditary leiomyomatosis and Renal Cell Carcinoma (HLRCC), it is still unclear how the loss of FH causes cancer in a tissue-specific manner and with such aggressive behaviour. It has been shown that FH loss, via the accumulation of FH substrate fumarate, activates a series of oncogenic cascades whose contribution to transformation is still under investigation. In this review, we will summarise these recent findings in an integrated fashion and put forward the case that understanding the biology of FH and how its mutations promote transformation will be vital to establish novel paradigms of oncometabolism.

Ahmad, Amar S.; Offman, Judith; Delon, Christine; North, Bernard V.; Shelton, Jon; Sasieni, Peter D.

doi: 10.1038/s41416-023-02422-8pmid: 37726479

BackgroundWe investigated the application of years of life lost (YLL) in routine cancer statistics using cancer mortality data from 1988 to 2017.MethodsCancer mortality data for 17 cancers and all cancers in the UK from 1988 to 2017 were provided by the UK Association of Cancer Registries by sex, 5-year age group, and year. YLL, age-standardised YLL rate (ASYR) and age-standardised mortality rate (ASMR) were estimated.ResultsThe annual average YLL due to cancer, in the time periods 1988–1992 and 2013–2017, were about 2.2 and 2.3 million years, corresponding to 4510 and 3823 ASYR per 100,000 years, respectively. During 2013–2017, the largest number of YLL occurred in lung, bowel and breast cancer. YLL by age groups for all cancers showed a peak between 60–64 and 75–79. The relative contributions to incidence, mortality, and YLL differ between cancers. For instance, pancreas (in women and men) made up a smaller proportion of incidence (3%) but bigger proportion of mortality (6 and 5%) and YLL (5 and 6%), whereas prostate cancer (26% of incidence) contributed 13% mortality and 9% YLL.ConclusionYLL is a useful measure of the impact different cancers have on society and puts a higher weight on cancer deaths in younger individuals.

Gannon, Melissa Ruth; Dodwell, David; Aggarwal, Ajay; Park, Min Hae; Miller, Katie; Horgan, Kieran; Clements, Karen; Medina, Jibby; Cromwell, David Alan

doi: 10.1038/s41416-023-02439-zpmid: 37741900

BackgroundMultiple drug treatments are approved for invasive breast cancer (IBC). We investigated uptake of NICE-recommended oncological drugs and variation by age, comorbidity burden and geographical region.MethodsWomen (aged 50+ years) diagnosed with IBC from 2014 to 2019, were identified from England Cancer Registry data and drug utilisation from Systemic Anti-Cancer Therapy data. Interrupted time series analysis assessed national-level changes in drug use after publication of NICE recommendations. Regression models analysed variation in use.ResultsThis national cohort included 168,449 women. Use of drugs recommended for first-line treatment varied, from 26.6% for CDK 4/6 inhibitors to 63.8% for HER2-targeting therapies. Utilisation of drugs with a NICE recommendation published between 2014 and 2019, increased among patients diagnosed around the time of publication, except in the case of pertuzumab for metastatic breast cancer (MBC) which was previously accessible via the Cancer Drugs Fund (though use of pertuzumab for MBC increased from 34.1% to 75.0% across the study period). Use of trastuzumab and neoadjuvant/adjuvant pertuzumab varied by geographical region. Use was low for ribociclib (2.2%), abemaciclib (2.3%) and for drugs recommended beyond the first-line setting. For all drugs, use after NICE recommendation varied by age at diagnosis and increased as stage increased.ConclusionsUse of NICE-recommended drugs for IBC in routine care is variable, with lowest use among women aged 70+ years. Improving access to effective treatments is an important step in improving outcomes.

Bremmer, Felix; Pongratanakul, Pailin; Skowron, Margaretha; Che, Yue; Richter, Annika; Küffer, Stefan; Reuter-Jessen, Kirsten; Bohnenberger, Hanibal; Pauls, Stella; Kresbach, Catena; Schüller, Ulrich; Stühler, Kai; Ströbel, Philipp; Albers, Peter; Nettersheim, Daniel

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Payne, Karl; Brooks, Jill; Batis, Nikolaos; Khan, Naeem; El-Asrag, Mohammed; Nankivell, Paul; Mehanna, Hisham; Taylor, Graham

doi: 10.1038/s41416-023-02428-2pmid: 37735243

BackgroundCirculating tumour cells (CTCs) are a potential cancer biomarker, but current methods of CTC analysis at single-cell resolution are limited. Here, we describe high-dimensional single-cell mass cytometry proteomic analysis of CTCs in HNSCC.MethodsParsortix microfluidic-enriched CTCs from 14 treatment-naïve HNSCC patients were analysed by mass cytometry analysis using 41 antibodies. Immune cell lineage, epithelial-mesenchymal transition (EMT), stemness, proliferation and immune checkpoint expression was assessed alongside phosphorylation status of multiple signalling proteins. Patient-matched tumour gene expression and CTC EMT profiles were compared. Standard bulk CTC RNAseq was performed as a baseline comparator to assess mass cytometry data.ResultsCTCs were detected in 13/14 patients with CTC counts of 2–24 CTCs/ml blood. Unsupervised clustering separated CTCs into epithelial, early EMT and advanced EMT groups that differed in signalling pathway activation state. Patient-specific CTC cluster patterns separated into immune checkpoint low and high groups. Patient tumour and CTC EMT profiles differed. Mass cytometry outperformed bulk RNAseq to detect CTCs and characterise cell phenotype.DiscussionWe demonstrate mass cytometry allows high-plex proteomic characterisation of CTCs at single-cell resolution and identify common CTC sub-groups with potential for novel biomarker development and immune checkpoint inhibitor treatment stratification.

Mahmood, Hanya; Shephard, Adam; Hankinson, Paul; Bradburn, Mike; Araujo, Anna Luiza Damaceno; Santos-Silva, Alan Roger; Lopes, Marcio Ajudarte; Vargas, Pablo Agustin; McCombe, Kris D.; Craig, Stephanie G.; James, Jacqueline; Brooks, Jill; Nankivell, Paul; Mehanna, Hisham; Rajpoot, Nasir; Khurram, Syed Ali

Day, Daphne; Park, John J.; Coward, Jermaine; Markman, Ben; Lemech, Charlotte; Kuo, James C.; Prawira, Amy; Brown, Michael P.; Bishnoi, Sarwan; Kotasek, Dusan; Strother, R. Matthew; Cosman, Rasha; Su, Rila; Ma, Yiding; Yue, Zenglian; Hu, Hui-han; Wu, Rachel; Li, Peiqi; Tse, Archie N.