---
title: "Early pathology input in biologically driven cancer trials: why it matters"
id: "british-journal-of-cancer-0-why-early-pathology-input-matters-in-biologically-rich-cancer-trials"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-why-early-pathology-input-matters-in-biologically-rich-cancer-trials"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03605-9"
published_at: "2026-09-01T05:42:07.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Early pathology input in biologically driven cancer trials: why it matters
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-why-early-pathology-input-matters-in-biologically-rich-cancer-trials
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03605-9)
- **Published At:** 2026-09-01T05:42:07.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Pathology is integral to biologically rich cancer trials, contributing beyond diagnosis to classification, staging, biomarker interpretation, eligibility assessment, response assessment, and endpoint evaluation. - Early involvement of pathology before protocols, budgets, and assays are fixed improves feasibility, specimen governance, assay selection, and quality assurance. - Multidisciplinary planning that includes pathologists with surgeons, radiologists, oncologists, trial managers, and laboratory scientists aligns tissue collection with scientific aims and decision points, reducing repeat procedures and screen failures. - The SPIRIT-Path extension provides a framework for specifying pathology responsibilities, laboratory locations, accreditation, specimen transport, and future translational use in trial protocols. - Pre-analytical variables (fixation, processing delays, decalcification, storage, tumour cellularity) and narrow consent can undermine molecular assays and reduce long-term sample value; pathology input can mitigate these risks. - Spatial biology and multiplexed imaging increase demands on tissue handling, annotation, and analytical standardisation, requiring early pathology planning. - Examples from the UK (FOCUS4, National Lung Matrix Trial, plasmaMATCH) demonstrate that rigorous pathology and laboratory design enable large-scale molecular profiling, low assay failure rates, high inter-laboratory concordance, and use of circulating tumour DNA to allocate patients without repeat biopsies. - For CTIMPs and biomarker-led studies, pathology links the intervention to mechanism by ensuring specimens and assays can support translational endpoints that answer who benefits, target engagement, and resistance mechanisms. - Embedding pathology early enhances trial readiness, aligns consent and governance with scientific aims, and increases the long-term translational value of collected tissue.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [british journal of cancer](https://www.nature.com/bjc) 3. [perspectives](https://www.nature.com/bjc/articles?type=perspective) 4. article Why early pathology input matters in biologically rich cancer trials [ Download PDF ](https://www.nature.com/articles/s41416-026-03605-9.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03605-9.pdf) * Perspective * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 01 September 2026 Clinical Study # Why early pathology input matters in biologically rich cancer trials * [Manas Dave](https://www.nature.com/articles/s41416-026-03605-9#auth-Manas-Dave-Aff1)[1](https://www.nature.com/articles/s41416-026-03605-9#Aff1), * [Maggie Chon U. Cheang](https://www.nature.com/articles/s41416-026-03605-9#auth-Maggie_Chon_U_-Cheang-Aff2) [ORCID: orcid.org/0000-0001-5718-2501](https://orcid.org/0000-0001-5718-2501)[2](https://www.nature.com/articles/s41416-026-03605-9#Aff2), * [Guy Betts](https://www.nature.com/articles/s41416-026-03605-9#auth-Guy-Betts-Aff3)[3](https://www.nature.com/articles/s41416-026-03605-9#Aff3), * [Tomoko Iwata](https://www.nature.com/articles/s41416-026-03605-9#auth-Tomoko-Iwata-Aff4) [ORCID: orcid.org/0000-0002-9634-9738](https://orcid.org/0000-0002-9634-9738)[4](https://www.nature.com/articles/s41416-026-03605-9#Aff4), * [Michelle Frost](https://www.nature.com/articles/s41416-026-03605-9#auth-Michelle-Frost-Aff2)[2](https://www.nature.com/articles/s41416-026-03605-9#Aff2), * [Chiara Braconi](https://www.nature.com/articles/s41416-026-03605-9#auth-Chiara-Braconi-Aff5-Aff6) [ORCID: orcid.org/0000-0003-4835-1259](https://orcid.org/0000-0003-4835-1259)[5](https://www.nature.com/articles/s41416-026-03605-9#Aff5),[6](https://www.nature.com/articles/s41416-026-03605-9#Aff6), * [Menna Shamma](https://www.nature.com/articles/s41416-026-03605-9#auth-Menna-Shamma-Aff7)[7](https://www.nature.com/articles/s41416-026-03605-9#Aff7) & * … * [Timothy J. Kendall](https://www.nature.com/articles/s41416-026-03605-9#auth-Timothy_J_-Kendall-Aff8) [ORCID: orcid.org/0000-0002-4174-2786](https://orcid.org/0000-0002-4174-2786)[8](https://www.nature.com/articles/s41416-026-03605-9#Aff8) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03605-9#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03605-9/save-research?_csrf=WXCgrIfQAzfdlliVcu5ot2bqf0cdM-xH) [ View saved research ](https://www.nature.com/saved-research) ## Abstract Pathology is central to many biologically driven cancer clinical trials. Biomarker-led and translational studies depend on robust tissue pathways, cellular and molecular assays, pathology-derived endpoints, and clinically meaningful interpretation of discovery science. Where trials depend on tumour material, biomarker-defined eligibility or mechanism-focused endpoints, pathology expertise should be embedded early, before protocols, budgets, and assays are fixed. Early pathology input strengthens feasibility, specimen governance, assay selection, quality assurance, and the long-term value of collected samples. In the UK, the Clinical Trials Pathology Advisory Group, now within the new Pathological Society of Great Britain and Ireland Clinical Trials Pathology subcommittee, provides a practical route for pre-submission specialist review. This Perspective argues that pathology is core infrastructure for biologically rich trials, linking discovery science to clinical translation. ### Explore related subjects Discover the latest articles and news in related subjects. * [Cancer](https://www.nature.com/subjects/cancer) * [Medical research](https://www.nature.com/subjects/medical-research) ## Article PDF ## Pathology is now part of trial architecture Many cancer trial teams, particularly within established clinical trials units, already involve pathology and laboratory expertise rigorously during trial development. The challenge is, therefore, not to correct an absence of pathology input but to ensure that the right expertise is available early and consistently wherever tissue, cellular, or molecular data are central to the study. In this context, pathology is not confined to diagnosis. Pathologists contribute to classification, staging, biomarker interpretation, eligibility assessment, response assessment, and endpoint evaluation. In biomarker-led, adaptive, umbrella, and window-of-opportunity studies, pathology-derived measures may define primary or key secondary endpoints, not simply exploratory analyses. Pathologists can also support tissue acquisition strategies by advising on the amount, quality, and processing of material required for downstream analyses, alongside key clinical trial stakeholders including surgeons, interventional radiologists, oncologists, cancer biologists, trial managers, and laboratory scientists. This multidisciplinary planning helps align clinical sampling with the scientific aims and decision points of the trial. It can reduce avoidable repeat procedures, protect tissue needed for patient care, minimise screen failures due to insufficient material, and ensure that assays and response assessments can be delivered reproducibly within the timelines required for recruitment, treatment allocation, and go/no-go decisions [[1](https://www.nature.com/articles/s41416-026-03605-9#ref-CR1 "Provenzano E, Driskell OJ, O’Connor DJ, Rodriguez-Justo M, McDermott J, Wong N, et al. The important role of the histopathologist in clinical trials: challenges and approaches to tackle them. Histopathology. 2020;76:942–9."),[2](https://www.nature.com/articles/s41416-026-03605-9#ref-CR2 "Matias-Guiu X, Raspollini MR, Kulka J, Ryska A, Al Dieri R, Schirmacher P. The role of the pathologist in the design and conducting of biomarker-driven clinical trials in cancer: position paper of the European Society of Pathology. Virchows Arch. 2025;486:207–14."),[3](https://www.nature.com/articles/s41416-026-03605-9#ref-CR3 "Nagtegaal ID, West NP, van Krieken JH, Quirke P. Pathology is a necessary and informative tool in oncology clinical trials. J Pathol. 2014;232:185–9."),[4](https://www.nature.com/articles/s41416-026-03605-9#ref-CR4 "Lim SJ, Gurusamy K, O’Connor D, Shaaban AM, Brierley D, Lewis I, et al. Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation. J Pathol Clin Res. 2021;7:191–202."),[5](https://www.nature.com/articles/s41416-026-03605-9#ref-CR5 "Kendall TJ, Robinson M, Brierley DJ, Lim SJ, O’Connor DJ, Shaaban AM, et al. Guidelines for cellular and molecular pathology content in clinical trial protocols: the SPIRIT-Path extension. Lancet Oncol. 2021;22:e435–e45."),[6](https://www.nature.com/articles/s41416-026-03605-9#ref-CR6 "Robinson P, Bacon CM, Lim SJ, Shaaban AM, Brierley D, Lewis I, et al. Assessment of clinical trial protocols for pathology content using the SPIRIT-Path guidelines highlights areas for improvement. J Pathol Clin Res. 2022;8:411–21.")]. Where trials depend on biological material, pathology input is, therefore, part of trial architecture: it weaves together the clinical question, the specimen pathway, the assay, the endpoint, and the timing of trial decisions. ## Why pathology input matters before funding submission For biologically driven cancer trials, pathology planning should be visible before funding submission, when protocols, budgets, timelines, and laboratory workflows are still modifiable. This is already routine in many well-developed trials, particularly within established clinical trials units. The aim is not to duplicate existing expertise but to encourage the adoption of a consistent framework where tissue handling, assay delivery, endpoint assessment, and translational use of samples are central to the study. The SPIRIT-Path extension provides such a framework. It was developed through an international Delphi consensus process to provide specific guidance on cellular and molecular pathology activity in clinical trial protocols as an extension to the SPIRIT 2013 statement [[7](https://www.nature.com/articles/s41416-026-03605-9#ref-CR7 "Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Annals of Internal Medicine. 2013;158:200–7.")]. SPIRIT-Path recommends that protocols define who is responsible for pathology activities, where analyses will be performed, what accreditation and quality systems apply, how specimens will move between sites and laboratories, and how tissue will be used for protocol-defined or future translational work [[4](https://www.nature.com/articles/s41416-026-03605-9#ref-CR4 "Lim SJ, Gurusamy K, O’Connor D, Shaaban AM, Brierley D, Lewis I, et al. Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation. J Pathol Clin Res. 2021;7:191–202."),[5](https://www.nature.com/articles/s41416-026-03605-9#ref-CR5 "Kendall TJ, Robinson M, Brierley DJ, Lim SJ, O’Connor DJ, Shaaban AM, et al. Guidelines for cellular and molecular pathology content in clinical trial protocols: the SPIRIT-Path extension. Lancet Oncol. 2021;22:e435–e45."),[6](https://www.nature.com/articles/s41416-026-03605-9#ref-CR6 "Robinson P, Bacon CM, Lim SJ, Shaaban AM, Brierley D, Lewis I, et al. Assessment of clinical trial protocols for pathology content using the SPIRIT-Path guidelines highlights areas for improvement. J Pathol Clin Res. 2022;8:411–21.")]. These details shape whether patients can be screened efficiently, if biomarker results can be returned in time for treatment allocation, whether samples can be used for primary or key secondary endpoints, and if response assessments can support interim go/no-go decisions. A project [[8](https://www.nature.com/articles/s41416-026-03605-9#ref-CR8 "Robinson P Update and remapping of SPIRIT-Path extension 2026: protocol \[Online\]. United States of America: Center for Open Science; 2026 \[Available from: https://osf.io/96yjp/overview .")] to revise the SPIRIT-Path extension to align with the SPIRIT 2025 update is now underway to ensure this guidance remains relevant [[9](https://www.nature.com/articles/s41416-026-03605-9#ref-CR9 "Chan A-W, Boutron I, Hopewell S, Moher D, Schulz KF, Collins GS, et al. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. BMJ. 2025;389:e081477.")]. Good pathology planning, therefore, strengthens trial readiness. It reduces avoidable screen failures, failed samples, protocol amendments, and loss of material needed for translational analyses. It also ensures that consent, specimen governance, and laboratory costing are aligned with the scientific aims of the study before funding decisions are made. ## Pathology links intervention to mechanism These considerations are especially important in clinical trials of investigational medicinal products (CTIMPs). Modern oncology CTIMPs often ask not only whether an intervention works, but who benefits, whether the intended pathway has been engaged, how resistance emerges, and which biomarkers should guide future studies or clinical implementation [[2](https://www.nature.com/articles/s41416-026-03605-9#ref-CR2 "Matias-Guiu X, Raspollini MR, Kulka J, Ryska A, Al Dieri R, Schirmacher P. The role of the pathologist in the design and conducting of biomarker-driven clinical trials in cancer: position paper of the European Society of Pathology. Virchows Arch. 2025;486:207–14."), [10](https://www.nature.com/articles/s41416-026-03605-9#ref-CR10 "Mateo J, Steuten L, Aftimos P, André F, Davies M, Garralda E, et al. Delivering precision oncology to patients with cancer. Nat Med. 2022;28:658–65.")]. These questions depend on translational endpoints that are only as robust as the specimens, assays, and laboratory systems that support them. The pre-analytical phase is critical. Specimen fixation, processing delays, decalcification, storage conditions, and tumour cellularity all influence downstream molecular performance [[11](https://www.nature.com/articles/s41416-026-03605-9#ref-CR11 "Bass BP, Engel KB, Greytak SR, Moore HM. A review of preanalytical factors affecting molecular, protein, and morphological analysis of formalin-fixed, paraffin-embedded \(FFPE\) tissue: how well do you know your FFPE specimen? Arch Pathol Lab Med. 2014;138:1520–30.")]. Degraded nucleic acid, low tumour purity, or unrecognised pre-analytical variation can make translational readouts uninterpretable even when samples have been collected successfully. Similarly, narrow consent can restrict secondary analyses and reduce the long-term value of collected tissue [[4](https://www.nature.com/articles/s41416-026-03605-9#ref-CR4 "Lim SJ, Gurusamy K, O’Connor D, Shaaban AM, Brierley D, Lewis I, et al. Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation. J Pathol Clin Res. 2021;7:191–202."), [5](https://www.nature.com/articles/s41416-026-03605-9#ref-CR5 "Kendall TJ, Robinson M, Brierley DJ, Lim SJ, O’Connor DJ, Shaaban AM, et al. Guidelines for cellular and molecular pathology content in clinical trial protocols: the SPIRIT-Path extension. Lancet Oncol. 2021;22:e435–e45.")]. Biologically rich trials may also seek to capture spatial biology through multiplex imaging and spatial-omics, placing further demands on tissue handling, annotation, and analytical standardisation [[12](https://www.nature.com/articles/s41416-026-03605-9#ref-CR12 "Lewis SM, Asselin-Labat M-L, Nguyen Q, Berthelet J, Tan X, Wimmer VC, et al. Spatial omics and multiplexed imaging to explore cancer biology. Nature Methods. 2021;18:997–1012.")]. Several UK studies have illustrated what rigorous pathology and laboratory planning can achieve. For example, FOCUS4 embedded molecular profiling within an umbrella trial in metastatic colorectal cancer and required pre-trial inter-laboratory validation before testing was used for cohort allocation [[13](https://www.nature.com/articles/s41416-026-03605-9#ref-CR13 "Richman SD, Adams R, Quirke P, Butler R, Hemmings G, Chambers P, et al. Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial. J Clin Pathol. 2016;69:35–41.")]. Across the trial, 1,291 tumour samples were analysed with low assay failure rates and concordance of at least 98% between laboratories where both produced a result [[14](https://www.nature.com/articles/s41416-026-03605-9#ref-CR14 "Richman SD, Hemmings G, Roberts H, Gallop N, Dodds R, Wilkinson L, et al. FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing. J Clin Pathol. 2023;76:548–54.")]. The National Lung Matrix Trial used central molecular profiling to allocate patients with non-small cell lung cancer to genotype-matched treatment cohorts at national scale [[15](https://www.nature.com/articles/s41416-026-03605-9#ref-CR15 "Middleton G, Fletcher P, Popat S, Savage J, Summers Y, Greystoke A, et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature. 2020;583:807–12.")]. plasmaMATCH showed that circulating tumour DNA testing could identify actionable genomic alterations in advanced breast cancer and direct cohort assignment across UK sites without requiring repeat tumour biopsy in every patient [[16](https://www.nature.com/articles/s41416-026-03605-9#ref-CR16 "Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer \(plasmaMATCH\): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21:1296–308.")]. These examples show that pathology and laboratory design are not ancillary to complex biomarker trials; they are part of how such trials function under rea
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