# Biomarkers are not validated or standardised

Source: https://onco.cc/bottlenecks/b-biomarker-validation/  
OnCo record `b-biomarker-validation` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.

## Summary

Modern oncology allocates drugs by biomarker, but the biomarkers are held to a lower standard than the drugs. PD-L1 is scored with several non-interchangeable antibodies and cut-offs; HER2-low, which now defines eligibility for trastuzumab deruxtecan, depends on distinguishing IHC 0 from 1+, where pathologist agreement is poor; TMB varies by panel, bioinformatic pipeline and tumour type; HRD assays disagree with each other; and TROP2 and other ADC targets are given without any validated assay at all. Most biomarkers are validated retrospectively within the pivotal trial of one drug, on one assay, then used with different assays in practice. The consequences are patients wrongly included or excluded, irreproducible subgroup results, and combination biomarkers that never reach the clinic. Analytical standardisation, external quality assurance, prospective biomarker-stratified trials, and AI quantification that removes inter-observer variability are the remedies.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: trials
- Severity: major
- Metrics: Pathologist concordance in classifying HER2 IHC 0 vs 1+ (the HER2-low boundary) across 18 pathologists: 26% agreement (Fernandez et al., JAMA Oncology 2022); PD-L1 assays in the Blueprint comparison project whose tumour-cell staining was interchangeable (22C3, 28-8, SP263) vs discordant (SP142): 3 concordant, 1 discordant (Hirsch et al., Journal of Thoracic Oncology 2017)
- Causes: Each drug sponsor develops its own companion assay and cut-off, with no obligation to harmonise.; Immunohistochemistry is semi-quantitative and subject to pre-analytical variation and inter-observer disagreement.; Retrospective validation within a single trial is accepted by regulators as sufficient.; External quality assurance schemes are voluntary in many countries.; Reimbursement for testing lags approval, so laboratories adopt cheaper, non-validated substitutes.

## Sources

- Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022): https://doi.org/10.1001/jamaoncol.2021.7239
- Hirsch et al., Blueprint PD-L1 IHC assay comparison project (JTO 2017): https://doi.org/10.1016/j.jtho.2016.11.2228
- Merino et al., Establishing guidelines to harmonize tumor mutational burden (JITC 2020): https://doi.org/10.1136/jitc-2019-000147

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cancer](https://onco.cc/key-papers/paper-taylor-integrative-genomic-profiling-cancer-cell-2010/), [Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack](https://onco.cc/key-papers/paper-iwai-pdl1-tumour-escape-pnas-2002/), [Jaiswal: clonal haematopoiesis, the pre-leukaemic clones in most people over 70](https://onco.cc/key-papers/paper-jaiswal-chip-nejm-2014/), [KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer](https://onco.cc/key-papers/paper-keynote-048-lancet-2019/), [KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer](https://onco.cc/key-papers/paper-keynote-177-nejm-2020/), [KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation](https://onco.cc/key-papers/paper-keynote-189-nejm-2018/), [KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context](https://onco.cc/key-papers/paper-draisma-lead-time-overdiagnosis-psa-jnci-2009/), [Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection](https://onco.cc/key-papers/paper-fahrmann-ca19-9-lead-time-gastroenterology-2021/), [Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones](https://onco.cc/key-papers/paper-martincorena-somatic-mutations-normal-skin-science-2015/), [Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes](https://onco.cc/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/), [Multitarget stool DNA testing for colorectal-cancer screening](https://onco.cc/key-papers/paper-imperiale-multitarget-stool-dna-screening-nejm-2014/), [Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-goya-obinutuzumab-vs-rituximab-chop-dlbcl-jco-2017/), [Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC](https://onco.cc/key-papers/paper-lu-laura-osimertinib-stage-iii-nejm-2024/), [PACIFIC: a year of durvalumab after chemoradiotherapy for stage III lung cancer](https://onco.cc/key-papers/paper-pacific-nejm-2017/), [Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer](https://onco.cc/key-papers/paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006/), [Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)](https://onco.cc/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/), [PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours](https://onco.cc/key-papers/paper-paola-1-nejm-2019/), [PATHFINDER: the first prospective test of a multi-cancer blood test in people without symptoms](https://onco.cc/key-papers/paper-pathfinder-lancet-2023/), [PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer](https://onco.cc/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/), [PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project](https://onco.cc/key-papers/paper-hirsch-j-thorac-oncol/), [Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer](https://onco.cc/key-papers/paper-scagliotti-cisplatin-pemetrexed-histology-jco-2008/), [POLARIX: swapping vincristine for the antibody-drug conjugate polatuzumab vedotin in first-line treatment of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-polarix-polatuzumab-rchp-nejm-2022/), [Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials](https://onco.cc/key-papers/paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017/), [PROMIS: diagnostic accuracy of multiparametric MRI and TRUS biopsy in prostate cancer](https://onco.cc/key-papers/paper-ahmed-promis-multiparametric-mri-lancet-2017/), [Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours](https://onco.cc/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/), [Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate](https://onco.cc/key-papers/paper-stamey-psa-serum-marker-nejm-1987/), [Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)](https://onco.cc/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/), [Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer](https://onco.cc/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/), [Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer](https://onco.cc/key-papers/paper-tempero-ca19-9-lewis-antigens-cancer-res-1987/), [RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-ruby-nejm-2023/), [SPOTLIGHT: zolbetuximab, the first Claudin 18.2 antibody, added to chemotherapy in gastric cancer](https://onco.cc/key-papers/paper-spotlight-lancet-2023/), [SU2C-PCF: integrative clinical genomics of advanced prostate cancer](https://onco.cc/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/), [TCGA: the molecular taxonomy of primary prostate cancer](https://onco.cc/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/), [The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma](https://onco.cc/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/), [Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer](https://onco.cc/key-papers/paper-topalian-anti-pd1-nejm-2012/), [TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer](https://onco.cc/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/), [TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse](https://onco.cc/key-papers/paper-tracerx-100-nejm-2017/), [TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration](https://onco.cc/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/), [TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/), [TROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival](https://onco.cc/key-papers/paper-tropion-breast01-jco-2024/), [Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer](https://onco.cc/key-papers/paper-leon-ferre-tils-tnbc-no-chemotherapy-jama-2024/)
- roadmaps: [Diagnostics roadmap: stains → gene panels → blood tests that decide treatment](https://onco.cc/roadmaps/diagnostics-roadmap/), [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials](https://onco.cc/roadmaps/gallbladder-cancer-roadmap/), [Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test](https://onco.cc/roadmaps/hormonal-therapy-roadmap/), [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- institutions: [Deutsches Netzwerk für Personalisierte Medizin](https://onco.cc/institutions/dnpm/), [Gemeinsamer Bundesausschuss / IQWiG](https://onco.cc/institutions/g-ba-iqwig/), [nationales Netzwerk Genomische Medizin Lungenkrebs](https://onco.cc/institutions/nngm/)

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JSON: https://onco.cc/api/v1/entities/b-biomarker-validation.json