{"entity":{"id":"opp-trop2-imaging-heterogeneity","kind":"opportunity","name":"TROP2 imaging where no tissue test is required","aka":["TROP2 PET","Trop-2 imaging"],"tldr":"Two approved breast cancer drugs work through a protein called TROP2, and neither requires any test for it before use. Tumours vary a lot in how much they carry, and a quarter of patients lose it over time, so nobody currently knows who is being treated for a target that is no longer there.","summary":"Sacituzumab govitecan and datopotamab deruxtecan are both approved TROP2-directed antibody-drug conjugates, and neither label requires a TROP2 assay. That is not because expression is irrelevant: in the ASCENT biomarker analysis, patients with high TROP2 expression had an objective response rate of 44% against 22% in the low group, with progression-free survival of 6.9 against 2.7 months. It is because the tissue test does not work well enough to gate treatment. A comparison of three immunohistochemistry assays found only fair-to-moderate concordance, there is no validated plasma or ctDNA assay, and a study of circulating tumour cells found no concordance between cell-based and tissue TROP2 status.\n\nHeterogeneity is documented in both space and time: in paired primary and brain-metastasis samples, 21.4% of cases were discordant, and in a longitudinal biopsy series 27.6% of patients showed a marked fall in TROP2 H-score between consecutive time points. Bone metastases showed lower TROP2 than other sites in a post-mortem multi-metastasis study.\n\nThe imaging programmes are Chinese, academic and moving quickly. The nanobody tracer 68Ga-MY6349 completed a 90-patient multi-tumour feasibility study and then a 73-patient breast-specific study published in Theranostics in 2026. Nobody has filed anywhere. Because no companion diagnostic exists to be displaced, an imaging agent here would not be competing with an approved assay but filling a space that both drug labels leave open.","asOf":"2026-09-23","links":[{"label":"68Ga-MY6349 in breast cancer, Theranostics 2026","url":"https://www.thno.org/v16p8117.htm"},{"label":"ASCENT TROP2 biomarker analysis","url":"https://pubmed.ncbi.nlm.nih.gov/34116144/"},{"label":"TROP2 biomarker review: no companion diagnostic, no validated plasma assay","url":"https://biomarker.onclive.com/breast-cancer/triple-negative-tnbc/biomarkers/trop2"},{"label":"Longitudinal fall in TROP2 expression during treatment","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13379550/"},{"label":"FDA approval of datopotamab deruxtecan, January 2025","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast"}],"tags":["target crossover","breast","heterogeneity","nanobody"],"related":["ga-68"],"indications":["breast-triple-negative"],"sections":[],"technologies":["trop2-pet","immuno-pet","pet-ct"],"targets":["trop2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"lens":"target-crossover","unmetNeed":"Neither approved TROP2 antibody-drug conjugate requires a test for TROP2, and no validated blood or tissue assay exists, so when a patient stops responding nobody can tell whether the target has been lost or the payload has failed.","useCase":"A breast oncologist would scan before starting a TROP2 antibody-drug conjugate in a patient with several metastatic sites including bone, and again at progression, to distinguish loss of target from resistance to the payload. In practice the first real use is inside trials, deciding whether target level predicts benefit well enough to justify a clinical test at all.","hypothesis":"Whole-body TROP2 quantification will predict benefit from TROP2-directed antibody-drug conjugates better than tissue immunohistochemistry, because the observed 21% primary-to-metastasis discordance and the 28% of patients with a marked longitudinal fall in expression are exactly the errors a single biopsy cannot avoid and imaging can.","rationale":"Unlike HER3, there is already a published expression-response gradient for a TROP2 drug: 44% against 22% objective response by expression level in ASCENT. The reason that gradient has not become a test is assay failure rather than absent biology, and the failures are specifically of sampling and standardisation, which is the class of problem imaging addresses. Nanobody constructs give same-day imaging, and one has already been through 90 patients across tumour types and then a 73-patient disease-specific study.","test":"A study embedded in a TROP2 antibody-drug conjugate trial: image before treatment, relate uptake to objective response and progression-free survival, and re-image at progression in a subset to measure change in target. The primary question is whether an imaging threshold separates responders better than the published immunohistochemistry cut-offs did in ASCENT.","maturity":"early-clinical","verdict":"companion-only","mostAdvanced":"68Ga-MY6349, a TROP2 nanobody tracer from Shanghai Novamab studied at Xiamen and Fudan, with a completed 90-patient multi-tumour study and a 73-patient breast-cancer study published in Theranostics in 2026.","dueDiligence":[{"domain":"target-biology","state":"moderate","why":"TROP2 is widely expressed in breast cancer but with marked intratumoral heterogeneity and discordance between primary and metastatic sites; membranous rather than cytoplasmic localisation appears to matter more than total intensity.","source":"TROP2 biomarker review","url":"https://biomarker.onclive.com/breast-cancer/triple-negative-tnbc/biomarkers/trop2","weighted":true},{"domain":"clinical-evidence","state":"moderate","why":"One nanobody tracer has a completed 90-patient feasibility study and a published 73-patient breast-specific study; all of it academic, single-country and not registrational.","source":"Theranostics 2026","url":"https://www.thno.org/v16p8117.htm"},{"domain":"diagnostic-performance","state":"thin","why":"No study relates tracer uptake to antibody-drug conjugate response. The comparator's performance is the strongest published signal: ASCENT reported 44% against 22% objective response by TROP2 expression level.","source":"ASCENT biomarker analysis","url":"https://pubmed.ncbi.nlm.nih.gov/34116144/","weighted":true},{"domain":"safety-dosimetry","state":"thin","why":"No adverse events reported in the published nanobody cohorts, but no formal dosimetry figure has been published that is worth quoting."},{"domain":"regulatory-path","state":"thin","why":"There is no TROP2 companion diagnostic to anchor a claim, and neither drug label requires testing, so an imaging agent would have to define its own indication, most plausibly as an adjunct rather than a selection gate.","source":"TROP2 biomarker review","url":"https://biomarker.onclive.com/breast-cancer/triple-negative-tnbc/biomarkers/trop2"}],"flags":[{"category":"technical","flag":"green","why":"A nanobody construct labelled with gallium-68 already images in humans with same-day kinetics, which is the format this kind of agent needs."},{"category":"unmet-need","flag":"amber","why":"Real heterogeneity and a published expression-response gradient, but both drugs are prescribed today without any test, so the clinical pull is weaker than the biology suggests."},{"category":"ip","flag":"amber","why":"The leading construct is owned by a Chinese biotech and studied with academic partners; no Western clinical programme is disclosed."},{"category":"commercial","flag":"amber","why":"Two approved drugs and expanding indications make the addressable population large, but a test that neither label requires has to earn reimbursement on its own evidence."},{"category":"isotope","flag":"green","why":"Gallium-68 on a nanobody; nothing scarce."},{"category":"competition","flag":"amber","why":"The Chinese programme is several years and roughly 160 patients ahead of anyone else."}],"competition":[{"name":"Shanghai Novamab with Xiamen and Fudan centres","what":"68Ga-MY6349 nanobody PET; completed 90-patient multi-tumour study and a published 73-patient breast-cancer study.","stage":"early clinical","url":"https://www.thno.org/v16p8117.htm"},{"name":"Gilead","what":"Sacituzumab govitecan, approved since 2020 across triple-negative and HR-positive breast cancer; no TROP2 test required.","stage":"approved","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-hziy-metastatic-triple-negative-breast-cancer"},{"name":"Daiichi Sankyo and AstraZeneca","what":"Datopotamab deruxtecan, approved January 2025 for HR-positive disease and later in triple-negative disease; no TROP2 test required.","stage":"approved","url":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast"}],"differentiation":"There is no approved companion diagnostic, no validated plasma or ctDNA assay, and circulating-tumour-cell TROP2 does not agree with tissue. A quantitative digital-pathology score has separated responders in lung cancer but remains investigational and has no role in breast cancer today. An imaging agent would therefore be competing against nothing, which is both the opportunity and the reason reimbursement would be hard.","metrics":[{"label":"Objective response rate, high against low TROP2 expression in ASCENT","value":"44% against 22%","source":"ASCENT biomarker analysis","url":"https://pubmed.ncbi.nlm.nih.gov/34116144/"},{"label":"Paired primary and brain-metastasis samples discordant for TROP2","value":"21.4% of 14","source":"Paired-sample immunohistochemistry study","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12531291/"},{"label":"Patients with a marked longitudinal fall in TROP2 H-score","value":"27.6%","source":"Longitudinal biopsy series","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13379550/"},{"label":"Concordance between three TROP2 immunohistochemistry assays","value":"fair to moderate (AC2 0.35)","source":"Assay comparison study","url":"https://ngdc.cncb.ac.cn/openlb/publication/OLB-PM-40914741"}],"risks":["Neither drug label requires a test, so oncologists have no workflow reason to order a scan and payers have no reason to fund it.","If the expression-response gradient does not reproduce in the datopotamab deruxtecan datasets, the predictive premise weakens.","The leading construct is already in a second disease-specific study, so a new entrant starts well behind."],"watch":["Any published relationship between TROP2 tracer uptake and antibody-drug conjugate response, which is the missing link in the whole case.","Whether a quantitative digital-pathology score reaches the breast cancer label, which would make a tissue test the standard and box in the scan.","Registration of a TROP2 imaging trial outside China, which would be the first sign of industry interest."]},"route":"/opportunities/opp-trop2-imaging-heterogeneity/","neighbours":{"isotope":[{"id":"ga-68","kind":"isotope","name":"Gallium-68","route":"/isotopes/ga-68/"}],"indication":[{"id":"breast-triple-negative","kind":"indication","name":"Triple-negative breast cancer","route":"/indications/breast-triple-negative/"}],"technology":[{"id":"immuno-pet","kind":"technology","name":"Immuno-PET","route":"/technologies/immuno-pet/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"},{"id":"trop2-pet","kind":"technology","name":"TROP2 PET","route":"/technologies/trop2-pet/"}],"target":[{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"}]}}