When the target changes, and when to stop blocking it
HER2-positive is a binary applied to a quantity that varies across a tumour and over time, and dependence on the receptor is a separate question from its presence.
HER2-positive is a binary category applied to a continuous and spatially variable quantity. Two consequences follow for metastatic management.
The first is heterogeneity at diagnosis. A tumour can contain amplified and unamplified compartments, and the arrangement matters as much as the proportion. In a neoadjuvant study of trastuzumab emtansine with pertuzumab, no patient with HER2 heterogeneity achieved a pathologic complete response against 55% of those without it1. The full argument is in HER2 heterogeneity.
The second is change over time. A biopsy at progression that reports HER2-negative disease is frequently an accurate measurement of what treatment has selected, not a laboratory error HER2 loss as an acquired resistance mechanism. Preclinical models with mixed high and low expressing populations reproduce this during the evolution of resistance2.
Advanced disease · HER2+ · any
Layering HER2 blockade and choosing what follows it
Can the next drug be chosen by measuring the target rather than by counting previous lines?
Rationale
A patient's HER2 status is usually assigned once, on the primary tumour, by an immunohistochemistry cut-off chosen to select for trastuzumab. Metastatic deposits are not obliged to match the primary, and they are not obliged to match each other. If the antigen can be measured in the disease actually being treated, the choice of the next drug could rest on the target rather than on the treatment history.
Experiment
Three ways of measuring rather than counting. Imaging the antigen with a labelled antibody before giving a conjugate, read alongside an early metabolic scan. An early metabolic response read embedded in the chemotherapy-free dual blockade study. A conjugate given to prespecified cohorts defined by immunohistochemistry score, from overexpressing through low down to no detectable staining. Set against those, the registration study that gave a newer conjugate to disease that had already failed an older conjugate aimed at the same antigen.
Finding
Antigen imaging found patients whose lesions took up no tracer, and found uneven uptake within single patients. Its predictive values against radiological response improved when the early metabolic scan was read with it. In the chemotherapy-free study, absence of an early metabolic response predicted failure to respond by imaging criteria, and did so in both cohorts. The conjugate produced responses in every staining cohort, most often in the overexpressing one and not rarely in the cohort scored as non-expressing. Failure of one conjugate aimed at HER2 did not predict failure of the next.
Limitation
These are measurement studies rather than allocation trials. A predictive value is computed in one cohort all treated the same way, against a radiological definition of response. It describes how a scan tracks an outcome rather than showing that acting on the scan changes one. Nobody has randomised patients to be allocated by imaging. DAISY's cohorts were cut from a central immunohistochemistry score, so the boundary between them is an assay convention rather than a biological class. Each cohort was single-arm, so activity in the non-expressing cohort may be reporting the floor of that assay rather than activity without the target. The metabolic read in TBCRC 003 sat inside a single-arm study, which gives its predictive claim the same shape. DESTINY-Breast01 had no control arm, so it cannot say whether the second conjugate worked because the antigen persisted or because its payload differs.
Next question
If measuring the target still leaves patients whose disease carries it and progresses anyway, can a mechanism other than HER2 blockade be added to extend what HER2 blockade can do?
ZEPHIRTBCRC 003DESTINY-Breast01DAISY
Three studies tried to replace the count of previous lines with a measurement of the target. They agree on what they found. The antigen is measurable, it is unevenly distributed within a single patient, and measuring it does not yet allocate treatment. ZEPHIR imaged HER2 with a labelled antibody before a conjugate. It found patients whose lesions took up no tracer, and it found uneven uptake within individual patients3. TBCRC 003 read an early metabolic response inside a chemotherapy-free dual blockade study, where absence of that response predicted failure to respond by imaging criteria in both cohorts4. DAISY gave a conjugate to cohorts cut by central immunohistochemistry score and produced responses in every cohort, including the one scored as non-expressing5.
They diverge in what they measured rather than in what they showed. None of them is an allocation trial. A predictive value is computed in one cohort all treated the same way, against a radiological definition of response. It describes how a scan tracks an outcome. It does not establish that acting on the scan changes one, and nobody has randomised patients to be allocated by imaging.
DESTINY-Breast01 carries the conclusion that actually changed practice, and it measured nothing. It gave a deruxtecan conjugate to disease that had already failed a conjugate aimed at the same antigen, and objective response occurred in 112 of 184 patients6. Failure of one HER2 conjugate does not predict failure of the next. Because there was no control arm, the trial cannot say whether that is persistence of the antigen or a difference in payload.
What none of this supports is a threshold. DAISY's cohorts were cut from a central immunohistochemistry score, so the boundary between them is an assay convention rather than a biological class. Each cohort was single-arm, so activity in the non-expressing cohort may be reporting the floor of that assay as much as activity without the target. The reproducibility of the boundary itself is poor7,8. The generalised version of this argument is Expression and alteration-defined treatment across subtypes.
The practical rule is to obtain recent tissue before a decision that depends on expression level, and to treat the result as a statement about the biopsied lesion at that time. A falling HER2 result does not mean that HER2-directed treatment is finished. Receptor discordance and how to interpret it is in Receptor discordance and conversion.
Interplay
HER2-positive disease is where the heterogeneity argument of Part VI is most directly operational. The mean expression level determines eligibility. The variance determines what survives. A conjugate with a membrane-permeable payload converts part of that variance problem into a delivery solution, which is why bystander-capable agents outperformed non-bystander agents in a disease whose antigen is unevenly distributed9,5. Mean and variance are separate axes, and current reporting gives only the mean.
Progression on a conjugate is not one event. A conjugate has to bind, internalise, traffic, release payload, retain it and kill with it. Antigen expression answers the first step only, and no routine assay measures the others. The mechanistic account is in Conjugate resistance, antigen loss, payload efflux, and repair capacity.
Two experimental results define the shape of the problem. Cell line models selected for resistance to trastuzumab emtansine failed by unrelated routes, one through reduced HER2 with MDR1 upregulation and the other through loss of the lysosomal transporter SLC46A3 with PTEN deficiency. The rescues were not interchangeable10. In patients, PTEN loss was associated with de novo resistance to trastuzumab deruxtecan and not with de novo resistance to sacituzumab govitecan11. The same payload class, and a genomic lesion that affected only one of the two agents.
The practical position is uncomfortable and should be stated. A patient progressing on trastuzumab deruxtecan may have lost antigen, may have lost payload handling, or may have lost a downstream dependency. Only the first is measurable in clinic. Measuring HER2 and finding it retained does not establish that a different HER2-directed conjugate will work.
What follows in practice is an antibody-independent or payload-independent option. A tyrosine kinase inhibitor combination changes both the delivery mechanism and the mode of killing Third line and beyond. That is a stronger argument than switching to a second conjugate with the same payload class.
3 · Treatment beyond progression and when to stop HER2 blockade
The convention in this disease is that HER2 blockade continues across lines while the backbone changes. It is a well-founded convention and it is worth knowing what founds it.
The argument is that HER2 amplification is a truncal event in most of these tumours, so the dependency usually persists even when a particular agent stops working. That is a claim about the genome and it is generally right. The claim it does not support is that continued blockade is therefore always beneficial, because dependence is a separate question from presence HER2-directed therapy resistance across antibodies and kinase inhibitors. A stable HER2 result at progression establishes that the antigen is still there.
Three situations argue for stopping.
The first is documented loss of the target on recent tissue, in a patient whose disease is now behaving like HER2-negative disease. That is selection rather than error HER2 loss as an acquired resistance mechanism, and it moves the patient to a different chapter.
The second is cardiac. Cumulative anthracycline exposure and years of antibody therapy produce declines in left ventricular function that are sometimes not recoverable. Cardiac surveillance and its management are in Treatment toxicity and supportive care.
The third is that continuing blockade is being used as a substitute for a conversation. Antibody therapy is easy to continue and hard to stop, because stopping is legible to the patient as a decision in a way that continuing is not.
In practice
Reassess HER2 on recent tissue before assuming the target is still present, particularly after conjugate exposure.
Check left ventricular function on schedule rather than on symptoms, and treat a fall as a reason to reconsider the whole regimen rather than to pause one drug.
When a patient has progressed through conjugates, kinase inhibitors and antibodies, say so plainly. Continuing an antibody alongside best supportive care is a reasonable choice made explicitly. It is a poor substitute for the conversation in Palliative and end-of-life care.
References
All 11 references
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Goyette MA, Graser C, Seehawer M, et al. HER2 heterogeneous breast cancer models reveal novel therapeutic targets and subclonal dynamics during evolution to resistance to HER2-targeted therapies. Cancer Discov 2026 16:1691-1710. PMID 41925564
Gebhart G, Lamberts LE, Wimana Z, et al. Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol 2016 27:619-624. PMID 26598545
Lin NU, Guo H, Yap JT, et al. Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003). J Clin Oncol 2015 33:2623-31. PMID 26169615
Mosele F, Deluche E, Lusque A, et al. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med 2023 29:2110-2120. PMID 37488289
Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020 382:610-621. PMID 31825192
Robbins CJ, Fernandez AI, Han G, et al. Multi-institutional assessment of pathologist scoring HER2 immunohistochemistry. Mod Pathol 2023 36:100032. PMID 36788069
Wolff AC, Somerfield MR, Dowsett M, et al. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO-College of American Pathologists guideline update. J Clin Oncol 2023 41:3867-3872. PMID 37284804
Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023 401:105-117. PMID 36495879
Li G, Guo J, Shen BQ, et al. Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol Cancer Ther 2018 17:1441-1453. PMID 29695635
Mai N, Klar Lieberman MM, Ferraro E, et al. Sequential antibody-drug conjugate therapy in patients with metastatic breast cancer treated with sacituzumab govitecan and trastuzumab deruxtecan. JCO Precis Oncol 2025 9:e2400898. PMID 40440568