A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers. This dossier gathers the 20 products (17 approved), 27 trials, 4 pathways and 6 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Ligand-less receptor that heterodimerises with HER3/EGFR to drive PI3K and MAPK signalling. Amplification is a true oncogenic driver; low expression is merely a delivery address for ADCs.
- HER2+ breast cancer (~15-20%)
- HER2-low breast cancer (~50%)
- Gastric/GEJ (~15-20%)
- HER2-mutant NSCLC (~2-3%)
- Colorectal (~3-5%)
- Biliary tract
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| HER2-positive breast cancer | 100% | IHC 3+ or ISH-amplified (defining) | Nature | |
| HR-positive / HER2-negative breast cancer | 55-65% | HER2-low (IHC 1+ or 2+/ISH-) | Nature | |
| Triple-negative breast cancer | 30-40% | HER2-low (IHC 1+ or 2+/ISH-) | Nature | |
| Gastric & gastro-oesophageal junction cancer | 15-20% | IHC 3+ or 2+/ISH+ | ToGA screening | Wikipedia |
| Biliary tract cancer | 10-20% | IHC 3+ or amplification | Higher in gallbladder/extrahepatic | Wikipedia |
| Colorectal cancer | 3-5% | Amplification/IHC 3+ | RAS wild-type enriched | Wikipedia |
| Non-small-cell lung cancer | 2-3% | ERBB2 exon 20 mutation | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| Exon 20 insertions (A775_G776insYVMA) 776 to 781 | Activating | About 2 to 4% of non-squamous NSCLC carries a HER2 mutation, mostly exon 20 insertions | Not amplification: HER2 IHC is often low. Trastuzumab deruxtecan and the mutant-selective TKIs zongertinib and sevabertinib are the approved routes. | — | DESTINY-Lung01, NEJM 2022 | |
| S310F / S310Y 310 | Activating | not sourced | Extracellular domain II; the most common HER2 point mutation across tumour types, sensitive to HER2 TKIs in basket trials. | — | Cancer Hotspots (MSK) | |
| L755S / V777L / D769H 755 | Activating | not sourced | Kinase-domain alleles enriched in HR-positive lobular breast cancer after endocrine therapy; L755S resists lapatinib but not irreversible TKIs. | SUMMIT, Nature 2018 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: ERBB2.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 | Withdrawn or failed |
|---|---|---|---|
| ADC 7 | |||
| Small molecule 6 | — | — | |
| Antibody 4 | — | — | |
| Bispecific antibody 2 | — | — | |
| Small-molecule pan-ErbB TKI 1 | — | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| HERIZON-GEA-01 NCT05152147 | 3 | Positive | First-line HER2-positive advanced gastro-oesophageal adenocarcinoma: zanidatamab + chemotherapy ± tislelizumab vs trastuzumab + chemotherapy | PFS 12.4 vs 8.1 months (HR 0.63-0.65); OS significantly improved. | |
| DESTINY-Breast05 NCT04622319 | 3 | Positive | High-risk HER2+ early breast cancer with residual invasive disease after neoadjuvant therapy: T-DXd vs T-DM1 | 3-year iDFS 92.4% vs 83.7%, HR 0.47. | |
| DESTINY-Breast09 NCT04784715 | 3 | Positive | First-line HER2+ metastatic breast cancer: T-DXd + pertuzumab vs THP | PFS HR 0.56. | |
| DESTINY-Breast11 NCT05113251 | 3 | Positive | Neoadjuvant high-risk HER2+ early breast cancer: T-DXd followed by THP vs ddAC-THP | pCR 67.3% vs 56.3%. | |
| DESTINY-Gastric04 NCT04704934 | 3 | Positive | Second-line HER2-positive gastric/GEJ cancer after trastuzumab: T-DXd vs ramucirumab + paclitaxel | OS 14.7 vs 11.4 months, HR 0.70. | |
| HER2CLIMB-05 NCT05132582 | 3 | Positive | First-line HER2+ metastatic breast cancer after induction with taxane + trastuzumab + pertuzumab: maintenance tucatinib + HP vs placebo + HP | PFS 24.9 vs 16.3 months, HR 0.64. | |
| HORIZON-Breast01 NCT05424835 | 3 | Positive | HER2+ metastatic breast cancer after trastuzumab and taxane (China): trastuzumab rezetecan (SHR-A1811) vs pyrotinib + capecitabine | PFS 30.6 vs 8.3 months, HR 0.22. | |
| ACE-Breast-02 NCT04829604 | 3 | Positive | HER2+ advanced breast cancer after trastuzumab and taxane (China): ARX788 vs lapatinib + capecitabine | PFS 11.3 vs 8.2 months, HR 0.64. | |
| DESTINY-Breast06 NCT04494425 | 3 | Positive | HR+ HER2-low/ultralow breast cancer after endocrine therapy, chemotherapy-naive: T-DXd vs chemotherapy | PFS HR 0.62. | |
| DESTINY-Breast12 NCT04739761 | 3 | Positive | HER2+ metastatic breast cancer with or without brain metastases: single-arm T-DXd | CNS ORR 71.7%; 12-month PFS 61.6% in brain-metastasis cohort. | |
| HER2CLIMB-02 NCT03975647 | 3 | Mixed | HER2+ metastatic breast cancer after trastuzumab and taxane: tucatinib + T-DM1 vs placebo + T-DM1 | PFS 9.5 vs 7.4 months, HR 0.76; OS no benefit. | |
| DESTINY-Breast04 NCT03734029 | 3 | Positive | HER2-low metastatic breast cancer after chemotherapy: T-DXd vs chemotherapy | OS HR 0.64. | |
| MOUNTAINEER & MOUNTAINEER-03 NCT03043313 | 3 | Recruiting | HER2-positive RAS wild-type metastatic colorectal cancer: tucatinib + trastuzumab (phase 2, pretreated); tucatinib + trastuzumab + mFOLFOX6 vs standard first line (phase 3) | Phase 2 ORR 38.1%, DOR 12.4 months; phase 3 ongoing. | |
| DESTINY-Breast03 NCT03529110 | 3 | Positive | HER2+ metastatic breast cancer after trastuzumab and taxane: T-DXd vs T-DM1 | PFS HR 0.33; OS HR 0.64. | |
| HER2CLIMB NCT02614794 | 3 | Positive | HER2+ metastatic breast cancer after trastuzumab, pertuzumab, and T-DM1, including active brain metastases: tucatinib + trastuzumab + capecitabine vs placebo + trastuzumab + capecitabine | OS 21.9 vs 17.4 months, HR 0.66; CNS-PFS HR 0.32. | |
| PERSEPHONE NCT00712140 | 3 | Positive | Adjuvant HER2+ early breast cancer: 6 vs 12 months of trastuzumab | 4-year DFS 89.4% vs 89.8%, non-inferior. | |
| KATHERINE NCT01772472 | 3 | Positive | HER2+ early breast cancer with residual invasive disease after neoadjuvant therapy: T-DM1 vs trastuzumab for 14 cycles | iDFS HR 0.50; OS HR 0.66. | |
| APHINITY NCT01358877 | 3 | Positive | Adjuvant HER2+ early breast cancer: pertuzumab + trastuzumab + chemotherapy vs placebo + trastuzumab + chemotherapy | 8-year iDFS HR 0.78; node-positive absolute +4.9%. | |
| CLEOPATRA NCT00567190 | 3 | Positive | First-line HER2+ metastatic breast cancer: pertuzumab + trastuzumab + docetaxel vs placebo + trastuzumab + docetaxel | OS 57.1 vs 40.8 months, HR 0.69. | |
| ToGA NCT01041404 | 3 | Positive | First-line HER2-positive advanced gastric/GEJ adenocarcinoma: trastuzumab + cisplatin/fluoropyrimidine vs chemotherapy | OS 13.8 vs 11.1 months, HR 0.74. | |
| HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab) NCT00045032 | 3 | Positive | Adjuvant HER2+ early breast cancer: one year of trastuzumab with or after chemotherapy vs chemotherapy alone | B-31/N9831 10-year OS 84% vs 75.2%, HR 0.63. | |
| HERIZON-BTC-302 NCT06282575 | 3 | Recruiting | First-line HER2-positive advanced biliary tract cancer: zanidatamab + standard of care (GemCis ± PD-1) vs standard of care | ||
| PHERGain NCT03161353 | 2 | Positive | HER2+ early breast cancer: chemotherapy-free trastuzumab + pertuzumab with early 18F-FDG PET response assessment to decide whether chemotherapy is needed | 3-year iDFS 95.4% in the PET-adapted arm; ~1 in 3 spared chemotherapy. | |
| DESTINY-CRC02 NCT04744831 | 2 | Positive | Pretreated HER2-positive metastatic colorectal cancer: T-DXd 5.4 vs 6.4 mg/kg | ORR 37.8% (5.4 mg/kg). | |
| DESTINY-PanTumor02 NCT04482309 | 2 | Positive | HER2-expressing (IHC 2+/3+) solid tumours after ≥1 line, seven cohorts including endometrial and cervical: trastuzumab deruxtecan | Endometrial ORR 57.5% (84.6% in IHC 3+); cervical ORR 50%. | |
| APT (adjuvant paclitaxel-trastuzumab) NCT00542451 | 2 | Positive | Small (≤3 cm), node-negative HER2+ breast cancer: 12 weeks paclitaxel + 1 year trastuzumab | 7-year DFS 93%; 10-year RFI 96.3%. | |
| SOHO-01 NCT05099172 | 1/2 | Positive | HER2-mutant NSCLC, previously treated and treatment-naive: sevabertinib single arm | ORR ~64%; accelerated approval Nov 2025. |
Resistance routes that involve this target
Unaddressed routes →TOP1 mutations (e.g., E418K) or reduced expression prevent trapping of the cleavage complex.
- Switch payload class (tubulin, DNA-crosslinking, degrader) rather than antigen
- Radioconjugates against the same antigen
Schlafen-11 is required for replication-stress-induced death; its epigenetic silencing confers resistance to TOP1 (and platinum) agents.
- ATR/CHK1 inhibitors re-sensitise SLFN11-low cells preclinically
- EZH2 inhibition to restore SLFN11 (preclinical)
SN-38 is an ABCG2 substrate; DXd and MMAE are ABCB1 substrates; mesenchymal states upregulate both.
- Payloads reported to be weaker efflux substrates (sac-TMT's belotecan derivative)
- Efflux-agnostic modalities: radiation, T-cell engagers
Reduced HER2 or TROP2 surface expression after treatment; less frequent than payload resistance for HER2-low disease.
- Antigen PET to detect loss and pick the next target
- Bispecific ADCs hitting two antigens
Defective endocytosis or lysosomal cathepsin activity limits payload release.
- Biparatopic antibodies that force receptor clustering (zanidatamab-type)
Without RB, CDK4/6 inhibition cannot arrest the cell cycle.
- Switch to chemotherapy or ADCs (T-DXd for HER2-low, sacituzumab, Dato-DXd)
Pathways where it is a node
Pathway-to-drug matrix →- Mitosis & the spindle assembly checkpointNode: Taxanes, vincas, MMAE, DM1 · 3 druggable nodes
When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
Which nodes have drugs → - NK-cell recognition: missing self & stress ligandsNode: CD16 ← IgG1 antibody (ADCC) · 2 druggable nodes
Natural killer cells patrol for cells that have lost their identity papers (MHC-I) or that display stress flags. Cancers that hide from T cells by dropping MHC-I become visible to NK cells, unless they also shed the stress flags, wrap themselves in a second inhibitory badge (HLA-E), or soak the neighbourhood in TGF-β.
Which nodes have drugs → - PI3K / AKT / mTORNode: RTK (HER2, EGFR) · 3 druggable nodes
The cell's 'grow and survive' circuit. Growth signals from the surface switch on PI3K, which switches on AKT, which switches on mTOR, which builds proteins and blocks self-destruction.
Which nodes have drugs → - The blood–brain barrier & brain metastasisNode: Brain-penetrant TKIs, FUS · 1 druggable nodes
The brain's blood vessels are sealed tight and fitted with pumps that eject most drugs. That protects the brain from poisons but also from chemotherapy and antibodies. Cancer cells that do squeeze through recruit the brain's own support cells, astrocytes, to feed and shield them.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| HercepTest Agilent (Dako) · FDA CDx 1998 | IHC | IHC 3+ (or 2+ confirmed by ISH) for trastuzumab; IHC 1+ or 2+/ISH-negative (HER2-low) for trastuzumab deruxtecan; IHC 0 with faint membrane staining (HER2-ultralow) for trastuzumab deruxtecan in HR-positive breast cancer | |
| PATHWAY anti-HER2/neu (4B5) Roche Diagnostics · FDA CDx | IHC | IHC 3+ (HER2-positive); IHC 1+ or 2+/ISH-negative (HER2-low) for trastuzumab deruxtecan; IHC 3+ solid tumours for tumour-agnostic trastuzumab deruxtecan | |
| HER2 IQFISH pharmDx and INFORM HER2 Dual ISH Agilent; Roche Diagnostics · FDA CDx | FISH/ISH | HER2/CEP17 ratio at least 2.0, or ratio below 2.0 with average HER2 copy number at least 6.0 (ASCO/CAP 2018) | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| Guardant360 CDx Guardant Health · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib), EGFR exon 20 insertions (amivantamab), KRAS G12C (sotorasib), ESR1 mutations (elacestrant), ERBB2 mutations (zongertinib); negative plasma reflexes to tissue |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| SK-BR-3 | CVCL_0033 · ACH-000017 | Breast, HER2-amplified. |
| BT-474 | CVCL_0179 · ACH-000927 | Breast, HER2-amplified, ER-positive; ADC xenograft standard. |
| HCC1954 | CVCL_1259 · ACH-000859 | Breast, HER2-amplified, trastuzumab-resistant. |
| NCI-N87 | CVCL_1603 · ACH-000427 | Gastric, HER2-amplified. |
| OE19 | CVCL_1622 · ACH-000679 | Oesophagogastric junction, HER2-amplified. |
| MDA-MB-453 | CVCL_0418 · ACH-000910 | Breast, HER2-low (IHC 1+ to 2+); used for HER2-low ADC bystander studies. |
| MCF-7 | CVCL_0031 · ACH-000019 | HER2-low breast line used as the HER2-low or negative comparator. |
| Ba/F3 ERBB2 exon 20 | not resolved | Engineered YVMA insertion lines for zongertinib- and sevabertinib-type TKIs. |
- MMTV-Neu (Rat Neu under the MMTV promoter) Guy et al., PNAS 1992
Open questions
All open questions →- 01
How should pathologists reliably separate HER2-low and HER2-ultralow from HER2-zero when the assays were designed to find HER2-high?
implementationregulatorWhy unresolved. DESTINY-Breast04 and 06 made IHC 1+ and faint IHC 0 staining actionable, yet inter-observer agreement at the low end is poor and the antibodies, controls and cut-offs were validated for amplification.
What would answer it. Ring studies with reference materials at the low end, AI-assisted scoring validated against trial outcomes, and label language tied to a reproducible assay.
Source: DESTINY-Breast04, NEJM 2022 - 02
After trastuzumab deruxtecan, does a second HER2-directed ADC with a different payload work, or is payload resistance shared?
clinicalclinicWhy unresolved. Resistance to topoisomerase-I payloads (TOP1 mutation, SLFN11 loss, efflux) is target-independent, so a second TOP1 ADC often fails; whether switching payload class restores benefit has not been tested prospectively.
What would answer it. Randomised or well-controlled sequencing studies with pre-treatment biopsies characterising TOP1, SLFN11 and HER2 status.
Source: DESTINY-Breast03, NEJM 2022
Ideas and companies
Key papers and the live literature
Preprints →- DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer · New England Journal of Medicine 2024
- DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer · New England Journal of Medicine 2022
- DESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group · New England Journal of Medicine 2022
- KATHERINE: switching to T-DM1 when HER2-positive breast cancer survives pre-surgery treatment · New England Journal of Medicine 2019
Query for this target: (TITLE:"HER2" OR ABSTRACT:"HER2" OR TITLE:"ERBB2" OR ABSTRACT:"ERBB2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about HER2, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/her2.json. Licence CC BY 4.0.