Teaching pack: HER2-positive breast cancer

HER2-positive breast cancer (15-20% of cases; HER2 IHC 3+ or ISH-amplified) was the most aggressive subtype until trastuzumab (1998) made it one of the most treatable. The modern curative pathway is response-adapted: neoadjuvant chemotherapy with dual HER2 blockade (or, since 2026, T-DXd followed by THP), surgery, then either antibody completion for patients with a pathologic complete response or an ADC for residual disease (T-DM1 from KATHERINE, now T-DXd from DESTINY-Breast05). Small node-negative tumours are cured with paclitaxel-trastuzumab alone; PHERGain showed that an early PET response can spare a third of patients chemotherapy altogether. Extended adjuvant neratinib and adjuvant pertuzumab add small gains in higher-risk, node-positive disease.

Metastatic disease has been transformed twice: by CLEOPATRA's pertuzumab (OS 57 months) and then by trastuzumab deruxtecan, which beat T-DM1 by a wide margin in second line (DESTINY-Breast03) and beat THP in first line (DESTINY-Breast09, PFS 40.7 months; approved 2025). Brain metastases, which develop in up to half of patients, are now treatable systemically with tucatinib (HER2CLIMB) and T-DXd (DESTINY-Breast12). HER2CLIMB-05 (tucatinib maintenance) and PATINA (palbociclib maintenance in HR+/HER2+, approved 2026) intensify chemotherapy-free maintenance, and a wave of Chinese HER2 ADCs (trastuzumab rezetecan, BL-M07D1, ARX788, disitamab vedotin) is producing Enhertu-scale results.

• Ten-year survival above 80% for early disease: the subtype with the poorest outlook in the 1990s is now one of the most treatable.
• Response-adapted curative therapy: pCR patients de-escalate, residual disease escalates to an ADC (now T-DXd, iDFS HR 0.47 vs T-DM1).
• T-DXd across the continuum: neoadjuvant (2026), post-neoadjuvant (2026), first-line metastatic with pertuzumab (2025, PFS 40.7 months), second line, and brain metastases.
• Systemic control of brain metastases (tucatinib, T-DXd) allowing deferral of radiation.
• Chemotherapy-free maintenance intensification: tucatinib (HER2CLIMB-05) and palbociclib for HR+/HER2+ (PATINA).
• Chemotherapy omission for a third of patients using early PET response (PHERGain).

1. 1987Slamon shows HER2 amplification marks aggressive disease, and a drug target
2. 1998Trastuzumab approved for metastatic disease
3. 2005Adjuvant trastuzumab halves recurrence (HERA, B-31/N9831)
4. 2007Lapatinib: first HER2 pill
5. 2012Pertuzumab and dual blockade (CLEOPATRA)
6. 2013T-DM1: first solid-tumour ADC; pertuzumab first pCR-based approval
7. 2015APT: de-escalation for small tumours
8. 2017First trastuzumab biosimilar; neratinib; APHINITY
9. 2018KATHERINE: T-DM1 for residual disease
10. 2019T-DXd approved; HER2CLIMB proves CNS benefit

• HER2 PET (technology)
• Zanidatamab (treatment)
• Disitamab vedotin (treatment)
• TQB2102 (treatment)
• HB1801 (treatment)
• JSKN003 (treatment)
• KN026 (treatment)
• IBI354 (treatment)
• A166 (treatment)
• Evorpacept (treatment)
• HLX11 (treatment)
• RPH-051 (treatment)

• HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab) (phase 3, n=9,000): Disease-free survival (B-31/N9831): pending
• NSABP B-32 (phase 3, n=5,611): Overall survival at 8 years (sentinel node-negative patients): 90.3% vs 91.8%, HR 1.2
• APHINITY (phase 3, n=4,805): 8-year invasive disease-free survival: 88.4% vs 85.8%, HR 0.78
• PERSEPHONE (phase 3, n=4,088): 4-year disease-free survival: 89.4% vs 89.8%, HR 1.07
• ACOSOG Z0011 (Alliance) (phase 3, n=891): Overall survival at 10 years: 86.3% vs 83.6%, HR 0.85
• DESTINY-Breast05 (phase 3, n=1,635): 3-year invasive disease-free survival: 92.4% vs 83.7%, HR 0.47

• Sequencing after T-DXd: no randomised data on which HER2 ADC or TKI works after TOP1-payload failure.
• Interstitial lung disease with T-DXd in curative settings, where patients would otherwise be cured.
• Over-treatment: which patients need pertuzumab, a full year of antibodies, or any chemotherapy at all (PHERGain-2, response-adapted trials).
• Brain metastasis prevention and whether systemic-first strategies preserve cognition.
• HR+/HER2+ ('triple-positive') disease: optimal integration of endocrine therapy, CDK4/6 inhibitors, and HER2 blockade.
• Cardiotoxicity surveillance burden versus event rates in low-risk patients.

1. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
2. What does 'triple-negative' mean in breast cancer?
   Answer

   The tumour lacks the three receptors other breast cancers can be treated through: oestrogen receptor, progesterone receptor, and HER2 (IHC 0-1+ or 2+/ISH-negative).
3. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
4. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
5. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).
6. What is a liquid biopsy used for in cancer care today?
   Answer

   A blood test reading tumour DNA fragments: to genotype a tumour when tissue is scarce, to track resistance mutations (EGFR T790M, ESR1), to detect minimal residual disease after surgery, and, experimentally, to screen for cancer.

• Wikipedia: https://en.wikipedia.org/wiki/HER2-positive_breast_cancer
• NCCN Guidelines for Patients and the NCCN breast cancer guideline summary (PMC): https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/
• SEER Cancer Stat Facts: female breast cancer subtypes (share of cases and five-year relative survival by receptor subtype and stage, SEER 21): https://seer.cancer.gov/statfacts/html/breast-subtypes.html
• Royal College of Pathologists G148: dataset for histopathological reporting of breast disease in surgical excision specimens of breast cancer, version 3, November 2024 (full review due November 2026): https://www.rcpath.org/resourceLibrary/g148-dataset-for-histopathological-reporting-of-breast-disease-in-surgical-excision-specimens-of-breast-cancer.html
• Rakha et al., Journal of Clinical Pathology 2023;76:217 to 227: UK recommendations for HER2 assessment in breast cancer, an update: https://doi.org/10.1136/jcp-2022-208632
• Wikipedia: https://en.wikipedia.org/wiki/HER2-positive_breast_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419