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.

• T-DXd across the disease continuum.
• Chemotherapy de-escalation guided by early response.
• Ten-year survival above 80% for early disease, from a subtype that was the deadliest in the 1990s.
• 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.

1. 1987Slamon links HER2 amplification to poor prognosis
2. 1987Slamon links HER2 amplification to poor prognosis
3. 1998Trastuzumab approved
4. 1998Trastuzumab approved for metastatic disease
5. 2005Adjuvant trastuzumab halves recurrence (HERA, B-31/N9831)
6. 2007Lapatinib: first HER2 pill
7. 2012Pertuzumab and dual blockade (CLEOPATRA)
8. 2013First solid-tumour ADC: T-DM1
9. 2013T-DM1: first solid-tumour ADC; pertuzumab first pCR-based approval
10. 2015APT: de-escalation for small tumours

• HER2 PET (technology)
• Zanidatamab (product)
• Disitamab vedotin (product)
• Trastuzumab rezetecan (product)
• Trastuzumab brengitecan (product)
• ARX788 (product)
• HER2CLIMB-05 (trial)
• HORIZON-Breast01 (trial)
• PHERGain (trial)
• Can T-DXd alone cure early HER2-positive disease? (idea)
• Systemic-first management of HER2-positive brain metastases (idea)
• Sequencing HER2 ADCs by payload after T-DXd (idea)

• HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab) (phase 3, n=9,000): Disease-free survival (B-31/N9831): pending
• 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
• DESTINY-Breast05 (phase 3, n=1,635): 3-year invasive disease-free survival: 92.4% vs 83.7%, HR 0.47
• KATHERINE (phase 3, n=1,486): 3-year invasive disease-free survival: 88.3% vs 77%, HR 0.5
• CLEOPATRA (phase 3, n=808): Progression-free survival: 18.7 months vs 12.4 months, HR 0.68

• Brain metastases in ~50% of metastatic patients.
• Which patients can skip chemotherapy entirely.
• 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.

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
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC13114725/
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419