Question 1

What is HER2 overexpression in breast cancer?

Accepted Answer

HER2 gene amplification leads to receptor overexpression on the tumour cell surface, forming constitutively active homodimers and heterodimers that signal through PI3K/AKT and MAPK without requiring ligand binding. HER2 amplification occurs in ~20% of breast cancers.

Question 2

Is HER2-positive breast cancer aggressive?

Accepted Answer

HER2-positive breast cancer was historically aggressive with poor prognosis, but targeted HER2 therapies have transformed outcomes. Five-year survival rates for HER2-positive early breast cancer now exceed 90% with trastuzumab, pertuzumab, and T-DM1, compared to ~50% in the pre-trastuzumab era.

Question 3

How does trastuzumab (Herceptin) work?

Accepted Answer

Trastuzumab binds the extracellular domain IV of HER2, blocking downstream signalling, promoting receptor internalisation and degradation, and recruiting natural killer cells via antibody-dependent cellular cytotoxicity (ADCC). The combination of direct signalling blockade and immune activation explains its clinical efficacy.

Question 4

Can HER2 be targeted in cancers other than breast cancer?

Accepted Answer

Yes — trastuzumab and trastuzumab deruxtecan (T-DXd) are approved for HER2-positive gastric, gastro-oesophageal, and colorectal cancers. HER2 amplification is an emerging actionable biomarker in lung adenocarcinoma and biliary tract cancers, with dedicated HER2-targeted trials in each histology.

Question 5

What is the difference between HER2-positive, HER2-low, and HER2-zero breast cancer?

Accepted Answer

HER2 status is traditionally scored by immunohistochemistry (IHC 0–3+) and FISH amplification: HER2-positive is IHC 3+ or IHC 2+/FISH-amplified (~20% of breast cancers). HER2-low is IHC 1+ or IHC 2+/FISH-non-amplified (~40–50% of breast cancers) — previously treated as HER2-negative and ineligible for HER2-targeted therapy. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate carrying 8 molecules of topoisomerase I inhibitor per antibody, showed substantial activity in HER2-low disease (DESTINY-Breast04, HR 0.64 for PFS), transforming the HER2-low category from a biological distinction without treatment implication to a clinically actionable category.

Question 6

How does trastuzumab deruxtecan (T-DXd) differ from trastuzumab and T-DM1?

Accepted Answer

All three are trastuzumab-based antibody-drug conjugates (ADCs) that deliver cytotoxic payload to HER2-expressing cells, but they differ critically in drug-to-antibody ratio and payload mechanism. Trastuzumab carries no cytotoxic payload (pure antibody — ADCC and signalling blockade only). T-DM1 (ado-trastuzumab emtansine) carries ~3.5 molecules of DM1 (microtubule inhibitor) per antibody via stable linker. T-DXd carries ~8 molecules of DeruxTecan (topoisomerase I inhibitor, similar to irinotecan) per antibody via cleavable linker — the high drug load and cleavable linker enable a 'bystander effect' where released payload kills adjacent HER2-low or HER2-negative tumour cells. This bystander effect is why T-DXd is active even in HER2-low disease.

Question 7

What causes trastuzumab resistance in HER2-positive breast cancer?

Accepted Answer

Trastuzumab resistance arises through several mechanisms: (1) PI3K/AKT pathway activation via PIK3CA mutations or PTEN loss bypasses HER2 signalling dependence and is the most common mechanism (~30–40% of resistant tumours); (2) MUC4 mucin overexpression sterically masks the HER2 domain II epitope that trastuzumab binds, preventing antibody contact; (3) p95-HER2 truncation removes the trastuzumab-binding extracellular domain, leaving a constitutively active transmembrane fragment; (4) EGFR or MET co-receptor overexpression provides parallel RTK signalling. Pertuzumab (blocking HER2-HER3 dimerisation), T-DM1, and T-DXd overcome most of these resistance mechanisms by exploiting different HER2 binding sites or delivering payload directly into HER2-expressing cells.

HER2 Gene Function

Overview

More Oncogenes