1998: Trastuzumab (Herceptin): HER2-Targeted Therapy (1998)

Trastuzumab (Herceptin), approved by the FDA in September 1998 for HER2-positive metastatic
breast cancer, represented a watershed moment in targeted oncology. Its development traced directly
to the work of Dennis Slamon at UCLA, who in 1987 demonstrated that amplification of the HER2
(human epidermal growth factor receptor 2) gene occurred in roughly 25–30 % of breast cancers
and correlated strongly with poor prognosis. This molecular characterisation gave drug developers
a specific target: a cell-surface receptor that was overexpressed on cancer cells but present at
low levels on normal tissue.

Genentech scientists generated a humanised monoclonal antibody—4D5, later humanised to
trastuzumab—that bound the extracellular domain of HER2 with high affinity. In cell culture
and animal models, antibody binding suppressed HER2 signalling, slowed cell proliferation, and
sensitised tumours to chemotherapy. The pivotal Phase III trial, published in the New England
Journal of Medicine in 1998, showed that adding trastuzumab to chemotherapy in HER2-positive
metastatic breast cancer reduced the risk of disease progression by 35 % and prolonged overall
survival from 20.3 to 25.1 months.

The approval prompted oncologists worldwide to begin routine HER2 testing of breast tumour
specimens, embedding companion diagnostics into standard practice. Subsequent trials confirmed
trastuzumab's benefit in the adjuvant (post-surgical) setting, where it roughly halved recurrence
rates in HER2-positive early breast cancer. Later extensions of the HER2 concept led to
pertuzumab, ado-trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan—each building on
the foundational principle that molecular subtyping can convert a single disease category into
multiple distinct targets amenable to precision therapy.