Trastuzumab was not the first targeted therapy for breast cancer. It’s likely that the first targeted therapy in modern times was oophorectomy mentioned over 100 years ago by Schinzinger in 1889 who proposed surgical oophorectomy to treat breast cancer at a congress for German surgeons. (1) Although Schinzinger personally never performed the surgery, Colonel Sir George Thomas Beatson did In 1896 and published a paper "On Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases." This study detailed his pioneering treatment of three patients with advanced breast cancer through bilateral oophorectomy. Interestingly, he never performed the procedure again and the mechanism of action of oophorectomy remained unknown for another 70 years until the estrogen receptor was described in 1958 by Elwood Jensen at the University of Chicago.
Jensen showed that only tissues that respond to estrogens had the ability to concentrate injected estradiol from the blood, suggesting that these cells must contain specific binding proteins he named “estrogen receptors.” In fact, by 1968, Jensen had developed a reliable test for estrogen receptors in breast cancer cells.
The second targeted therapy was the selective estrogen receptor modulator (SERM), identified by V. Craig Jordan, Visiting Scientist at the Worcester Foundation for Experimental Biology in Massachusetts. He began investigating tamoxifen’s (a failed contraceptive) ability to block the estrogen receptor in breast tumors. The rest, as has been said many times, is history.
In 1986, Alex Ullrich, a scientist working at the biomedical company, Genentech, first presented the HER2 protein at a conference attended by Dr. Dennis Slamon, currently the chief of oncology at UCLA. It was Slamon who suggested that a mutation in the HER2 gene might cause cancer. Then, between 1985-92, preclinical studies showed that transgenic mice (DNA from another source put into mice DNA) that overexpressed the HER2/neu gene in mammary tissue had an increased risk of breast tumors. The tumors also regressed when the mice received a monoclonal antibody that targeted the HER2 protein. But there is little doubt that it was through the incitement of Dennis Slamon that Genetech eventually funded research leading to the development of the HER2 monoclonal antibody, Herceptin, as depicited in a Lifetime movie, “Living Proof.” For his work on Herceptin and HER2, President Clinton appointed Slamon to the three-member President’s Cancer Panel.
In 1998, the HER2/neu gene and protein were found to be associated with an adverse outcome; announcing the entrance of HER2 as a new biomarker. HER2 measurements began to determine both prognosis and the need for chemotherapy with its gene amplification occuring in 15-30% of all breast cancers. For several years HER2, measured by IHC was used solely for prognostic information and correlated well with other adverse prognostic markers.
A monoclonal antibody to HER2 was reported in several phase 1 studies as well as studies in laboratory animals from 1991-1996, followed by Baselga et al. reporting improved survival in HER2 positive metastatic breast cancer using a recombinant humanized monoclonal antibody (rhuMab). That monoclonal antibody was trastuzumab (Herceptin) .
Trastuzumab demonstrated excellent clinical activity in the metastatic setting while being well tolerated and HER2 testing became rapidly and widely adopted. It also stimulated worldwide interest (both positive and negative) in breast cancer targeted therapy.
These many advances over the last decade have put us at the doorstep of the future of targeted therapy. There are at least 6 drugs available that inhibit HER2 and several antibody-drug conjugates currently in clinical trials. This is just the beginning.