There is some evidence that amplification of the c-erb B2 gene may cause resistance to nolvadex (Tamoxifen) therapy for breast cancer. This resistance can be a direct or an indirect effect. For example, in vitro studies suggest that there exists a "cross talk" pathway between the Her-2/neu and the Estrogen Receptor (ER) signal transduction pathways. Once the Human Epidermal Growth Factor protein binds to its receptor, Her-2/neu, multiple signals are initiated with in the cell. One of these secondary signals may modulate the expression of the ER. Other theories on how amplification of c-erb B2 renders breast cancer cells hormone resistant includes modification of the ER itself and its independent activation.
There have been several trials showing that Her-2/neu overexpression confers hormone resistance. The first of these was a cooperative Italian trial, published in 1996 in the Journal of Clinical Oncology (JCO). The trial assigned node negative patients to either nolvadex or observation for 2 years. Patients in the nolvadex arm had a much better overall survival and 10-year disease free survival than the untreated arm in c-erb B2 negative patients. In sharp contrast, patients with c-erb B2 overexpression who used nolvadex had a much worse overall survival and 10 year disease free survival than the group of patients not taking nolvadex.
A similar trial done in node positive patients conferred the same results. Premenopausal node positive women were assigned to receive Cyclophosphamide, Methotrexate, and Fluorouracil (CMF) with and without nolvadex for a two-year period. Postmenopausal women were treated only with hormones. The results were identical in that the benefit from nolvadex was not seen in Her-2/neu overexpressors. In fact, a statistically insignificant trend towards a poorer outcome was noted in the c-erb B2 positive tumors.
In a landmark paper published in the JCO in 2001, nolvadex and letrozole (Femara, Novartis) were compared as neo adjuvant therapy for hormone receptor positive patients. In the same trial, a retrospective analysis, found that Her-2/neu overexpression did not affect response to Letrozole whereas it did confer nolvadex resistance. These data are provocative, however, they are insufficient to use Her-2/neu overexpression as a criteria to select hormone therapy.
Other trials showed no impact of c-erb B2 amplification and response to hormone therapy. For example, a Danish Breast Cancer Cooperative group looked at more than 1000 women with early stage breast cancer treated with nolvadex or with observation. C-erb B2 amplification was not associated with a worse five or even ten year disease free survival in patients treated with nolvadex.
To further confuse the issue, yet other studies suggest Her-2/neu overexpression to positively affect response to nolvadex therapy. Premenopausal, node negative and positive, women were split into two groups; one receiving combination ovarian ablation and nolvadex therapy and the other close observation. Her-2/neu overexpression was associated with a significantly greater benefit from hormone therapy versus observation.
Similar conflicting studies exist in the metastatic breast cancer literature. Despite contradictory results, however, the American Society of Clinical Oncology does not recommend the use of Her-2/neu overexpression as a criteria for giving or choosing hormone therapy in either adjuvant or metastatic disease settings. It is thought that Her-2/neu overexpression is a reflection of a poor prognosis in general, rather than a predictive factor as to who will respond to hormone therapy. On going studies are actively trying to answer this complicated and interesting question.
The association of c-erb B2 gene amplification and response to chemotherapy was initially suggested by the observation of improved chemotherapy action by the addition of Trastuzumab (see part Her-2/neu part I). At least in vitro, the toxic effects of various chemotherapy agents were enhanced by the addition of this monoclonal antibody. In vivo, however, the data again are contradictory. It is generally accepted that Her-2/neu positive patients would benefit from an anthracycline-based chemotherapy. However, that is likely due to the fact, that Her-2/neu positive patients tend to have a worse prognosis and need to be treated with the most powerful agents available. If synergy exists between c-erb B2 amplification and drugs like Doxorubicin as is suggested by some in vitro data, then that is another reason to use these agents.
Trastuzumab belongs to a class of cancer drugs called monoclonal antibodies. It is a recombinant, humanized, monoclonal antibody, which binds to the Her-2/neu receptor protein on the outside of the cell. This binding, blocks the interaction of the Her-2/neu receptor with the human epidermal growth factor protein. By blocking the communication between a receptor and its complementary protein, the drug effectively shuts off growth and differentiation signals to the cell. The theory is that if there is no signal communicated to the cell telling it to grow and divide, it will not do so. Trastuzumab only works in patients who have an increased amount of Her-2/neu protein and has little effect in cancers that do not overexpress this receptor.
Trastuzumab is given by an IV drip. It can be given in the outpatient setting and does not require admission. Because it works primarily on cancer cells that overexpress the receptor, it has little effect on normal tissue and side effects seem to be mild. It is currently given only for the treatment of metastatic breast cancer.
Trastuzumab has shown activity as a single agent in both chemotherapy naive and previously treated patients with metastatic breast cancer. However, the most promising data is reported when trastuzumab is given in combination with other chemotherapy. Pre-clinical data has shown that trastuzumab has synergistic activity with a variety of chemotherapeutics including paclitaxel (Taxol, Bristol-Myers Squibb), and docetaxel (Taxotere, Aventis).
Two important trials established the use of this monoclonal antibody in the metastatic setting. One trial looked at survival and time to progression in patients receiving chemotherapy alone or chemotherapy with trastuzumab. The women in the combination arm of the study had slower tumor growth, greater reduction in tumor size, and longer survival than those who received chemotherapy alone. The other pivotal trial showed that 14% of patients receiving trastuzumab by itself had tumor regression.
Many clinical trials using trastuzumab alone or in various combinations have been conducted since these data were made available. Researchers are investigating the best chemotherapeutic regimen to use with trastuzumab and its effect on endocrine therapy.
Many more clinical trials are on the way using trastuzumab in the adjuvant setting rather than in metastatic disease. We eagerly await these data. Breast cancer is not the only cancer that may overexpress Her-2/neu. Stomach and pancreatic cancer are two additional examples. Research is also being done to evaluate the role of this antibody in other malignancies.
More interestingly, the current data is both perplexing and often inconsistent in the overall treatment of Her-2/neu positive patients. There is a body of literature that claims e-erb B2 amplification may be associated with hormone therapy resistance. Furthermore, some contend that there is a predictable association between Her-2/neu overexpression and response to certain chemotherapeutic regimens. The latter claim is suggested by the observation that trastuzumab's activity is enhanced by the addition of certain chemotherapeutics. Next week, we will evaluate and critically analyze these confusing and conflicting data.
Special thanks to Dr. Steven Stein for help in navigating the massive literature for Her-2/neu that resulted in the summaries found in this column.
For more information, please see Her-2/neu and Its Significance: Science in Action: Part I.
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