Who will benefit and what is the optimal treatment protocol?
HER2 is short for Human Epidermal Growth Factor Receptor 2 (also be called Her-2/neu or ErbB2). All normal breast cells contain copies of the HER2 gene, which gives instructions to the cell on how to make the HER2 protein. The HER2 protein, also called the HER2 receptor, is found on the surface of normal cells. These proteins help send signals to the inside of the cell telling it to grow and divide. In HER2-positive breast cancer, there are extra copies of the HER2 gene (amplification), leading to extra HER2 protein (overexpression). Too much HER2 protein is thought to cause cancer cells to grow and divide more quickly.
Trastuzumab (Herceptin®) has been used to treat more than 420,000 women with HER2-positive breast cancer worldwide (Genentech Inc., 2010). Heralded as a major advance in targeted cancer therapies when first introduced, the drug has been included in breast cancer treatment protocols in the U.S. since receiving approval for use by the Food and Drug Administration (FDA) in 1998. Despite widespread use and extensive research, however, the mechanism by which trastuzumab acts is not completely understood (National Cancer Institute, 2010). And many questions about which patients will get the most benefit from trastuzumab and the optimal treatment protocols remain unanswered.
The FDA originally approved trastuzumab to treat breast cancer in September 1998. Approval was limited to use in patients with metastatic breast cancer who had tumors that were HER2-positive, and there were strict rules regarding how trastuzumab could be administered. The drug could only be given in combination with a specific chemotherapy drug (paclitaxel) in women who had not previously received chemotherapy for metastatic breast cancer, or as a stand-alone treatment for women who had received prior chemotherapy (U.S. Food and Drug Administration, 2010).
In November 2006, FDA approval was expanded beyond the metastatic setting to include treatment of HER-2 positive breast cancer in combination with chemotherapy following primary treatment for early stage breast cancer (often referred to as the adjuvant setting). Similar to the initial approval, there were strict controls regarding how trastuzumab could be administered. Only a chemotherapy regimen containing specific agents (doxorubicin, cyclophosphamide, and paclitaxel) could be used. Furthermore, only patients with breast cancer that involved the lymph nodes were eligible to receive trastuzumab as part of their treatment regimen.
In January 2008, FDA approval was revised to include trastuzumab for use as stand-alone treatment (without chemotherapy) in the adjuvant setting. As with prior approvals, use was limited to patients with HER2-positive breast cancer but could be prescribed to patients regardless of lymph node involvement.
Progress Requires Evidence
The path trastuzumab has taken is a demonstration of how progress is made. Treatment changes as evidence accumulates and new knowledge is acquired. However, the path is also a demonstration of how slow and tedious the process can be. The problem is in not knowing if and how trastuzumab will benefit different groups of patients, for example, those at different stages of disease or those with different tumor characteristics. Other questions still needing answers concern optimal timing, optimal dose, and how trastuzumab behaves when combined with other treatments.
Treatment protocols currently in use are based on scientific evidence from completed clinical trials. Clinical trials by their very nature investigate specific treatment regimens in subjects who are carefully selected based on their personal and clinical characteristics. Study results can be translated to others with the same characteristics, but generalizing results to a broader population of patients is not appropriate.
Tumor Characteristics and Trastuzumab
Researchers continue to investigate tumor characteristics that might make breast cancer more or less responsive to trastuzumab therapy, such as lymph node involvement (node-positive or node-negative) and HER2 status (positive or negative). Based on the best available evidence, FDA approval dictates which patients can be treated with trastuzumab, suggesting that these are the only cases in which trastuzumab therapy is beneficial, but this is not necessarily true.
Historically, clinical trials have enrolled only women with HER2-positive breast tumors that were either node-positive or, if node-negative, the tumor was of larger size. Additional studies that address HER2-negative and/or smaller tumors are currently underway. Those patients who can safely and effectively use trastuzumab will be re-defined as more scientific evidence is gathered.
Chemotherapy and Trastuzumab
Uncertainty exists regarding whether patients who will undergo chemotherapy as part of their treatment regimen should receive trastuzumab along with or following completion of chemotherapy. It is thought that chemotherapy and trastuzumab might work in concert to exert a beneficial effect, but this needs to be confirmed. Preliminary findings from one clinical trial suggest that, in the adjuvant setting, initiating trastuzumab at the same time as chemotherapy leads to better outcomes than when introduced following chemotherapy (Perez, 2009). However, another clinical trial showed that receiving trastuzumab following chemotherapy was more beneficial (Piccart-Gebhart, 2005). Therefore, the optimal timing of trastuzumab initiation is still under investigation.
In the metastatic setting, trastuzumab has been used in combination with chemotherapy as well as a stand-alone therapy (sometimes called monotherapy). Both methods have demonstrated clinical benefit (Cobleigh, 1999; Slamon, 2001; Vogel, 2002). However, there are concerns about serious heart problems that have occurred in some clinical trials when certain chemotherapy drugs and trastuzumab are administered at the same time. Research that confirms who is at risk of such adverse outcomes needs to be completed.
How much, how often and how long?
There is also controversy surrounding ideal dosing (how much), timing (how often), and duration (how long) of trastuzumab therapy. Clinical trials in the adjuvant setting have used different protocols for dosing (2 mg to 6 mg), drug timing (weekly, every several weeks, or a combination of the two), and duration of therapy (weeks, months, or years). All of the trials showed reductions in disease recurrence and mortality (Joensuu, 2008; Piccart-Gebhart, 2005; Romond, 2005; Slamon, 2005; Vogel, 2002), but differences in study design have made it difficult for clinicians to compare trial results and to reach agreement as to the best treatment approach. Answering these questions is important because a lesser exposure to this drug could reduce the probability of drug toxicity and also reduce the time and expense involved in treatment.
Safety of Trastuzumab
Trastuzumab treatment can cause reduced heart function and congestive heart failure. The risk is highest when trastuzumab is taken in combination with a certain type of chemotherapy (anthracyclines), according to the latest results of the BCIRG 006, an international trial of combination treatment regimens for HER2-postive breast cancer (Slamon, 2009). See the anthracycline controversy for more information.