Trastuzumab (Herceptin, NO 34) is a monoclonal antibody that targets cancer cells overproducing the HER2 protein, which is a member of the HER family of TK receptors that we have discussed extensively, particularly in the context of our discussion with the TKI lapatinib.
Breast cancer is the most common female malignancy with approximately 194,000 new cases diagnosed in 2009 and 46,000 deaths. This means one in every eight women will develop breast cancer in her lifetime. Approximately 15-25% of breast cancers overexpress HER2, and tend to grow faster and be more aggressive than breast tumors that do not overproduce HER2. The amount of HER2 protein in the tumor is measured in the laboratory using a scale from 0 (negative) to 3+ (strongly positive). The numerical result is used to help decide whether a patient might benefit from treatment with trastuzumab. For women whose tumors are strongly positive for HER2 protein overexpression (a score of 3+ on the lab test), the potential benefit is greatest. In contrast, there is no evidence of benefit in patients whose tumors do not overexpress HER2 (a score of 0 or 1+ on the laboratory test). Trastuzumab is an antibody that binds selectively to the HER2 protein. Specifically, trastuzumab is a humanized monoclonal antibody that binds to domain IV of the extracellular segment of the HER2/neu receptor. When it binds to defective HER2 proteins, the HER2 protein no longer causes cells in the breast to reproduce uncontrollably. This increases the survival of people with cancer. However, cancers usually develop resistance to trastuzumab over time.
Trastuzumab was developed by Genentech and granted FDA fast track status in late 1997. Within 4.5 months, the drug received FDA approval in September 1998. In doing so, it became the second monoclonal antibody approved to treat cancer. The first was rituximab, which was approved in November 1997 for patients with non-Hodgkin's lymphoma, a cancer of the immune system. A full review of the clinical trials concerning trastuzumab is beyond the scope of this review, but some of the most important trials will be reviewed. Trastuzumab has demonstrated activity as a single agent in breast cancer with partial responses (PR) ranging from 20-35% in patients with HER2/neu positive metastatic breast cancer (MBC). Trastuzumab has also been demonstrated to enhance the effects of cytotoxic chemotherapy. An important trial in the New England Journal of Medicine published in March of 2001 demonstrated that the addition of trastuzumab to chemotherapy (either doxorubicin/epirubicin and cyclophosphamide or paclitaxel) improved response rates, median duration of response, and overall survival.
Initially, the benefit seen from trastuzumab was observed in women with metastatic breast cancer (MBC). Many subsequent clinical trials have demonstrated an improved time to progression and/or overall survival in patients with HER2/neu positive tumors when combined with standard chemotherapy in non-metastatic patients. We will now take a closer look at the use of trastuzumab in these settings. First, however, we should define the terms “adjuvant” and “neoadjuvant” which have special meanings in oncology. Adjuvant therapy refers to additional treatment usually given after surgery or radiation where all detectable disease has been removed, but where there remains a statistical risk of relapse due to microscopic or occult disease (undetected cancer cells). If known disease is left behind following surgery, then further treatment is not technically "adjuvant". “Neoadjuvant therapy,” in contrast to adjuvant therapy, is given before the main treatment. For example, chemotherapy that is given before surgical removal of a breast is considered neoadjuvant chemotherapy. The most common reason for neoadjuvant therapy is to reduce the size of the tumor to allow more effective surgery or shrinking the radiation field size.
Returning to our in-depth look at trastuzumab, two of the largest trials were NSABP B-31 and NCCTG 98331, the combined results of which were published October 2005 in the New England Journal of Medicine in the form of an interim analysis and were updated at ASCO 2007 (OncoLink review here). Although there were minor variations in the sequencing of the agents and radiation treatments, the overall design was quite similar and the results were pooled for greater statistical power. Both patients enrolled high-risk lymph node negative patients that were HER2 positive (required FISH amplification or 3+ by IHC) and required axillary lymph node dissections. Both trials used four cycles of Adriamycin and Cytoxan followed by weekly Paclitaxel with or without trastuzumab. In the 2007 update, among the 3,969 women enrolled, the four year disease-free survival rate (DFS) and overall survival rate (OS) were 85.9% and 92.6% in the trastuzumab group and 73.1% and 89.4% in the non trastuzumab group, indicating a substantial improvement in outcomes with the addition of trastuzumab to chemotherapy.
The Herceptin Adjuvant (HERA) study Breast International Group (BIG) 01-01 trial was a randomized trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant (or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer). 5,102 women participated in the trial and initial results were published in The Lancet in January of 2007; however, the HERA study is ongoing and final results are not expected until 2011. The primary endpoint is disease-free survival (DFS), and the secondary endpoints are overall survival (OS) and cardiac safety. With 2 years of median follow up, the HERA study demonstrated that one year of treatment with trastuzumab given at three-weekly intervals after the completion of adjuvant chemotherapy and/or radiotherapy achieved a highly significant improvement in DFS versus the observation group (no trastuzumab), reducing the relative risk of relapse by 36%. Trastuzumab also reduced the risk of death by 34% compared to observation. Upon publication of these results, more than 50% of the patients in the observation arm opted to receive trastuzumab (‘crossed-over’ to trastuzumab treatment). An unpublished update to these data released in 2009 revealed that at a median of four years of follow-up, the results of the analysis including all women involved in the trial showed a 25% reduction in risk of cancer recurrence for women receiving trastuzumab compared to those on observation (no trastuzumab). At four years of follow-up, nearly 79% of women receiving trastuzumab remained cancer-free, a significant increase compared to 73% of women in the observation arm.
Combining trastuzumab with a non-anthracycline-based chemotherapy was evaluated in another important trial conducted by The Breast Cancer International Research Group (BCIRG) known as 006. The most recent results (second interim analysis) were presented at the 29th Annual San Antonio Breast Cancer Symposium in 2006 and demonstrated that the benefit of trastuzumab was preserved when combined with docetaxel and carboplatin in a regimen known as TCH without an anthracycline. At a median follow-up of 23 months, this study demonstrated that one year of trastuzumab improved DFS as compared to adjuvant chemotherapy alone.
Prior to the seminal the New England Journal of Medicine article from March of 2001, the use of trastuzumab alone had not been associated with increased rates of cardiac toxicity. In this trial and subsequent analysis, however, a higher rate of congestive heart failure (CHF) was observed in women treated with trastuzumab. More patients suffered cardiac toxicity in the anthracycline (doxorubicin)/trastuzumab arm than the paclitaxel/trastuzumab arm, although the outcomes were still improved when all patient outcomes were examined. Examination across multiple trials has demonstrated that approximately 2-3% of women will develop symptomatic congestive heart failure (CHF) who undergo one year of trastuzumab following anthracycline-based chemotherapy. A higher percentage (nearly 1/5 of all patients) will suffer from an asymptomatic decrease in their left ventricular ejection fraction (the blood pumped with each heart beat from the left ventricle). For this reason, patients being considered for therapy with trastuzumab need to have their baseline cardiac function checked prior to beginning chemotherapy.
Other antibodies targeting HER2 are at earlier stages of development and there are many planned or ongoing trials designed to assess the benefit of antibody therapy against EGFR in combination with irinotecan or carboplatin in the treatment of triple negative breast cancers (ER-, PR-, HER2/neu negative).
In summary, here are the currently approved FDA indications for trastuzumab: