Herceptin: a Promising Advance in the Treatment of
Early-stage HER2-positive Breast Cancer

KEY POINTS

• Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein that is responsible for transmitting growth signals into cells.
• HER2-positive (also called HER2 over-expressing) breast cancer cells have more HER2 receptors than normal cells; consequently, HER2-positive breast cancer has the potential to grow quickly and generally has a poor outlook.
• Herceptin (trastuzumab) is a treatment used specifically for HER2-positive cancer.
• In patients with advanced HER-2 positive cancer, adding Herceptin to chemotherapy increases the length of time until the cancer progresses and increases life-expectancy.
• In women with early-stage HER2-positive breast cancer, adding Herceptin to chemotherapy after surgery reduces the risk of cancer recurring by up to half compared with chemotherapy alone.
• Clinical studies also show that 12 months of Herceptin treatment increases the number of women still alive by around 35% 2 to 3 years after completing treatment. Its long-term effectiveness, including how long life is prolonged, is not yet known.
• The side effects of Herceptin are generally mild; however, serious heart problems can develop in a small number of patients.

HER2-positive breast cancer is an aggressive type of breast cancer
Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor that is responsible for transmitting growth signals into cells. HER2-positive breast cancer cells have higher than normal levels of the HER2 protein. Consequently, HER2-positive breast cancer tends to grow and spread rapidly and is more likely to return after chemotherapy than cancers that have fewer HER2 receptors, called HER2-negative breast cancers. Approximately 20-30% of breast cancers are HER2 positive and around 600 women are diagnosed with HER2-positive breast cancer each year in New Zealand.

Herceptin is a treatment targeted at HER2-positive cancer
Herceptin (trastuzumab) is a manufactured humanized antibody that can help stop the growth of HER2-positive breast cancer. Its mechanism of anticancer activity is not fully understood but appears to involve a complex combination of actions, including disruption of receptor integrity and growth signal transmission, impairment of tumour blood supply and stimulation of the body’s immune response. Herceptin works best in cancers that are HER2-positive i.e. cancers that have strong HER2 over-expression, and have many HER2 receptors on their surface. Tests are available to check whether patients have HER2-positive cancer. Herceptin has already been used for several years to treat advanced HER2-positive breast cancer, which is cancer that has spread to other parts of the body. More recent research has shown it is also beneficial in women with early-stage breast cancer that is HER2-positive, which is cancer is that is present only in the breast or underarm lymph nodes (glands) and has not spread elsewhere in the body.

Herceptin helps prolong survival in women with advanced HER2-positive breast cancer.

Herceptin is already an established component of treatment for patients with advanced HER2-positive breast cancer. When given in combination with chemotherapy as initial treatment in patients with advanced HER2-positive cancer, Herceptin produces meaningful increases the length of time until the cancer starts  growing again (time to disease progression) and the time patients remain alive (overall survival) compared with chemotherapy alone.

Herceptin reduces the risk of recurrence and death in early-stage HER2-positive breast cancer
More recently, interim results from clinical trials in women with early-stage HER2-postive breast cancer showed that Herceptin given in addition to chemotherapy increased the time that patients lived without their cancer coming back (disease-free survival), halving the risk of it returning compared with treatment with chemotherapy alone.

Four controlled clinical trials, known as NSABP B-31, NCCTG N9831, HERA and BCIRG006, have evaluated the addition of 12 months of Herceptin to the usual chemotherapy given to early-stage HER2-postive breast cancer patients after surgery (known as adjuvant therapy). The trials varied in terms of the precise treatments used and the specific type of patients studied, but the main aim of all of them was to assess whether Herceptin improved disease-free survival (remaining alive and without the return of cancer). To date, the available results cover 1 year of treatment with Herceptin plus another 2-4 years of follow-up.

These trials showed that, compared with chemotherapy alone, adding Herceptin reduced the risk of the cancer recurring by 33-52% during the first 2-4 years after completing treatment. For example, the disease-free survival rate after 3 years in the HERA study was 81% among women who had received 1 year of treatment with Herceptin (with 2 years of follow-up), compared with 74% of women who had not received Herceptin. This represents a reduction of 37% in the risk of the cancer recurring. In a combined analysis of two of the other trials (NSABP B-31 and NCCTG N9831), the disease-free survival rate after a total of 4 years was 86% for women treated with Herceptin for 1 year (with 3 years of follow up) compared with 73% among those who received only chemotherapy, indicating that the risk of recurrence was reduced by 52%.

The combined analysis also showed that after a total of 4 years of follow-up, the number of deaths among women who received Herceptin was reduced by 35% relative to those who did not receive Herceptin. The overall survival rate after 4 years of follow-up was 93% in patients treated with Herceptin plus chemotherapy versus 89% who received chemotherapy alone. After a follow-up period in the HERA study of only 2 years, there was a 34% improvement in the overall survival rate of patients treated with 12 months of Herceptin compared to those who did not receive it.

In a small trial known as the FinHer (Finland Herceptin) study, 232 patients with early-stage HER2-positive breast cancer received either 9 weeks of Herceptin with chemotherapy or chemotherapy without Herceptin as post-surgical treatment. This trial used an unconventional chemotherapy regimen. After a total of 3 years, more patients were free of disease in the group that received Herceptin but the trial was too small to allow detection of a statistically significant difference in overall survival between treatments. Although the disease-free data is promising, the small number of patients treated in this trial and serious imbalances between the Herceptin and no Herceptin treatment groups, means the results have to be interpreted with great caution and are less certain than for the four larger studies involving 12 months of Herceptin treatment and more data are needed to confirm possible benefits of this short course.

In many countries, regulatory approval agencies, which evaluate available clinical and cost effectiveness data for pharmaceutical treatments, have fast-tracked their assessments of Herceptin. 24 OECD countries now fund 12 months of Herceptin treatment for patients with early stage HER2-positive breast cancer. As of 1st July 2007, New Zealand became the only country to fund only 9 weeks of treatment, based on the FinHer results.

Unknown long-term outcome in women with early-stage HER2-positive breast cancer
It is important to note that to date the period of follow-up for the trials in early-stage HER2-positive breast cancer is only 2-4 years, and so the available results are considered short-term. Long-term outcome in women with early-stage breast cancer taking Herceptin is not yet known; for example, it is not clear how many lives may be saved each year, nor for how long women’s lives may be prolonged by treatment with Herceptin. Follow-up in these studies will continue for up to 10 years, so additional information will become available over time, which may change the results seen so far.

Side effects are usually mild but some serious problems can occur.

As with any treatment, side effects can occur with Herceptin, but they are usually mild. The most common events are temporary flu-like symptoms including fever and chills, which usually occur during or shortly after administration of the first dose. Other possible side effects include diarrhoea, headache, pain, and cough. Among more serious events, allergic reactions and serious breathing problems can occur rarely. Heart failure has occurred in 0.6% of patients when Herceptin is given following chemotherapy, and up to 4% when given at the same time as taxane-based chemotherapy. In some cases specific drug treatment was required but in most patients, heart function recovered after stopping Herceptin. No cardiac-related deaths were reported after 2 years follow-up in the HERA trial, a median of 3 years follow-up in an interim analysis of data from BCIRG 006 or at least 4 years of follow-up according to an interim analysis of cardiac safety data from the NSABP B-31 study. Cardiac risk seems to be greater if Herceptin is given with the anthracyclines, which is a class of chemotherapy drugs that includes doxorubicin (Adriamycin) and epirubicin (Pharmorubicin), and in women with previous heart problems. Therefore, patients need to be checked for heart problems before being given Herceptin and their heart function monitored during treatment to detect any problems that might be developing.  In the vast majority of patients, the risk of heart damage is small compared to the risk of the cancer advancing.

Where to from here?
Currently available findings from studies in early-stage HER2-positive breast cancer are encouraging, most notably the near 50% reduction in the risk of cancer recurrence and the reduction in risk of death of around one third. These early benefits compare well with those of adjuvant chemotherapy with aromatase inhibitors, which require longer patient follow-up for advantages in disease-free survival and overall survival to become apparent. Notwithstanding the current absence of data on long-term outcome, Herceptin has become a preferred component in the treatment of early-stage HER2-positive breast cancer, since it gives women with this aggressive disease a chance of staying healthy and staying alive for longer than they otherwise might.

September 2007

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