Key Points Trastuzumab (Herceptin), a drug developed in the 1990s to target HER2+ breast cancer, consists of a monoclonal antibody that once injected into patients, latches on to the portion of the HER2 protein that sits on the outer surface of the cancer cell. (Question 3) Lapatinib (Tykerb) is an oral, small-molecule drug that is designed to strike multiple targets. It is a tyrosine kinase inhibitor that enters a cancer cell and binds to the part of the HER2 protein that juts beneath the cell surface, but researchers believe that it can also alter the function of other ErbB proteins that may be fueling cancer growth. (Question 4) ALTTO is a trial that has been designed to examine which agent is more effective, which is safer for patients, and what benefit will be derived by taking the drugs separately, in tandem order, or together. (Question 6)

1. What are the different ways in which breast cancer is treated?

Breast cancer is the most commonly diagnosed cancer in women worldwide. Targeted therapies for treating breast cancer have helped to reduce the death rate, according to results from clinical studies. These treatments disable specific molecules in cancer cells that are necessary for growth and survival of a tumor, unlike more general treatments, such as chemotherapy, that interfere with all cells that may be dividing. Because targeted therapies are more precise, they generally have fewer side effects. However, they also may have limited effectiveness in some patients whose tumor growth depends on molecules that are not exclusively targeted by the agents or whose cancer mutates to other growth pathways.

2. How is the HER2+ type of breast cancer different from other cancers?

A specific type of breast cancer called HER2+ (HER2-positive) is caused by an excess of HER2 genes or by over-production of its protein, the HER2 cell surface receptor. HER2 is a member of the epidermal growth factor receptor (ErbB) family of genes which code for protein products known as surface-bound tyrosine kinase proteins. Mutations or over-production of these molecules stimulates cell division and uncontrolled growth. Twenty to 25 percent of breast cancers are HER2+. These tumors tend to grow faster and are generally more likely to recur than tumors that do not overproduce HER2.

3. What drugs are available to treat HER2+ breast cancer?

There are two targeted agents that are U.S. Food and Drug Administration (FDA) approved for the treatment of HER2+ breast cancer:

• Herceptin (trastuzumab), a drug developed in 1990s to target HER2+ breast cancer, consists of large antibodies that once injected into patients, latch on to the portion of the HER2 protein that sits on the outer surface of the cancer cell. It was approved for use in the United States in 1998 and in Europe in 2000 to treat metastatic HER2+ breast cancer, in combination with chemotherapy. In 2006, European and U.S. regulators approved the use of trastuzumab, with chemotherapy, to treat early stage HER2+ breast cancer. Trastuzamab is given intravenously (into the vein).
• Tykerb (lapatinib) was approved in 2007 in combination with capecitabine (a type of chemotherapy) for the treatment of advanced or metastatic HER2+ breast cancer in patients who have received prior treatment, including an anthracycline, a taxane and trastuzumab. It acts by entering a cancer cell and binding to the part of the HER2 protein that lies beneath the surface of the cell. Lapatinib is given orally (a pill by mouth).

4. Is trastuzumab always effective in HER2+ women?

While trastuzumab has reversed the course of HER2+ breast cancer in many patients, some patients do not respond and others will acquire resistance to the agent. Edith Perez, M.D., an oncologist at Mayo Clinic in Jacksonville, Fla., led a North Central Cancer Treatment Group (NCCTG) study that showed a 52 percent reduction in cancer recurrence among women with early cancer who used trastuzumab. Martine Piccart, M.D., Ph.D., professor of oncology at the Universite Libre de Bruxelles, Belgium, led the HERA (HERceptin Adjuvant) trial, a Breast International Group (BIG) study that showed very similar results.

5. How is lapatinib different from other drugs used to treat breast cancer?

Lapatinib is a second generation drug that is designed to strike multiple targets. It is a tyrosine kinase inhibitor that enters a cancer cell and binds to the part of the HER2 protein that juts beneath the cell surface. Its effect on the function of other ErbB proteins that may be fueling cancer growth is also being studied. As a small molecule, it may be able to cross the blood-brain barrier to treat the spread of breast cancer to the brain and central nervous system that trastuzumab cannot reach.

6. What studies have been done to prove the effectiveness of lapatinib?

To date, more than 60 clinical trials have been conducted for lapatinib. Specifically, the U.S. FDA approval was based on a Phase III trial of 399 patients which showed that lapatinib plus capecitabine provided a 28 percent to 43 percent reduction in risk of the disease progressing in women with advanced or metastatic HER2+ breast cancer compared to chemotherapy alone.

Some studies have suggested that lapatinib can offer clinical benefit in HER2+ breast cancer that does not respond to trastuzumab. While lapatinib is associated with side effects, it may not produce the same kind of heart toxicity that can be seen with use of trastuzumab. Researchers really won't know how promising lapatinib is until it is tested against trastuzumab.

7. What are some of the potential side effects of lapatinib and trastuzumab?

Both drugs have potential side-effects:

• Lapatinib has been associated with reports of effects on the heart, in particular with a decrease in left ventricular ejection fraction. Diarrhea was the most common effect, resulting in discontinuation of study medication. Lapatinib has been associated with lung disease and pneumonitis (inflammation of lung tissue). Harm can occur to the fetus when administered to a pregnant woman and women should be advised not to become pregnant when taking the drug. Some of the most common adverse effects (greater than 20 percent) during treatment with lapatinib plus the chemotherapy drug capecitabine were diarrhea, vomiting, nausea, fatigue, and rash.
• Trastuzumab's side effects that most commonly occur during first treatment include fever and/or chills. Other possible side effects include pain, weakness, nausea, vomiting, diarrhea, headaches, difficulty breathing, and rashes. These side effects generally become less severe after the first treatment.
  
  Patients who receive trastuzumab along with chemotherapy may experience side effects that are different from those of patients who take trastuzumab by itself. For example, anemia (a condition in which the number of red blood cells is below normal) and infection, primarily mild upper respiratory infection, have been seen more often in patients given trastuzumab with chemotherapy compared with those receiving trastuzumab alone.

8. What is the ALTTO trial?

ALTTO is a trial designed to compare trastuzumab and lapatinib in women with early stage HER2+ breast cancer who have recently completed chemotherapy. Specifically, ALTTO will examine which agent is more effective, which is safer for patients, and what benefit will be derived by taking the drugs separately, in tandem order, or together. The ALTTO clinical trial is unique in that for all 8,000 patients, there will be a central pathology review of the primary tumor, including re-evaluation of the cancer's estrogen receptor (ER), progesterone receptor (PR), and HER2 status before patients are randomized. Then, patients with HER2+ tumors will be stratified according to their ER/PR profile, lymph node involvement and chemotherapy use to determine whether hormone status affects treatment. About 70 percent of breast cancer is predominantly HER2-negative and ER/PR-positive, but HER2+ cancer can also exhibit estrogen receptors and/or progesterone receptors on cancer cells.

9. What is the primary goal of ALTTO?

The trial's main goal is to determine disease-free survival, which is usually defined as the period of time for which a patient shows no sign of disease. Secondary study endpoints include:

• overall survival, which is the percentage of patients who are alive for a given period of time after diagnosis or treatment. This is often measured for five years after diagnosis or treatment and called the 5-year survival rate
• serious or severe adverse events
• cardiovascular events, such as heart attacks or strokes
• incidence of brain metastases, because when breast cancer recurs, it sometimes spreads to the brain. Because researchers believe that lapatinib can cross the blood-brain barrier, patients who receive this drug may have a lower risk of brain metastases.

10. How are tissue samples examined and stored in the ALTTO trial?

For ALTTO patients included in North America, paraffin samples of their tumors will be tested and stored at the Mayo Clinic in Rochester, Minn. The European Institute of Oncology in Milan, Italy, will test and store paraffin samples for Europe and the rest of the world. The data from these studies can be used in future translational research studies. The outcome of that research will enable researchers to better understand which patients are the best candidates for these targeted treatments.

11. What molecules will the ALTTO investigators focus on in the tumor samples?

Among the molecules evaluated from tumor samples will be the c-Myc oncogene (over-expression of which is believed to make cancer extremely sensitive to trastuzumab), and the PTEN tumor suppressor gene (because cancer which has lost this gene is thought to respond best to lapatinib). Researchers will also collect information on p95 HER2, which are common truncations of the normal HER2 protein that researchers suspect do not respond to trastuzumab.

12. What other biological samples will ALTTO collect?

Blood samples will be collected on all 8,000 patients to look for molecular markers that may predict clinical outcome, and in a subset of 2,000 patients, additional blood and frozen tumor samples will be gathered for future research on circulating tumor cells and proteomics (the study of protein interactions). Those biological materials will be kept in Rochester, Minn., and in Brussels, Belgium. All data resulting from the study will be held at BIG, and will be controlled and analyzed by academic researchers.

13. How will ALTTO be funded?

Funding for ALTTO is provided by the National Cancer Institute (NCI), part of the National Institutes of Health, and GlaxoSmithKline (GSK), the pharmaceutical company that developed lapatinib. The NCI will contribute to each U.S. site a standard $2,000 per patient cost for the ten-year study as well as the basic infrastructure for running all trials via existing grants. GSK's contribution is considered proprietary information.

For a press release on the ALTTO trial, please go to http://www.cancer.gov/newscenter/pressreleases/ALTTO.

For Spanish translations of the press release and Q&A, please go to http://www.cancer.gov/espanol/noticias/ALTTOSpanishRelease.

For more info on BIG, please go to http://www.breastinternationalgroup.org.

For more info on Mayo, please go to http://clinicaltrials.mayo.edu or contact the Mayo Clinic Cancer Center Clinical Trials Referral Office at 507-538-7623.

For more information about cancer, visit http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4 CANCER.

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