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|HER2 Breast Cancer|
HER2 (human epidermal growth factor receptor-2) Positive Breast Cancer
Breast Cancer Is Many Different Diseases Researchers now understand that breast cancer is not one disease, but many different diseases. Even when tumors are classed together based on their appearance, they can act differently because of different genetic makeup. Only recently have researchers begun to understand this and to use it in predicting how a disease may progress — for example, the likelihood of a tumor to grow, spread, or recur. This is an important new area of research.
HER2-positive breast cancer is one form of breast cancer. Characterized by aggressive growth and a poor prognosis, it is caused by the overexpression of a gene called HER2 in tumor cells.
HER2 in Normal Cellular Function Every one of the millions of cells in our body carries out its life cycle in a relatively orderly fashion dictated by its function and various other factors. The process can be altered by intra- and extra-cellular pressures that change the cell's environment. In the development of cancer, a key factor is a change in the growth rate of the cell and the ability of various control mechanisms to get the cell back on track.
The HER2 gene is responsible for making HER2 protein. When two copies of the gene are present in normal amounts, the protein plays an important role in normal cell growth and development. The HER2 protein transmits signals directing cell growth from the outside of the cell to the nucleus inside the cell. Growth factors — chemicals that carry growth-regulating orders — attach to the HER2 protein and signal normal cell growth.
Role of HER2 in Tumor Growth In approximately 25 percent of women with breast cancer, there is a genetic alteration in the HER2 gene that produces an increased amount of the growth factor receptor protein on the tumor cell surface.
This overexpression can cause cells to divide, multiply, and grow more rapidly than normal. Research has shown that women with HER2-positive breast cancer have a more aggressive disease, greater likelihood of recurrence, poorer prognosis, and decreased survival compared to women with HER2-negative breast cancer.
It is important to understand that the HER2 gene abnormality is only present in the breast cancer cells, not in the rest of the cells in the body, and cannot be passed onto other family members.
Discovering HER2 HER2 is a normal gene; however, when amplified, it causes cancer and is called an oncogene. Many scientists had postulated that oncogenes were related to growth factors. In the early 1980s, a Genentech scientist, a British protein chemist, and an Israeli protein expert together proved that growth factors are related to cancer. They found an oncogene that was a mutated form of the epidermal growth factor (EGF) cell-surface receptor gene. By linking the study of cell-growth signals and cancer, this finding explained how an oncogene worked.
Genentech researchers then began searching for oncogenes similar to the EGF-receptor gene. They named the first one they found "HER2," for human epidermal growth factor receptor 2. With cloning technology, they discovered the protein the gene produced. They subsequently set out to find the link between HER2 and specific types of cancer. In collaboration, Dennis Slamon, M.D., Ph.D., of UCLA, looked for "matches" between the HER2 oncogene and tumor samples.
Slamon observed that the HER2 oncogene caused breast cancer cells to produce the normal HER2 protein, but in abnormally high amounts, and that the women with metastatic breast cancer whose tumor cells overexpressed the HER2 protein had an especially aggressive form of the disease. When the gene overexpresses the protein, he determined, the cell is overloaded with signals that cause it to grow out of control and become cancerous.
Taking the Biology of HER2 from Basic Research to Treatment A Genentech research team began working on the basic science of HER2 in hopes that they could develop a potential treatment. They figured out how to transform normal cells into cancerous ones by adding copies of the HER2 gene. Next, they designed a targeted monoclonal antibody to "shut off" the HER2 gene, making the cancerous cells grow more slowly.
Antibodies are proteins made by the body's own natural immune system that are directed against foreign and infectious agents, called antigens. Monoclonal antibodies engineered through biotechnology are produced as therapeutic drugs to provide specific anti-tumor action within the body. A monoclonal antibody contains millions of identical copies of a single antibody, all of which attack the same targets.
Researchers injected samples of the monoclonal antibody into mice with tumors that overexpressed the HER2 protein. In many cases, the tumors, which were human breast cancers, shrank. The results were encouraging and researchers were anxious to test the therapy in humans. But the antibody was made of mouse protein, which might be rejected by the human body as a foreign substance. They had to figure out a way to "humanize" the antibody so the human body would accept it.
Working for more than a year, Genentech scientists developed a "humanized" version of the monoclonal antibody — Herceptin® (trastuzumab). Now, they were ready for early-stage human clinical trials. Phase I monitored for side effects and determined dosing, Phase II helped the understanding of the drug's efficacy and safety, and a large-scale Phase III trial proved Herceptin's safety and efficacy in the treatment of metastatic breast cancer.
Herceptin on the Market The FDA first approved Herceptin in September 1998. Herceptin is the first monoclonal antibody approved for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein. It is indicated for the treatment of these patients, both as a first-line therapy in combination with paclitaxel and as a single agent for those patients who have received one or more chemotherapy regimens.
Herceptin was proven effective in clinical trials, both as a single agent and in combination with paclitaxel. In the Phase III combination trial, Herceptin plus chemotherapy, improved overall survival rates and slowed disease progression of women as a first-line therapy.
In November 2006, the FDA approved Herceptin, as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel, for the adjuvant treatment of patients with HER2-positive node-positive breast cancer. Adjuvant therapy is given to women with early-stage (localized) breast cancer who have had initial treatment — surgery with or without radiation therapy — with the goal of reducing the risk of cancer recurrence and/or the occurrence of metastatic disease.
This approval was based on data from a planned interim joint analysis of more than 3,700 patients enrolled in two NCI-sponsored Phase III clinical trials conducted by a network of researchers led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG). These results showed that the addition of Herceptin to standard adjuvant therapy significantly reduced the relative risk of breast cancer recurrence, the primary endpoint of the studies, by 52 percent (or a hazard ratio of 0.48) in women with HER2-positive breast cancer, compared to those who received standard adjuvant therapy alone.
In January 2008, the FDA approved Herceptin as a single agent for the adjuvant treatment of HER2-positive node-negative (ER/PR-negative or with one high-risk feature) or node-positive breast cancer, following multi-modality anthracycline-based therapy based on the HERA one-year data. The FDA approval expanded Herceptin's adjuvant label to include the use of Herceptin as a single agent and in patients with early-stage HER2-positive node-negative disease, including tumors that are hormone receptor-negative, grade 2 or 3 or >2 cm, or age <35. Herceptin also may be administered as a single agent in an every-three-week dosing schedule for one year, which may provide another treatment option for patients.
In May 2008, the FDA approved two new Herceptin-containing regimens for the adjuvant treatment of HER2-positive node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer based on the results of the BCIRG 006 study. The first regimen is in combination with docetaxel and carboplatin, (also known as TCH for Taxotere®, carboplatin, and Herceptin) which does not contain an anthracycline component. The second is part of a treatment regimen containing anthracycline (doxorubicin), cyclophosphamide, and docetaxel (AC-TH). The approval of the non-anthracycline TCH regimen added an important treatment option for patients as it reduced the rate of congestive heart failure (0.4% vs. 2%) as compared to the Herceptin anthracycline-containing regimen in the 006 study and significantly reduced the relative risk of recurrence by one-third, compared to chemotherapy alone. In comparison to AC-TH, TCH provided a similarly effective treatment option with less cardiotoxicity, which may potentially allow more patients to benefit from Herceptin therapy.
Boxed WARNINGS and Additional Important Safety Information Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF). The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.
Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment. More frequent monitoring should be employed if Herceptin is withheld in patients who develop significant left ventricular cardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin containing regimens.
Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
Exacerbation of chemotherapy-induced neutropenia has also occurred.
Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman.
The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.
Mechanism of Action Herceptin is a humanized monoclonal antibody (also called a biologic therapy). Antibodies are part of the body's normal defense against bacteria, viruses and abnormal cells such as cancer cells. Therapeutic monoclonal antibodies are created and produced in a laboratory through a complex and resource-intensive process. Their name comes from the fact that they are produced from a single cell.1
Based on preclinical studies, Herceptin works on both the extracellular and the intracellular domains of the HER2 receptor.2-5
3 Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidyli-nositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Research. 2002;62:4132-4141.
6 Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Nat Cancer Inst. 2004;96:739-749.
7 Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825-2831.
|Last Updated on Thursday, 18 March 2010 07:02|