Introduction Surpassing heart disease in 2004, cancer is now the leading killer in the United States. According to the American Cancer Society, more than 1,500 people die each day from cancer and over 16 million people have been diagnosed with cancer since 1990.

In recent years, medical science has taken great strides in understanding and treating cancer. However, prior to 1997, the majority of treatments such as chemotherapy and radiation, were not based on the underlying biology of cancer growth. These treatments are also often associated with serious side effects.

In November 1997, the FDA approved the first targeted treatment for cancer — a therapeutic antibody called Rituxan® (Rituximab) — for patients with a certain form of non-Hodgkin's lymphoma. This advancement was followed closely in 1998 by the approval of Herceptin® (Trastuzumab), which, like Rituxan, is a therapeutic antibody. Herceptin is the first molecular-based targeted treatment for metastatic breast cancer and was developed to inhibit cancer cells carrying excessive amounts of the HER2 gene, a member of the HER family of genes and pathway, that has been linked to a particularly aggressive form of breast cancer. 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. In January 2008, the FDA approved Herceptin as a single agent for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR-negative or with one high-risk feature) or node-positive breast cancer, following multi-modality anthracycline-based therapy.

Since the discovery of the HER2 gene, researchers from around the world have elucidated that HER2 is a main component of a complex signaling pathway that includes numerous family members, many of which are also involved in the formation of cancer and other diseases.

Cancer Growth and the Genesis of Cancer Cancer begins when the DNA of a normal cell changes, or "mutates", making normal cells grow uncontrollably.

There are two types of mutations:

• Somatic mutations, which are caused by environmental factors such as sunlight or carcinogens; and
• Hereditary cancers, which are harmful mutations passed down from one generation to another.

Each type of mutation eventually "expresses" itself by producing chemical signals within the cell that tell the cell to grow. The cell then enlarges, divides and reproduces itself, creating two new identical copies of the original. In normal cells, growth occurs at a steady, regulated rate. In cancer cells, growth is unregulated and continues as long as the tumor obtains the requisite nourishment it needs from the surrounding environment.

Communication by Signal Transduction Signal transduction is a means by which one cell communicates to another. The "conversation" between two cells involves a molecular messenger (called a ligand) from the sender and a site (called a receptor) on the membrane surface of the cell receiving the signal. When the signal is received, it is passed along within the cell in the same way a bucket of water might be passed along a bucket brigade. In this way, the message is communicated from the outer surface of the cell into the cell's nucleus. Messages can be healthy or harmful. For example, some messages might be signals telling the cell to grow (which can lead to cancer) or a growth signal might be used by the immune system to increase the amount of white blood cells needed to fight and infection. In other cases, signals may cause cells to store materials such as fatty acids, which is healthy in moderation but when uncontrolled, may lead to obesity. This process is referred to as signal transduction.

Some of the more common signaling pathways involve proteins called receptor tyrosine kinases, which have three components:

• An extracellular ligand-binding domain receptor that is located outside the cell and receives incoming signals;
• A transmembrane domain that crosses the cell membrane and conveys information from the outside to the inside; and
• An intracellular tyrosine kinase domain that adds a phosphate molecule to tyrosine, a type of protein. This process initiates an internal messaging cascade and is referred to as "phosphorylation."

Introduction to the HER Pathway In oncology, one of the most important tyrosine kinase signaling networks is a group of receptors belonging to the "HER" family, also known as the ErbB signaling network. The ErbB receptors are named after the Avian erythroblastosis tumor virus, which encodes an aberrant form of the human epidermal growth factor receptor (from which "HER" originates).

The HER family of receptors consists of four main members commonly referred to as HER1/EGFR, HER2, HER3 and HER4. Each of these receptors is in some way culpable in the development of malignant tumors, although some are more involved than others. There is a considerable amount of "cross-talk" between the receptors, meaning that activation or inhibition of one can have collateral effects on the others.

Understanding the biological role of the HER family has led to the discovery of other important signaling systems, such as receptors that are distinct from the HER family but have the ability to "quiet" HER-generated tumor-stimulating signals.

One of many important discoveries resulting in an exploration of the HER-based signaling pathways includes the PTEN gene, which appears to be abnormal in as many as 50-60 percent of advanced prostate cancers. PTEN is thought to be a tumor-suppressor gene, and works in complete opposition to the HER genes although it uses the same signaling pathways. Unlike kinases, which make cells grow, the PTEN gene produces an enzyme called a phosphatase, which halts cell growth. The PTEN phosphatase regulates growth in a common signal transduction pathway activated by receptor tyrosine kinases.

Identifying the Source of Dysfunction In all cells, some level of growth-signal transduction is normal and is part of the regular growth cycle. It is the overexpression, or activation, of these signals — or the failure to counterbalance or block those signals — that leads to uncontrollable growth. In the case of the HER2, for example, overexpression is the result of a genetic alteration that generates multiple copies of a gene that encodes a growth receptor. Because of the surplus of growth receptor genes in the cell, excessive numbers of growth receptors are created that, when activated, enlarge the number growth signals stimulating the cell, accelerating cell division and tumor growth.

Key Players in the HER Pathway The four members of the HER family are called HER1, HER2, HER3 and HER4. Each is implicated in the development of cancer although the degree of involvement varies.

Name	Other Names	Type(s) of Dysregulation	Cancer Types
HER1	EGFR	Overexpression Mutation leading to constitutive (non-stop) activity	Head and neck, bladder, prostate, renal, non-small-cell lung cancer, ovarian, pancreatic and glioblastoma.
HER2	c-erbB-2 ErbB2	Overexpression Co-expression with HER-1 improves ability to predict aggressiveness of breast cancer	Breast, ovarian
HER3	ErbB3	Co-expression with HER-2 improves ability to predict aggressiveness of breast cancer	Breast, colon, gastric, prostate, other carcinomas
HER4	ErbB4	Reduced expression produces differentiated phenotype Co-expression with HER-2 has prognostic value	Breast, prostate, childhood medulloblastoma

A Closer Look at the HER Pathway Players An physical feature of the HER pathway is that the signaling system always involves two receptors in combination, in a formation called a "dimer." Homodimers are combinations of two similar receptor types, such as HER1/HER1 and HER3/HER3. Heterodimers contain two different receptors, such as HER1/HER2; HER1/HER3; and HER4/HER3. The various hetero- and homo-dimer pairs affect the signal strength within the cell. For example, the co-expression of certain pairs (such as HER3/HER2) is more powerful than others such as the HER3/HER- homodimer, which is inactive. Research is underway to better understand why certain pairings have different effects and how those effects manifest themselves.

HER1/EGFR: Another abbreviation for the human epidermal growth factor receptor is EGFR, a name that is often used due to the observation of clinical benefits associated with its inhibition.

HER1 overexpression enhances tumor cell motility, adhesion and metastatic potential while normal HER1 signaling disrupts cell cycle control (leading to proliferation) and apoptosis (programmed cell death).

HER2: Perhaps the best-known member of the HER family, overexpression of the HER2 gene is correlated positively with an especially aggressive form of breast cancer that occurs in approximately 25 percent of all breast tumors. HER2 also is overexpressed in a variety of other solid tumors and may interact with certain steroid hormone networks, suggesting that it could affect patient response to anti-estrogen therapies.

HER3: Expression of HER-3, when activated in a conjunction with HER-2, is linked to increased tumor aggressiveness.

HER4: Some studies have shown a lower expression of HER-4 in breast and prostate tumors relative to normal tissue.

Validating the HER Pathway: Herceptin In one of the first attempts to exploit the underlying molecular causes of cancer, Genentech developed a therapeutic antibody called Herceptin that specifically targets and blocks the HER2 receptor, leading to validation of the concept of molecularly targeted therapeutics. The FDA approved Herceptin in 1998 for use in combination with the chemotherapy paclitaxel for the treatment of HER2-positive metastatic breast cancer and as a single agent in second- and third-line therapy.

On March 14, 2001, the New England Journal of Medicine published a study demonstrating that patients treated weekly with Herceptin and standard cycles of chemotherapy until disease progression as a first-line therapy had an increase in median overall survival as compared to women treated with chemotherapy alone. In first-line combination use in the pivotal clinical trial, patients given Herceptin plus chemotherapy* showed median survival of 25.1 months versus 20.3 months for chemotherapy alone. This represents a 24% increase. In the same trial, patients given Herceptin plus paclitaxel showed median survival of 22.1 months versus 18.4 months for paclitaxel alone.

Herceptin Safety Profile 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.

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.

Full Prescribing Information

Leveraging the HER Pathway Building on its extensive knowledge of the HER pathway, Genentech has a number of product development programs:

Tarceva® (erlotinib): Tarceva is approved for second- /third - line therapy in patients with non-small cell lung cancer and in combination with gemcitabine chemotherapy for the treatment of locally advanced, inoperable or metastatic pancreatic cancer in patients who have not received previous chemotherapy. Tarceva is a small molecule tyrosine kinase inhibitor that was co-developed with OSI Pharmaceuticals and Roche. As a small molecule that inhibits HER1/EGFR pathway, Tarceva inhibits the intracellular phosphorylation of TK associated with the Epidermal Growth Factor Receptor (EGFR). The National Cancer Institute will also be evaluating Tarceva in different cancers in which HER1 may play a role. Tarceva, an inhibitor of the HER1/EGFR pathway, has been shown to improve survival with some advanced non-small cell lung cancer patients.

Pertuzumab: Directed against the HER2 family, pertuzumab is a humanized potential therapeutic antibody in Phase II testing. Pertuzumab is designed to directly attack tumor cell growth by inhibiting the signaling pathway of the entire family of HER kinases.

Future of Cancer Therapy and the HER Pathway Having established the HER pathway's role in a variety of solid tumors, molecular-targeted therapies are a valid and rationale approach to cancer treatment. Scientists are now utilizing the underlying biological mechanisms involved in cancer growth and metastases to develop clinical strategies to treat patients with cancer. While researchers continue to study the biological inner-workings of the HER pathway and other pathways involved in cancer, Genentech clinicians and collaborators are using the acquired knowledge to identify new and innovative ways to treat cancer patients.

Since certain receptors in the pathway work together to produce malignancy, one of the clinical strategies being explored today involves the possibility of combining several targeted HER molecules as well as other targeted therapies into a single treatment regimen - based on the biology of disease - that potentially have a synergistic or additive effect on the tumor and could on day lead to cancer becoming a more chronic disease.

HER Pathway Timeline

1980 -	Discovery of EGFR (earliest review article)
1985 -	Discovery of HER2 gene's distinctiveness from HER1
1985 -	Characterization of the Promoter Region of the Human c-erbB-2 Protooncogene - Proceedings of the National Academy of Science
1987 -	HER2 linked with breast cancer
1987 -	Human Breast Cancer; Correlation of Relapse and Survival with Amplification of the HER2/neu oncogene
1998 -	FDA approval of Herceptin
2006 -	FDA approval of 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
2008 -	FDA approval of Herceptin as a single agent for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR-negative or with one high-risk feature) or node-positive breast cancer, following multi-modality anthracycline-based therapy.

* Chemotherapy = either doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel.