Personalized cancer medicine is the use of information about an individual person and an individual cancer to provide specific strategies to find, treat, and prevent cancer. It includes the genetic characteristics of the cancer and the patient's overall health, genetic factors, and treatment preferences. This issue of Cancer Advances explains personalized cancer medicine and related concepts, such as genetics and cancer, individualized cancer treatment, and targeted treatment. The information in this publication was presented at an ASCO Meet the Expert event in New York City in December 2006.

Personalized cancer medicine marks a departure from the approach to cancer prevention and treatment during the past 30 years. The promise of personalized medicine is that prevention, screening, and treatment strategies can be developed that are more effective and less toxic because they are based on the unique features of both the individual person and the tumor.

The applications of personalized cancer medicine include:

• Evaluating a person’s risk of developing cancer



• Designing screening strategies to lower this risk



• Predicting the risk of recurrence (the return of the cancer) and survival



• Improving the effectiveness of cancer treatment by identifying patients with cancers that are most likely to benefit from that treatment



• Reducing the side effects of treatment by identifying patients that are best able to tolerate specific treatments

"We are witnessing a revolution in the understanding of human cancer," said Julie R. Gralow, MD, Chair of ASCO's Meet the Expert Event and Associate Professor of Medicine/Oncology at the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center in Seattle. "The personalization of cancer medicine represents a tremendous potential for prevention and early detection of cancer and improvement of the effectiveness and tolerability of therapy."

Cancer develops from a series of genetic changes that transform a healthy cell into a cancer cell. Understanding the genes and related proteins that are associated with the development and spread of cancer can improve treatment. In fact, many of the recently developed cancer drugs reflect this knowledge.

In addition, the inherited genetics of the patient can influence both the risk of developing cancer and the response of both the healthy body tissue and the cancerous tissue to cancer treatments. Although humans are genetically 99% identical, that 1% difference is important for determining how a person's body gets rid of carcinogens (substances that cause cancer), how quickly cancer drugs are metabolized (broken down by the body), and the type and severity of side effects a person experiences. Other medical, emotional, and practical concerns also play a role in a person's decisions about cancer prevention and treatment.

In the future, it is possible that advances in personalized medicine will lead to a shift in the classification of cancers, so that the cancer will be named according to its genetic characteristics and not by the location in the body (such as the colon).

Dear Friends,

Personalized medicine represents the future of cancer research. Instead of following a "one-size-fits-all" approach to cancer treatment, we are starting to personalize cancer therapy based both on the biology of the individual tumor and various characteristics of the person with cancer.

Cancer Advances: Information from the Experts is the most recent issue of Cancer Advances, a series of consumer information resources from the American Society of Clinical Oncology (ASCO) designed to help patients and their families learn about new developments in cancer. This issue provides the latest information about personalized medicine, including an introduction to the topic, the role of genetics in the development and treatment of cancer, the ways that cancer treatment can be individualized, and the development of new treatments that target specific factors in a cancer cell.

To promote the development of personalized medicine, ASCO created a Translational Research Task Force last year to advise ASCO leadership on how to develop the most effective educational content about molecular targets, biomarkers, molecular imaging, and targeted therapies. As a result, a number of new initiatives are being implemented to provide our members with the latest information about personalized medicine, attract professionals with the greatest expertise in this field to our organization, and develop the tools that our members can use to provide the most advanced care to their patients.

I hope you find this newsletter helpful in understanding personalized medicine. For more information about cancer, visit ASCO's People Living With Cancer website at www.plwc.org.

Sincerely,

Gabriel Hortobagyi, MD, FACP
President, American Society of Clinical Oncology

Cancer is a genetic disease. That is, cancer develops because of specific changes to genes that transform a healthy cell into a cancerous cell. Sometimes, these changes are caused by inherited cancer genes, such as the breast cancer susceptibility genes (BRCA1 and BRCA2). More often, the genes within cells undergo changes that allow the cells to become cancerous. Understanding the genes responsible for the development of cancer is the first step towards finding better detection methods and treatment strategies.

Mutations and Cancer Risk

The most common genetic change is a mutation (a change to the gene's DNA, or genetic code). Sometimes, a gene malfunctions because of an increase or decrease in the copy number (the number of copies of a gene in a cell). For example, there are too many copies of the human epidermal growth factor receptor 2 (HER2) in approximately 20% of breast cancers.

There are two types of mutations: acquired and hereditary. Acquired mutations occur spontaneously or from exposure to carcinogens, such as tobacco or ultraviolet (UV) rays. These mutations are not passed to one's children. Most cancers are the result of acquired mutations.

Hereditary mutations are passed from parent to child. BRCA1 and BRCA2 are examples of hereditary mutations. Many hereditary mutations that increase the risk of cancer are associated with family cancer syndromes. For example, people with mutations in either the BRCA1 or BRCA2 genes have hereditary breast and ovarian cancer syndrome. Familial syndromes have been identified for other types of cancer, such as colon cancer, sarcoma, thyroid cancer, skin cancer, and kidney cancer. Only a small percentage of cancer is thought to be due to inherited mutations.

Identifying these genetic syndromes in a person and their family is important because the information can be used to lower the person's risk of these cancers. For example, women with specific mutations to the BRCA1 or BRCA2 genes may elect to have their ovaries removed to reduce the risk of breast and ovarian cancers. Or, their doctors may recommend they start having mammograms at an earlier age.

In addition to specific gene mutations, the interactions between a person's genes and their environment may make some people more likely to develop cancer. For example, unrepaired DNA damage from tobacco or UV radiation may lead to cancer much sooner in one person than in another person. Or, one person's body may metabolize carcinogens slower than another person, exposing this person to these harmful substances longer and increasing this person's risk of cancer.

"Our challenge is to define how the genetic makeup and other factors that people have been exposed to interact to increase the risk of cancer," said Mark E. Robson, MD, Assistant Attending Physician of the Clinical Genetics and Breast Cancer Medicine Services in the Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York City. "Once we define individuals as being more or less at risk, we have to learn how to use this information for preventing, diagnosing, and treating cancer."

Gene Profiling

Gene profiling is the process used to discover which genes are turned on or off in a specific tumor to help plan the best treatment for a patient and/or predict response to treatment. With gene profiling technology, thousands of genes in a tumor can be analyzed. "The technology of genetic profiling has transformed the way medical research is done," said Joseph A. Sparano, MD, Director, Breast Evaluation Center at the Montefiore-Einstein Cancer Center in New York City. "We can analyze up to 30,000 or 40,000 genes or proteins in an individual tumor."

Genes, proteins, and other molecules that predict the behavior of cancer are called biomarkers. The presence or absence of these biomarkers influences how cancer is treated. For example, breast cancer tumor samples are tested for the estrogen receptor (ER). Cancers that have the ER (ER positive) can be treated with drugs like tamoxifen (Nolvadex) that reduce the level of estrogen.

Approximately 50% of newly diagnosed breast cancers in the United States are ER positive, node negative (meaning the cancer has not spread to the lymph nodes). The typical treatment for this cancer is surgery, with or without radiation therapy, and later, hormone therapy. Adjuvant chemotherapy (chemotherapy after surgery) is often recommended for every patient to lower the chance of recurrence; however, it is not known which patients are actually at risk of recurrence. New gene profiling tests are helping to answer this question.

In summary, gene profiling helps identify markers that can be used to estimate a patient's prognosis and predict the results of treatment. Some tests are commercially available, and others are being developed for additional types of cancer, including brain and lung cancers. In the future, doctors hope to expand the use of these markers to higher-risk populations and focus treatment on the patients who can benefit the most, while sparing treatment for the patients who don't need it.

Gene Profiling Tests

Gene profiling tests are starting to become a part of the treatment plan for some patients. In the United States, a test called Oncotype DX evaluates 21 genes to predict breast cancer recurrence in women with early stage (stage I or II), node-negative, ER-positive breast cancer. This test provides a recurrence score (RS) that indicates whether the tumor is at low, intermediate, or high risk of recurrence. This score helps patients and their doctors determine whether adjuvant chemotherapy is helpful based on the patient's risk of recurrence. Other tests, such as Mammaprint, use other sets of genes to test tumor samples to define prognosis (chance of recovery).

A new breast cancer clinical trial called the Trial Assigning Individualized Options for Treatment (TAILORx) is designed to learn if women with tumors at an intermediate risk of recurrence can safely avoid adjuvant chemotherapy. "This is perhaps the first clinical trial where we are trying to subtract therapy rather than add therapy or evaluate a new therapy using these gene profiling tests," said Dr. Sparano. A similar clinical trial called Microarray In Node Negative Disease May Avoid Chemotherapy (MINDACT) is ongoing in Europe.

A person's, age, health, personal preferences, and genetic makeup all affect the choice of cancer treatment.

Age, Health, and Clinical Trials

Because cancer is a disease of aging, the average person diagnosed with cancer is around 67 years old. As the population becomes older, the number of people diagnosed with cancer will likely grow. Cancer clinical trials are the best vehicle for testing new cancer treatments for patients of all ages. Unfortunately, few people with cancer participate in clinical trials, especially older people.

"Participation in clinical trials is important to determine the value of all of these potential breakthroughs in cancer," said Hyman B. Muss, MD, Professor of Medicine at the University of Vermont College of Medicine in Burlington.

A study by the Cancer and Leukemia Group B (CALBG) found that only 35% of patients older than 65 were offered the chance to participate in a clinical trial, compared with 51% of patients younger than 65. However, roughly half of the patients who were offered a clinical trial participated in one, regardless of age.

Older people may face the following barriers to participating in clinical trials:

• Strict eligibility criteria (guidelines that regulate the health of participants), which often rule out co-existing health conditions or prior cancers



• A potential for more intense or more frequent side effects



• A perception that treatment in older patients is less helpful than in younger patients

A person's age and health may influence decisions about other cancer treatments. Often, older people with cancer have other medical conditions and diseases, such as high blood pressure or diabetes. These conditions and the medications for these conditions may interfere with cancer treatment or the recovery from cancer treatment. If one of these conditions impairs mobility, it may make travel to distant treatment centers difficult. For more information about cancer in older adults, visit www.plwc.org/olderadults.

Personal Preferences

With any treatment option, balancing the side effects of treatment with the effectiveness of treatment requires careful consideration. This balance is usually based on the goals of the treatment and should be discussed with your doctor. For example, most people are willing to tolerate some unpleasant side effects, such as pain, nausea, vomiting, or losing hair, if there is a proven, significant benefit to the treatment. If proven anticancer benefits of a treatment are small (or unknown), however, then people may not accept those side effects, but instead want to focus on treatments that improve their quality of life.

For women with hormone-responsive breast cancer, hormone therapy with tamoxifen and/or aromatase inhibitors is often recommended. Although both types of drugs reduce the risk of breast cancer recurrence, they have different side effects: aromatase inhibitors can cause bone loss and tamoxifen can increase risk of uterine (endometrial) cancer. A woman's choice between these drugs might depend on whether she has a family history of osteoporosis (thinning of the bones) or is more concerned about developing uterine cancer.

In addition to side effects, other factors affecting treatment choice include confidence in doctors, attitudes toward clinical trial participation, educational level, preferences about oral or intravenous medications, and convenience and cost of treatment. For example, patients with existing financial problems or limited financial resources may have difficulty paying for cancer treatment and related costs, and some insurance policies may offer limited coverage for newer therapies.

Pharmacogenomics

Pharmacogenomics is the study of how inherited variations in the genes that activate or break down cancer drugs can lead to differences in how effective a drug is or the side effects it causes. For example, people whose bodies process medications quickly may need a higher dose of that drug to get the same effect as people whose bodies process medications at a regular rate. Or, people whose bodies process medications slowly may experience more side effects because the drug stays in the bloodstream longer. About 5% to 10% of people's bodies aren't able to process tamoxifen very well, and studies show that cancer comes back more often in these people. In the future, doctors hope to be able to test for the ability to metabolize tamoxifen in these patients with breast cancer so that another treatment option can be used.

Studies to Advance Personalized Medicine

The Cancer Genome Atlas (TCGA)

In 2005, the National Cancer Institute (NCI) and the National Human Genome Research Institute launched TCGA to improve the understanding of the genetic basis of cancer by systematically exploring all of the genetic changes involved in all forms of cancer. The goal of TCGA is to create a database to compare these genetic changes with the result of various treatments.

The Oncology Biomarker Qualification Initiative (OBQI)

The OBQI is a collaborative effort of the U.S. Food and Drug Administration, NCI, and the Centers for Medicare and Medicaid Services to develop and evaluate biomarkers. Biomarkers validated by OBQI will be used to speed up the process of drug development and approval, shorten clinical trials, improve the linkage between drug approval and drug coverage, and increase the safety and appropriateness of drug choices for people with cancer.

Targeted therapy is treatment designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metastasis of a specific cancer cell. Examples of targets include ligands, receptors, and enzymes.

• Ligands are proteins that bind (attach) to a receptor (see below) to cause an action. For example, estrogen is a ligand, and it binds to the estrogen receptor. Another way to think of this is that the ligand is a key and the receptor is the lock.
  
  
• Receptors are the proteins that the ligand binds to. Many receptors used as targets for drug development have one part that sticks outside of the cell (so the ligand can bind) and one part that remains in the cell (so that chemical signals can be sent to the rest of the cell).
  
  
• Enzymes are proteins that catalyze (speed up) biochemical processes, such as muscle contractions and food digestion. They also help the cell communicate important chemical messages that control the cell's growth, movement, and death.

Drugs can be designed to stop the interaction between receptors and ligands and prevent the cancer cell from growing. For example:

• The ligand can be removed or changed so that it can't bind to the receptor. For example, aromatase inhibitors (such as anastrozole [Arimidex], letrozole [Femara], and exemestane [Aromasin]) are breast cancer drugs that reduce the amount of estrogen in the body.
  
  
• The receptor can be blocked with another, larger protein. This is similar to sticking gum in the lock so that the key no longer works. One way to block the receptors is through a monoclonal antibody (an antibody made in the laboratory).
  
  
• The receptor can be eliminated. Fulvestrant (Faslodex) is a drug that destroys the estrogen receptor.
  
  
• The receptor can be disabled with drugs, such as erlotinib (Tarceva). These drugs inhibit the enzymes associated with the receptor that help the receptor communicate with the rest of the cell.

Drug Development

Designing anticancer drugs begins with identifying the genes and proteins that are specific to the development of cancer and testing whether blocking those genes and proteins gets rid of the cancer. Sometimes, a drug will inhibit the target, but not stop the growth of cancer. "Not all genes and proteins have a critical role in the survival and growth of cancer cells," said Gabriel Hortobagyi, MD, FACP, 2006-2007 ASCO President and Chair of the Department of Breast Medical Oncology and Professor of Medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

Inside the Cancer Cell

Two of the most successful targets in cancer drug development are those of the epidermal growth factor receptor (EGFR) family, also called the human epidermal growth factor receptor (HER) family. These receptors are found in high levels of many types of cancer cells. In a healthy cell, these receptors allow cells to grow and divide. When there are too many receptors, as is the case for cancer cells, the cancer cell continues to grow and divide. Examples of drugs that target the EGFR/HER family of receptors include:

• Cetuximab (Erbitux), a monoclonal antibody that blocks EGFR (also called HER1)
  
  
• Trastuzumab (Herceptin), a monoclonal antibody that blocks the HER2 receptor
  
  
• Erlotinib and gefitinib (Iressa), which block the activation of EGFR
  
  
• Lapatinib (Tykerb), which blocks the activation of both EGFR and HER2
  
  
• Pertuzumab (Omnitarg), an investigational drug that prevents the dimerization (when two receptors join together to become active) of the HER2 receptor

Outside the Cancer Cell

The cancer cell doesn't exist alone. It is usually part of a tumor, which itself is part of a larger network of tissue and blood vessels, and these components are another source of potential targets for drug development. Vascular endothelial growth factor (VEGF) is a protein that helps new blood vessels form. In cancer, these new blood vessels help feed the tumor. Several cancer drugs that inhibit VEGF to stop tumor growth include:

• Bevacizumab (Avastin), a monoclonal antibody
  
  
• Sorafenib (Nexavar) and sunitinib (Sutent), drugs that are taken by mouth

Translational Research

Targeted treatments are developed differently than earlier generations of cancer drugs. Previously, thousands of potential drugs were screened and studied with the hopes of ending up with one successful drug. In targeted therapy, the drugs are designed after the target is identified. In other words, the researchers have a specific idea of how the drug works before the drug is tested. "We are starting to insist on evidence that a drug works for a specific target, and we expect to see evidence of that from the beginning," said Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service and Associate Attending Physician at Memorial Sloan-Kettering Cancer Center in New York City.

This is the idea behind translational science—that knowledge of the biology of the cancer cell is translated in new therapies for patients. One recent success is with the drug lapatinib for breast cancer. In studies of women with HER2-positive advanced breast cancer that no longer responded to trastuzumab, adding lapatinib to chemotherapy slowed the growth of the cancer. Laboratory tests were first done to understand how lapatinib worked. Once HER2 was identified as a target of that drug, it was tested in patients who were likely to benefit from this drug (those with HER2-positive cancer). The clinical trial was stopped early because it was so successful.

"Lapatinib is looked at optimistically as a triumph of translational science, that in just a small number of experiments, the drug can go from the laboratory to the patient without spending many, many years in development," said Dr. Hudis. He also noted that, at this stage, these drugs aren't curing metastatic cancer, but they are a step in the right direction.

Future drug targets will come from identifying potential targets in the cancer cell or in the tissues around the tumor that help that cancer develop and spread, understanding the role of these targets in healthy cells and cancerous cells, and testing the targets by blocking them with a drug to see if the tumor shrinks.

Clinical trials are research studies that test new treatment and prevention methods to find out if they are safe, effective, and better than the current standard of care (the best known treatment). They are governed by a rigorous review and oversight process designed to protect the rights and safety of the people who enroll. Clinical trials are performed in distinct segments called phases.

• Phase I clinical trials find a safe dose and timing of the new treatment.



• Phase II clinical trials provide more detailed information about the safety of the new treatment and evaluate its effectiveness.



• Phase III clinical trials take a new treatment that has shown promising results when used to treat a small number of patients with a particular disease and compare it with the current standard of care for that disease.

Talking with your doctor is usually the best way to find a clinical trial. Because new trials are continually enrolling, many people also look in other places to find clinical trials. The organizations below list cancer clinical trials.

CancerTrialsHelp.org: This is the website of the Coalition of Cancer Cooperative Groups, Inc., a network of cancer clinical trials specialists. Their members include cooperative groups, cancer centers, academic medical centers, community hospitals, physician practices, and patient advocate groups. TrialCheck is a search tool designed by the Coalition of Cancer Cooperative Groups to assist you in locating cancer clinical trials.

CenterWatch: A publishing and information services company that offers a list of institutional review board (IRB)-approved clinical trials.

National Cancer Institute (NCI) Clinical Trials: The NCI, part of the National Institutes of Health, is the federal agency that provides funding for most cancer clinical trials. This site provides information on both open and closed cancer clinical trials that are funded by the government, pharmaceutical companies, and some international organizations.

People who want more guidance on finding a clinical trial may want to try these sources.

• Getting a second opinion from an oncologist with expertise in cancer clinical trials



• Contacting a patient information resource for a specific type of cancer



• Calling a local or regional cancer center



• Contacting the company that makes a specific drug or treatment

More information about clinical trials can be found at www.plwc.org/clinicaltrials.

Biomarkers: Genes, proteins, and other biologic molecules that predict the behavior of cancer; they are sometimes called markers

Cell: The structural and functional unit of any living thing. A group of cells (such as muscle cells) make up tissue, and tissues make up organs (such as the heart). All cells contain the genes needed to function, including those that produce future generations of cells.

DNA: Deoxyribonucleic acid, the chemical that makes up a gene

Gene: A basic functional and physical unit of heredity that is passed on from parent to child

Gene profiling: The technique to identify genes that are turned on or off in a specific tumor to help plan the best treatment for a patient and/or predict response to treatment

Genetics: The study of how genes are passed from parent to child

Inherited: A characteristic, such as eye color, that is genetically received from one's parents

Personalized medicine: The use of information about an individual person and an individual cancer to provide specific strategies to find, treat, and prevent cancer

Protein: A chemical compound that is necessary for the function of any living thing

Targeted therapy: A treatment designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metastasis of a specific cancer cell