Personalized Cancer Treatment

Biomarkers + Targeted Therapy = Personalized Cancer Treatment

The increased understanding of the molecular biology of tumors and the discovery of targeted therapy are perhaps the greatest advances in cancer treatment. The identification of a biomarker is the first step toward personalized cancer treatment, but many steps are involved before a personalized treatment can be approved for a specific type of cancer (Figure 1).

What Is Targeted Therapy?

Researchers have learned about the cell pathways that can lead to many types of cancers and also have learned how to develop drugs that block those pathways. These drugs are known as targeted drugs (or agents), and treatment with these drugs is known as targeted therapy.

“Targeted therapy is attacking the Achilles’ heel of cancer development, if you will,” says John Niederhuber, MD, former Director of the National Cancer Institute and currently Executive Vice President & CEO, INOVA Institute for Translational Research and Personalized Medicine. “It involves blocking the communication between cells to interrupt cell function in some way.” Targeted agents block the signals that proteins and other molecules send along signaling pathways, systems in the body that direct basic cell functions, such as cell growth, cell division (proliferation) and cell death.

“We have a windfall of new options based on research into signaling pathways and the design of drugs to target those pathways,” notes Jeff Allen, PhD, Executive Director of Friends of Cancer Research. He adds that some targeted drugs may cause fewer side effects because they are less harmful to normal tissues. Targeted therapy can be given alone (called monotherapy) but it is often given in addition to chemotherapy.

Effective targeted therapy depends on two factors: identifying targets that play an important role in the growth and survival of cancer cells and developing agents that can attack those targets.

Types of Targeted Agents

Most targeted agents are either small-molecule drugs or monoclonal antibodies. Both types of agents are made in a laboratory and are designed to locate and bind to specific substances on tumor cells. Small-molecule drugs can pass through the cell membrane and act on a target inside the cell. Many small-molecule drugs are tyrosine kinase inhibitors, which act against specific cell signaling pathways involved in tumor growth.

One signaling pathway that has been found to be involved in the development of many different kinds of cancer is directed by the epidermal growth factor receptor (EGFR). Mutations in the EGFR gene activate the EGFR protein, which, in turn, triggers a complex process that leads to increased growth and division of cancer cells and development of metastases. EGFR is overexpressed in many different types of cancers, which has led researchers to develop targeted therapy drugs that block the activity of EGFR. These drugs are known as EGFR inhibitors.

Another type of tyrosine kinase inhibitor greatly changed the treatment for people with chronic myelogenous leukemia. The targeted agent, imatinib (Gleevec), was developed to block the production of tyrosine kinase by the abnormal BCR-ABL gene. This gene is a fusion of two genes, created as a result of a translocation of both genes. This fused gene is found in almost all people with chronic myelogenous leukemia. Large studies have shown that imatinib produces much better results than traditional chemotherapy for people with this type of leukemia.

The success of imatinib for chronic myelogenous leukemia led to use of the drug for people with gastrointestinal stromal tumors (GISTs), a type of sarcoma. Studies of imatinib for people with GIST showed response in more than 50% of people compared with less than 5% of people treated with standard chemotherapy.

Monoclonal antibodies cannot pass through the cell membrane and instead are used against targets found on the cell surface. One example of a monoclonal antibody is rituximab (Rituxan), which was created to target CD20, a special molecule on white blood cells that is a biomarker for non-Hodgkin’s lymphoma. Rituximab is perhaps the most notable advance in lymphoma treatment over the past decade. The addition of this targeted drug to standard treatment has greatly improved response to therapy and overall outcomes.

Benefits and Drawbacks of Targeted Therapy

“There is a dual benefit to targeted therapy,” says Dr. Balch. “First, we’re able to identify people who are more likely to benefit from a particular drug. Second, we’re able to avoid treatment that is unlikely to be effective for an individual.”

Targeted therapy offers many other advantages, but there some disadvantages, as well (Table 1). As the results of many studies have shown, targeted therapy is usually more effective than standard chemotherapy alone. In addition, as noted earlier, targeted agents may help people avoid the side effects of treatment that may be less likely to be effective.

For many types of cancers, targeted therapy has changed cancer into a chronic condition, which requires long-term treatment with the targeted therapy drug. These drugs can usually be taken by mouth rather than intravenously, which makes treatment more convenient. But because targeted drugs are typically taken for a long time, people may forget to take the drug as a pill, especially when they feel good. You must take a targeted therapy drug exactly as your doctor has prescribed it.

One of the most important disadvantages of targeted therapy is that researchers have discovered that cancer cells often become resistant to the drug, or the drug becomes less effective over time. Researchers continue to explore ways to overcome resistance.

“In order to understand resistance, we must not only understand the pathway directed or altered by a particular mutation, but we must also gain a better understanding of how that pathway connects with other pathways,” says Dr. Niederhuber.

Dr. Niederhuber adds that treatments that involve multiple agents that target multiple pathways are more likely to be effective. “We have to attack more than one pathway to produce durable [lasting] responses,” he says. He explains that targeting the main pathway is important but signals may be able to “escape” by going down other pathways instead. “We must identify those [escape] pathways and target them as well,” says Dr. Niederhuber.

Table 1. Benefits and Drawbacks of Targeted Therapy

Future of Targeted Therapy

“The goal for future cancer therapy is the right drug for the right target for the right person,” says Dr. Niederhuber. To achieve this goal, researchers must better understand what cells, signals and interactions are the most important in the growth and proliferation of cancer cells. The success of developing new targeted therapy drugs depends on clinical trials to evaluate the drugs, and these trials will become more difficult to do as researchers learn more about the genetic profiles of cancers, leading to more and more molecular subtypes of what was once a single type of cancer.

“The old way of doing business (clinical trials) will be much different because the populations of people with a particular subtype of tumor will become smaller as more molecular subtypes are defined,” explains Dr. Allen. In addition, the new approach to cancer treatment calls for a more efficient way to carry out cancer research (see box above). As always, cancer research relies on the willingness of people with cancer to participate in clinical trials. Talk to your doctor about clinical trials that may be appropriate for your particular type of tumor (see box below) and how you can donate tissue for genetic profiling (see Tissue, Please).

Personalized Cancer Treatment

Personalized cancer treatment is now possible with three of the most common cancers — breast, colorectal and non-small cell lung cancer. Researchers are exploring options for personalized therapy for other types of cancer, and early research has shown promising results for personalized treatment of malignant melanoma. Another recent discovery is paving the way for targeted treatment of acute myeloid leukemia.

“As we learn more and more about the genetic underpinnings of cancer, we hope to achieve a similar level of molecular understanding for all cancers and eventually to generate recipes of highly targeted therapies suited to an individual patient,” says Dr. Niederhuber.

Even if you have a type of cancer for which no genetic mutations have been identified, your treatment plan will be personalized. Your treatment will be selected on the basis of more traditional factors such as features of your tumor (type of cancer, stage and grade), as well as other personal factors such as your age and general health. In addition, the availability of more treatment options offering similar effectiveness allows you to choose treatment based on what is important to you about quality of life.

Breast Cancer

Breast cancer is one of the first types of cancer for which the identification of biomarkers dramatically changed treatment options and outcomes. Since the discovery of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and the HER2 gene, treatments targeted to these biomarkers have helped hundreds of thousands of women with breast cancer live longer. Personalized breast cancer treatment is based on the presence of hormone receptors and/or the overexpression of HER2 in the tumor (Table 2). In addition, the availability of gene expression tests that can predict recurrence allows physicians to personalize treatment to the specific risk of an individual woman.

The growth of some breast cancers is driven by the female hormone estrogen. In those tumors, ER and PR will be overexpressed, which is known as ER+ and PR+. Hormone therapy is effective for these tumors; it will not be effective for women with breast cancer that is ER- and PR- breast cancer. The hormone therapy drugs used for breast cancer treatment are used to reduce the effects of estrogen. These drugs, known as antiestrogen agents, lower the amount of estrogen in the body or block its action so that cancer cells will no longer get signals to grow and will eventually die.

The most common antiestrogen drug is tamoxifen, which has been used for several decades as part of adjuvant breast cancer treatment, or treatment given after primary treatment, such as surgery. Studies have shown that the use of tamoxifen for 5 years after surgery for early-stage ER+ breast cancer reduces the chances of cancer recurrence by 39% each year and the odds of death by more than 30% each year.

Aromatase inhibitors (AIs) are a newer class of antiestrogen agents. AIs differ from tamoxifen with respect to how they work, who they can be used for, and what side effects they can cause. The choice of hormone therapy depends mainly on a woman’s menopausal status, and other factors are also considered. AIs have been shown to offer improved benefit over tamoxifen for postmenopausal women and are thus recommended as a first choice for hormone therapy. However, many questions remain about the best hormone therapy, and women should talk to their doctor about which type of hormone therapy will be best for them.

Breast cancer treatment is also personalized according to HER2 status. Approximately 20% of breast cancers have HER2 amplification, or a high level of HER2 (either the gene or the protein), known as HER2+ breast cancer. The anti-HER2 agent trastuzumab (Herceptin) was approved as targeted therapy for HER2+ breast cancer in 1998. Since then, studies have consistently shown that trastuzumab helps women with HER2+ breast cancer live much longer overall and without cancer recurrence. Trastuzumab is usually given in combination with specific chemotherapy drugs, but may also be used alone or with other treatment.

Another anti-HER2 agent is lapatinib (Tykerb). Lapatanib has been approved by the US Food and Drug Administration (FDA) for use with the chemotherapy drug capecitabine to treat HER2+ metastatic breast cancer that has stopped responding to other chemotherapy drugs.

A particularly innovative agent still in early clinical trials is a form of trastuzumab that is chemically fused to a chemotherapy drug. This agent, currently known as trastuzumab-DM1 (T-DM1), has been called “targeted targeted therapy” because of the way it works: trastuzumab targets HER2, bringing the chemotherapy directly to its target — cancer cells. The drug has shown good response among women with metastatic HER2+ breast cancer.

Treatment for breast cancer may also be personalized according to the status of both the hormone receptors and HER2. Breast cancer cells that overexpress ER/PR as well as HER2 have been less responsive to some hormone therapies, and targeting both ER/PR and HER2 has emerged as a potential way to address this problem. In general, treatment consists of a combination of agents known to be effective for each tumor marker status. For example, research has shown that when postmenopausal women with ER+/PR+, HER2+ tumors were treated with the combination of letrozole (an AI) and lapatinib (an anti-HER2 agent), the time before disease progressed was nearly three times as long as for women treated with letrozole alone. On the basis of these findings, in February 2010, the FDA approved the use of this combination.

Research is also beginning to show that some treatments may be more effective for tumors that test negatively for ER/PR and HER2, which are known as triple-negative breast cancers. These tumors, which represent about 10%-20% of all breast cancers, have the disadvantage of not being eligible for either hormone therapy or anti-HER2 agents. They also tend to be associated with a higher risk of recurrence, and the effectiveness of chemotherapy is often limited. As a result, investigators are searching for combinations of drugs that may be more effective. Preliminary data from studies have shown that the combination of ixabepilone (Ixempra) and capecitabine offers benefit for women with metastatic triple-negative breast cancer.

The limited effectiveness of chemotherapy and the fewer treatment options for triple-negative breast cancer that does not respond to chemotherapy call for new agents targeted to this particular type of tumor. Because of this, many studies of targeted therapy agents are focused on triple- negative disease.

Advances in technology have given oncologists other tools to help them personalize breast cancer treatment by making more informed predictions about the course of disease and the response to treatment. The ability to predict the likelihood of recurrence is especially important for women with early-stage ER+ breast cancer (that has not spread to the lymph nodes) because it relates to the issue of adjuvant therapy (treatment given after primary treatment, such as surgery). Decisions about adjuvant therapy for women with early-stage breast cancer are among the most challenging in cancer treatment because studies have shown that adjuvant therapy offers large benefit in some cases and little benefit in others.

Oncologists can now use a gene expression profiling test, Oncotype DX (Genomic Health, Redwood, CA), to estimate the likelihood that cancer will recur. The test measures the activity of 21 genes (16 cancer genes and 5 control genes) and calculates a Recurrence Score® of 0 to 100 points. A low score indicates low risk and a high score indicates high risk of recurrence within 10 years after diagnosis. Women with a low risk can be spared the effects of chemotherapy without risking a lower survival, and women with a high risk can reduce the likelihood of recurrence with adjuvant chemotherapy and close follow-up to ensure early intervention if cancer does recur.

Groups of oncology experts, such as the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), have recommended the use of Oncotype DX to identify women who may be successfully treated with tamoxifen and may not require adjuvant chemotherapy. Proof of the difference this test has made in decision-making comes from a study of physicians in several cancer centers. The study showed that the physicians’ treatment recommendation changed for almost one third of women on the basis of the test results.

Another gene expression profiling test, MammaPrint (Agendia, Amsterdam, Netherlands), is similar to OncotypeDX. MammaPrint is an assay of 70 genes that research has found to be related to distant recurrence of breast cancer. The results of testing indicate either a high or low risk of the cancer recurring within 10 years after diagnosis. Several studies have demonstrated that MammaPrint is a reliable predictor of disease-free survival, and in 2007, the FDA cleared the test for use in the United States (not a requirement for use). At present, the MammaPrint test requires a specimen of fresh tissue, so plans for the test must be made before surgery so that tissue can be taken at that time.

Table 2. Personalized Treatment Options for Breast Cancer

Colorectal Cancer

Testing for genetic mutations in colorectal cancer tumors has helped to personalize treatment for some people by identifying those who may not have a response to specific drugs. In addition, gene expression profiling is beginning to help physicians determine which people with colorectal cancer are most likely to benefit from adjuvant chemotherapy.

Overexpression of EGFR is found in more than 85% of metastatic colorectal tumors, which led researchers to evaluate the effectiveness of treatment with EGFR inhibitors. Several clinical trials showed that two EGFR inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix), were of benefit for people with metastatic colorectal cancer. However, when researchers analyzed data from these studies, they found that a subgroup of people had tumors that did not respond to these targeted therapies. The subgroup of people all had tumors with alterations in the KRAS gene. Specific alterations in this gene have been found in about four out of 10 colorectal tumors.

Because of these results, ASCO and the NCCN recommend that testing for KRAS mutation be done for all people with metastatic colorectal cancer and note that cetuximab and panitumumab should not be used for people who have tumors with the mutation. The FDA also requires that the labels for these drugs state that they are not recommended for treatment of colorectal tumors with KRAS mutations. Other types of treatment, such as standard chemotherapy, are available to treat people with KRAS mutations in the tumor.

Mutation of the BRAF gene has also been found in some people who have colorectal cancer. This mutation occurs less often than KRAS mutation; it is found in about 5%-8% of colorectal tumors. BRAF mutations have been found only in tumors that do not have KRAS mutations, and the prognosis for tumors with BRAF mutations is worse than for tumors without the mutation. The BRAF mutation may be a factor in the decision to use an EGFR inhibitor, but studies have provided differing results. The findings of some studies have shown that tumors with BRAF mutations do not respond to EGFR inhibitors, but the findings of other studies have suggested that cetuximab is of benefit as first- line treatment. More studies are needed before this biomarker is a factor in treatment decisions.

Testing for mutations in the DNA mismatch repair (MMR) genes may also be helpful for some people with colorectal cancer. A mutation in the MMR gene leads to a low level of MMR protein in the tumor. This low expression is found in about 15%-20% of sporadic colorectal cancers. MMR mutation also causes DNA alterations, with abnormal shortening or lengthening of DNA sequences. This abnormality is known as microsatellite instability (MSI), and measuring MSI is another way to determine a low amount of the MMR protein in the tumor. Tumors that have signs of microsatellite instability are known as MSI-high, which represents a low amount of MMR protein.

Studies have shown that people with stage II colorectal cancer who have low expression of MMR protein in the tumor do not benefit from adjuvant treatment with 5-FU, a chemotherapy drug. In contrast, people with high expression of MMR protein do have improved outcomes after such adjuvant treatment. In addition, a low risk of recurrence is linked to low expression of MMR protein. On the basis of these findings, the NCCN recommends that people with stage II colorectal cancer be tested for expression of MMR protein in the tumor. People who have tumors with low expression can avoid adjuvant chemotherapy without risk to the outcome.

A low amount of the MMR protein is found in about half of people with Lynch syndrome, a hereditary form of colorectal cancer that is also known as hereditary nonpolyposis colon cancer (HNPCC). Because of this, the NCCN also recommends that MMR testing be strongly considered for people with colon cancer who are younger than 50 years. The likelihood of Lynch syndrome is higher in people in that age category.

Another test is now available to help physicians and their patients with stage II colorectal cancer decide on adjuvant chemotherapy. An OncotypeDX test has been developed to provide more information about the risk of recurrence and the need for adjuvant treatment for people with this stage of disease. The test works the same way as the OncotypeDX test for breast cancer. The test for colon cancer measures 12 genes within the colon tumor, and the Recurrence Score is an estimate of how likely it is that the cancer cells will spread within 3 years after diagnosis. The Recurrence Score is considered along with other clinical factors, such as the stage and grade of the tumor and the number of lymph nodes involved.

The OncotypeDX test is not yet recommended for routine practice because not enough studies have been done yet with the test. But testing may be right for some people. Talk with your doctor about whether this test would be useful for you.

Non-small Cell Lung Cancer

The options for personalized treatment of non-small cell lung cancer are limited, but studies are beginning to show that three genetic mutations are factors to consider when selecting treatment. These three mutations are mutually exclusively; that is, none is found with another in the same tumor. Determining which mutation may be present is important, as the most effective treatment differs according to the mutation.

The first mutation found is in the EGFR gene. Mutations in this gene are detected in about 15% of people with non-small cell lung cancer overall. The mutation is found at much higher rates among people who have never smoked, women, people of Asian descent and people with a tumor known as adenocarcinoma.

Large studies of people with non-small cell lung cancer have shown that the tumor response to an EGFR inhibitor is far better in people who have tumors with EGFR mutations. In one study, the EGFR inhibitor gefitinib (Iressa) led to a response in about 70% of people who had tumors with EGFR mutations compared with about 1% of people who did not have the mutation. A review of several studies showed progression-free survival (the length of time without disease getting worse) was longer for people with EGFR mutations who were treated with either gefitinib or erlotinib than for those who were treated with standard chemotherapy drugs.

Based on the results of these studies, many cancer centers are now routinely testing lung cancer specimens for the presence of EGFR mutations. In addition, EGFR testing is recommended for people who have recurrence of non-small lung cancer (adenocarcinoma) or have metastatic adenocarcinoma at the time of diagnosis.

Identifying people with non-small cell lung cancer who have KRAS mutations may also be helpful in personalizing treatment. This mutation is found in about 25% of cases overall and more frequently among people who have smoked. As with colorectal cancer, non-small cell lung tumors with KRAS mutations have been found to be resistant to treatment with an EGFR inhibitor. Chemotherapy alone has produced better response rates for people with KRAS mutations than chemotherapy with an EGFR inhibitor.

Researchers recently identified another mutation that may affect the treatment of some people with non-small cell lung cancer. A genetic rearrangement that causes the fusion gene EML4-ALK has been reported to occur in about 2%-13% of non-small cell lung cancers. People who have a tumor with this rearrangement do not benefit from treatment with an EGFR inhibitor. Studies are now being carried out to evaluate the effectiveness and safety of targeted therapy directed at inhibiting ALK.

Melanoma

The identification of BRAF mutations in 40%-60% people with metastatic melanoma led to the creation of a targeted drug designed to selectively attack the mutated BRAF protein. An early study showed that the drug (as yet unnamed) led to partial or complete response in most people who had a BRAF mutation. The first results from a later, larger study showed the benefit of the drug extends to survival. People in the study who received the drug lived longer, and lived longer without disease progressing, than people who received the current standard of care.

“The identification of this mutation, along with the development of a targeted therapy, is a significant advance for people with advanced, stage IV melanoma for two reasons,” says Dr. Balch. “First, we have not been able to categorize people with melanoma according to biomarkers before, as we can in breast, colorectal, and lung cancer. Second, the currently available treatment options for people with this advanced disease are limited; we finally may have a better option.”

Leukemias

Another recent discovery in genetic mutations is the detection of a mutation in the DNMT3A gene in some people with acute myeloid leukemia. The mutation is linked to a lack of response to standard chemotherapy and is the first biomarker to predict response to treatment for this type of leukemia. Researchers also have found that people with the DNMT3A mutation do not survive as long as people without the mutation after treatment with chemotherapy.

The discovery of this genetic mutation will help researchers find a target for a new drug that will block the cellular activity produced by the mutation. Until a targeted therapy agent is developed, the researchers suggest that better results may be obtained by using initial treatment that is more aggressive than standard chemotherapy, such as bone marrow transplantation.

Multidisciplinary Approach to Treatment

Personalized treatment according to biomarker information and/or targeted therapy may involve input from many medical professionals. Both diagnostic and clinical specialists as well as support staff may be among the members that are part of a biomarker-driven treatment team. The multidisciplinary team may include:

• Radiologist (takes x-rays for diagnostic purposes)
• Radiation oncologist (specializes in radiation therapy to treat cancer)
• Pathologist (examines tissue samples and bodily fluids to diagnose disease)
• Physician specialist (such as a gastroenterologist or gynecologist)
• Surgeon
• Hematologist (a physician who specializes in treating conditions that involve the blood)
• Geneticist (a specialist in the science of genes and heredity)
• Genetic counselor (specializes in providing information and support for genetic issues)
• Psychologist
• Physician assistant/nurse practitioner
• Nutritionist/dietician
• Nurses
• Social worker
• Physical therapist
• Occupational therapist
• Support staff
• Team coordinator

With a multidisciplinary approach, team members work together to develop a complete and unified treatment plan. Team members typically meet on a regular basis to discuss patients under their care and to assess the effectiveness and progress of therapy.

Additional Sources of Information

• Agendia: www.agendia.com
  Mammaprint
• American Cancer Society: www.cancer.org
  Breast Cancer: Targeted Therapy
• American Society of Clinical Oncology patient Web site: www.cancer.net
  What to Know: ASCO’s Guideline on Tumor Markers for Breast Cancer
• BreastCancer.org: www.breastcancer.org
  Research News on Targeted Therapy
• Colon Cancer Alliance: www.ccalliance.org
  OncotypeDx for Stage II Colon Cancer
• Colorectal Cancer Coalition: http://fightcolorectalcancer.org
  Should You Be Tested for KRAS?
  Webinar: Stage II Colon Cancer Decision Making
• Genomic Health: www.genomichealth.com
  OncotypeDx
• Melanoma International Foundation: www.melanomaintl.org
  Webinar: Targeted Therapies
• National Cancer Institute: www.cancer.gov
  Targeted Cancer Therapies
• National Comprehensive Cancer Network: www.nccn.com
• Patient Web site sponsored by Pfizer Oncology: www.canceritspersonal.com