Personalized Cancer Treatment

Biomarkers + Targeted Therapy = Personalized Cancer Treatment

Treatment for most types of cancer was once chosen only according to the size of the tumor, whether cancer had spread, and how the cancer tissue cells looked under a microscope. These classifications remain important, but the discovery of molecular drivers of cancer and the development of technology to identify biomarkers in tissues have led to an additional layer of classification for some cancers – one based on molecular subtypes.

However, biomarkers alone do not complete the puzzle. In fact, routine biomarker testing is recommended only when the test results will affect treatment decisions. Often, the answer to a genetic testing result is targeted therapy. The identification of biomarkers and the discovery of targeted therapies have led to recent advances in cancer treatment. Identifying a biomarker is the first step to personalized cancer treatment, but many other steps are involved before a personalized treatment can be approved for a specific type of cancer (see Figure 1).

What is targeted therapy?

As researchers have learned about the cell pathways that can lead to many types of cancers, they have also 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 agents block the signals that proteins and other molecules send along signaling pathways, which are systems in the body that direct basic cell functions, like cell growth, cell division and cell death. One signaling pathway found to be involved in the development of many different kinds of cancer is directed by the epidermal growth factor receptor (EGFR). Abnormalities in the EGFR gene activate the EGFR protein, which, in turn, triggers a complex process that leads to increased growth and spread of cancer cells. Excess amounts of the EGFR protein are found in many different types of cancers, which has led researchers to develop targeted therapy drugs that block the activity of EGFR.

Sometimes, genetic alterations like this are common among a specific cancer, and sometimes the alterations are less frequent. Researchers often compare the response to treatment for both types of cancers. Learning more about how cancers respond to treatment based on genetic alterations can help in the development of drugs to target the alteration, offering a new treatment option.

Types of targeted agents

Most targeted agents are drugs known as either small-molecule drugs or monoclonal antibodies. Both of these types are made in a laboratory, and they are designed to locate and bind to specific substances on or inside tumor cells. Small-molecule drugs can pass through the cell membrane and act on a target inside the cell. Monoclonal antibodies cannot pass through the cell membrane and instead are used against targets found on the cell surface.

Many small-molecule drugs are tyrosine kinase inhibitors, which act against specific cell signaling pathways involved in tumor growth. For example, EGFR inhibitors are one type of tyrosine kinase inhibitors. Several tyrosine kinase inhibitors and monoclonal antibodies are now available to treat a wide range of cancers.

Benefits and drawbacks of targeted therapy

The primary benefit of biomarker-driven targeted therapy is the ability to identify people more likely to benefit from a particular drug and to avoid treatment unlikely to be effective. Avoiding ineffective treatment has its own advantages, like preventing the side effects of that treatment as well as avoiding the financial burden.

Targeted therapy offers many other benefits but some drawbacks as well. 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 and believe that the answer requires a better understanding of how cell pathways connect with each other. Targeting a main pathway may be effective for a while, but over time, signals may be able to “escape” by going down another pathway. Treatments that involve multiple agents that target multiple pathways may be more effective than treatment that targets a single pathway. Research in this area continues.

Targeted therapy may not be the answer to every cancer. For some cancers, conventional chemotherapy or radiation therapy (or both) may still be the best treatment option. Also, targeted therapy agents are often given in combination with chemotherapy. But targeted therapy is a major step forward for many cancers, especially advanced cancers, and is creating a new era of personalized cancer treatment.

Future of targeted therapy

The goal for cancer treatment is to match the right drug with the right target for the right person. To achieve this goal, researchers must better understand what cells, signals and interactions are the most important in the growth and spread of cancer cells. As we learn more about the genetic profiles of cancers, what was once a single type of cancer (like breast cancer) becomes many different types of cancer.

This increase in the types of cancer will make clinical trials on targeted therapy more challenging to carry out. Traditionally, the clinical trials that lead to new drugs are done with large groups of patients. But the number of patients in clinical trials will become much different because treatments will be evaluated in smaller groups of people with a particular subtype of cancer. Although this change will create challenges, it also offers outstanding opportunities for new treatments. The results of these trials will give doctors more precise information about which patients are likely to have a response to treatment and which patients should avoid treatments that are likely to be of no benefit.

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 and how you can donate tissue for genetic profiling (see here).

Personalized cancer treatment

Personalized cancer treatment is now possible with many of the most common cancers – breast, colorectal and non-small cell lung cancer – as well as malignant melanoma, many leukemias and lymphomas, and some sarcomas. Even if you have a type of cancer for which no biomarkers have been identified, your treatment plan will still be personalized. Your treatment will be based on more traditional factors, such as the 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 allows you to choose a treatment based on what is important to you about quality of life.

Breast cancer

Breast cancer is one of the first types of cancer impacted by the identification of biomarkers. 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 (or absence) of hormone receptors and/or the overexpression (excess) of HER2 in the tumor (Table 1). In addition, the availability of gene expression tests that can predict how likely it is that the cancer will come back (recurrence) allows physicians to personalize treatment to the specific risk of the individual.

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+ (positive) breast cancer. Hormone therapy is effective for these tumors, but it will not be effective for women with ER- and PR- (negative) breast cancer. The hormone therapy drugs used for breast cancer treatment 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 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 five years after surgery for early-stage ER+ breast cancer substantially reduces the chances of cancer recurrence and the odds of death each year.

Aromatase inhibitors (AIs) are a newer class of antiestrogen agents. AIs differ from tamoxifen in how they work, who they can be used for, and what side effects they can cause. The choice of hormone therapy depends mainly on whether a woman has gone through menopause. AIs have been shown to offer improved benefit over tamoxifen for postmenopausal women and are now 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 one in five breast cancers has a high level of HER2 (either the gene or the protein), known as HER2+ (positive) breast cancer. The anti-HER2 agent trastuzumab (Herceptin) was approved as targeted therapy for HER2+ breast cancer in 1998. Since then, studies have 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, lapatinib (Tykerb), was developed as a way to overcome resistance to trastuzumab. This drug has been approved for use with the chemotherapy drug capecitabine to treat HER2+ metastatic breast cancer that has stopped responding to trastuzumab and chemotherapy drugs. The newest anti-HER2 agent is pertuzumab (Perjeta), which is approved for use with trastuzumab and docetaxel for HER2+ metastatic disease.

Everolimus (Afinitor) is a drug approved for metastatic breast cancer in 2012. It belongs to a different class of targeted therapy agents called mTOR inhibitors. These are small-molecule agents that block the mTOR signaling pathway, which is activated in breast cancer. Everolimus is approved for treatment of metastatic breast cancer that is ER+/PR+ (HER2-) that has stopped responding to hormone therapy.

A particularly innovative agent still being evaluated in clinical trials is a form of trastuzumab that is chemically fused to a chemotherapy drug. This agent, trastuzumab emtansine, or 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 and, in the latest studies, has led to longer survival.

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. 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.

Research is also beginning to show that some treatments may be more effective for tumors that test negatively for ER/PR and HER2, known as triple-negative breast cancers. These tumors, which represent about 10 to 20 percent 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 chemotherapy is often less effective. As a result, investigators are searching for drug combinations that may be more effective, and early study results have shown that the combination of ixabepilone (Ixempra) and capecitabine offers benefit for women with metastatic triple-negative breast cancer.

Advances in technology have given doctors other tools to help them personalize breast cancer 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 a large benefit in some cases and little benefit in others. Oncologists can now use a gene expression profiling test, Oncotype DX, to estimate the likelihood that cancer will 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 a test like this to identify women who may be successfully treated with tamoxifen and may not require additional chemotherapy. These tests have proven effective: A study of physicians in several cancer centers showed that their treatment recommendation changed for almost one third of women on the basis of the test results.

Another gene expression profiling test, MammaPrint, is similar to Oncotype DX and indicates either a high or low risk of the cancer recurring within 10 years after diagnosis. At present, the MammaPrint test requires a specimen of fresh tissue, so plans for the test must be made before surgery so tissue can be taken at that time.

Table 1. Personalized treatment options for breast cancer

Treatment base Type of breast cancer according to biomarkers Approved/recommended treatment Notes
Hormone therapy      
trastuzumab (Herceptin)
HER2+










HER2+ metastatic breast cancer
▪ In combination with a chemotherapy regimen
  of doxorubicin plus cyclophosphamide,
  followed by either paclitaxel or docetaxel
 
▪ In combination with a chemotherapy regimen
  of docetaxel and carboplatin
 
▪ As a single agent following chemotherapy that
  includes an anthracycline (doxorubicin,
  epirubicin, pegylated liposomal doxorubicin)

▪ In combination with paclitaxel for first-line
  treatment
 
▪ As a single agent after failure of one or more
  chemotherapy regimens
Approved for use in 1998
lapatinib (Tykerb) HER2+ metastatic breast cancer ▪ In combination with capecitabine after failure
  of anthracyclines, taxanes (paclitaxel or
  docetaxel) and trastuzumab
Approved for use in 2007
  ER+/PR+, HER2+ breast cancer ▪ In combination with letrozole Approved for use in 2010
pertuzumab (Perjeta) HER2+ metastatic breast cancer ▪ In combination with trastuzumab and
  docetaxel
Approved for use in 2012
everolimus (Afinitor) ER+/PR+, HER2- metastatic breast cancer ▪ In combination with exemestane after failure
  of letrozole or anastrozole
Approved for use in 2012
ixabepilone (Ixempra) Triple-negative (ER-/PR-, HER2-) metastatic breast cancer ▪ In combination with capecitabine Used in clinical trials only

Colorectal cancer

Testing colorectal cancer tumors has helped to personalize treatment for some patients by identifying those who may not have a response to specific drugs. In addition, gene expression profiling is beginning to help doctors determine which patients with colorectal cancer are most likely to benefit from adjuvant chemotherapy (Table 2).

An excess of EGFR is found in more than 85 percent of metastatic colorectal tumors, which led researchers to evaluate the effectiveness of EGFR inhibitors.

Several clinical trials showed that two of these, cetuximab (Erbitux) and panitumumab (Vectibix), were beneficial for patients with metastatic colorectal cancer. However, researchers also found a subgroup of patients with tumors who did not respond to these targeted therapies. This subgroup all had tumors with alterations in the KRAS gene, which have been found in about four out of 10 colorectal tumors.

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

Mutation of the BRAF gene has also been found in some people with colorectal cancer. This mutation occurs less often than the KRAS mutation and is found in about 5 to 9 percent 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 it. Some studies have shown that tumors with BRAF mutations do not respond to EGFR inhibitors, but other studies have suggested that cetuximab is beneficial as a first-line treatment. More studies are needed, however, 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 this gene leads to a low level of MMR protein in the tumor. This low level is found in about 15 to 20 percent of sporadic colorectal cancers (cancers that are not hereditary). The MMR mutation also causes DNA alterations, known as microsatellite instability (MSI), and measuring this 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 a low level of the MMR protein in the tumor do not benefit from adjuvant treatment with 5-FU, a conventional chemotherapy drug. In contrast, people with high expression of MMR protein do better after such adjuvant treatment. In addition, a low risk of recurrence is linked to a low expression of the 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 any 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 MMR testing for people with colon cancer who are younger than 50 years old. (The likelihood of Lynch syndrome is higher in people in that age category.)

The Oncotype DX test is also available for colorectal cancer, and the test can help doctors and their patients with Stage II colorectal cancer decide on adjuvant chemotherapy. The Recurrence Score is an estimate of how likely the cancer cells are to spread within three years. Your doctor will consider the Recurrence Score along with other clinical factors. The Oncotype DX test is not yet recommended for routine practice, so talk with your doctor about whether this test would be useful for you.

Table 2. Treatment options for colorectal cancer

Type Treatment Notes
EGFR cetuximab (Erbitux), panitumumab (Vectibix) Beneficial for patients with metastatic colorectal cancer
KRAS Standard chemotherapy, other treatments cetuximab (Erbitux) and panitumumab (Vectibix) should not be used
BRAF More studies are needed  
MMR 5-FU (conventional chemotherapy) Effective for those with a high expression of MMR protein

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 alterations should be considered when selecting treatment. The three genetic variations never occur in combination in the same tumor, so determining which one may be present helps decide the most appropriate treatment.

The first gene alteration determined to be significant in non-small cell lung cancer is a mutation found in the EGFR gene. This mutation is detected in up to 35 percent of patients with non-small cell lung cancer. The mutation is found at much higher rates among those who have never smoked as well as in women, patients of Asian descent and patients with a tumor known as adenocarcinoma.

Large studies have shown that the tumor response to an EGFR inhibitor is far better in people who have tumors with EGFR mutations. For example, in one study, the EGFR inhibitor gefitinib (Iressa) led to a response in about 70 percent of patients who had tumors with EGFR mutations compared with about 1 percent of patients 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 those 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 now routinely test lung cancer specimens for the presence of EGFR mutations. In addition, EGFR testing is recommended for patients who have recurrence of non-small lung cancer (adenocarcinoma) or have metastatic adenocarcinoma at the time of diagnosis.

Identifying patients with non-small cell lung cancer who have KRAS mutations may also be helpful in personalizing treatment. This mutation is found in about one-quarter of cases overall and more frequently among those 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 patients with KRAS mutations than chemotherapy with an EGFR inhibitor.

The most recently identified mutation is a genetic rearrangement that causes the formation of the fusion gene EML4-ALK. This genetic alteration – known as an ALK gene rearrangement – has been found in a small number of non-small cell lung cancers—about 3 to 5 percent. Patients with this gene rearrangement do not benefit from treatment with an EGFR inhibitor, but a new targeted therapy agent, crizotinib (Xalkori), was approved in 2012 for patients testing positive for EML4-ALK rearrangement.

Melanoma

The identification of BRAF mutations in 40 to 60 percent of patients with metastatic melanoma led to the creation of the first targeted drug for malignant melanoma. The drug, vemurafenib (Zelboraf), attacks the mutated BRAF protein, and studies have shown that the targeted agent has at least some effect in about half of melanomas with the mutation. This new treatment is a significant advance for patients with Stage IV melanoma because the treatment options have traditionally been limited for those with this advanced disease.

Leukemias

The first cancer-related genetic alteration to be discovered was the Philadelphia chromosome. This altered chromosome is created when pieces of chromosomes 9 and 22 switch locations, which creates the fusion gene BCR-ABL. This fused gene is found in up to 95 percent of patients with chronic myelogenous leukemia (CML) and in about 20 percent of patients with acute lymphocytic leukemia (ALL). A targeted therapy agent was developed to attack Philadelphia-positive (Ph+) leukemia, and the agent has been called a breakthrough in the treatment of cancer. In addition, other drug classes have also been developed to target other biomarkers in the treatment of leukemias (Table 3).

A recent discovery in genetic biomarkers is the detection of a mutation in the DNMT3A gene in some patients with AML. 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 patients with this mutation do not survive as long as those without the mutation after treatment with chemotherapy. The discovery will help researchers find a target for a new drug that will block the cellular activity produced by the mutation. However, until a targeted therapy agent is developed, researchers suggest that better results may be obtained by using an initial treatment that is more aggressive than standard chemotherapy, such as bone marrow transplantation.

Table 3. Treatment options for leukemias

Class of drug Name of drugs Notes
Tyrosine kinase inhibitors
▪ imatinib (Gleevec)



▪ dasatinib (Sprycel)
▪ nilotinib (Tasigna)
▪ bosutinib (Bosulif)
▪ ponatinib (Iclusig)
Produces much better results than conventional chemotherapy for people with Ph+ leukemias, according to recent studies.

May be helpful for leukemias that become resistant to imatinib.
Monoclonal antibodies
▪ rituximab (Rituxan)
▪ ofatumumab (Arzerra)
Target the CD20 antigen on the surface of B lymphocytes; used for CD20+ chronic lymphocytic leukemia (in combination with conventional chemotherapy).

Lymphoma

Many of the same monoclonal antibodies used to treat leukemias have been effective in the treatment of some lymphomas. For example, rituximab targets a protein called CD20, found on the surface of B lymphocytes in about 90 percent of patients with B cell non-Hodgkin lymphoma. The drug is also used for nodular lymphocyte-predominant Hodgkin lymphoma with CD20+ cells as part of treatment that also involves chemotherapy and/or radiation therapy.

Sarcomas

Targeted therapy with imatinib for one type of sarcoma has been very effective. Unresectable and/or metastatic gastrointestinal stromal tumors (GISTs) with a mutation in the c-KIT gene has responded well, and studies using the drug for people with GIST showed response in more than 50 percent of patients compared with less than 5 percent of those treated with conventional chemotherapy. In fact, imatinib is now the standard of care. As with CML, other similar targeted agents can be used when a GIST stops responding to imatinib.

The team approach to treatment

Personalized treatment may involve input from many medical professionals. Both diagnostic and clinical specialists as well as support staff may be among those who 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 patient support for genetic issues)
  • Psychologist
  • Physician assistant/nurse practitioner
  • Nutritionist/dietitian
  • 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.

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