Understanding the Genomics and Genetics of Cancer
Treatment Options
Treating cancer based on its specific mutations is now possible. As a result of years of research, doctors are able to treat some types of cancer with therapies that target genes, proteins and other substances that cause and contribute to the growth of cancer. This more precise way of treating cancer is offering many patients hope for slowing or curing their cancer, often with a better quality of life.
Once the results of your genomic tests are available, you will work closely with your doctor to determine whether you are a good candidate for certain therapies that are approved for specific mutations.
It is important to understand that not all tumors test positive for a mutation. Still others might have a mutation for which an approved therapy does not yet exist. However, clinical trials are underway to find effective treatments for these additional genetic abnormalities and may offer more options soon.
To develop a treatment plan tailored to you, your doctor considers many factors, including the tumor’s stage, grade and biomarker status; your general health; and your preferences concerning quality of life in regard to potential treatment side effects.
Following are descriptions of therapies that are available to treat some mutations. These drugs can be given orally, intravenously or subcutaneously (see Figures 1 and 2).
Figure 1 (on left) and Figure 2 (on right)
Targeted Therapy
Targeted therapy is a personalized drug strategy that uses the results from genomic testing to select drug therapy that targets specific genes, proteins, mutations, abnormalities or other factors that are involved in the development and support of the tumor. These drugs are designed to kill cancer cells or stop the progression of disease. The drugs travel throughout the body via the bloodstream looking for specific proteins and tissue environments to block cancer cell signals and restrict the growth and spread of cancer.
By targeting specific mutations in proteins, genes and receptors, targeted therapies can attack cancer in the following ways:
- Preventing cancer cells from growing and from living longer than normal
- Blocking or stopping signals that help form blood vessels to the tumor
- Delivering cell-killing substances to cancer cells
- Causing cancer cell death
- Starving cancer of the hormones it needs to grow
Targeted therapies work in different ways and can be classified as small molecule drugs, angiogenesis inhibitors and mono- clonal antibodies (mAbs).
Small molecule drugs are able to get inside of a cell and affect its internal components. They are used for targets inside cells. Some types of these drugs include the following:
- Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called apoptosis. Apoptosis is one method the body uses to get rid of unneeded or abnormal cells, but cancer cells have strategies to avoid apoptosis. Apoptosis inducers can get around these strategies to cause the death of cancer cells.
- Gene expression modulators modify the function of proteins that play a role in controlling gene expression.
- Histone deacetylase (HDAC) inhibitors affect gene expression inside tumor cells.
- Proteasome inhibitors target enzymes to kill cancer cells.
- Selective inhibitors of nuclear export (SINE) enhance the anticancer activity of certain proteins in a cell.
- Signal transduction inhibitors block signals passed from one molecule to another inside a cell. Blocking these signals can affect many functions of the cell and may kill cancer cells.
Angiogenesis inhibitors (also called anti- angiogenic inhibitors) block new blood vessel growth that feeds tumor cells. Tumors need a blood supply to survive and grow.
Monoclonal antibodies (mAbs) are laboratory-made antibodies designed to target specific tumor antigens. They can flag targeted cancer cells for destruction, block growth signals and receptors, and deliver other therapeutic agents directly to targeted cancer cells. When a mAb is combined with a toxin, such as a chemotherapy drug, it travels through the system until it reaches the targeted cancer cell. Then it attaches to the surface, gets swallowed by the tumor cell and breaks down inside the cell, releasing the toxin and causing cell death. Different types of mAbs are used in cancer treatment, but they should not be confused with mAbs that mark cancer cells so the immune system can better see them and destroy them, which is a type of immunotherapy.
Immunotherapy
Immunotherapy harnesses the potential of the body’s own immune system to recognize and destroy cancer cells. To determine whether you are a candidate for immunotherapy, doctors test for specific biomarkers, including PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).
Genomic testing is used specifically to qualify for treatment with immune checkpoint inhibitors and monoclonal antibodies (mAbs).
Immune checkpoint inhibitors prevent the immune response from slowing down, which allows the immune cells to continue fighting cancer. They also help the immune system to better recognize cancer cells as foreign cells.
Normally, the immune system is kept in check through the use of biological checks and balances called checkpoints. Checkpoint-inhibiting drugs prevent connections between checkpoints so that the immune system does not slow down and can keep up its fight against cancer (see Figure 3 below).
Some immune checkpoint inhibitors are also approved as tumor-agnostic treatment, which means they are approved to treat any kind of cancer that has the molecular alterations known as microsatellite instability-high (MSI-H), deficient mismatch repair (dMMR) or tumor mutational burden-high (TMB-H).
MSI-H describes cancer cells that have a greater-than-normal number of genetic markers called microsatellites, which are short, repeated sequences of DNA. Every time a cell reproduces itself, it makes a copy of its genes and DNA. During the process, errors in duplication can be made, much like a misspelled word. The body normally corrects the error, but sometimes it is not caught and fixed (dMMR). It then becomes a mutation that is reproduced in later versions of the cell. Cancer cells that have large numbers of microsatellites may have defects in the ability to correct mistakes that occur when DNA is copied.
When cancer cells have this feature, they are more sensitive to destruction by immune checkpoint inhibitors. MSI is also tested to determine which tumors may have developed because of a deficiency in correcting cellular errors made when it divides.
TMB measures the number of mutations within a tumor to predict a patient’s response to immune checkpoint inhibitor treatment. TMB-H describes cancer cells that have a high number of gene mutations.
Monoclonal antibodies (mAbs) are laboratory-made antibodies designed to target specific tumor antigens. They can flag targeted cancer cells for destruction, block growth signals and receptors, and deliver other therapeutic agents directly to targeted cancer cells. They can also be created to carry cancer drugs, radiation particles or laboratory-made cytokines (proteins that enable cells to send messages to each other) directly to cancer cells.
When a mAb is combined with a toxin, such as a chemotherapy drug, it travels through the system until it reaches the targeted cancer cell. Then it attaches to the surface, gets absorbed by the tumor cell and breaks down inside the cell, releasing the toxin and causing cell death.
Different types of mAbs are used in cancer treatment, but they should not be confused with mAbs that directly attack certain components in or on cancer cells, a type of targeted therapy.
Hormone Therapy
This treatment blocks the stimulating effect of hormones. It can be used to block the body’s ability to produce hormones and interfere with how hormones behave in the body. It is primarily used to treat breast and prostate cancers, which use hormones to grow.
This type of therapy targets specific hormones. For example, in breast cancer, the hormone biomarkers estrogen receptor (ER ) and progesterone receptor (PR ) are routinely tested during the diagnostic process and have treatments available to reduce the levels of these hormones that are stimulating the breast cancer.
In prostate cancer, androgen-deprivation therapy (ADT) slows tumor growth by preventing the body from producing androgens or by blocking the effect that the androgens have on the tumor.
Chemotherapy
Genomic testing may be used in specific instances to determine whether chemotherapy may be an effective treatment option. Doctors know that some types of cancer respond better to chemotherapy. Genomic tests may be used to choose or avoid chemotherapy in certain circumstances.
Ongoing Monitoring and Drug Resistance
It is common for the treatment strategy you begin with to change. Your doctor will continually monitor your condition and make adjustments for a number of reasons. Sometimes a therapy becomes less effective over time; other times, a new mutation may be discovered and a different therapy may offer more promise; or you may reach remission, among other things. Keep in mind that cancer is a fluid condition, so flexibility and patience are important.
When cancer cells stop responding to a drug, it is known as drug resistance. which is known to happen with some targeted therapies. In some cases, patients will have access to other targeted therapies that are designed for other targets within the cancer. Research is ongoing to identify why resistance occurs and to develop new therapies that target multiple genetic mutations at the same time to avoid the development of resistance.
Next Steps
Medication Adherence : Commit to taking your oral medication and keeping your appointments. Taking your drug therapy on time is crucial to maximizing the success of the treatment. Most cancer therapies are designed to maintain a specific level of drugs in your system for a certain time. To be fully effective, every dose must be taken with accuracy, precise timing and safety precautions, whether you receive it via IV, injection or pill form. If your medications are not taken exactly as prescribed, the consequences can be serious, even life-threatening.
Symptom Management : Before beginning any therapy, it is a good idea to know the potential side effects that may accompany your treatment. There are varying degrees of side effects ranging from minor to severe. Ask about the symptoms to watch for and what you should do if they happen. Some may require alerting the health care team as soon as symptoms begin. Prompt treatment may help prevent more serious complications. Your health care team will rely on you to communicate openly about how you feel.
