by Dr. C.H. Weaver M.D. 9/2020
What is Precision Cancer Medicine?
Following your diagnosis of cancer, your reaction may be one of shock and disbelief. If you have been told that chemotherapy or radiation therapy are an important part of your treatment, many unpleasant images may come to mind. But as you move beyond that initial shock to begin the journey of surviving your cancer, you have good reason to be optimistic. Medicine has made—and continues to make—great strides in treating cancer and in making cancer treatment more personal and tolerable. The greatest recent advances are in Precision Medicine.
It’s safe to say that precision medicine is now considered one of the pillars of cancer therapy, joining the three longstanding pillars or surgery, radiation therapy and chemotherapy.
Treating Abnormalities That Are Cancerous
It is now understood that most cancers result from abnormal genes or gene regulation. The cause of these changes can be environmental, spontaneous, or inherited. By identifying the genomic changes and knowing which genes are altered in a patient, cancer drugs that specifically attack that gene (or the later consequences of that gene) can be used to target the cancer and avoid the more general side effects of chemotherapy.
Because precision cancer medicine seeks to define the genomic alterations that are driving a specific cancer, rather than relying on a simple broad classification of cancer solely based on its site of there is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with cancer originating in the same tissue or organ, the behavior of the cancer and its response to treatment can vary widely.
The idea of matching a specific treatment to an individual patient is not a new one. It has long been recognized, for example, that hormonal therapy for breast cancer is most likely to be effective when the breast cancer contains receptors for estrogen and/or progesterone. Testing for these receptors is part of the standard clinical work-up of breast cancer. What is new, however, is the pace at which researchers are identifying new tumor markers, new tests, and new and more targeted drugs that individualize cancer treatment. Tests now exist that can assess the likelihood of cancer recurrence, the likelihood of response to particular drugs, and the presence of specific cancer targets that can be attacked by new anti-cancer drugs that directly target individual cancer cells.
Genomics vs Genetics
Genomic tests are used to identify the specific genes in a cancer that are abnormal or are not working properly. In essence, this is like identifying the genetic signature or fingerprint of a particular cancer. Genomic testing is different from genetic testing. Genetic tests are typically used to determine whether a healthy individual has an inherited trait (gene) that predisposes to a specific health condition.
How Does Precision Cancer Medicine Work?
The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancers DNA that are driving that specific cancer.
Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Normal cells have control systems that allow them to replicate only as needed for growth – in children, for example – or to replace damaged or worn-out cells. Most normal cells are firmly anchored to one area of the body, such as the lung or the breast. When damage to a cell cannot be repaired or when a cell reaches the end of its useful life span, it is programmed to die, a process called apoptosis.
What’s Not Normal?
Cancer cells don’t follow these rules. Gene mutations, chromosome alterations, and changes in other molecules enable them to replicate endlessly, ignoring signals ordering them to self-destruct, and to migrate to distant sites in the body, such as the bones, liver, or brain, where they set up satellite tumors. Usually, several genomic abnormalities are driving the cancer, but these can be different in different cancers that otherwise seem to be the same. Two people with the same type of lung cancer, for example, may not respond to treatment in the same way if their cancers are driven by different combinations of mutations.
Cancer-driving abnormalities may occur spontaneously (de novo) or be passed from parent to child (hereditary). Spontaneous changes happen all the time – thousands of times a day in single cell – often due to DNA damage caused by factors like sunlight, diet, or smoking. Some abnormalities are harmless, some cause the cell with the mutation to die, and some are fixed by the body’s elaborate repair mechanisms or are eliminated before cell replication occurs. A very small minority of these changes, however, can evade repair and alter the cell in a way that, rather than die, develops an improved ability to grow or survive. These alterations lead to cancer or predisposes them to developing cancer. Genomic tests evaluate the genes in a sample of diseased tissue (cancer) from a patient who has already been diagnosed with cancer. In this way, genes that have mutated, or have developed abnormal functions, are identified in addition to those that may have been inherited.
Personalized Medicine’s Quest to Utilize the Patient’s Own Immune System
The immune system is an elaborate network of cells and organs that protect the body from infection. The immune system is also part of the body’s innate disease-fighting capability to treat cancer. With cancer, part of the problem is an ineffective immune system. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check. Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system and avoid immune destruction. The immune system may not attack cancer cells because it fails to recognize them as foreign and harmful.
Our immune systems work around the clock protecting our bodies from “foreign” substances such as bacteria, and viruses. We know that this immune “surveillance” also protects us from cancer, by recognizing a cell that has become cancerous as something foreign. When this surveillance system fails, cancers begin to grow.
Precision Immunotherapy seeks to utilize a person’s own immune response to treat their cancer. The goal of immunotherapy is to help the immune system recognize and eliminate cancer cells by either activating the immune system directly, or by inhibiting mechanisms of suppression of the cancer.
Stimulating the immune system to attack unwanted substances in the body is not a new concept; vaccines, which have traditionally been used to prevent infectious diseases such as measles and the flu, work in this way. What is new, is applying this idea to cancer treatment with the development of precision immunotherapies that stimulate the immune system to attack a specific individual’s cancer.
Antigens Are the Key!
All cells including cancer cells have unique proteins or bits of protein on their surface called antigens. Specific antigens that are present in abundance on a cancer cells surface distinguish them from normal cells. A person’s normal cells carry “self-antigens” that are unique to that individual. Cells with self-antigens are typically not a threat. Invading germs, however, do not come from within the body, so they do not carry self-antigens. Instead, they carry “nonself-antigens.” Cancer cells may also have “nonself” antigens that distinguish them as foreign. The immune system is designed to identify cells with non-self antigens as harmful and respond appropriately.
Immunotherapies work in two ways: First, they alert the immune system that cancer-specific antigens—or antigens that are abundantly present on cancer cells—are foreign. Second, immunotherapies stimulate the immune cells to attack cells that have these antigens on their surface.
Immune cells called dendritic cells start to “eat” the invaders and their nonself-antigens. This process causes the dendritic cells to transform into antigen-presenting cells (APCs). These APCs expose the invader cells to the primary immune cells of the immune system the B and T-lymphocytes. These cells can recognize the invading cells and work to destroy them; . B-cells work rapidly to produce antibodies, and T-cells are activated then multiply into an army equipped with the necessary weapons to defeat the invader.
Some cancers however are able to evade our immune system. Spontaneous mutations in the genes of a cancer cell cause the cells to be altered in such a way that they are not recognized by our bodies as something foreign. Cancer cells can also produce substances or proteins that can shield them from the immune system.
Kinds of Immunotherapy
General types of immunotherapy include interferon, interleukin, and colony stimulating factors (cytokines), which generally activate the immune system to attack the cancer. These general immunotherapies however are not specific, and their activation of the immune system can cause severe side effects by attacking normal cells along with cancer cells. Immunotherapy treatment of cancer has progressed considerably over the past 30 years and has evolved from a general to more precisely targeted immunotherapy treatment. Examples of precision immunotherapy include checkpoint inhibitors, CAR T cells, and vaccines.
Immune Checkpoint Inhibitors
Immune checkpoint inhibitor drugs are currently the most widely used and publicized precision immunotherapy treatment. A patient’s cancer cells can express molecules that activate PD-1 or CTLA-4 inhibitory “receptors” on their “T-cells” or other cells in the immune system. When these receptors are activated on the T-cells, they are prevented from attacking the cancer cells and evade the immune response. Checkpoint inhibitor drugs that block PD-1, PD-L1, or CTLA-4 work to “release the brakes” allowing the cancer cells to be detected and attacked by T-cells.
Chimeric Antigen Receptor (CAR) T-cell Immunotherapy.
In CAR T-cell therapy, a patents immune systems T-cells are collected and reprogrammed in the laboratory to recognize and attack a patient’s cancer cells. Once the T-cells multiply and reach a certain number in the laboratory (usually hundreds of millions to billions), they are re-infused into the patient. The infused T-cells then circulate throughout the body, attacking the patient’s cancer cells. The key step is to genetically modify a patient’s T-cells to express a CAR that is designed to target an antigen protein expressed on the cell surface. As a result, the reprogrammed T-cells, or CAR T-cells, make protein that find and attach to antigens on cancer cells to help destroy the cancer cells. CAR-T-cells appear promising for the treatment of B-cell acute lymphoblastic leukemia (ALL) and other hematologic malignancies.
CTL019 CAR T-cell Therapy-engineers a patient’s own T cells to teach them to recognize and attack myeloma cells. CTL019 is designed to attack myeloma stem cells, a cell type that can give rise to many more myeloma cells. A pilot study reported that this approach was safe and feasible.
BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). This approach was reported to have promise in treating myeloma in patients who had already failed other therapies. There are several ongoing trials with BCMA as a target.
Cancer vaccines work to reeducate the body’s immune system to recognize cancer as foreign and trigger an active immune response against the cancer. A vaccine is designed to stimulate a response by the immune system against specific targets, or antigens. When cells in the immune system perceive the antigen, which is part of the vaccine, they multiply to fight it off.
Vaccines can be either preventive or therapeutic. The cervical cancer vaccine Gardasil®, is a preventive vaccine. It prevents cervical cancer in women by providing protection against several strains of the human papillomavirus, including those responsible for causing many cases of cervical cancer.
Therapeutic vaccines, by contrast, are designed to stimulate the cells of the immune system to kill cancer cells, stop a tumor from growing, or stop a tumor from coming back. Although experimental vaccines to treat cancer have been around for more than 20 years most are currently available only in clinical trials.
Provenge® (sipuleucel-T) was the first “dendritic cell” vaccine approved by the U.S. Food and Drug Administration. Its intended use is for the treatment of metastatic, hormone-refractory prostate cancer. Provenge is custom-made for each patient. First, a patient’s immune cells are collected and exposed to a protein that is found in most prostate cancers, linked to an immune-stimulating substance. Next, the patient’s own cells are returned to the patient to stimulate an immune response against the cancer.
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Clinical Trials and Precision Medicine
Impact of Precision Medicine on Clinical Trial Design
Historically, clinical trials enrolled patients with a single type of cancer, such as lung cancer. A treatment was administered to that group of patients, and the response to that treatment was measured without ever assessing the genomic makeup of the cancer. In order to evaluate precision medicines clinical trials are being revised because evaluating precision medicines requires measuring the genetic makeup of the cancer before beginning treatment.
To conduct clinical trials of precision medicines, patients must be evaluated and enrolled early so that a sample of the cancer can be genotyped.
One new clinical trial model, a so-called “basket” trial, enrolls patients with similar genetic mutations, rather than simply the same type of cancer.
Ongoing “basket” trials include the Lung Cancer Master Protocol (Lung-MAP) trial and the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST).
The Lung-MAP Trial
In Lung-MAP (Lung-MAP.org), researchers with several public institutions, including the National Cancer Institute (NCI), are working with pharmaceutical companies to study treatment for advanced squamous cell lung cancer. Though only some lung cancers are squamous cell, it’s an important area of research, as there are few treatment options for these patients.
Lung-MAP will evaluate several investigational treatments and match patients with the therapy most likely to benefit them. Participants will undergo genomic profiling and then be treated with a drug designed to target genetic mutations involved in the growth of that cancer. Researchers will use genomic profiling to match patients with the therapy designed to target the particular genomic alterations that their cancer expresses.
This more comprehensive approach marks a change in the typical clinical trial model for targeted therapies, in which separate studies for the same disease focus on particular genomic abnormalities and treatments. Potential participants are tested for that genomic biomarker and only individuals who test positive are enrolled in the study.
In Lung-MAP, however, everyone who’s tested will be eligible for a therapy. And several treatments for advanced squamous cell lung cancer will be evaluated under one protocol in an effort to accelerate safe drug development.
The ALCHEMIST Lung Cancer Trials
The ALCHEMIST trials include three clinical trials for patients with certain types of early-stage NSCLC that has been treated surgically. The trials will study targeted therapies that have been approved for advanced lung cancer but are currently not approved for treatment of patients with early-stage disease.
Each participant will be matched with the targeted therapy most likely to work for them. In the screening component of the ALCHEMIST trials, researchers will screen tumor samples for specific genetic mutations that may be involved in the development of cancer. Once specific mutations are identified patients will be assigned to one of two different treatment arms, where they’ll receive drugs approved to target their mutation in advanced lung cancer. The ALCHEMIST trials will assess whether these treatments are safe and effective in early-stage NSCLC that has been surgically removed.
Researchers will look for genetic mutations in two genes thought to drive cancer growth, ALK and EGFR. Therapies are available that target both of these mutations. Patients who have one of these alterations will then be referred to one of the two treatment trials. One study is evaluating the drugs Xalkori® (crizotinib) and the other Tarceva® (erlotinib)—both as treatment after surgery for patients with early-stage NSCLC. Patients will be monitored for recurrence and survival.
More information on each component of the ALCHEMIST trials is available at:
What Is a Liquid Biopsy?
Patients are benefiting from an innovative technique to test for the presence of cancer cells—at diagnosis and beyond.
The term liquid biopsy is being used with increased frequency within the context of cancer treatment. What, exactly, is a liquid biopsy, and how is it different from other biopsies?
What Is a Biopsy?
The National Cancer Institute defines biopsy as “the removal of cells or tissues for examination by a pathologist.” To establish a diagnosis of cancer, all patients must first undergo a biopsy. This is essentially the only way to truly distinguish whether a tumor or atypical cells are the result of a benign condition or of cancer.
Historically, biopsy procedures used to obtain a tissue or cell sample were either an incisional biopsy, in which a sample of suspicious tissue is removed; an excisional biopsy, in which the entire area of suspicion is removed; or a needle biopsy, in which a needle is used to remove fluid or a small sample of tissue. Needle biopsies can be performed with a thin needle, referred to as a fine-needle aspiration biopsy, or a wide needle, referred to as a core biopsy. Although these methods are still standard, liquid biopsies are an area of extensive research and are proving to have the potential to become a critical tool for patients with cancer.
How Are Liquid Biopsies Different?
A liquid biopsy is performed by testing a sample of blood for the presence of circulating cancer cells, known as circulating tumor cells. Perhaps more importantly, samples of blood obtained from a liquid biopsy can also be tested for cell-free tumor DNA (cfDNA), which are fragments of DNA shed by cancer cells into a patient’s bloodstream.
Because cancer cells are constantly “shedding” parts of their DNA, specific genetic mutations (alterations) within these pieces of DNA can provide invaluable information to healthcare providers and ultimately help guide optimal treatment options for each patient.
Importantly, the bits of cf DNA obtained from a liquid biopsy can provide information to healthcare providers in the following areas:
- If or to what extent the cancer is responding to treatment
- Optimal treatment options specific to the DNA mutations of the cancer cells
- Earlier detection of cancer compared with standard screening measures
- Molecular and genetic real-time changes occurring in a patient’s cancer cells in response to treatment and growth
Guiding Treatment Options
Treatment for cancer is rapidly becoming more individualized and targeted toward specific molecular characteristics and/or genetic mutations of a patient’s cancer cells. Because these individualized treatment approaches rely completely on very specific characteristics of cancer cells, identification of these characteristics from liquid-biopsy samples can be an important determinant in the choice of medication most likely to be effective for each individual. Furthermore this information can possibly eliminate treatment choices to which the cancer cells will likely not respond.
Over time cancer cells tend to develop different genetic mutations in response to treatment and/or as they spread and grow. Therefore multiple samples obtained from liquid biopsies throughout the treatment period can help healthcare providers understand whether the patient’s cancer cells are continuing to respond to treatment, as well as the ways in which the cells are changing. This allows for ongoing modification of treatment regimens based on identified changes of the cancer cells. This is in contrast to other types of biopsies, which are performed prior to initiation of treatment for a “onetime snapshot” of a cancer’s characteristics and which don’t allow for continued monitoring of changes over time within cancer cells’ DNA.
Potential for Early Detection
Liquid biopsies have the potential to detect cancer cells in a patient’s body at an earlier stage than many standard screening methods. This may play an important role in both initial screening measures for early detection of cancer, as well as early detection of a cancer recurrence.
To produce the DNA detectable by a liquid biopsy, often fewer cancer cells are required than the number needed for a scan or other laboratory method. Because earlier cancer detection tends to be associated with improved patient outcomes, liquid biopsies may ultimately play a critical role in how cancer screening is performed.
An Easier, Less-Invasive Biopsy
Biopsies that require the removal of tissue samples are often associated with pain during and after the procedure, the potential for infection, the potential for scarring, required medication, anxiety, and the need for extended periods of time in the clinic.
Scans used for detection of cancer recurrences sometimes require intravenous medication, dietary changes prior to the test, significant time for the scanning process, and significant financial resources.
A liquid biopsy can circumvent many of these issues, as all that is required from the patient is a blood sample.
The cornerstone of cancer treatment has undergone a rapid and monumental shift toward targeting very specific molecular and genetic characteristics of cancer cells. Liquid biopsies can quickly identify these targets to determine which medications will be most effective in treating an individual’s cancer. They can also offer real-time monitoring of genetic changes in cancer cells that invariably occur over time. This innovation allows providers not only to move ahead with timely implementation of effective treatment according to identified genetic characteristics but also to avoid treatment that is not likely to be effective or to which the cancer cells have developed resistance.
Furthermore, the use of liquid biopsy reduces burdensome time and financial commitments associated with scans, invasive biopsies, and other laboratory procedures; it can potentially identify earlier stages of initial cancers and sites of recurrences; and it does not carry the risk of pain, scarring, anxiety, additional medication, and potential for infection associated with other, earlier methods of biopsy.
Research is continuing to standardize liquid biopsies, as well as to expand the understanding of how the information obtained from liquid- biopsy samples can truly guide continuous treatment decisions for those affected by cancer.
Genomic Testing & Precision Cancer Medicine –What You Need to Know
Q: What is genomic testing?
A: Genomic testing looks at a group of genes and their varying levels of expression. This gene expression or activity can characterize how genes interact with one another and predict the behavior of certain tissues within the body. This is in contrast to genetic testing, which looks at a specific change within an individual chromosome or gene, often as part of an inheritable trait.
Q: What role does genomic testing play in a cancer diagnosis?
A: Genomic testing can provide information about a patient’s prognosis based on the gene expression within an individual’s cancer tissue and can often predict if certain therapy (chemotherapy or precision cancer medicines) will be of benefit.
Q: At what point in the diagnostic process does genomic testing occur?
A: Genomic testing can occur at any time after a tissue sample (biopsy or resection) of cancer has been acquired.
Q: What if tissue is not available to perform genomic testing?
A: There are two options: an additional biopsy can be performed if feasible or an individual can consider a “liquid biopsy” A liquid biopsy is performed by testing a sample of blood for the presence of circulating cancer cells, known as circulating tumor cells. Samples of blood obtained from a liquid biopsy can also be tested for cell-free tumor DNA (cfDNA), which are fragments of DNA shed by cancer cells into a patient’s bloodstream.
Q: What questions should I ask my healthcare team about genomic testing?
A: The following are the primary questions to ask your healthcare provider.
- Is genomic testing available for the type of cancer I have, to aid in determining my overall prognosis?
- Will the results of this testing have the potential to change your management of the cancer? Specifically: Will the test be able to tell me if certain therapies will be of benefit in my treatment?
- Have you had positive outcomes in using this testing with other patients?
- Is this testing covered by my insurance plan? (This type of testing can run in the thousands of dollars, though many plans cover the tests without an out-of-pocket expense.)
Q: Are there specific cancer types for which the role of genomic testing is especially significant?
A: Genomic testing is developing at a rapid pace. Established testing is particularly advanced in all blood cancers and leukemia as well as colon, lung and breast cancer where several precision cancer medicines have already been developed. Genomic testing is also increasingly playing an important role in individuals with rare cancers, cancer of unknown primary and those with widely metastatic disease.
Undergoing genomic testing that looks at expression across a wide variety of genes may identify certain genes that could potentially be a target for therapy that is otherwise not considered. A change to a precision cancer medicine would have the potential to markedly improve survival.
Further Reading and Other Resources
Reference: National Cancer Institute Dictionary of Cancer Terms, s.v. “biopsy,” accessed September 28, 2016, www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45164.