Indicator of cancer predisposition

Although the majority of cancers arise spontaneously, several genetic mutations can be inherited and increase the risk of developing cancer. For example, individuals carrying a mutated retinoblastoma (RB1) gene are at increased risk of developing retinoblastoma, a type of cancer arising in the retina of the eye at a very young age. Children with a family history of retinoblastoma can be tested for the presence of a RB1 mutation and should obtain frequent eye screening that enables earlier detection of this cancer. In this case, RB1 is used as a biomarker for cancer predisposition. Many other cancer predisposition gene mutations have been discovered over the past decades.

Biomarkers help in diagnosis

The gold standard for diagnosing cancer is by observation of malignant cells under the microscope which is performed by a pathologist, a medical doctor with specialized training in identifying abnormal cells and cell activity. Pathologists look at the size, shape, and number of cells to help determine whether a cell is cancerous and identify the type of cancer. In addition, the cells are stained for different types of proteins that are specific to the suspected cancer. This process allows the pathologist to increase the accuracy of the diagnosis.

Neuroblastoma is a pediatric cancer of the peripheral nervous system that expresses a protein called PHOX2B. This protein is not found in healthy tissues after birth and can be used as a specific biomarker for the diagnosis of neuroblastoma.

Occasionally, the origin and type of tumor can be difficult to determine only from the way the cells appear under the microscope. In these situations, testing for specific genes known to be altered can aid in diagnosing the type of cancer. For example, a class of pediatric tumors, called NTRK-fusion positive tumors, are characterized by an alteration in one of three genes in the Neurotrophic Tyrosine Receptor Kinase (NTRK) family. The DNA coding for this gene is fused to another DNA molecule and form a fusion gene. This group of tumors can appear almost anywhere in the body, and it is therefore difficult to make a diagnosis based solely on the cellular appearance. In this case, the NTRK gene is used as a diagnostic marker and also as a biomarker for very specific treatments designed to “turn off” these unusually “turned on” fusion genes that instruct a cell to continue to grow (see below).

Biomarkers that guide therapy

Biomarkers can also help clinicians choose the appropriate therapy for a child’s cancer (Table 6-2). For example, as described above, NTRK-fusion cancers are treated with drugs that were developed to inhibit the protein which is the product of the fusion NTRK-gene. One such drug is called Larotrectinib and allows for a more effective and less toxic treatment for this group of cancers. Here, the NTRK-fusion gene serves as a biomarker to guide therapy.

The Philadelphia chromosome that was described earlier is another example of a biomarker used to guide therapy. Currently, clinicians routinely test for the presence of the BCR-ABL1 fusion gene (the medical term for the Philadelphia chromosome) in patients with acute lymphoblastic leukemia. A positive test warrants the incorporation of drugs that inhibit the action of the fusion protein. Other examples of biomarkers used to guide therapy include the same fusion protein BCR-ABL1 in chronic myeloid leukemia (CML) and mutated BRAF in pediatric brain tumors called gliomas. Both of these cancers can be targeted with drugs known to inhibit the corresponding abnormal gene product.

A large clinical effort to use various genetic biomarkers to guide therapy is exemplified by the Molecular Analysis for Therapy Choice (MATCH) trial. This is a clinical trial in which patients with cancer are assigned to receive a treatment tailored to the genetic characteristics of their type of cancer. A sample of the patient’s tumor is then subjected to genetic analysis (see below) and if a genetic change matches a drug being used in the trial, the patient may receive the treatment with that drug if eligible. In this case, the genetic changes of the cancer are biomarkers that guide specific drug therapy. Finally, genetic analysis of pediatric tumors may identify mutations that match to an FDA-approved drug for the same mutation found in adult cancers. Clinicians may recommend “off label” drug treatment for children when a clinical trial is not available.

Prognostic marker

A prognostic marker is a biomarker used to predict the course of disease, also known as prognosis. The products of certain genes (e.g. RNA and proteins mentioned above) and the quantity in tumors can be used as a biomarker to determine how aggressive the tumor is. For example, the gene MYCN is amplified in a subset of neuroblastomas. That is, the cancer cells have multiple DNA copies, usually hundreds, of the gene MYCN instead of the normal two copies. The presence of MYCN amplification in neuroblastoma tends to require more intense therapy. Prognostic biomarkers are used to stratify patients in clinical trials and/or assign appropriate treatment.

Biomarkers that monitor response to therapy

Biomarkers can be used to determine if a patient responds to therapy. In acute lymphoblastic and other leukemias, a bone marrow aspirate and biopsy are performed during treatment to measure a set of cell surface markers present on the leukemic cells collectively known as minimal residual disease (MRD). The absence of MRD suggests that therapy was successful in eliminating the cancer cells. In solid cancers, technology now allows detection of genetic mutations in blood samples or from the fluid removed from a spinal tap, also called liquid biopsies. The detection of circulating tumor DNA (ctDNA) is increasingly being used to monitor response to therapy and also to detect gene mutation-drug matches, especially when performing a tumor biopsy might be dangerous to the patient.

Biomarkers that guide drug dosing

Certain genes in our DNA are responsible for the way our body responds to drugs. Changes in these gene can result in accumulation of several drugs in the body and lead to side effects. Measuring the presence of the changes in these genes can help your healthcare provider/oncologist decrease the dose of a drug and prevent accumulation. Such genes are considered biomarkers for drug dosing. For example, an enzyme called thiopurine methyltransferase (TPMT) is required for metabolizing the drug mercaptopurine used in leukemia therapy. High levels of mercaptopurine result in decreased white blood cells leading to increased susceptibility of infections. Individuals with DNA changes in the gene coding for TPMT are unable to metabolize mercaptopurine appropriately and need dose reduction of this drug. In this case, the gene TPMT is considered a biomarker for drug dosing.

Biomarkers in post-treatment surveillance

Following completion of cancer therapy, patients usually undergo routine surveillance studies, such as magnetic resonance imaging (MRI) or positron emission tomography (PET) scans, to ensure that the cancer does not recur. These studies can only detect tumors that are large enough to be seen by the naked eye.

The emerging group of biomarkers mentioned above called ctDNA or liquid biopsies are based on the DNA content of cancer cells that are released into the bloodstream. Levels of cancer cell-free DNA can be monitored before, during, and after therapy and be used to detect disease recurrence earlier than current imaging methods.