Biomarkers and Precision Medicine

By Iva Fedorka

The concept of using the body’s own immune system to fight cancer is not new. As early as the 1960s, scientists and physicians talked about “personalized” medical treatments that were customized based on the unique traits of the individual. Today, personalized medicine is a reality, and biomarkers are used to help determine which cancer treatments will be the most successful.

A Series of Discoveries

Gregor Mendel (1822-1884) is celebrated as the "Father of Genetics" based on his experiments with pea plants during the 1850s and 1860s. Many other scientists built upon Mendel’s principles of heredity, and studies of nucleotide crystals and radiographs in the 1940s and 1950s led to a clearer understanding of the composition and structure of DNA and RNA.

More recently, the techniques of SNP (single nucleotide polymorphism, or changes in a single DNA molecule) genotyping and microarray biochips have been key to the latest treatment successes. Microarray biochips give researchers a means to rapidly evaluate an entire patient genome in a very short time, and can be used to efficiently perform SNP genotyping. Specific SNPs are inherited, and have been found to affect patient susceptibility to disease and response to chemical therapies.

Biomarkers for Cancer Drug Trial Success

Recently, former U.S. President Jimmy Carter was successfully treated for melanoma using a medication produced by the pharmaceutical company Merck. As happens in science, the drug was discovered by accident while scientists were looking for compounds to suppress immune responses by stimulating T-cells. (T-cells are a type of lymphocyte, or white blood cell, that can recognize and destroy “foreign” particles or tissue.)

Although several manufacturers were working simultaneously on similar compounds and drug mechanisms, Merck demonstrated the drug’s effectiveness by screening the study subjects for the presence of a specific biomarker. By focusing on the 30 percent of patients who were most likely to respond, Merck’s clinical trial produced more promising results that those of their competitors.

Biomarkers for Drug Responses

The drug Abacavir, which is used to treat HIV, causes allergic reactions in some patients within six weeks of treatment. While such reactions are usually diagnosed by clinical symptoms, two independent studies in 2002 established a potential genetic link between the reaction and the histocompatibility allele HLA-B*57:01. Follow-up studies showed that patients without that genetic marker had no reactions, while “positive” patients had a 60 percent chance of developing a reaction to the medication.

Precision medicine can also help with determining drug doses. Warfarin, a vitamin K antagonist, is commonly used as an anticoagulant or “blood thinner,” but its very narrow therapeutic range can make it difficult to find a dose that prevents both clotting and excess bleeding. Recent studies have shown that a variation in three genes (CYP2C9, VKORC1, and CYP4F2), along with patient age and weight factors, can account for 60.5 percent of the dosing variability.

These findings convinced the U.S. Food and Drug Administration and the European Medicines Agency to recommend testing for the HLA-B*57:01 allele before starting the specific HIV therapy, and Warfarin  labels now warn clinicians about the effects of the known genetic variations.

The Future of Precision Medicine

Initial results from the NCI-MATCH (National Cancer Institute Molecular Analysis for Therapy Choice) trial, the largest precision medicine trial of its kind, provide a wealth of data. Although researchers expected that about 25 percent of the first 6,000 patients would have a rare cancer, 62.5 percent had tumors other than breast, colorectal, non-small cell lung, and prostate cancers. 

Ongoing research into the human genome is expected to ultimately translate into increasingly customized medical treatments based on a patient’s genetic abnormalities and the molecular profile of the tumor, regardless of cancer type.