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Know Your Target: Precision Medicine 101

TON - September 2018, Vol 11, No 4 - ONS
Meg Barbor, MPH

Washington, DC—Precision medicine may help clarify tumor diagnoses and guide treatment selection, but using precision medicine effectively depends on knowing your target, according to James L. Chen, MD, Assistant Professor, Departments of Biomedical Informatics and Internal Medicine, Division of Medical Oncology, The Ohio State University College of Medicine, Columbus.

“This is a right target, right drug issue, and results might change based on the type of testing you use. So in order for you to pick the right drug, you need to know your target,” Dr Chen said at the Oncology Nursing Society 2018 Congress.

What Is Precision Medicine?

Standard medicine operates under the assumption that all patients and all diseases are similar, and treatment results in similar outcomes. Precision medicine, however, dictates that no 2 patients or diseases are exactly alike, and similar treatments in similar patients can lead to different outcomes.

Most cancer therapies are designed for the “average patient” as a “one-size-fits-all approach.” But, in actuality, there is no average patient, and thus most treatments will only be successful for some patients, and not at all successful for others. Targeted therapies have revolutionized the cancer treatment landscape, and precision medicine drugs are becoming standard practice.

The field of precision medicine compounds and targeted biologics has grown exponentially, now crowding out cytotoxic chemotherapy agents, Dr Chen observed.

There are more than 850 targeted compounds currently in development, more than 3200 active clinical trials supporting new drug development, and more than 500 drug companies developing targeted therapeutics.

“Half of the drugs now in development by pharmaceutical companies are targeted agents. But, if you don’t know what the target is, you can’t use their agents,” he said.

Precision Medicine’s “Dirty Little Secrets”

Dr Chen went on to discuss a few limitations, or “dirty little secrets,” of precision medicine. Standard molecular tests can miss cancerous changes. Half of the genomic alterations described in the National Comprehensive Cancer Network guidelines for non–small-cell lung cancer can be missed using hot spot panels without supplemental fluorescence in situ hybridization (FISH) assays, and approximately one-third of targetable ALK fusions in non–small-cell lung cancer are missed using FISH.

FISH and polymerase chain reaction assays are effective at finding known genomes, whereas the hot spot approach only sequences select regions of a gene. Hot spot panels can identify select base substitutions, short insertions/deletions, few copy number alterations, and no rearrangements.

“If you know what you’re looking for, FISH and polymerase chain reaction assays are really good, because you know how to build your primers. Hot spot panels are great because they pick up mutations and changes that you don’t have to be aware of ahead of time, but the limitation is that they have to be in that spot,” Dr Chen noted.

“But everybody’s a snowflake. So, if you say that all people will have a mutation in this particular spot, you’re wrong,” he said. That leads us to comprehensive genomic profiling, which sequences the entire exon, and can identify all base substitutions, all insertions/deletions, all copy number alterations, and select rearrangements.

“Instead of looking at a block, you’re now looking at a whole neighborhood,” he explained.

Whole gene sequencing looks at the entire gene and can identify all sub­stitutions, insertions/deletions, alterations, and rearrangements.

“Not all of the tests are created equal and they all look at different things. So you have to have an idea of what the test is actually looking at in order to be successful in finding the alteration at hand,” Dr Chen advised.

In addition, results may change based on the type of testing being performed. From one sequencer to another, there may not be exact concordance between samples in terms of what is considered pathogenic, although a lower number of targets will result in better agreement.

“They’re not perfect,” he warned. “They’re tests.”

Interpreting the Data

Precision medicine results depend on the testing and subsequent analysis performed, and DNA data by itself are worthless without annotations. Knowing that a gene is mutated does not answer the question of whether that change is going to cause cancer or change the function of the gene.

Variants of unknown significance are genes that are mutated in some way and different from their reference genome. This classification means that, at the time of testing, the laboratory could not determine whether the gene change increases the risk for cancer. More data are needed to classify these mutations.

“The future is now, and precision oncology is here. It’s part of our guidelines and our practice patterns,” Dr Chen said. For example, lung cancer cannot be treated without sequencing; a physician needs to know whether a patient has an ALK fusion or an EGFR mutation.

Remember that biopsies are only snapshots of a tumor in time and place, he noted. The tumors in an individual’s body are genetically distinct from one another (intrapatient heterogeneity), and the longer a patient is treated, the more their tumors change and become resistant.

“I tend to re-biopsy and re-profile when the tumors change, because I want to see if any new mutations cropped up,” he said.

“To make it even more complicated, not only do we have variations from tumor to tumor, but within the tumor, depending on where you biopsy, the genetics are different. There’s still a lot we need to learn,” Dr Chen concluded.

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Last modified: September 9, 2019