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Precision Oncology

“I’m very confident that, in the future, we will actually be able to develop therapies, either single therapies or, more likely, combinations of therapies that target multiple weak links within these pathways and that work together to improve the outcome for cancer patients with these mutations.”

Lee S. Schwartzberg MD, FACP

Watch the video – http://www.practiceupdate.com/expertopinion/670elsca1=emc_enews_daily-digest&elsca2=email&elsca3=practiceupdate_onc&elsca4=oncology&elsca5=newsletter

This is Dr. Lee Schwartzberg for PracticeUpdate. Today we are going to discuss the evolution of personalized oncology, a growing area of interest for medical oncologists.

What do we mean by personalized, or precision, oncology? It’s the use of information that is related to the genomic makeup of a particular cancer to treat that cancer or to prognosticate for that cancer.

We’ve learned over the last couple of years that there are specific genetic mutations seen in a variety of human cancers, which are called driver mutations. These driver mutations can potentially be drugable; that is, we can develop therapeutics against them and impact the course of the disease. The biology that we’ve learned so much about over the last few years is really starting to pay off now with therapies that can improve the lives of patients with cancer who have these genomic alterations.

Perhaps the best example is chronic myelogenous leukemia, which has one specific mutation, BCR-ABL, against which drugs have been developed. There are now at least five different drugs that target the BCR-ABL mutation and that have transformed chronic myelogenous leukemia from a disease that was fatal within 3 to 4 years to a disease in which virtually all patients live essentially completely normal lives, taking one pill a day.

In solid tumors, the situation is a little more complex because there’s not usually just one type of mutation that drives the tumor. But, even here, we have made substantial progress. For example, in breast cancer, we understand that the group of patients who have HER2-positive breast cancer can be targeted with anti-HER2 therapies, which has transformed that particular subgroup of patients from those with the worst prognosis to those with, arguably, the best prognosis. In many other solid tumors, we’re starting to understand how personalized medicine can make a difference.

Today we have the technology that allows us to interrogate multiple genes that are important in cancer progression and to find out if they have a mutation. Today we can do gene panels that are available commercially for 50, 150, or as many as 409 different genes that are important in cancer genesis, and to find out if a specific mutation exists for which there is a drug.

Non–small cell lung cancer, which years ago was a disease with a dismal prognosis, has now been found to have mutations in over half of the patients who present with advanced disease. Many of these mutations can be targeted with therapies that can transform the outcome for these patients. For example, we know patients with EGFR mutations respond to small-molecule tyrosine kinase inhibitors, like gefitinib or erlotinib. Patients who have a translocation in the ALK gene or in the ROS gene respond to crizotinib, the first-generation ALK inhibitor, and there are several other drugs in development now that are even more potent for this particular alteration.

Some of the gene mutations we see have not yielded therapies yet. For example, in non–small cell lung cancer, the most common mutation seen is in the KRAS gene. As of yet, we don’t have a therapy that targets KRAS, but, as we understand the biology better, we understand why that is. It appears that downstream signaling of KRAS, particularly with the marker called MET, may be an escape mechanism by which this particular mutation does not respond to anti-KRAS therapy. And it is looking as if combinations that include a MET inhibitor, like an anti-MET antibody, may improve response rates for patients with KRAS mutations.

As we understand more about the pathways that are involved with these mutations and the specific types of mutations that are involved and the way that all of these genes interact and the way their proteins interact, I’m very confident that, in the future, we will actually be able to develop therapies, either single therapies or, more likely, combinations of therapies that target multiple weak links within these pathways and that work together to improve the outcome for cancer patients with these mutations.

Cancer remains very complicated, and solid tumors can find multiple ways to get to their final endpoint of unregulated growth and spread; but, if we can target multiple pathways with drugs that can be combined, and that are not very toxic to be combined in full doses, we have a very good chance of curing the majority of patients with cancer. And I am confident now that personalized oncology, although it’s still in its infancy, has a very bright future.

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