Expert Discusses Impact, Importance of Genetic Testing in Cancer

Howard A. “Skip” Burris, MD

In treating metastatic disease, the molecular profile of a patient is the most critical piece of information, says Howard A. “Skip” Burris III, MD.

At the 2017 Community Oncology Conference, Burris, president of clinical operations, chief medical officer, Sarah Cannon, detailed the benefits of performing next-generation sequencing tests on patients with cancer. Burris stressed to community oncologists that performing genetic testing is worth the time, effort, and money.

“It’s really exciting to see that a simple molecular profile, with no additional work for us except ordering the test, [can give] a result that will change the life of the patient,” Burris said.

In his presentation, Burris listed the many genetic driver mutations in patients with lung cancer, including KRAS, EGFR, MET, ALK, as well as a list of targeted agents—both FDA-approved and in clinical trials—that are available to treat patients with these mutations.

Burris used the ROS1 rearrangement as an example, which is found in approximately 2% of patients with lung cancer. “While none of us ever see a patient with a ROS mutation,” Burris said, he noted that patients with these rearrangements that are treated with crizotinib (Xalkori), a tyrosine kinase inhibitor that is FDA approved to treat patients with ROS1-positive non—small cell lung cancer, can achieve a complete remission. The discovery of this mutation in these patients can change their lives, allowing for a greater chance at a complete response by targeting the driving cause of the cancer. That would not be possible without molecular testing, however, to reveal that these patients have targetable mutations.

The challenge with molecular testing is understanding the results as well as differentiating between the many tests that are available to order. For example, results from molecular tests can include lists of many variants of unknown significance (VUS) that patients have. It is unknown how these variants in their genetic profile impact their cancer, if at all, but future knowledge may prove the importance of these variants.

A great number of genetic tests and types of platforms are becoming available, making the decision over which platform to use increasingly complex. Burris listed 24 different testing platforms available for use. “Forget about taxol versus taxotere, now which test should you order [is the big question],” he quipped.

Among the types of genetic testing available are single-marker molecular tests, multi-gene “hot spot” tests, and comprehensive genomic profiling, looking at a range of 1 gene to all genes known to be clinically relevant. While a single-marker test may show if a patient definitively does or does not have a genetic mutation that is targetable, Burris stressed the role for complete genomic profiling.

“It makes sense, particularly in the patient embarking on a metastatic journey, to know the whole story, to know everything about it,” he said.

For example, Burris explained that in patients treated with PI3K inhibitors, other variables including additional mutations may affect the patient’s outcome. Patients with a PI3K mutation that are also hormone receptor—positive may respond well to treatment with PI3K inhibitors, but those that are HER2-positive may not respond as well, Burris said, with these preliminary findings from clinical trials with PI3K inhibitors.

By building up a database of information of patient outcomes and genetic mutations from clinical trials and basket trials, more can be discovered over time about how to treat patients with various mutations, and perhaps more about other VUS.

Patients undergoing treatment often develop resistance to their treatments. Yet the mechanism of their resistance can only be found upon further testing. “Only a rebiopsy is going to tell you what happened in that particular patient,” Burris said.

However, a new biopsy may be necessary before patients can receive further testing, he said, as the molecular status of a historical sample of a patient’s tumor may not reflect how their disease has changed over time. Yet many patients may not want a second biopsy, as they can be invasive. As such, the question of tissue versus liquid biopsies has risen.

While tissue biopsies are the golden standard, there is a growing role for liquid biopsies, with many platforms having proven sensitivity and specificity to find mutations in the blood or urine. Burris also mentioned that he believed that there was a possibility for liquid biopsies to be used in monitoring patients frequently for their response to therapy or potential resistance, however, it would depend on decreasing the cost of these liquid biopsies.

The cost of both liquid biopsies and next-generation sequencing may seem prohibitive, but each makes a big impact on determining how to treat a patient and potential lasting responses from targeted therapies.

“In the setting of the price of immunotherapy, the price of modern chemotherapy, and PET CT scanning, who knows where the cost of next-generation sequencing will settle in, but it’s probably a reasonable dollar [amount] to spend when you’re making a decision on $10,000/month worth of therapy,” Burris said.