Sitting outside a sarcoma conference hall, she could have been anyone. She was down-to-earth and answered questions with the patience of a teacher.
|Elaine Mardis, PhD|
The human genome is a genetic blueprint – a complete set of DNA – to tell our bodies how to develop. Physicians and scientists study the genome in hopes of finding the genetic changes that cause cancer or allow it to grow out of control. The goal is precision medicine (also called targeted therapy), in which treatments are matched to specific gene mutations. This differs from traditional chemotherapy with cytotoxic drugs that kill some healthy cells along with the cancer.
A famous example of precision medicine is the use of imatinib (Gleevec) for gastrointestinal stromal tumors (GISTs) that express the protein KIT.
A decade ago, I wrote about the hype surrounding precision medicine. It had not – and still has not – paid off as much or as soon as many predicted. Nevertheless, I still have great hope for it, and I was surprised recently to encounter doctors who thought it had little future.
“I don't think there are many people saying there is little future for precision medicine, really, who have any position of expertise/experience in the field,” Dr. Mardis said. “Fact is, we now are seeing reports emerge in the peer-reviewed literature that are indicating strong clinical benefit for these [genetic] tests in cancer patients. These large-number trials are establishing strong evidence that testing patients to predict their best drug/treatment options is worthwhile and should be pursued.”
For example, Nationwide Children’s is planning a trial using exome-sequencing to find targetable gene mutations in pediatric patients with treatment-refractory sarcoma, she said. This testing looks at the DNA that encodes proteins.
“The aim is to identify kids that might benefit from a targeted therapy or to detect those who might benefit from checkpoint-blockade therapy.” Checkpoint blockade is one tool of immunotherapy.
For those who say immunotherapy isn’t worth it, Dr. Mardis responds: “Ask someone who was at death's door and now is living a normal life. There are plenty [of immunotherapy drugs] to choose from already, and it's early days.
“I think the challenge in immunotherapy is that we need to better be able to define which patients will respond to it, and to be able to clinically monitor those likely to have adverse responses so they can be properly cared for during the difficult clinical period, thereby experiencing the long-term benefit of these therapies.
“The other open question in checkpoint blockade is the specifics around dosing, because it is quite clear we have patients who receive only one or a few rounds of therapy and have a durable response.”
Another hotly debated issue in precision medicine is the use of randomized controlled trials. In a recent panel discussion, one oncologist “indicated the trials for targeted therapies are not appropriately designed because patients with mutations in druggable target genes weren't being randomized to a placebo or standard-of-care arm.”
This may be appropriate for a phase IIa trial involving only a few patients, Dr. Mardis said. Once a targeted therapy has shown promise, however, patients don’t want to sign up for a phase IIb trial in which they may get a placebo or the older standard of care, she said.
“The ethics of putting a patient onto SOC [standard-of-care treatment] when they are likely to respond based on phase IIa results is questionable, in my mind. Some trials have solved this by using a ‘cross-over’ potential for patients who clearly are having no response, so they can get the drug being trialed.
“Medicine is an evidence-based practice, and all doctors do the best they can for their patients, but since this is such a new area, there are likely to be disagreements. The fundamental differences in targeted versus cytotoxic chemotherapies also evoke new ideas about clinical-trial design that are controversial.”
I often hear people complain that the FDA approves expensive new drugs that give cancer patients only a few more months of life than the older drugs do. These complaints are misleading, Dr. Mardis said, because those few months are an average of everyone’s response on the clinical trial. Some people may live for years while others get no benefit.
“Furthermore, there are myriad examples of patients who achieved a short benefit that bought them sufficient time for a better therapy to come along,” she said. “I was just speaking to the mother of one such patient with low-grade glioma. When we identified her daughter's driver BRAF mutation (a three nucleotide insertion that added an amino acid after position 600) in 2011, nobody had ever enrolled on a BRAF inhibitor trial (that we could identify) with that type of insertion and so her likelihood of response was unknown.
“As an alternative, she got a MEK inhibitor but didn't have a response after six months, which was long enough for someone to have seen a similar BRAF mutation who did respond to RAF inhibition. She then switched to a second-generation RAF inhibitor and has been responding now for over a year.”
“From Basic Science to Clinical Translation” will be the AACR’s next conference on sarcoma May 16-19 in Philadelphia. Its general meeting will be April 1-5 in Washington, D.C. I'm grateful for winning a scholarship to attend, as part of its Scientist↔Survivor Program. Sarcoma Alliance board member Dave Murphy participated in this program in 2004 and 2005. He returned in 2014 as an advocate mentor.