Robert L. Coleman, MD
At the 2016 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, The ASCO Post sat down with the SGO’s outgoing President, Robert L. Coleman, MD, and discussed the revolutionary potential of blood biomarkers, why enhanced recovery after surgery protocols is a significant innovation, and the need to rethink U.S. Food and Drug Administration (FDA) trial designs. Dr. Coleman is Professor in the Department of Gynecologic Oncology and Reproductive Medicine and Vice Chair of Clinical Research at The University of Texas MD Anderson Cancer Center.
Moving Forward Through Biology
Congratulations on a successful meeting. What have been some of the highlights?
Genetics and genomics have been a focal point from the first session on, and there have been several presentations breaking down the standard barriers of dogma.
We all know that BRCA1 and BRCA2 mutations occur in a small subgroup of patients, but because of the development of these PARP (poly ADP ribose polymerase) inhibitors, we have started to expand the catchment circle of people who might be able to get a drug like that and have it work for patients who have homologous recombination deficiency. The first abstract of the meeting looked at the impact of platinum-based therapies in these groups (see more on this study in the April 25 issue of The ASCO Post). The study by Barbara Norquist, MD, confirmed that finding, showing that these other markers are going to be relevant.
Although there’s been a lot of focus on platinum responsiveness, homologous recombination deficiency also applies to nonplatinum drugs that cause direct DNA damage, including PARP inhibitors. The dogma of isolating the effect to just BRCA1 and BRCA2 alterations is breaking down. As many as 50% of our patients may be able to receive these therapies and perform better than expected. Understanding that biology will be critical for the field moving forward.
Another highlight was the presentation by John Martignetti, MD; it showed the ability to predict treatment response and survival in gynecologic cancers with personalized circulating tumor DNA biomarkers. (See the April 25 issue of The ASCO Post for more on this study.) Right now, because of the difficulty of doing biopsies, clinicians do a single point-in-time assessment. Using free circulating DNA in the blood gives us a tremendous opportunity to analyze and monitor patients serially.
Microfluidic Devices Are Here
Why are blood biomarkers so important?
One of the biggest barriers to progress is having a suitable tool to analyze patients because you can’t biopsy the patient every week or even every month. If you can figure out a way to get the information in the blood and put it on a plate with a gene chip or some type of analytic, you could produce this in the office, and do it every cycle, and you’d be responding to the environment in real-time.
One of the points I found interesting from this talk was that when you stress a cancer cell, it reacts just like you or I would. Those inducible events are important in understanding the biology of cancer…. If we could identify what’s going on as we attack a tumor population—and do this on a continuous basis—we would learn from each iteration. And if we did that 1 million times across the globe, we would learn amazing things about, say, what ovarian cancers or endometrial cancers do in response to chemotherapies or immunotherapies. These microfluidic devices are here, and a lot of investigators are already exploring their use and potential; they just need to be optimized.
These microfluidic devices are here, and a lot of investigators are already exploring their use and potential; they just need to be optimized.— Robert L. Coleman, MD
Significant Surgical Innovation
Enhanced recovery after surgery was a major topic of conversation at this meeting. What are your thoughts about its potential?
Enhanced recovery after surgery is the single-most significant innovation in surgery happening today. The concept is not new, but its system-wide integration is, and the preliminary data are delivering on its promises.
What is needed for more hospitals to implement these protocols?
Conceptually this strategic look at all aspects affecting the patient from preop to postop recovery is digestible. However, while individual surgeons may have their “way of doing things”—measures they consider to be valuable in achieving enhanced recovery—an enhanced recovery after surgery program invites a critical look at every aspect in management a patient may experience in the perioperative setting. This includes issues like how close and what kind of food a patient can take before surgery to enhance immune surveillance and wound healing. Or, is there a need to use inhaled anesthetics? How much and what kind of fluid is necessary during surgery to promote early bowel recovery?
Questions at every point of contact require complete engagement of the patient, nurses, anesthesia personnel, operating room staff, and caregivers, along with mutually agreed-upon standardization of management plans. It a big undertaking, but the early data reveal some amazing outcomes: earlier recovery from surgery, lower amounts of narcotics, lower complication rates, and earlier hospital discharge. My recommendation for health-care systems that want to explore this paradigm is to identify a “champion” to learn from the other successful programs and form a team or individual service to pilot the program, monitoring all aspects of intervention.
Once we got everybody on board at MD Anderson and implemented the program, we also started looking at research questions, such as intraoperative stress markers. Surgical stress is an immune-depleting event that can release all kinds of growth factors, which can negatively impact tumor biology, wound healing and even recovery. So, we started building a research program around the program. It’s been a delightful experience.
And the literature has shown the cost benefits. This will save the health-care system unbelievable amounts of money.
Rethinking Trial Designs
You’ve had many conversations with the FDA about rethinking trial designs. What are some of the barriers to drug approval, and why the need for change?
The big problem is not showing proof of mechanism—we can do that pretty easily—it’s what data or outcomes will animate the FDA in its considerations for regulatory approval.
If you take diseases as common as breast cancer and lung cancer and aggressively subclassify them by discoverable aberrations, you can end up with some very small cohorts. How do you study and ultimately register new agents in these situations? At the extreme, it would be essentially an N of 1, which would be very challenging. However, that’s the ultimate endpoint of precision medicine—the right drug at the right time for the right patient. What we need to do is figure out the benchmark or reference standard that makes sense clinically and is sustainable from a development business model.
One of the reasons health care is so expensive in this country is that we administer a lot of ineffective therapy. Even large phase III trials that lead to the approval of a new agent fail to demonstrate a universal effect, which leads to many unselected, or poorly selected, patients receiving therapy with little change to benefit them. The downstream impact of better patient and tumor characterization should help optimize effective therapy and minimize ineffective exposures. We have a lot of work to do to reach that zenith, but the pace of scientific discovery and the potential for big data analytics offer more hope in this domain than ever before.
Commensurate with this discovery is the need for our trial designs to be nimble enough to address proof of mechanism, safety, and efficacy without requiring the enormous patient investment of the past. Hopefully, 3,000- and 4,000-patient trials will be relics in the archeology of science. It’s going to be a challenge; statistically there are just too many drug combinations that can be done in different sequences. But, if we were able to break down the barrier of what it takes to actually get something registered, we might be able to do it faster. ■
Disclosure: Dr. Coleman reported no potential conflicts of interest.