Waun K. Hong, MD, PhD
Over the past 25 years, multiple lung cancer chemoprevention trials have missed the mark with agents that looked good on paper but lacked the molecular biology support to make a difference. To effect meaningful change in the persistently dismal long-term prognosis for lung cancer, research must focus on identifying specific molecular targets and then attacking those targets with appropriately targeted agents, said Waun K. Hong, MD, PhD, a physician and lung cancer researcher at the University of Texas MD Anderson Cancer Center in Houston. The feasibility of such an approach was demonstrated in the Biomarker- Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study. Following the guidance of serial lung biopsies, investigators examined the effect of therapy on molecular responses and then modified the therapy as indicated to ensure that patients received the treatment that was most likely to provide a benefit. This strategy is known as adaptive therapy.
In a review of the “landscape” of lung cancer chemoprevention during an AACR plenary session, Hong also emphasized the importance of reverse migration (ie, developing chemoprevention strategies from the top down): learn what drives advanced-stage lung cancer and then work back to the drivers of preneoplastic lesions.
OBTN: What is your assessment of the current status of chemoprevention in lung cancer?
We haven’t made much progress in long-term survival. Lung cancer is still a great killer. Five-year survival is only about 17%. Additionally, more than 90% of lung cancer is due to smoking. Less than 10% of lung cancer is unrelated to smoking. These figures emphasize the need for chemoprevention. Half of lung cancer cases occur in people who have quit smoking. Quitting smoking reduces the risk of lung cancer, but clearly, that is not enough. Former smokers have a lower risk of lung cancer, but it still is not the same as neversmokers. We have to think about intervention.
In the last 25 years, the chemoprevention trials have failed. The agents people used —vitamin A compounds, beta-carotene, selenium—were associated with no difference whatsoever in the risk of lung cancer. People who continued to smoke got worse. My theory is that tobacco carcinogenesis is so powerful that the agents we have tried to use for chemoprevention simply are not strong enough to overcome the tobacco carcinogenesis.
More than 100,000 patients have participated in chemoprevention studies. We have devoted a lot of time, effort, and expense, but obviously, we have not been using the right approach. So, that’s the problem.
How do we find a solution?
First, we have to understand the target. We have to find a molecular target that can be a driver of neocarcinogenesis. Then we use an agent that can inhibit that target. The agents that have been used in lung cancer chemoprevention trials have been chosen on the basis of epidemiologic data, not molecular biology. To kill an enemy, you have to understand the enemy and its strengths. Then the strengths become the molecular targets. Otherwise, you’re just shooting in the dark.
So, I went back to the drawing board, and my hypothesis now is that we have to start at the end, not at the beginning. We first have to figure out what is the major molecular target of advanced lung cancer through molecular profiling studies. Then we have to prove it. Find the target and match it with the right targeted agent and see whether there is any effect.
This was the approach used in the BATTLE trial. We had patients with advanced, heavily pretreated lung cancer. We mandated tissue biopsy and performed molecular profiling. We identified a target and then we tried to eliminate it. Once that has been done, then the same approach can trickle down to earlier lung cancer. We have applied that approach in the BATTLE adjuvant trial. We are examining the lung cancer resection sites as the source for molecular profiling. We have found that specific genes are expressed at the tumor site and specific genes are expressed adjacent to the resected site. Our analysis showed there are oncogenes, such as PI3 kinase (PI3K). It looks like PI3K plays a major role as a driver of lung cancer.