Healio spoke with Edward S. Kim, MD, chair of the department of solid tumor oncology at Levine Cancer Institute at Atrium Health in Charlotte, North Carolina, about stress management and how stress hormones can promote epidermal growth factor receptor inhibitor resistance in non-small cell lung cancer.
Edward S. Kim, MD
Lung cancer research is a model for precision medicine. Patients with lung cancer can now be treated with better drugs that have fewer adverse effects and are more effective. Years ago, medical students and fellows were not interested in lung cancer because the field lacked sophistication, but now many physicians have become interested in lung cancer because of the science, drug development and improved patient outcomes. When I first got into the field in the early 2000s, it did not matter which cytotoxic chemotherapy doublet you gave to a patient with stage IV lung cancer — the outcomes were all the same. Compare that to today — in 2018 — when oncologists conduct biomarker analysis on all patients, and in close to 50% of patients who receive a diagnosis of NSCLC, oncologists can find a targeted therapy to match up with each patient’s tumor profile.
In the past, patients with lung cancer were not likely to live longer than a year beyond diagnosis. Through advances in research, this stigma has passed, and today patients with stage IV lung cancer can live for years. This is largely due to the identification of the progression of the identification of specific biomarkers and the development of specific therapies that target these biomarkers. In addition, I feel immunotherapy has really become like a new type of chemotherapy in lung cancer. Today, almost every patient with lung cancer is receiving immunotherapy in some way, shape or form that is helping them live longer and with a better quality of life.
One of the studies with which I was involved was the phase 2 BATTLE trial that looked at personalizing lung cancer treatment through biomarker identification. To do this, researchers obtained repeat biopsies in patients and used those biopsies to measure biomarkers, attempting to match patients with appropriate treatments.1 Obtaining multiple biopsies has become routine because oncologists need to evaluate how effectively the patient has been treated and to monitor changes in the affected tumor. Through biopsies, genomic profiling can be performed to see what has changed about that tumor in the hopes of finding the right drug. Changes in the tumor can reveal mutations such as T790M, which can only be identified through repeat biopsy procedures. This practice has accelerated the field of lung cancer by identifying unique markers that occur, which, in turn, accelerates drug development to target those markers.
Lung cancer is a prevalent cancer and has the highest death rates, so improvements and advances tend to feel more impactful. There is a stigma associated with lung cancer because of its association with smoking, and patients may feel that lung cancer is almost viewed as a punishment for that choice. I think this in an unfair stigma because a large population of patients who have never smoked — approximately 25,000 to 30,000 a year – develop lung cancer. Also, twice as many women die of lung cancer every year than breast cancer, a statistic that is not commonly known about lung cancer. Devoted resources, committed investigators and dedicated patients continue to push the envelope every day in the study of and promoting awareness in the field of lung cancer.
Research shows that EGFR mutations are important and supports that EGFR TKIs work well in patients with EGFR-activating mutations. However, TKIs do not work for a lengthy period, and approximately 55% to 60% of patients who are being treated with EGFR TKIs develop resistance mediated by T790M. The research Monique B. Nilsson, PhD and team performed sought to determine why these EGFR TKIs stop working, and it has been determined it was not because of the most common way — the development of a resistance mechanism called T790M.2 However, there are still 40% of patients for whom these drugs stop working, and researchers are still not sure why.
This preclinical research focused on whether stress hormones may affect cancer cells and result in resistance to TKIs. Several of these stress hormones were measured and showed that perhaps use of a beta blocker would decrease some of the stress hormone levels and therefore, decrease the chance of resistance. Further testing is needed in the clinic, but these findings hint that oncologists could personalize a cancer drug for a patient by simply being on a beta blocker.
Researchers have found that stress hormone levels are elevated in patients in which the resistance occurs outside of T790M. So, specific stress hormones such as interleukin-6, liver kinase B1 and others, are elevated and so by using a beta blocker to decrease their elevation, they discovered that stress hormones were a factor in tumor growth.
Stress is damaging and affects patients in different ways. Anything that a patient can do to reduce or manage stress can be beneficial. Physicians can attempt to counsel patients, refer patients to services like supportive oncology and address mental health concerns, but it is hard to tell a newly diagnosed patient to relax. So, it is challenging. If a patient is already on a beta blocker for existing reasons, I would not tell him or her to stop taking it, but I am not yet to the point in which I would proactively put a patient on a beta blocker if the EGFR drug was not working.
Numerous FDA-approved drug therapies are available, such as some checkpoint inhibitors or chemotherapies, within the second- or third-line setting that provide good treatment opportunities for patients with lung cancer. But still, some lung cancer therapies will be given arbitrarily. If a treatment stops working, oncologists will often switch to a different treatment without much rationale to use one treatment over another because there is no biomarker to use as a guide. EGFR is unique in that again, about 50% to 60% of patients who are being treated with an EGFR TKI will develop T790M. One drug, osimertinib (Tagrisso, AstraZeneca), has been developed and has been successful in targeting T790M. But for a patient on chemotherapy, if the patient is on immunotherapy, we still have not figured out the exact mechanisms of resistance and whether we can give a drug a single target to help overcome that resistance.
Some promising treatments coming down the road include different classes of immunotherapy that target different aspects of the immune system, different combinations with existing drugs, and the development of new drugs, which have all opened a whole new perspective in drug development in lung cancer. The National Cancer Institute’s Molecular Analysis for Therapy Choice, or MATCH, trial is a precision medicine cancer treatment trial in which patients’ treatment is determined on the results of genomic sequence testing, and investigators found genetic changes in the tumor. In addition, ASCO’s Targeting Agent and Profiling Utilization Registry, or TAPUR, trial is a study in which physicians match patients to a specific treatment from the multiple available drugs and, based on the marker profile of the tumor, treat each patient.
Oncologists are optimistic and enthusiastic about the opportunity for more drugs and learning more about the possible drug combinations in lung cancer treatment. As mentioned earlier, more and more patients are undergoing broad genomic testing, which helps reveal markers in each tumor. The progress in this field has been impressive in recent years, and today, it continues to explode.
I think it is important to reinforce that there is a need to continue to collect adequate amounts of tissue and blood so that researchers have these precious resources that patients are volunteering to provide as they enroll in studies. Having these resources allows researchers to continue to study disease markers and helps shape which types of drugs may match up best.
Physicians should know that precision medicine is the new way to practice medicine. We need to be diligent in ordering the biomarkers and, more importantly, utilizing them up front to make treatment decisions for our patients.
I hope that, in 10 years, lung cancer is a boring field because patients are living so long and that I will have to move into a different field. Lung cancer has come a long way and will continue to develop. My hope is that lung cancer becomes a chronic disease in which patients are not worried about it as much and can live longer with improved quality of life. This field has made such important strides in the last 5 years, and hopefully, we can continue to see that.
Fred R. Hirsch, MD, PhD
Biomarker identification: Connecting the right patients to the right lung cancer therapies
Karen L. Reckamp, MD, MS
The field of lung cancer has evolved significantly over the past 10 years.
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