Lung cancer patients and providers live in a much more hopeful world than the one I entered as a physician/scientist at the turn of the century. Proof of that improved landscape can be seen in a recent annual report on cancer rates in the United States, which shows a 30 percent drop in lung cancer mortality over the last 20 years. This amazing progress has led me to ponder the past and future of cancer care.
I entered hematology/oncology driven by a passion for taking care of the very ill, and by excitement about the emerging science of cancer treatment. Elusive genes and proteins with magical names such as “K-ras,” “p53,” and “Myc” grabbed our attention—but the cancers also had seemingly magical abilities to evade any types of targeted treatment interventions, despite the best efforts of researchers and physicians. Back then our treatment options resembled throwing darts in the dark at a moving target. Using random combinations of toxic chemotherapies, we were constantly hoping to hit a cancer target while preserving healthy cells. We were not nearly so successful as we had hoped to be.
This was especially the case in thoracic oncology—my chosen subspecialty—where the most pivotal study of the era showed that regardless of how you assembled the chemotherapy building blocks, the ultimate outcome for many of those facing advanced lung cancer was a rapid path to disease progression and then death. In the United States, this resulted in 160,000 deaths each year, making lung cancer the number one cause of cancer deaths in both men and women.
Looking for Cancer Targets
Fortunately, a sequence of key discoveries—such as learning that kinase proteins can be inhibited fairly well by small sized chemicals—yielded the first real success in molecular oncology and the development of imatinib (Gleevec) for the treatment of chronic myeloid leukemia. Concurrently, we recognized that antibodies targeting important cell-surface proteins can add greatly to the effectiveness of conventional therapies. The ability to be more precise meant that we had a chance of providing patients with treatments that would be less harmful to them than chemotherapy alone.
Another area of improvement came from the efforts to attack the epidermal growth-factor receptor (EGFR) protein. This protein is present in a large majority of lung cancers. Despite our high expectations that this would lead to the next breakthrough in lung cancer management, the initial reality was sobering. But a few patients using EGFR kinase inhibitors did amazingly well, and we quickly learned that this was related to a unique activating mutation of EGFR found only in a subset of these patients. This finding quickly transformed the field by calling for molecular testing for EGFR and then other genes in all our lung cancer patients.
As a young oncologist working in a molecular research lab, I saw the limited success of these drugs, and that fueled my desire to make a contribution to the field. My chance came when one of my patients, who had had a tremendous response to an EGFR drug, started to show signs of resistance and allowed us to test his tumor specimen again. His tumor cells harbored a key EGFR mutation and then, over time, acquired a second mutation, which suddenly made his tumors exceedingly medicine resistant. We learned that this gatekeeper mutation occurred in approximately 60 percent of secondarily resistant tumors. To overcome this resistance, we found novel drugs, such as osimertinib (Tagrisso), that were able to do the job; now testing for these resistance mutations is routine.
Continued Progress in Cancer Treatment
Fast-forward 20 years; the pace of progress is impressive. Molecular testing to determine the presence of a series of key molecular alterations is now part of our everyday practice. Technology has been developed to allow testing in a “bundled” fashion, sequencing hundreds of genes at the same time, including those in the bloodstream. And we’re now detecting trace amounts of circulating tumor DNA in about 80 percent of advanced lung cancer cases. This lets us monitor molecular changes in tumors over time in a noninvasive fashion.
The wave of advances means that about a quarter of all patients with advanced lung cancer can be offered targeted therapies. These are usually oral, well-tolerated agents with a great chance of efficacy—far exceeding that of chemotherapy. Dramatic discoveries have propelled lung cancer to the forefront of molecular oncology. Our initial hope was that if we looked hard enough, we might find similar vulnerabilities in other types of tumors. As it turns out, with many tumor types completely sequenced, it has become clear that there are fewer easy tumor targets in other cancer types. It seemed we were once again stumped.
Just as we seemed to reach the limits of molecular oncology, however, another class of drugs, called checkpoint inhibitors, entered the picture. These drugs target cell pathways blocking certain proteins, allowing for an immune response against cancer cells. We soon learned that immunotherapy is quite effective, particularly for lung cancer patients. Researchers are now sharpening molecular tools such as checkpoint inhibitors so we can understand how to make the best use of immunotherapy. We now believe that a third of patients with advanced lung cancer will have excellent outcomes using the immunotherapy drug pembrolizumab (Keytruda) alone, without the need for chemotherapy.
We are finding an increasing number of less-toxic, more-effective treatments. And more-powerful tools for matching the right drug to each patient are helping us extend life spans and improve the patients’ quality of life. The idea of a “cure” for advanced lung cancer is gradually becoming a realistic treatment goal for some of our patients.
We are also making advances in treating earlier stages of lung cancer, which could have an even bigger impact. These advances come on the heels of public health efforts to prevent and treat the disease. Robust smoking-cessation programs have reduced smoking rates from 40 percent to closer to 10 percent; lung cancer screening is yielding early detection and drastic cuts in mortality; and advanced surgical and radiation technology can cure most early-stage lung cancers with limited associated morbidity. If we can maintain this tremendous pace, lung cancer in the coming years could lose its long-held spot as the number one cause of cancer deaths. And that’s precisely what we are working toward.
