How a NSCLC Pioneer Helped Unravel the Mysteries of EGFR

OncologyLive, Vol. 20/No. 10, Volume 20, Issue 10

A 2018 Giants of Cancer Care award winner for Lung Cancer, Bruce E. Johnson, MD, has helped define the genomic era in lung cancer care. His notable contributions include characterizing the role that EGFR mutations play in non–small cell lung cancer.

Bruce E. Johnson, MD

Before running his own laboratory, discovering mutations in lung cancer, and serving as president of the American Society of Clinical Oncology (ASCO), Bruce E. Johnson, MD, grew up on his family’s dairy farm in St. Peter, Minnesota.

He learned the value of hard work and self-discipline at a young age—his father requested that 5-year-old Bruce and his brother do their fair share of chores on the farm.

But young Bruce quickly realized that farming was a difficult way to make a living. In his early childhood, he committed to pursuing an education— a fancy one, as Johnson calls it, because his brother was off to the Air Force Academy.

He was accepted into Harvard University in Cambridge, Massachusetts, where he completed his undergraduate degree in 1975. “My classmates were a rather well-educated, motivated bunch,” Johnson said. “It took a little while to find my way, but I did so after about a year.”

After working at a job washing pea combines at Green Giant, Johnson embarked on his lifelong journey into medicine, earning his medical degree from the University of Minnesota in Minneapolis in 1979. He completed his postgraduate training at the University of Chicago Hospitals and Clinics in Illinois and the National Cancer Institute (NCI) in Bethesda, Maryland.

Today, Johnson serves as chief clinical research officer and institute physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, Massachusetts, as well as a professor of medicine at Harvard Medical School in Boston. And, he recently held the title of ASCO president, which he calls one of the best jobs in the world, for the 2017—2018 term.

Navigating the Medical Journey

Medicine was on Johnson’s mind beginning in high school, where he scored high on an aptitude test.

“When I got to college, I was drawn to science,” he said. “I felt very comfortable in that area and was able to take lectures from some of the leading scientists in the world. Some of the Nobel Prize winners, like George Wald, were there.”

It wasn’t until he rotated through oncology during medical school that the field sparked his interest. Johnson was exposed to studies conducted by Clara D. Bloomfield, MD, a 2015 Giants of Cancer Care® award winner who was one of the pioneering women physicians of her generation. She studied leukemia and was Johnson’s medical school adviser; he has been interacting with Bloomfield ever since. “She led by example,” he said. “She would round on all the leukemia patients every night to make certain they were well taken care of, and she worked very hard to study her patients’ cytogenetics—characterizing their chromosomes—and the relationship between the chromosomal changes and the outcomes. I learned from her the importance of linking the patients and the patients’ tumors.”

But leukemia didn’t particularly interest him. Johnson saw his future in lung cancer during his training in internal medicine at the University of Chicago. He began to work with Harvey M. Golomb, MD, who opened a lung cancer service and tested an investigational 4-drug regimen. Afterward, Johnson decided to pursue additional training where he could obtain both oncology and laboratory experience: the NCI, which offered training in a number of cancers, including lung cancer.

“I was very interested in having a laboratory and doing laboratory experiments,” Johnson said. When he first started out, there was no established therapy for most lung cancers. Johnson hoped to move laboratory observations into the clinic faster and was able to do some of that while he worked at the NCI. “[At the NCI], a lot of barriers [to] doing clinical research were pretty low in that you didn’t have to worry about [persuading] a drug company to fund the trial or take whatever industry-sponsored trial was there, but rather you got to decide how and what you would treat people with,” he added.

Treating patients has been a critical role for Johnson, who sees patients in clinic and continued to do so even during his year as ASCO president. “I’ve always thought that if you’re going to make laboratory observations and make decisions about improving the treatment of people, it’s important to participate in the process,” Johnson said.

Johnson ran his own laboratory for about 10 years, eventually turning it over to a colleague. However, he has found his way back to the place where his passion began. A few years ago, Levi Garraway, MD, PhD, left Dana-Farber, and Johnson was asked to serve as interim director of the Center for Cancer Precision Medicine, which Garraway had created. Johnson says it has been gratifying and eye-opening to work in a laboratory with newer technologies that can help define tumors by their cellular makeup and explore insights into immunotherapy.

Mutations and What's to Come

Over the course of his nearly 40-year career, Johnson has dedicated time to testing novel therapies for the treatment of lung cancer, collaborating on innovative research, lecturing on the most recent findings throughout the world, and training others in the thoracic oncology field.

Under his leadership as the director of the Lung Cancer Program at Dana-Farber from 1998 to 2013, Johnson increased the program’s National Institutes of Health funding 5-fold.

But his proudest accomplishment was the discovery of an association between mutations of the EGFR gene and being able to treat patients up front with targeted agents. Johnson and colleagues collected tumor cell lines from women with adenocarcinoma who either did or did not smoke cigarettes and characterized their response to gefitinib (Iressa). In the laboratory, they learned that most patients who have a clinical response to the treatment have either point mutations or deletions of amino acids from the EGFR tyrosine kinase domain. The investigators showed that lung cancer cell lines with EGFR point mutations or deletions are 100-fold more sensitive to treatment with gefitinib than cell lines with EGFR wild-type disease.

Johnson said he and his co-investigators made the decision to publish information about the mutations in both cell lines and patients during an afternoon seminar. His colleague, Matthew L. Meyerson, MD, PhD, was presenting study findings from a group of patients in Japan who were found to have a specific EGFR mutation—the same one that Johnson’s laboratory had found.

“We figured that same mutation couldn’t be an accident,” Johnson said. The team moved forward with writing a paper and had it published in Science—part of the findings that shifted the standard of care for patients with non—small cell lung cancer (NSCLC) who harbor an EGFR mutation toward targeted therapy and away from chemotherapy. The testing for EGFR mutations has become part of the standard evaluation for patients with metastatic NSCLC. And, there are now 5 FDA-approved drugs that patients with NSCLC and EGFR mutations can take orally. The drugs continue to improve in both their efficacy as well as their capability to reduce adverse effects.

“There is now a medication, osimertinib [Tagrisso], that works for about 20 months, whereas the chemotherapy used to work about 4 to 6 months, and the [adverse] effects are dramatically less,” Johnson said. “Having [been personally involved with the development] of the EGFR mutation testing and the laboratory events, that, in part, led to the development of a drug similar to osimertinib is something that I’m most proud of having been a part of.”

Since then, other genomic changes in NSCLC have come to light: ALK, ROS1, and BRAF, all of which have FDA-approved anticancer agents. Johnson says that at Dana-Farber, they characterize more than 400 genomic changes in 400 to 600 patients a year. Then they track the results and treat the patients accordingly. A quarter of patients with NSCLC are treated with targeted agents at the cancer institute.

Immunotherapy is another area that has Johnson hopeful. There are now 4 immune checkpoint inhibitors approved for patients with NSCLC, including combinations with chemotherapy in frontline settings.

However, big challenges remain. For instance, more than 37 million Americans smoke cigarettes, according to a 2016 report from the CDC. “The most important thing for lung cancer is to try to get more people to quit smoking so they can put us out of business,” Johnson said. He added that providing adequate resources and tools for those who want to stop is necessary, as is expanding screening practices to help reduce the number of deaths from lung cancer.

Despite the contributions he already has made to the field, Johnson maintains future career goals. Over the next several years, he hopes to work toward determining why checkpoint inhibitors do not work in certain subsets of patients. Once he figures this out, he would then like to come up with combination agents to increase the proportion of people who get a dramatic response from immunotherapy.

“It looks like at least half of the patients can get targeted therapy or immunotherapy rather than chemotherapy. And that’s all happened in the last 14 years,” he said. “The part that has been kind of revolutionary is being able to treat people for years rather than months and seeing immunotherapy come on the stage as something that actually works.”

Becoming the Patient

For Johnson, the continuation of advancements in cancer treatment is meaningful not only professionally but personally as well. The disease has hit his family twice—first his father and then Johnson himself. Both received a diagnosis of prostate cancer. Johnson had surgery and admits that at times the disease became distracting. He now has firsthand understanding of what patients often refer to as “scan-xiety.”

“I sit and wait, and after I see the internist every year, I log on to see what my PSA [prostate- specific antigen] is,” Johnson said. “I breathe a sigh of relief every time it’s less than 0.02. [The waiting is] anxiety provoking.”

But he has learned not to focus on it too much, thinking only of his own cancer while he’s being taken care of and then moving on. One strategy he employs is spending time with his family. Johnson, a father of 3, loves to downhill ski, attend the symphony orchestra, and travel with his wife of more than 40 years, Georgia. In recent years, he has added another title to his resume—grandpa.

Each morning, Johnson begins his day with coffee and the morning news. He then heads to work, making important decisions that will have great impact on the lives of the hundreds of thousands of people diagnosed annually with lung cancer. Knowing this, Johnson follows this philosophy: “I’d rather take the time to do it well than to rush it,” he said. “I don’t want to be having this same conversation in 5 years.”