The Most Important Thing About a Master Plan Is Not Having One: Pasi A. Jänne Is a Giant of Cancer Care in Lung Cancer

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Partner | Cancer Centers | <b>Dana-Farber</b>

Pasi A. Jänne, MD, PhD, discovered a new way to treat lung cancer by following his intuition and staying flexible to pursue opportunities as they arise

As director of 3 centers at Dana-Farber Cancer Institute, a professor of medicine at Harvard Medical School, and head of The Jänne Lab, you might wonder what master plan Pasi A. Jänne, MD, PhD, drafted in his youth to make him so successful.

The truth? He never had one. Rather, he’s always done what has felt right by following his intuition and curiosities, a concept that he tries to instill in his fellows to this day.

“So many people want to have a 1-, 3-, and 5-year plan, but it may not work. Sometimes if you’re too rigid and you can’t see it any other way or any other things, there may be opportunities that are missed along the way,” said Jänne.

Born in Helsinki, Finland, and raised in a rural town with a brother 4 years his junior, Jänne was no stranger to the scientific world. His father worked as a biologist, and in 1980, when Jänne was 12, his father’s employer sent the family to the United States.

The move was supposed to be temporary, but the family came to enjoy living in New York, New York. Eventually. Jänne needed some time to adjust to his new surroundings.

“[The transition] was not easy at first, but I learned how to quickly navigate the city and how to get back and forth from school. I grew to love living in New York City with everything it had to offer,” he said.

Jänne eventually enrolled in Vassar College, a liberal arts school about 2 hours north of New York City and the alma mater of former first lady and style icon Jacqueline Kennedy Onassis and chef, and author Anthony Bourdain, among others. Having worked in science labs since high school, Jänne had pictured attending a larger university that was known for science. At Vassar, he was exposed to the college’s highly regarded art history program, an opportunity he might have missed at a larger scientific research university.

“I learned how to appreciate art, and now when I travel to major cities, I always try to go to the art museums to see those pieces that I learned about in college in real life,” he said. “Living in NYC was, of course, a gift because of the many wonderful museums that are there.”

Following graduation in 1989, Jänne enrolled in a 7-year, combined MD/PhD program at the University of Pennsylvania in Philadelphia. Apart from knowing he wanted to pursue medicine and science in some capacity, Jänne was not sure where he wanted to focus. But, guided by his unwavering passion for research and with direction from his PhD mentor, a human geneticist, he pursued a doctorate in human genetics. The decision, coupled with his interest in medicine and prior exposure to hematologists and oncologists during his medical rotations, led him to oncology. Jänne felt the discipline would allow him to explore the overlap between science and medicine.

“As I was thinking about fields of medicine, I wanted to think about where the application of genetics in medicine was likely to happen,” he said. “Certainly, hematology/oncology seemed like a reasonable place compared with, for example, cardiology or neurology.”

It was also during graduate school that Jänne met his wife, Karen Cichowski, PhD, now a cancer biologist and head of the Cichowski Lab at Brigham and Women’s Hospital and Harvard Medical School, as well as a Harvard professor.

Upon graduation, Jänne, began seeking out fast-track residency programs in internal medicine while his wife applied for postdoctoral positions.

She was the first to receive an offer, in Boston, Massachusetts, so Jänne followed her, landing at the Brigham and Women’s Hospital. He found Beantown’s notoriously harsh weather suited him just fine and was a welcome reprieve from the 90-plus–degree summers in Philadelphia. “I like winter, being from the North Pole,” Jänne joked. “We’ve lived in Boston for a long time, and I don’t see any reason to leave here either. It’s a wonderful place to live, and it suits my Scandinavian genes very well.”

Stuff happens and Things Change

Jänne explained that his decision to specialize in lung cancer was first influenced by the etiology and multidisciplinary management of the disease.

“I was interested in lung cancer as a kind of medical illness because, having just trained in internal medicine, lung cancer was a disease where all disciplines of medicine are involved, and people get sick in very different ways,” he said.

Second, but equally as important, Jänne received guidance from Bruce Johnson, MD, the 2018 Giants of Cancer Care® award winner for lung cancer. “[Bruce Johnson], my primary mentor, was somebody that guided me, looked out for me, and opened doors for me,” said Jänne.

“I have always tried to identify folks who I thought were incredibly talented and to interest them in the work that I shared in,” Johnson said. “Dr Jänne was one of the real standouts from his years as a hematology/oncology trainee at Dana-Farber Cancer Institute.”

Finally, Jänne saw a career in lung cancer as an opportunity to make a difference for patients with advanced disease whose prognosis was measured in months. “That’s what we’re here for—to serve our patients and provide them with the best care possible,” he said.

At the time, Jänne was the first fellow at Dana- Farber in 5 years to pursue lung cancer.

“It wasn’t this big, planned thing,” he said. “People sometimes feel like they have to plan the next 10 years of their life, but stuff happens and things change. This is what I tell all the fellows who come and talk to me about this kind of stuff.”

Jänne shares a similar mentality when it comes to his 2 children, who are not as scientifically inclined as he and his wife.

“We quite honestly have never pushed [science on our kids],” Jänne said. “We have never said that they need to do science or anything like that. [My wife and I] love our jobs. We wouldn’t trade our jobs. When you find something that you’re passionate about and love, it doesn’t feel like a job anymore. That’s all we want for the kids. I don’t care what they do, as long as they find their passion.”

His children have helped Jänne recover some of his own passions, especially hockey. Approximately 10 years ago, his son had expressed interest in joining a team. Jänne played in Finland but gave up the sport when he moved to New York.

After attending his son’s games, Jänne realized that he wanted to get back on the ice himself. Following a brief stint coaching his son’s team, Jänne began skating again and eventually joined the annual Dana-Farber Rink Rats hockey game between Boston Bruins alumni and Dana-Farber physicians, faculty, and staff. Since 2015, the annual hockey game has helped raise more than $165,000 for cancer care and research at Dana-Farber.

The Jänne family also enjoys traveling whenever possible, particularly to visit his parents, who have since returned to their hometown in Finland. Because the COVID-19 pandemic has slowed travel, Jänne says that he and his wife now spend more time creating their own dishes, a pastime they shared prior to having children.

“It’s in part about experiencing different cultures, and food is a wonderful way to experience that culture—although it doesn’t ever quite taste as good when you make it at home as it does when you’re [abroad],” said Jänne, adding that once travel restrictions have lifted, he is eager to return to Japan, a country he’s particularly fond of because of the “fascinating culture and great food.”

Over the years, Jänne has become close friends with Tony S.K. Mok, MD, the 2020 Giants of Cancer Care® award winner for lung cancer. Mok is a well-known food and wine connoisseur who has hosted 3 television shows about dining and cooking in Hong Kong where he lives and the 2 men share an appreciation for good food and good wine. They were together in Hong Kong when Jänne tried baby pigeon for the first time.

“I’m pretty adventurous in terms of eating. In Finland, food is monotonous and bland, but I can eat anything in any spiciness,” Jänne said. “There’s not really much that I won’t eat. That’s the fun of trying things.”

A Bridge Between Medicine and Science

Jänne began studying early-generation EGFR inhibitors in mesothelioma and lung cancer early on in his career. At the time, the expectation was that fellows in their second or third year would decide whether to focus on research or clinical work. Jänne saw that as a false choice.

“There [wasn’t] this middle ground, and wanting to maintain my interest in science and medicine, I wanted to continue to do both,” he said. “Part of the reason why I haven’t left Dana-Farber is that I have found a place where I can bridge medicine and science.”

To that end, he continued doing research in the laboratory and seeing patients in the clinic with Johnson. They decided to enroll patients in a clinical trial for gefitinib (Iressa), a first-generation EGFR tyrosine kinase inhibitor, which was under investigation as a postchemotherapy treatment for patients with advanced non–small cell lung cancer.

“At that time, we had nothing but chemotherapy, and we were a big center, so we enrolled approximately 200 patients,” said Jänne. “That allowed us to see the exceptional responders [with] lights-out responses.”

At that same time, Matthew L. Meyerson, MD, PhD, this year’s Giants of Cancer Care® award winner for prevention/genetics, and his colleague, William Sellers, MD, were conducting first-generation lung cancer sequencing studies with samples from treatment-naïve patients who had undergone surgery.

However, because the patients were untreated, investigators couldn’t correlate the presence of EGFR mutations with response. Instead, they noticed that the incidence of EGFR mutations was higher in Asian patients.

At the same time, Jänne was analyzing the patients who had outstanding responses to gefitinib, as well as studying model cell lines from patients in the laboratory.

“We knew that clinically, patients responded, but it wasn’t an even distribution, meaning that there were some clinical characteristics that were associated with the response, especially being a never smoker, Asian, and female—female probably being surrogate for being a never smoker,” Jänne said. “We noted that one of the cell lines was just lights-out sensitive compared with the others and was very much like the patient.”

Jänne and his colleagues independently sequenced the EGFR gene from the sensitive and nonsensitive cell lines and realized that the sensitive cell line, H3255, had a sensitizing EGFR L858R mutation––the very same EGFR mutation that Meyerson and his colleagues observed in their patients.

“That was our ‘Aha’ moment, and it was great because I remember this was right [around] when my daughter was born, so I was holding my daughter in one hand [while] we were having a phone call about this [realization],” Jänne said.

The next step was identifying the patients who’d had lights-out responses to gefitinib, all of whom were found to have an EGFR mutation.

EGFR is the Key

In June 2004, Jänne and his colleagues published their findings correlating response to gefitinib with EGFR mutations. That same summer, pathologists at Dana-Farber had already begun to establish a first-generation clinical sequencing protocol.

“If patients were found to have an EGFR mutation, we could get them on an EGFR inhibitor,” Jänne said, which also paved the way for the investigation of EGFR inhibitors in the frontline setting, where they are primarily used today.

“[From there], the whole story came together. It came from all these independent pieces, but the mutation was the thread that unified it all,” he added. “I’m not even sure that we fully appreciated the significance of the finding at the time [in terms of] what it would do and how it would change lung cancer and medicine.”

Now physicians have a range of targetable alterations, including ALK, RET, MET, ROS1, NTRK, and KRAS.

Three years later, Jänne and colleagues published research demonstrating that not only was the loss of response to gefitinib driven by MET amplification, but that inhibition in MET signaling could restore sensitivity to gefitinib, paving the way for further study of resistance mechanisms to both earlier- and next-generation inhibitors.

In 2009, Mok and colleagues published the results of the phase 3 IPASS trial (NCT00322452) that provided evidence proving Jänne’s team correct. Those findings demonstrated that patients with an EGFR mutation derived significantly more benefit from gefitinib vs chemotherapy in the frontline setting.

That same year, Jänne and colleagues published the first paper demonstrating efficacy for an agent directed at EGFR T790M, setting the stage for research with the third-generation inhibitor osimertinib (Tagrisso). Osimertinib is now a standard of care for patients with resected and metastatic EGFR-mutant non–small cell lung cancer, its latter use extending median survival to 3 years.

“One of the things that really distinguishes scientists who make an important contribution to our body of scientific information is the ability to make consistent, insightful observations about what is driving the sensitivity and resistance to our therapeutic agents,” Johnson said. “The series of observations that Dr Jänne has made consistently over the past 20 years have contributed to how we treat our patients in the clinic.”

In 2020, Jänne became the founding director of the Chen-Huang Center for EGFR-Mutant Lung Cancers at Dana-Farber. The new job compounded his administrative work as director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science, positions that have allowed Jänne to further facilitate contributions that have helped advance the field. Findings from the Belfer Center’s research into the development and validation of the first cell-free DNA assay specific to EGFR have since been adopted into clinical practice.

“One always hopes that what you do scientifically or medically has an impact in such a way that it will ultimately change what ends up happening or how people are treated, but you never can know that,” Jänne said. “When it does, and now I can say that it has, it’s pretty spectacular.”