In 2006, Diana Lindsay, who had never so much as held a cigarette, was diagnosed with stage 4 lung cancer.
It had metastasized to both lungs, her brain and lymph nodes. Keith Eaton, MD, PhD, clinical director of thoracic, head and neck medical oncology at Fred Hutch Cancer Center, told her that a typical patient in this situation would have about nine months to live. But he also observed that she seemed remarkably strong and vital. “He said, ‘You don’t look like my normal lung cancer patient,’” said Lindsay, who had just returned from a business trip to Europe. She was 54 at the time. “He didn’t want to take away the health I had for the limited time I had to live.”
Eaton suggested that as a never-smoker, Lindsay may benefit from a new class of drugs — a targeted therapy called EGFR inhibitors, short for epidermal growth factor receptor — that had only recently been approved by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic non-small cell lung cancer, a type of cancer that accounts for about 80% of lung cancer cases.
A couple of years earlier in 2004, a seismic event had rocked the field of lung cancer research. Fred Hutch president and director Thomas J. Lynch Jr., MD, was lead author on an academic paper deciphering the role that a mutation in the EGFR gene plays in the treatment of lung cancer. The paper, published in The New England Journal of Medicine, highlighted how targeted therapies could alter outcomes for lung cancer patients with EGFR mutations.
At the time, Lynch, who holds the Raisbeck Endowed Chair at Fred Hutch, was part of a research team at Massachusetts General Hospital. The discoveries that his team made 20 years ago reshaped the landscape for lung cancer patients just as the introduction of imatinib (known by the brand name Gleevec) had reshaped the landscape several years earlier for people with chronic myeloid leukemia.
A feel-good story
Lung cancer patients can thank Mass General’s media team for training the spotlight on EGFR. In 2003, Lynch fielded a call from the team. They wanted to pitch a feel-good story for the holidays. Did Lynch have any patients in mind? He suggested a 36-year-old woman with advanced lung cancer, Kate Robbins, to whom he had delivered a prognosis of eight to 10 months. Yet to his surprise, Robbins had responded incredibly well to a drug that no one had really expected her to respond to.
The drug, gefitinib, had been made available to some lung cancer patients on an experimental basis by drug company AstraZeneca in a process known as compassionate use, which allows doctors to administer drugs for otherwise untested applications. It’s aimed at those patients in need of a Hail Mary, patients who didn’t have time to wait for the laborious process of governmental drug approval. Mass General put 200 patients on the drug and collected data on their responses as part of a clinical trial. “About 25 to 30 people had unbelievable responses, but we didn’t know why,” Lynch said.
Robbins was one of them. Her story ran in The Boston Globe in 2003 during the week of Thanksgiving. Robbins had gone from keeping a “death journal” for her children to read one day about how much she loved them to no evidence of disease the following year.
Daniel Haber, MD, PhD, a breast cancer geneticist who was director of Mass General Cancer Center, read the Globe article and called his colleague, Lynch. "He was thinking about oncogene addiction and what causes cancers to become exquisitely addicted to an aberrant gene,” said Lynch. “He said, 'I think your patient has an EGFR mutation that caused them to respond.’"
Together with Haber, Lynch published the journal paper about the first nine patients with EGFR mutations. "Kate got to see her kids grow up,” Lynch said.
Until EGFR was implicated in lung cancer, medical oncologists were accustomed to telling patients that their options were few. Even when the disease was diagnosed early and surgery was successful, survival rates were grim.
But Lynch’s discovery paved the way for approval of a type of drug known as EGFR inhibitors that has revolutionized the field of oncology. These inhibitors do exactly what their name implies, acting like a brick wall that blocks the activity of the EGFR protein, which is connected to cell growth and division. For some patients, “they turned lung cancer into a disease that could often be managed for years with pills,” Eaton said.
CT scans from patients enrolled in a clinical trial of gefitinib — the first FDA-approved EGFR inhibitor and the one that Lynch examined in his journal paper — documented impressive results, most notably shrinking tumors. The drug didn’t work for everyone, but it seemed to be particularly effective in patients who shared some characteristics, including Asians, women and never-smokers.
“The EGFR protein is expressed in most lung cancers, so initially they gave gefitinib to everyone,” Eaton said. “Most people did not respond but some people had a remarkable response. We called it the Lazarus effect because they rose from the dead. But we didn’t really understand why it was happening.”
Genetic testing pinpoints therapies
In the mid-2000s when Lindsay was diagnosed, there was no routine genetic testing to identify if a patient had an EGFR mutation. But Eaton suspected that Lindsay had the genetic change. She wasn’t Asian, but she was female and a stranger to tobacco. Those characteristics — ethnicity, gender, smoking status — were proxies for molecular targets, or mutations, before science had evolved to identify the genetic changes that made someone more likely to develop lung cancer. "Now that we have identified the mutations, we don’t need to use those criteria,” Eaton said.
As genetic testing has become more routine — at Fred Hutch, all lung cancer patients undergo genetic testing to help pinpoint the most effective therapies — the rate of mutations in people with lung cancer has become clearer. Eaton says up to 15% of people with lung cancer have a mutation, increasing to up to 25% if mutations that smokers have are included. Among his patients, about half have a “driver mutation” that raises the risk of developing lung cancer.
As it turns out, that was the case for Lindsay. Even though Eaton didn’t know it at the time, he acted on his hunch that she had an EGFR mutation and prescribed erlotinib, an EGFR inhibitor. Lindsay stayed on that drug until 2017 when she switched to osimertinib, the third generation of these targeted therapies. It acts against the main mechanism of resistance, a secondary mutation that nonsmokers can develop called T790M (790 refers to the position of the amino acid). Amino acids are the building blocks of proteins; osimertinib kinks the protein so that it can’t bind at the active site of the mutation.
Lindsay’s response to treatment has stunned even Eaton. Osimertinib’s median survival rate is 28.4 months, but Lindsay has been taking it for seven years. All told, she has been on an EGFR inhibitor for 18 years. "She is an outlier, but our life as oncologists is enriched by outliers,” said Eaton. “When something unusual happens, we have to ask ‘Why?’ That is the spirit of what drove the discovery of these drugs in the first place."
18 years with cancer and not a day of chemo
Lindsay, now 72, is a retired tech consultant. She stopped working when she found out she had cancer. “I thought if I have three months to live, I’m not going to spend it working,” she said.
“I’ve been on an EGFR drug the entire time since being diagnosed,” said Lindsay, who lives on Whidbey Island, about 40 miles north of Seattle. Her main side effect from the daily pill she takes is diarrhea. “In 18 years, I’ve never had chemo."
The cancer has grown and spread at points, but each time, it’s been beaten back with blasts of specialized radiation therapy such as stereotactic radiosurgery (CyberKnife and Gamma Knife) or newer EGFR inhibitors.
"Here she is almost 20 years from diagnosis with stage 4 lung cancer and if she hadn’t had access to these drugs, she probably would have lived about a year,” said Eaton.
Lindsay wrote a book about her experience. Along with her husband, who has since died of brain cancer, she created Healing Circles Langley and Healing Circles Global, which provide community cancer support and other healing services. She had one baby granddaughter when she was diagnosed; now she has five grandchildren.
When she’s asked Eaton about her survival, Lindsay says he attributed it to “some of what we did, some of what you did, good luck and a miracle.”
She has her own explanation. “Maybe the good luck is Dr. Lynch discovering EGFR,” she said, “and the miracle is that it got to me in time.”
