In the past several years, our understanding of lung cancer has become much more detailed and nuanced. “When I started [practicing medicine about 20 years ago], lung cancer was just small cell lung cancer or non-small cell lung cancer,” says Dr. Nathan Pennell, director of the lung cancer medical oncology program at the Cleveland Clinic‘s Taussig Cancer Institute. “But now we have small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, EGFR-mutant lung cancer, ALK-positive lung cancer, ROS1-positive lung cancer, BRAF-positive lung cancer, and then there’s a half dozen more that are coming down the pike.”
These new, more precise variations on how lung cancer is defined are resulting in better treatments. “The field by and large is moving away from treating everyone with lung cancer as having the same disease. We’re breaking [lung cancer] down into smaller and smaller diseases that all happen to start in the lungs,” Pennell says. “And we’re trying to personalize the treatment for the individual characteristics of each person’s tumor.”
[See: 7 Things You Didn’t Know About Lung Cancer.]
EGFR is leading the way forward with this more targeted approach to diagnosis and treatment. EGFR stands for epidermal growth factor receptor. It’s a protein on the surface of many cells in the body that binds with epidermal growth factor, another protein that helps cells grow and divide normally. Both EGF and EGFR are part of a normal, healthy cell, the American Society of Clinical Oncology reports. But, “when there are too many receptors caused by a mutation, as happens in cancer, the cancer cells continue to grow and divide. In the United States, about 15 percent of patients with non-small cell lung cancer have mutations to the EGFR.”
A mutation to the gene controlling EGFR production also results in changes to the way the receptor behaves, says Dr. David P. Carbone, director of the Thoracic Center and professor of medicine at the Ohio State University James Cancer Hospital in Columbus. These mutations can cause genetic “sequence alterations” that result in the receptor “acting like it’s stuck on,” meaning that the receptor continues to attract epidermal growth factor proteins to the cells’ surface. This can fuel abnormal cell growth, which is what cancer is. Carbone says EGF was initially discovered in the 1960s and by the late 1990s, researchers had begun finding ways to exploit the relationship between EGF and EGFR for therapeutic ends.
“I think the thing that really turned the field on its head was that [ treatments targeting EGFR] had a very different pattern of response than the typical cancer drugs did,” Carbone says. Chemotherapy tends to have a “continuous spectrum of responses with most people having partial responses and less people having good responses.”
Not so with EGFR-based treatments. “Responses are very binary. Most people had no response, but then a few people had an amazing and a durable response. That led to a search for why those people did so well and that led to the discovery that a subset of lung cancers, about 10 or 15 percent in the U.S., have what’s called driver mutations in EGFR. When those people are treated with EGFR-targeted drugs, they generally have fantastic responses.”
Carbone says almost all of the patients with these EGFR mutations had major tumor shrinkage with fewer side effects than is typical with standard chemotherapy treatment. “And that observation,” which occurred around 2004 or 2005, “really was a quantum leap in lung cancer management and drug development and understanding of how lung cancer works. It really changed the mindset of a whole generation of lung cancer oncologists toward a better identification of targets and rational design of drugs.”
[See: 7 Innovations in Cancer Therapy.]
Where once every lung cancer patient was offered the same blunt instrument of chemotherapy, which often results in severe side effects, doctors began genetically testing cancer patients to see whether they had an EGFR mutation that could better guide treatment. That’s led to better treatments for the 10 to 15 percent of lung cancer patients who have this mutation, but what about the other 85 percent?
“We’ve looked hard, and it turns out that there are probably six or eight other such genetic driver mutations that happen in lung cancer,” Carbone says. EGFR is the most common, followed by ALK. Further, BRAF and ROS1 add to the alphabet soup of known genetic mutations associated with lung cancer, and researchers are working on targeted therapies for all of these and others.
This all means that there’s been a “total seismic shift in the way we manage lung cancer, so that now before we start treatment on lung cancer patients we generally do a complex and comprehensive genetic analysis to see if the patient has any of these so-called driver mutations. That’s so different than when I started in lung cancer 25 years ago,” Carbone says. Previously, “everybody got the same drugs and they didn’t work very often and they were very toxic. Now we have patients on these drugs,” often taking just one pill a day “for more than 10 years sometimes” and many are able to have a “normal quality of life,” Carbone says.
This extension of life is encouraging because lung cancer tends to be a swift killer. Looking nationally from diagnosis to death, “the average survival with lung cancer is about six months,” Carbone says. “Chemotherapy can improve that, but these targeted therapies have an average survival in the multiple years range,” he says.
But there’s still more work to be done. Even among people who respond well to these targeted therapies, “most of the people have tumors that become resistant to any of the available drugs, and so I think an important area of research is looking at why these tumors aren’t killed off completely by these drugs and how to combine them with other things.” It’s thought that combining several therapies might be more effective in combating resistance, leading to longer survival timelines.
In addition, although these drugs are generally better tolerated than chemotherapy, they can still have some side effects, which vary depending on the specific target. With EGFR inhibitors, side effects tend to include skin rashes and diarrhea because the EGFR protein is preset in the skin and GI tract. “But the pharmaceutical companies have learned to engineer out some of the activity against the normal receptor and focus on the mutated receptor,” Carbone says, meaning that newer drugs tend to have fewer side effects.
Another area where more work needs to be done is bringing better treatments to earlier stage disease. Carbone notes that most of these advances have occurred in treating patients with metastatic or late-stage disease that has already spread to other organs and is considered incurable. “There are multiple clinical trials open that move these therapies into earlier stage diseases, in patients who can have surgery or radiation as a curative intent treatment but still often recur even after those procedures.” More research could eventually lead to a combination approach for some patients that may offer better outcomes.
[See: What Not to Say to Someone With Lung Cancer.]
But the fact remains “that there’s still a lot of cancer patients who are being diagnosed today who have no targetable genetic lesions, [and for whom] i mmunotherapy,” another treatment approach that leverages the body’s immune system to fight the cancer, “doesn’t work. Still, their only option really is chemotherapy. So we do need to work harder to find better options” for all forms of lung cancer, Carbone says.
Nevertheless, advances in the treatment of EGFR-mutant lung cancer bode well for improved therapies for all forms of lung cancer in the future. Pennell says the pace of discovery and development related to genetic mutations in lung cancer offers much hope. “In the last couple of years, it seems every six months, something is changing. It’s a very exciting time to be an oncologist because for the first time we’re actually seeing patients who are living dramatically longer than when I started my career.”
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What Is EGFR and How Does It Relate to Lung Cancer? originally appeared on usnews.com
