Dr. Karen Reckamp, was studying the immune system during her specialty fellowship, training her sights on a career as an oncologist focused on stem cell transplantation, when a new discovery shook the cancer world.
Dr. Karen Reckamp works to improve lung cancer care from diagnosis to treatment.
In 2004, researchers identified a specific mutation in some lung cancer cells, a breakthrough that changed the understanding of lung cancer biology. Rather than being divided into two simple categories—small cell lung cancer and non-small cell lung cancer—lung cancer became a group of diseases defined by their genetic underpinnings.
"Before this, you treated patients with various chemotherapies depending on whether they had small cell or non-small cell lung cancer—no other factor mattered and the outcomes were not very good," says Dr. Reckamp, associate director of Clinical Research for Cedars-Sinai Cancer and director of Medical Oncology in the Department of Medicine. "Suddenly, lung cancer became a completely different disease. It was exciting, and I was all in."
This breathtaking shift in lung cancer medicine ushered in the possibility of treatments that home in on tumor-cell DNA, and the cascading effects of this change continue to be felt. For decades, the statistics on lung cancer told the same sobering story: It’s the leading cause of cancer death in the United States and the world, causing more deaths than breast, colon and prostate cancers combined. Today, death rates from lung cancer are in an accelerated decline due to progress across the spectrum of cancer care. Outcomes are better. People who are diagnosed are living longer with enhanced quality of life.
The decline is significant enough that it cannot be explained by the drop in smoking rates alone. A sophisticated understanding of genetics, an expanding arsenal of personalized treatment options, the availability of lung cancer screening and public health efforts have all combined to transform the landscape for those who treat and live with this formidable disease.
However, only a very small fraction of eligible high-risk patients undergo screening. Access to treatment and care can be challenging for many. And, while treatments are good, few patients are declared cured: Living longer with lung cancer is different from being free of the disease.
While more sophisticated understanding of lung cancer biology and groundbreaking treatments offer reason to be hopeful, stigma and fear attached to the disease also persist—and feed into the gulf between the ability to screen for the disease and catch it early, and the number of people willing to be screened. Cedars-Sinai investigators are working to bridge that diagnosis gap while advancing treatments for the cancer that still kills the most people worldwide.
Not Just a Smoker’s Disease
Di’Ann Smith is the beneficiary of targeted therapy for her lung cancer.
The first time Di’Ann Smith, 74, ever saw a Los Angeles Rams game at SoFi Stadium, she was there to do more than cheer for her home team. She was a guest of honor promoting lung cancer awareness as she stood by Reckamp, her longtime oncologist. Smith was especially interested in sharing one fact: Anyone with lungs can get lung cancer.
She would know.
"Back when I quit smoking in 1992, everyone said that after five years your lungs go back to being pink and healthy and you’re free," she says. "That wasn’t the case for me. My lung cancer showed up 15 years after I quit."
According to the American Cancer Society, within 10 years of quitting smoking, a person’s lung cancer risk drops to half that of those who still smoke.
Despite the public’s perception that the disease only affects smokers, up to 20% of lung cancers nationwide occur in people who have never smoked. Environmental or genetic factors may play a role.
"We’re still trying to understand all risk factors associated with lung cancer," Dr. Reckamp says. "In many cases, we cannot be entirely sure why someone develops the disease—especially as it occurs in people who never smoked."
Homing In On Targeted Therapies
The success of targeted therapies is one of the most powerful driving forces behind the decline in lung cancers.
Every cancer cell has its own genetic fingerprint and, like all cells, cancer cells have different systems for communicating and replicating. While a cancer might be commonly called lung cancer or breast cancer, they are groups of diseases with considerable genetic distinctions.
Traditional chemotherapies work by attacking any cells that are dividing rapidly—whether they’re healthy or malignant. Targeted therapies work differently, disrupting cancer cells by selectively interfering with proteins on those cells that carry specific genetic alterations. While chemotherapy kills the cells it touches, targeted therapies typically prevent new cells from growing. The targets vary from cancer to cancer, and not every cancer has a mutation that matches one of the therapies currently available.
The Food and Drug Administration (FDA) has approved a multitude of drugs for eight genetic targets in lung cancer.
Smith’s lung cancer was initially treated in North Carolina, where she had surgery to remove the upper right lobe of her lung, followed by two rounds of chemotherapy. When she moved to California, she started seeing Dr. Reckamp. New traces of cancer in her lungs are now being treated with targeted therapy in the form of a daily pill. The treatment is working well enough that the frequency of her visits has dropped from four times a year to three.
"I’m so grateful there’s a targeted therapy that works for me," Smith says. "My mind is at ease knowing that I’m taking a medication that is taking care of whatever is happening in my lungs."
The cancer mutation that changed the trajectory of lung cancer occurs in EGFR, which stands for "epidermal growth factor receptor." EGFR is a protein found in healthy cells that stimulates cell growth. Cancer cells that have a mutation in this protein send faulty instructions to healthy cells, causing them to grow too much and spawn new cancer cells. The discovery of this mutation led to the development of drugs that block EGFR from sparking cell overgrowth.
As many as 15% of lung cancers in the United States are positive for EGFR mutations, and they are more common on the West Coast due to its higher concentration of nonsmokers and people of Asian descent—two groups more likely to develop EGFR-positive lung cancers. Thanks to targeted therapies, outcomes are improving for these patients, even if their lung cancer has spread.
"We know we’re actually improving survival for patients with advanced disease," Dr. Reckamp says. "They’re living longer because of the treatments we have available now, and that’s largely due to treating EGFR mutations."
An Underused Tool
Even as treatments for lung cancer advance at an extraordinary rate, and screening is at last available and covered by insurance, the number of people being screened is lagging, especially in California.
One reason lung cancer has historically been such a deadly disease is that it is often in a late stage by the time symptoms arise. In 2015, Medicare started covering screening with a low-dose CT scan for those at highest risk for lung cancer, a measure that could save as many as 12,000 lives annually—if everyone eligible gets scanned.
According to the American Lung Association, only 5.7% of those eligible were screened for lung cancer in 2021. Experts project that as many as 20% of lung cancer deaths could be prevented through early detection. Lack of access to healthcare and limited awareness among patients and providers contribute to the low screening rates.
"Screening is an area where we have enormous potential to save lives—but we’re not there yet," says radiologist Dr. Christopher Lee, who is developing Cedars-Sinai’s lung cancer screening program with Dr. Sara Ghandehari, director of Pulmonary Rehabilitation in the Women’s Guild Lung Institute at Cedars-Sinai. "California is dead last in the country—only screening 1% of those at high risk—so we may not be seeing as much of a decline in lung cancer deaths as we could here in our state."
In building the new program, Dr. Lee, Dr. Ghandehari and their colleagues examined obstacles to screening.
For starters, the guidelines, which were updated in 2021 to include more people, are complicated. Screening is recommended for those ages 50 to 80 who are in "fairly good health" and either smoke or have quit in the last 15 years. They also must have a smoking history of at least 20 pack-years. (A pack-year is the number of cigarette packs smoked per day multiplied by the number of years the person smoked. Someone who smoked a pack a day for 20 years would qualify, as would someone who smoked two packs daily for 10 years.)
Another difficulty is that people must have access to a primary care physician to discuss their smoking history, assess their eligibility and receive appropriate education before getting screened.
"Many people—especially here in California—got the message about smoking and quit," Dr. Lee says. "Once you quit, the topics of smoking and lung cancer risk almost never come up again with your doctor, despite the fact that you’re still at high risk for many years after you quit."
Previously, Dr. Lee worked with Cedars-Sinai’s Cancer Research Center for Health Equity on a two-year pilot study the center conducted with Watts Healthcare Corporation in South Los Angeles that successfully screened more than 500 patients. The program used a combination of strategies, including providing transportation to screening appointments, training community navigators, and working with churches and community organizations to promote screening.
The successful community navigator approach is now being tested in other neighborhoods.
Dr. Ghandehari and Dr. Lee are designing a program based on a strong multidisciplinary team to support patients and coordinate their care through every step of the process. A key aspect of the program, Dr. Ghandehari explains, is the nurse-navigator, who can identify which patients qualify for screening and provide education and smoking-cessation counseling when needed. In addition, the nurse-navigator also discusses risks and benefits of screening.
"We want to give patients robust support through the screening process and also through follow-ups when the results return," Dr. Ghandehari says. "We want to be strong partners for patients and their doctors."
All in a Day’s Work
The average time between a lung cancer diagnosis and surgery to remove the tumor is 52 days.
Dr. Harmik J. Soukiasian, director of the Division of Thoracic Surgery at Cedars-Sinai, is aiming to dramatically reduce that wait time. In fact, for some patients, he is cutting it down to a single day for biopsy, diagnosis, surgery and treatment—with some robotic assistance.
"We now have technology that allows us to meet and treat the patient all in one day,” says Dr. Soukiasian, who is the Tawil Family Chair in Thoracic Surgery.
For patients who are appropriate candidates for the procedure, Dr. Soukiasian first performs a biopsy with a robotic platform that creates a 3D map of the patient’s lung. The surgical team uses the map and a camera to precisely navigate the robot to the suspicious mass and obtain a sample. The tissue sample is delivered to a pathologist who, in 15 minutes, can determine whether the mass is cancerous.
If the diagnosis is cancer and it’s confined to the lung, the patient undergoes a second robotic procedure. The surgeon operates from a console, directing the robot using magnified 3D images and video to precisely remove the mass, lymph nodes and, if necessary, a lobe of the lung through several small incisions.
The combined procedures can be completed in about three hours.
"We can shorten the time that patients and their loved ones struggle with the unknown and get them clear of their disease faster,” Dr. Soukiasian says.
Resolving Disparities
California lags behind the rest of the nation in providing treatment to patients diagnosed with lung cancer. According to the American Lung Association, 27% of people diagnosed with lung cancer in California are never treated at all: The state ranks 46th out of 49 ranked states for treatment. Nationally, 21% of patients are untreated.
The numbers are worse for minority populations, especially Black patients. They’re less likely to be diagnosed at an early stage—21% compared to 26% among white patients. They’re also more likely to have their cancer go untreated: 30% of Black Californians with lung cancer receive no treatment at all. They’re the least likely of any ethnic group to undergo surgery for lung cancer, tied with the national rate of 17%, but lower than the 22% rate among white lung cancer patients in the Golden State.
"We know lung cancer disproportionately affects minority communities, who are also less likely to have access to care," says Zul Surani, MPH, director of Community Outreach, Engagement and Operations at the Cancer Research Center for Health Equity at Cedars-Sinai. "We know we have the treatments and technology to improve lung cancer outcomes. Now, we have to go to those high-risk communities and help them get the screenings and treatments they need."
As a lung cancer survivor, Smith hopes to see disparities experienced by her community addressed so that everyone has access to the care that has kept her alive for more than 15 years. "Dr. Reckamp was the first doctor to ever talk to me about targeted therapies," she says.
Not enough patients undergo the tests that make targeted therapies possible, and that is especially true among minority groups, Dr. Reckamp says. She hopes that efforts aimed at improving outcomes for all will help address the gap.
"We will test every person who comes through the door to determine the best treatment based on their DNA and the genetics of their cancer," Dr. Reckamp says. "It’s simply a best practice that will get every patient from their diagnosis to the right treatments as quickly as possible."
Next Frontiers
A broadening understanding of lung cancer biology has opened doors to treating the disease, Dr. Reckamp says.
Immunotherapy is a novel treatment that harnesses a patient’s own immune system to identify and attack cancer cells. These therapies have changed the way physicians treat advanced lung cancer since 2015, but in 2021 the FDA approved immunotherapy in early-stage lung cancer following surgical removal of part of the lung. This is especially promising for patients whose cancer will not respond to targeted therapy.
The five-year survival rate for lung cancer patients has climbed from 14.5% to 23.7% nationally, according to the American Lung Association’s most recent report. It’s a dramatic statistic that illustrates the lifesaving power of these scientific advances.
With chemotherapy, ever-advancing surgical techniques, precision targeted therapies and immunotherapy, doctors have a more robust toolkit than ever before to address the deadliest of cancers.
The numbers reflect the progress. The five-year survival rate for lung cancer patients has climbed from 14.5% to 23.7% nationally, according to the American Lung Association’s most recent report. It’s a dramatic statistic that illustrates the lifesaving power of these scientific advances.
Those numbers also reflect the urgency felt by the lung cancer community—patients, their loved ones, and healthcare providers and scientists who are determined to find better solutions.
"Despite all these amazing advances and our deeper understanding of the biology, despite the fact that we’re benefiting patients and they’re living longer lives, we’re still not curing enough people," Dr. Reckamp says. "Until we have better cures, we still have a long way to go."
Overcoming Resistance
Targeted therapies are major contributors to the diminished impact of lung cancer. However, over time, the disease tends to find a way around these treatments. Often, the response in the research world is to go back to the lab to find a medication that bypasses the new mutation.
"There will always be more mutations, and we can keep trying to find more and more drugs that work against them, but that’s a race you would never win," says Neil Bhowmick, PhD, director of the Cancer Biology Program at Cedars-Sinai.
He knows the path from "managed" cancers to "cured" cancers has to traverse the cellular resistance problem. So Bhowmick teamed up with Dr. Reckamp to look for a mechanism to explain how cancer cells find a way to overcome EGFR-targeted therapies.
They began with a drug called osimertinib, which has a good track record for slowing down cancer and is given to anyone whose tumor tests positive for EGFR—until the tumor cells grow resistant.
Bhowmick and his colleagues study the role of a favored communication pathway of many cancer cells called the bone morphogenetic protein, or BMP. This protein sends information to cancer cells and surrounding healthy cells. The research team discovered a potentially important link between the EGFR-targeted drug osimertinib and BMP that could help explain the resistance that develops: While the drug successfully fights the cancer on other fronts, it seems to promote BMP-based communication as a means of survival and expansion.
Manish Thiruvalluvan, PhD, a postdoctoral fellow on Bhowmick’s team, discovered that, over time, cancer cells escaped osimertinib by going into a state called "cancer dormancy," meaning they’re essentially asleep. This adaptation slows their growth but also makes the cells invisible to the immune system and to the targeted cancer drugs seeking them out. BMP acts like a lifeline for these sleeping cells, keeping them in touch with both malignant and healthy cells in the body while evading medications.
The team found a way to wake them up using a drug that thwarts the BMP pathway. In preclinical cell and mouse models, where a combination-therapy strategy was used to block BMP communication, the cancer again became vulnerable to osimertinib.
Dr. Reckamp will soon lead a Phase I trial testing the safety of the combination—the drug that wakes up the cells by blocking the BMP pathway and the EGFR-fighting osimertinib—building on the laboratory work of Bhowmick’s team.
"Hitting cancer dormancy could be an effective strategy to extend the efficacy of targeted therapies," Bhowmick says. "It could get us away from the never-ending whack-a-mole story of going after the next new mutation."
The combination strategy is known as "synthetic lethality." To continue the whack-a-mole metaphor, the first drug blocks other avenues for the cancer or "mole" so it can only pop up from one hole. The hammer—the second drug—thus knows exactly where to hit.
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