To combat the deadliest cancer in the world, investigators are learning its origin in at-risk patients to prevent it altogether.
The results of the National Lung Screening Trial (NLST) shifted what was known to be possible in lung cancer diagnostics.
The National Cancer Institute-funded research, published originally in August 2011, showed low-dose computed tomography (CT) scanning for high-risk patients could provide a relative 20% reduction in mortality risk from lung cancer versus standard radiography.
At the time, multi-detector CT was theorized to make high-resolution volumetric imaging possible through just a single breath, Denise R. Aberle, MD, and colleagues wrote.
Though the results provided an affirmative answer that, yes, low-dose CT screening is more beneficial than chest radiography in reducing risk of death from lung cancer before a patient is even diagnosed—in just 3 rounds of screening.
But it more importantly set questions to answer in the pursuit of this new paradigm:
Aberle and colleagues even concluded on a question: could biomarkers in blood, sputum, and urine help identify low-dose CT screening patients?
Namely, is there an earlier level by which clinicians can predict who is at risk of the deadliest cancer in the world?
The NLST research team’s work generated change. The US adopted screening practices including CT scans that would be covered by Medicare. Millions suddenly had access to a window of better interpreted lung cancer risks. But the questions raised by the study investigators remained unanswered.
Steven Dubinett, MD, was among those to see a challenge among the trial results. The director of the UCLA Clinical & Translational Science Institute and a colleague of Aberle told HCPLive® that only a “fraction” of patients who should be or are eligible for screening are actually doing so.
“As these screening programs roll out in the US, we need to actually decide how we will actually improve screening to make it more accurate,” Dubinett said. “And part of that is to understand how lung cancer develops, and really understand how we might be able to use additional biomarkers to help us make the diagnosis.”
Ten years ago, investigators learned to spot lung cancer risk. Now, they wish to intercept it altogether.
A Growing Challenge
What Dubinett sees is incremental successes backdropped against rapidly growing problems. Through the diagnostic advancements of his peers like Alberne, and through therapeutic innovation, the five-year survival rate of lung cancer in the US has improved from 13% to 18%. At the same time, a lesser rate of the population is smoking combustible cigarettes—one of the greatest known drivers of lung cancer risk.
Globally, though, the situation worsens. A ten-year observation of worldwide lung cancer cases ending in 2018 found there is about 2 million new cases annually—and nearly just as many deaths. Lung cancer has increased by nearly 40% worldwide in a decade, Dubinett said.
What’s more, nearly half of all newly diagnosed patients are in advanced stages and unamenable to possibly life-saving surgeries—still the optimal method of lung cancer care.
Lung cancer interception, in theory, would grant clinicians the confidence to streamline the most at-risk patients to invasive care before even a symptom could occur—treating stage 1 patients rather than stage 4. Its foundation is set by the low-dose CT scan benefits observed by the NLST team, and its potential could mean complete prevention of lung cancer progression.
Dubinett currently serves as co-leader of the Lung Cancer Interception Dream Team, a multi-million figure-funded national research team supported the American Lung Association (ALA), Stand Up 2 Cancer (SU2C), and the LUNGevity Foundation.
The team, led by Avrum Spira, MD, Professor of Medicine, Pathology and Bioinformatics, and the Alexander Graham Bell Professor in Health Care Entrepreneurship at Boston University, has been seeking diagnostic breakthroughs that would differentiate guidance on chest scans and establish greater confidence in observed lung cancer risk in a patients’ tissues.
As Spira told HCPLive in an episode of Lungcast earlier this year, the team is aiming to understand the very first cellular molecular changes which lead to the development of precancerous tissues in at-risk patients. This gap of knowledge is integral to their overall goal of intercepting the deadliest cancer in the world.
“Those findings are going to provide insights into novel targets that we can go after to intercept someone before they develop fully-blown lung cancer,” Spira said.
Finding Step One
Where experts like Dubinett are currently fixed is in the pre-malignant lesions of would-be patient’s tissues: what makes them abnormal? How does it lead to cancer?
The dream team is sequencing the information collected from pre-malignant lesions to define DNA, RNA, and cellular phenotypes. Spira described the final work as an “atlas” of both squamous cell and adenocarcinoma, the 2 most common cancer subtypes.
“The concept here is to put together very unique cohorts of patients that have pre-cancerous lesions in their airway or lung and are being followed over time, to see whether those lesions progress onto invasive cancer, and study those lesions with the best molecular profiling tools we have available,” Spira said.
The greatest challenge in this venture, Dubinett explained, is the occult status of tissues with pre-malignant lesions. Unlike other cancers, lung cancer does not have a currently-understood clinical pathway which allows researchers to find these specimens—Dubinett, Spira, and their peers have to blaze the trail.
“These abnormal cells in the lung provoke our immune systems to attack the cells,” Dubinett explained. “And at the same time, those abnormal areas of pre-malignancy that become invasive have an immune suppression happening within the area of the abnormality.”
In layman’s terms, investigators now understand that the balance of immunity—when the body turns on immune response to attack bacteria or viruses—is compromised by abnormal cells which becomes cancerous. As such, it is difficult for Dubinett and colleagues to distinguish the “foreignness of cancer cells” from the immune system itself.
Through funding and time, the teams have begun to uncover the trail.
In beginning to interpret the immune deficits driven by the abnormal cancer cells, clinicians may be able to pinpoint timely opportunities to aid the immune system prior to invasive care which would significantly reduce the burden of a cancerous tumor. Such research is already underway.
“And that suggests to us, in fact, that in the early stages of lung cancer, before the immune system becomes fully depressed, we have this opportunity to really go after the tumor cells, boost the immune system, and have the patient's own body help and be involved in destroying those abnormal cells,” Dubinett explained.
A Future of Interception
Dubinett endorses the idea that the future of medicine is dictated by the research being done today. Laboratory-based trials, fixed on the very fundamental pathology of disease, can improve the aim of clinical trials, improve the standard of care, and help set models for efficient clinical practice.
It’s that mindset which explains why the work of Aberle and the NLST research team was integral to the current opportunities of the Interception Dream Team. That mindset also evidences the need for more lung cancer screening via CT scans—a practice evidenced by foundational research, which could only advance such research even further.
Primary research is only half the puzzle, of course. Financial backing from invested institutions including the ALA, LUNGevity, and SU2C are integral to the right discoveries being made in due time. Dubinett called on federal and state agencies to continue their support of cancer research which aims to uncover preventive care outcomes.
Today’s ideas of lung cancer interception are feeding screening, diagnostic, and immunotherapy studies of the coming years, racing against a growing wave of global lung cancer cases and deaths.
The individual patient it may save could be a post-surgery patient with ill-defined patterns on their CT scan. They may have benefitted from an innovative PET scan, or were monitored with a new-wave bronchoscopy device that can find Dubinett’s and Spira’s found areas of abnormalities. They may be a smoker, or not. They may be older, or surprisingly young. But what they must be is early-stage—afforded enough time to make a difference in their would-be disease.
“This might be individuals who, for example, are in screening programs, who have a heavy smoking history, and are being monitored in annual CT scans. It could be patients following surgery for lung cancer,” Dubinett said. “This is a way that we could really make progress toward really effective interception, that makes a profound change in what we're able to accomplish for patients with lung cancer—that is, preventing them from actually having it.”
The research being done today to understand millions of new cases could direct the therapeutic decisions which eventually save as many lives.