Can Lung Cancer Biomarkers Predict My Prognosis?

AS OUR UNDERSTANDING OF lung cancer, its causes and treatments advances, it's becoming clearer that lung cancer is not a single disease. Rather, it's a constellation of many subtypes of diseases that may result from various genetic mutations that give rise to the abnormal growth of cells.

Although the Centers for Disease Control and Prevention reports that lung cancer is still the second most common cancer and the leading cause of cancer death, recent discoveries in the field of genomics – and the identification of the biomarkers that can help pinpoint them in individual patients – is helping some patients access better treatments and live longer.



"There's a lot of work being done to develop clinically useful biomarkers for lung cancer, and it spans the spectrum of indications," says Dr. Peter Mazzone, director of the lung cancer program at the Cleveland Clinic in Ohio. These indications include more precisely identifying who's at risk for getting lung cancer, identifying very early stage lung cancers before symptoms surface and predicting which patients will respond to certain treatments after diagnosis. Some researchers are also looking into whether biomarkers can more accurately predict how long someone will live with lung cancer.

The term biomarker refers to a measurable indicator of a disease or condition, and in the context of lung cancer, "we're talking mainly about the molecular biomarkers," or the tiny genetic mutations that drive cancer cells to grow and multiply. These variations in the tumor cells are measured through a biopsy of the tumor or increasingly, through analysis of tumor DNA in the blood in what's called a liquid biopsy.

Liquid biopsies are an exciting innovation because they're less invasive than a tissue-sample biopsy. With lung cancer and other cancers of internal organs, getting a sample of tissue from a suspected tumor site deep inside the body poses a significant challenge, and for some patients may carry too many risks. For example, an older person with other health conditions may not be well enough to undergo the surgery required to collect a tissue sample, but nearly everyone can have a vial or two of blood drawn. Currently, a tissue biopsy is the best way to confirm the presence of a genetic mutation, but liquid biopsies are gaining in accuracy.

Mazzone says other techniques of measuring metabolites in the breath, a so-called breath biopsy, are also being researched as another potential means of getting information about a person's disease profile in a less-invasive way.

"There's also a lot of imaging-based biomarkers as well," Mazzone says. Using sophisticated data analysis techniques such as radiomics and deep learning models, researchers have begun to analyze images of lung nodules and compare them to scores of other images to identify fine variations in cancer types that may predict the cancer subtype and potential outcome. Although the science is still in its infancy, the hope is that these analyses can lead to more precise diagnoses with fewer complications.

And there's a whole alphabet soup of potential lung cancer biomarkers that scientists are looking for that may contribute to better outcomes. "EGFR is the most established one," says Dr. Christina Baik, a researcher at the Fred Hutchinson Cancer Research Center and attending physician at the Seattle Cancer Care Alliance. EGFR stands for epidermal growth factor receptor and describes a protein on the surface of many cells in the body that binds with epidermal growth factor, a hormone that helps cells grow and divide normally. A genetic mutation can lead to the development of too many of these receptors on tumor cells, causing the cells to grow and divide uncontrollably and become cancerous. The American Cancer Society reports that about 15 percent of patients with non-small cell lung cancer have EGFR mutations.

Other biomarkers you might hear about include ROS1, ALK and BRAF. All of these designations refer to various genes that may mutate and give rise to cancer. The Lung Cancer Foundation reports that about 1 to 2 percent of lung cancer cases in the U.S. are ROS1-positive. The National Cancer Institute reports about 5 percent of lung cancer tumors are ALK-positive and about 1 to 2 percent have an alteration on the BRAF gene. And there are others being investigated, Baik says. "I think we'll have a better idea in the next 5 or 10 years. These biomarkers will predict one's response to immunotherapies," and can also guide your oncologist in selecting the best treatment that offers you the greatest chance of a longer survival time.

Recent strides in this area of cancer research have resulted in a handful of new drugs that are doubling life expectancy for some patients by targeting these specific genetic mutations. "The area where biomarkers have reached common clinical use is characterizing the changes and determining what's driving it to become a cancer and determining whether there are treatments that can treat that driver," Mazzone says.

More work remains to be done to expand other applications of biomarkers in lung cancer. "The purely prognosticating biomarkers that aren't really looking at a driver mutation in a tumor but are just saying, 'here's a panel of genes that suggest this person will not do as well with their lung cancer as someone else,' are certainly of great interest, but for the most part haven't been translated into clinical utility," Mazzone says. Currently, he says the more relevant question is "if you use the biomarker and it predicts someone is going to do worse, do we have a treatment that's going to help that patient do better because we have that information?"

That said, Mazzone notes that there are some biomarkers that may suggest a patient will live longer than someone who doesn't have it. "Those who have EGFR mutations – even without EGFR-targeted treatment – tend to have better behaving cancers. The cancer will ultimately still lead to the patient's death, but survival would be longer even without treatment," he says.

It's important to note that when we talk about biomarkers and targeted treatments, we're mostly referring to metastatic, or advanced, non-small cell lung cancer. And as Baik says, "when we talk about genetic tests for lung cancer, we're really talking about the tumor. If we find the mutation in the tumor, it doesn't mean it's in the normal cell of the patient. These mutations are not going to be present when someone is not sick and doesn't have a tumor." So unlike with some other hereditary cancers (such as breast cancer caused by mutations on the BRCA1 or BRCA2 gene) when we talk about genetic mutations in lung cancer, there isn't yet a genetic screening test that says you're at higher risk of developing the disease than someone else.


"Having said that, there's a lot of work being done to figure out why some patients get cancer and some don't, and to determine whether there are any genetic risk factors that we could test for upfront," Baik says. It's possible that eventually you'll be able to have a genetic screening panel done that helps pinpoint whether you're are higher risk of developing lung cancer in the future. But she says it's unlikely that there will be a definitive test, "because cancer is not a purely genetic disease. It's a very close interplay between the gene and the environment and the particular exposure that person had. I don't think we'll have a panel at birth that would accurately predict somebody's health down the line."

Nevertheless, Baik says it's very important that lung cancer patients be tested for known biomarkers soon after diagnosis, as this information may offer better treatment options or entry to a clinical trial, all of which can improve prognosis. "Based on the literature, we know that not everyone gets tested for these. I think it's important for patients to ask their physicians to make sure that all these markers have been tested for if it's appropriate for their particular type of lung cancer." Anything that can help guide more precise treatment is likely to result in a better outcome for the patient.

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