How They Affect Lung Cancer


When you hear the word “genes,” you might think about the ones you inherit from your parents. But while genes and lung cancer do have a tie, very few known genes can transfer a higher chance of lung cancer from parent to child.

“We don’t see those [people] very often at all, because most [people] with lung cancer don’t have a hereditary cause,” says Kerry Kingham, lead cancer genetic counselor at Stanford Health Care.

There are some exceptions, she says. Where multiple members of a family have lung cancer with no obvious outside cause (like smoking), you might want to see a genetic counselor.

“But even in those [people], we don’t often find the cause.”

Only about 1% of these cases show inherited mutations.

“And when we do find the hereditary mutations and we are able to test other family members, there’s no really good guideline that tells us exactly what to do for them outside of more careful screening,” Kingham says.

What’s far more important, she says, is testing cancer cells after diagnosis.


The More Common Tie

Tiny pieces of genetic material (which your doctor may call “proteins”) inside previously healthy lung tissue cells can change, or “mutate,” to form cancer cells. As the cells divide, they continue to pass on these changes, or “mutations,” to new cells, which form tumors.

Doctors don’t know what causes these mutations. But you don’t inherit them from your parents and you can’t pass them on to your children. Nor is it your fault if you get them. These mutations “just happen,” says Kingham. They’re not due to something you did or didn’t do.

“It’s nobody’s fault. It’s not what you ate. It’s not because you looked at the moon wrong or lived an unhealthy lifestyle, for most people” she says.

“It’s just sometimes, cells make mistakes when they divide.”


When Gene Testing Matters Most

Some lung cancer gene mutations can help doctors figure out a treatment plan. Doctors call these mutations “biomarkers.”

Certain lung cancer biomarkers are important to understand and treat differently, says Heather Wakelee, MD, a thoracic oncologist, professor, and chief of the Division of Medical Oncology at Stanford University Medical Center.


EGFR (epidermal growth factor receptor) is probably the most common one. About 10%-15% of non-small-cell lung cancers are EGFR-positive, which means they have a cancer mutation of the EGFR gene.

It’s what doctors call a “driver mutation,” which means it’s the reason why there’s cancer at all. This mutation is often in certain people with lung cancer, such as:

  • Nonsmokers
  • Women
  • People of Asian or East Asian heritage
  • Those with lung adenocarcinoma (a type of lung cancer)
  • Young adults with lung cancer (Half of these cases are EGFR-positive.)

But everyone with a non-small-cell lung cancer (NSCLC) diagnosis should get an EGFR test, not just those in these high-risk groups, Wakelee says.

“It’s really critical that every non-small-cell lung cancer tumor is tested for EGFR, regardless of stage,” she says.

And not just for EGFR. There are at least seven more gene biomarkers that your doctor should test for if they diagnose you with lung cancer.

They include:

  • ALK
  • ROS1
  • RET
  • MET
  • BRAF
  • NTRK

  • HER2

Each accounts for up to 5% of NSCLC cases.

The reason these tests are so critical for people with NSCLC is that scientists have designed targeted cancer therapies for tumors with these particular gene mutations.

“If we find a tumor mutation, we can treat it with a better medication — often a better-tolerated medication in addition to being more effective,” Wakelee says. “That’s true now for eight different genes, and so it’s really important that tumors are tested for those before treatment has started, whenever possible.”

In simple terms, these drugs target a protein that’s stuck in the “on” position and turn it “off.”

You can take most of the targeted medications as a pill at home instead of chemotherapy by IV at the hospital. And they’re not only more effective, they’re usually far easier on your system than other cancer treatments, Wakelee says.

When there’s a viable gene to target, these therapies shrink tumors more than chemotherapy or immunotherapy, and the treatment often works longer.

For people with early stage NSCLC who have had surgery, an EGFR drug called osimertinib (Tagrisso) can delay the cancer’s return and make it less likely that the cancer will spread to the brain.

People with stage IV EGFR-positive NSCLC can get also get Tagrisso because it’s much more likely to shrink the tumor and work longer than any other type of treatment.

Small-cell lung cancer doesn’t have any approved targeted therapies yet, though clinical trials continue to explore the possibility.


The Importance of Patience

Along with your genetic panel of tests (sometimes called “molecular tests”), your doctor should test for another biomarker called PD-L1. Levels of this protein suggest whether you’re more likely to respond to treatment with immunotherapy drugs.

That can make things more complicated, Wakelee says, because the PD-L1 results typically come in well before the mutation results.

High PD-L1 often means immunotherapy can be successful.

“And so it’s tempting to just act on that,” Wakelee says. But that’s not always the best route. If you have certain mutations, like EGFR, immunotherapy could do more harm than good. And it could make future targeted therapies more toxic to your system.

That’s why, says Wakelee, it’s important to wait until you get back all of the results before you make any decisions.

And that’s just one example of the possible complications. In some cases, there are so many complex tumor factors that your health care team will convene with a group called a molecular tumor board made up of some combination of:

  • Expert doctors
  • Medical oncologists
  • Surgeons

  • Radiation therapists
  • Researchers
  • Geneticists
  • Pathologists

“For someone just diagnosed with stage IV lung cancer, waiting can be incredibly stressful,” Wakelee says. “Most people want to start treatment immediately. But it’s really important to wait to get the full story about the tumor to understand the best option.”


It’s Not Just Smokers

There can be an ugly stigma that if you have lung cancer, you must have caused it by smoking. That’s unfortunate, says Yasir Y. Elamin, MD, a thoracic medical oncologist and assistant professor of thoracic medical oncology at the University of Texas MD Anderson Cancer Center.

He says it’s also false.

Though smoking is still the biggest risk factor for the disease (outside of age), up to 1 in 5 people who die of lung cancer each year never smoked. That puts lung cancer near the top of the list of the most fatal cancers in the United States in people who never smoked.

“I don’t think anyone deserves to get lung cancer, whether smoker or nonsmoker. But I think we have to increasingly understand that lung cancer is not a disease exclusively related to smoking,” Elamin says.

That’s particularly true of the lung cancers that respond to targeted therapy.

“For the most part, they’re not linked to smoking.” Elamin says. “I think it’s a very painful reminder that lung cancer is not related only to smoking. So hopefully, it will help us to remove some of the stigma around that.”


The Future of Targeted Therapies

Targeted therapies can improve quality of life with fewer side effects and better outcomes. But there are frustrations with these treatments. One of them is that people tend to build up a resistance to them.

“It’s one of the sad realities of targeted therapy,” Elamin says.

It might take 2 or 3 years, but eventually, virtually all people who take targeted therapies build resistance, especially those who start treatment in the later stages of the disease. A lot of new research concentrates on how to overcome this issue.

“We are focusing on how and why the resistance develops,” Elamin says.

The hope is to come up with ways to delay or overcome the resistance, or better yet, prevent it.

Overall though, Elamin is very hopeful. He points to a recent study of the drug alectinib (Alecensa), a targeted therapy for the ALK biomarker. The research found that more than 60% of people with late-stage NSCLC who took the treatment lived for at least 5 more years.


“Imagine the difference,” he says. “When I was doing my training, the 5-year survival for the same group was 5 to 6%. It’s unbelievable.”

Of course, 60% is not the goal, but Elamin remains encouraged.

“We hope to have it 90 or 100% one day. But I think we’ve made advances and, in this case, the numbers speak for themselves.”



Sources

SOURCES:

Heather Wakelee, MD, thoracic oncologist, professor of medicine, Stanford University Medical Center.

Yasir Y. Elamin, MD, thoracic medical oncologist, assistant professor of thoracic medical oncology, MD Anderson Cancer Center.

Kerry Kingham, lead cancer genetic counselor, Stanford Health Care. 

American Cancer Society: “Lung Cancer Risks for Non-smokers,” “Tests for Lung Cancer.”

CDC: “Lung Cancer Among People Who Never Smoked.”

Lung Cancer Foundation of America: “What is EGFR-positive lung cancer and how is it treated?”

Memorial Sloan Kettering Cancer Center: “Lung Cancer Genomic Testing (EGFR, KRAS, ALK).”

UC San Diego Health: “Molecular Tumor Board, Center for Personalized Cancer Therapy.”



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