Lung Metastases Imaging: Practice Essentials, Radiography, Computed Tomography
Your Guide To Genetic Mutations In Lung Cancer
Gene mutations associated with non-small cell lung cancer include EGFR, HER2, and more. Lung cancer mutations can determine your options for testing and treatment.
Genes are the instructions that inform how your body functions. They tell your cells which proteins to make. Proteins control how quickly cells grow, divide, and survive.
Sometimes genes change. This may happen before a person is born or later in life. Gene changes are called mutations, and they can affect certain functions in the body.
Gene mutations can prevent your DNA from repairing itself and can also cause cells to grow uncontrollably or live for too long. Eventually, these extra cells can form tumors, which is how cancer starts.
Certain gene mutations are linked to non-small cell lung cancer (NSCLC). Having one of these mutations could affect the type of treatment a doctor recommends.
The gene mutations that cause lung cancer can happen in one of two ways.
Germline mutations are hereditary mutations. They're passed genetically from a parent to their baby through an egg or sperm. Up to 10% of all cancers are caused by hereditary mutations, according to the National Cancer Institute.
Somatic mutations are acquired mutations. They're the most common cause of cancer.
Somatic mutations occur when you're exposed to damaging substances over the course of your lifetime. These substances may include:
A few different gene mutations help NSCLCs spread and grow.
Tumor protein p53 (TP53)
The TP53 gene is responsible for the production of the tumor protein p53. This protein monitors cells for DNA damage and acts as a tumor suppressor. This means it keeps damaged cells from growing out of control or growing too fast.
TP53 mutations are common in cancers and are found in 40% to 51% of all cases of NSCLC. They're usually acquired and happen in both smokers and people who have never smoked.
Research suggests that TP53 mutations combined with EGFR, ALK, or ROS1 mutations are linked to a shorter survival time for people with NSCLC.
Because there's not yet an established targeted therapy for TP53 mutations, there's debate about whether doctors should always test for them in people with cancer. Research into targeted TP53 therapies is ongoing.
KRAS
The KRAS mutation is found in about 30% of all NSCLCs. It's more common in people who smoke.
The outlook for people with this type of mutation is less favorable than it is for people who don't have it.
The STK11 mutation often appears with the KRAS mutation. Experts are unsure if the STK111 mutation is significant or what effect it has on treatment options.
Epidermal growth factor receptor (EGFR)
Epidermal growth factor receptor (EGFR) is a protein on the surface of cells that helps them grow and divide. Some NSCLC cells have too much of this protein, which makes them grow faster than usual.
According to the American Lung Association, EGFR-positive cancers account for around 10% to 15% of all lung cancers in the United States.
These mutations are more common in certain groups, including women and nonsmokers.
EGFR mutations include the:
The EGFR exon 19 deletion mutation and EGFR exon 21 L858R point mutation are the most common. They respond to targeted therapies known as EGFR inhibitors.
Less common EGFR mutations don't typically respond to these targeted therapies.
Anaplastic lymphoma kinase (ALK)
Research from 2017 found that about 5% of NSCLC cases have the anaplastic lymphoma kinase (ALK) gene mutation. It allows cancer cells to grow and spread.
The ALK mutation is common in younger people and nonsmokers.
The EML4-ALK mutation occurs when the ALK gene fuses with the echinoderm microtubule-associated protein-like 4 (EML4) gene. It's also more common in people who have never smoked.
Mesenchymal–epithelial transition (MET) and METex14
The MET gene is changed in up to 5% of all NSCLCs. MET-positive lung cancers tend to be more aggressive than lung cancers without the mutation.
MET exon 14 deletion (METex14) is a type of MET mutation that's been linked to around 3% of NSCLCs.
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)A 2024 study found that the PIK3CA gene mutation was present in 46 of 810 (up to 6%) of lung cancer samples. It's more common in squamous cell lung carcinomas than in adenocarcinomas.
Did you know?
The three main types of non-small cell lung cancer (NSCLC) are:
BRAF and BRAF V600E
Up to 3.5% to 4% of NSCLCs test positive for BRAF mutations.
Most people who have these mutations are current or former smokers. These mutations are also more common in females than in males.
One subtype is known as the BRAF V600E mutation. It accounts for half of all BRAF mutations.
Human epidermal growth factor receptor 2 (HER2)
Between 1% and 4% of NSCLCs involve the human epidermal growth factor receptor 2 gene mutation, more commonly known as HER2.
It's most common in people with adenocarcinomas and people who have never smoked.
Other mutations
Some of the less common mutations linked to NSCLC include:
When you're first diagnosed with NSCLC, your doctor may test you for certain gene mutations.
These tests are called molecular analysis, biomarker tests, or genomic tests. They give your doctor a genomic profile of your tumor.
Knowing whether you have one of these mutations may help your care team decide which treatments might work best for you. Targeted therapies work on some lung cancer mutations but not all.
Genetic tests use a sample of tissue from the tumor, which your doctor removes during a biopsy. The tissue sample is sent out to a lab for testing. A blood test can also be used to detect the EGFR gene mutation.
According to the American Lung Association, it may take 1 to 2 weeks to get the results of your genetic tests.
The treatment your doctor recommends will be based on the results of your genetic test as well as your type and stage of cancer.
A few targeted drugs treat NSCLC gene mutations. You may take these as a solo treatment. They can also be paired with another targeted therapy, chemotherapy, or other lung cancer treatments.
At the moment, there are no targeted therapies for cancers involving TP53, NRAS, or PIK3CA gene mutations. If no drug is currently available for your specific mutation, you may qualify for a clinical trial. These studies test new targeted therapies.
Getting into a trial could give you access to a new drug for your NSCLC type before it's available to everyone else.
KRAS
In 2021, the Food and Drug Administration (FDA) approved sotorasib (Lumakras), the first KRAS inhibitor for lung cancer.
EGFR
The EGFR protein helps cancers with the EGFR mutation grow. EGFR inhibitors block signals from the EGFR protein.
These EGFR inhibitors can treat the EGFR exon 19 deletion and EGFR exon 21 L858R point mutations:
These drugs are specifically used to treat the EGFR exon 20 insertion mutation:
Osimertinib (Tagrisso) is the only drug currently available to treat the EGFR exon 19 deletion, EGFR exon 21 L858R point, and EGFR exon T790M mutations.
Other drugs used to treat various EGFR mutations include:
These may be used for certain cases of metastatic EGFR-positive lung cancer.
ALK
Drugs that target ALK gene mutations include:
People who have cancer with the EML4-ALK mutation would also take these targeted drugs.
MET and METex14
Treatments for the METex14 mutation include the drugs:
There are currently no FDA-approved targeted therapies for other MET mutations. But if you participate in a clinical trial, you may be able to receive a MET inhibitor that targets these mutations.
BRAF and BRAF V600E
The drugs that target BRAF V600E mutations are:
These medications must be taken in combination.
Other BRAF mutations are currently treated with immunotherapy or chemotherapy as opposed to targeted therapies.
HER2
In August 2022, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu), the first targeted therapy for people with the HER2 mutation.
Enhertu was previously approved to treat other cancers, such as breast and stomach cancers.
Other mutations
Two drugs are available to treat cancers caused by the NTRK mutation:
The following drugs are RET inhibitors:
These targeted therapies treat ROS1-positive lung cancers:
The FDA has only approved ceritinib (Zykadia) and lorlatinib (Lorbrena) to treat NSCLCs with ALK mutations. Using these medications to treat ROS1-positive lung cancers is considered off-label drug use.
OFF-LABEL DRUG USEOff-label drug use means a drug that's approved by the FDA for one purpose is used for a different purpose that hasn't yet been approved.
However, a doctor can still use the drug for that purpose. This is because the FDA regulates the testing and approval of drugs but not how doctors use drugs to treat their patients.
So your doctor can prescribe a drug however they think is best for your care.
NSCLC treatment used to be one-size-fits-all. Everyone received the same regimen, which often involved chemotherapy.
Today, a number of treatments target specific gene mutations. Your doctor should test your tumor when you're diagnosed and let you know if you're a good candidate for a targeted drug.
In some cases, you may also qualify for a clinical trial.
Beyond Early Stage: Biomarker Testing's Role In Advanced Lung Cancer
In part 1 of our interview with David P. Carbone, MD, PhD, The Ohio State University, he addressed why it is important to conduct biomarker testing in both lung cancer overall and non–small cell lung cancer more specifically.
In part 1 of our interview with David P. Carbone, MD, PhD, director, Thoracic Oncology Center, The Ohio State University (OSU) in Columbus, he addressed why it is important to conduct biomarker testing in both lung cancer overall and non–small cell lung cancer more specifically. Here he continues the discussion on biomarker testing by explaining the cost breakdown and how even in late-stage disease, biomarker testing serves its purpose.
Carbone is also a professor of internal medicine and coleader of the Translational Therapeutics Program at OSU, and president of the International Association for the Study of Lung Cancer.
Transcript
What is the cost impact of biomarker testing in lung cancer on value-based care?
Health care is expensive, and these tests are not cheap. Usually they run a few thousand dollars. Some of the simpler tests can be less expensive, but the fact is, a single dose of some of these drugs is way more than that cost. A dose of [pembrolizumab] can be over $10,000. The fact is, these biomarker tests are so important in selecting therapy—and you only need to do this once at the time of diagnosis, in general. I mean, we do repeat testing in resistant disease, but this is not a test that you need to do every 3 weeks. This is a test you do at the beginning of therapy, and it makes such a huge difference in the way a patient is treated, in the selection of which treatment is appropriate, that it's incredibly cost-effective in my mind. It costs less than a PET scan or other things that we don't think about charging for. So this is, to me, an absolutely essential expense in appropriate management of lung cancer.
What purpose does biomarker testing serve in late-stage disease?
It's very similar in early- and late-stage disease, in theory. If you have a patient with an ALK fusion abnormality in their tumor, that patient should be started on first-line alectinib or other drugs targeting ALK. And the same thing if you have an early-stage patient who gets a surgical resection and it's found to be ALK-fusion positive; that patient should receive alectinib as an adjuvant therapy. It's used to select therapies in exactly the same way, but in an advanced-stage patient, they usually start those therapies right away and in an early-stage patient, often surgery is followed by the targeted therapy.
We always try to have curative intent. But for immunotherapies, PD-L1–positive patients, especially have a chance of being effectively cured of their lung cancers, even in advanced stage, stage IV. There are many patients who are alive 5, 6, 7, 8 years later with no evidence of disease off therapy. So I do say that there is some chance of cure with immunotherapy. Overall, it's about 20% of people who are alive at 5 years—which doesn't sound great, but it's a whole lot better than decades ago, when almost no one survived even 2 or 3 years with advanced lung cancer.
With the targeted therapies, though, these right now are not thought to be curative, and eventually the cancer will become resistant and come back. But recent data, especially with ALK-fusion positive tumors, there are patients that are on therapy without recurrence for a decade, and that's that's very exciting. When you think about the average survival for metastatic lung cancer, it historically was 4 to 6 months from diagnosis to death. Now we're talking about 5 to 10 years. It's a huge improvement.
Not everybody benefits from these and not everybody has a biomarker match, but it's important to look. And if you miss a biomarker match that's there because you didn't test or you didn't interpret the test properly, that's a real tragedy for that patient where they could have been helped more effectively. But it is true that some patients have no targetable biomarkers and a PD-L1 of 0 and don't respond to anything. We need to work harder to find therapies for those people.
Postsurgical Durvalumab Does Not Boost DFS In Lung Cancer
Adjuvant durvalumab failed to improve disease-free survival in resected EGFR- or ALK-negative non-small cell lung cancer.
Adjuvant durvalumab did not improve disease-free survival, regardless of PD-L1 status in certain patients with non-small cell lung cancer, research showed.
Adjuvant durvalumab (Imfinzi) did not improve disease-free survival (DFS) compared to placebo in patients with EGFR- or ALK-negative non–small cell lung cancer (NSCLC) whose disease was completely resected and who were eligible for optional chemotherapy.
These results were consistent across PD-L1 expression subgroups, according to data from the phase 3 BR.31 trial (NCT02273375) presented at the 2024 European Society of Medical Oncology (ESMO) Congress.
The median DFS in patients with PD-L1 expression of 25% or more in the durvalumab arm was 69.9 months (95% CI, 57.6-not reached [NR]) vs 60.2 months (95% CI, 47.7-NR) in the placebo arm (HR, 0.935; 95% CI, 0.706-1.247; P = .642). The 18-month DFS rate in the durvalumab arm was 75.1% (95% CI, 69.9%-79.6%) vs 70.5% (95% CI, 62.5%-77.1%) in the placebo arm. The 24-month rate was 71.2% (95% CI, 65.7%-75.9%) vs 68.5% (95% CI, 60.4%-75.3%), and the 36-month rate was 63.9% (95% CI, 58.2%-69.0%) vs 62.4% (95% CI, 54.1%-69.6%).
The median DFS in patients with PD-L1 expression of 1% or more was 59.9 months (95% CI, 48.4-77.9) in the durvalumab arm and 60.3 months (95% CI, 43.8-80.9) in the placebo arm (HR, 0.989; 95% CI, 0.788-1.248; P = .926). The 18-month DFS rates were 73.4% (95% CI, 69.0%-77.2%) vs 70.1% (95% CI, 63.6%-75.7%); 24-month rates were 68.6% (95% CI, 64.1%-72.7%) vs 67.0% (95% CI, 60.4%-72.7%); and 36-month rates were 60.2% (95% CI, 55.4%-64.5%) vs 60.1% (95% CI, 53.4%-66.3%), in the durvalumab and placebo arm, respectively.
For patients in the PD-L1 all-comer population, the median DFS was 60.0 months (95% CI, 49.6-74.9) in the durvalumab arm and 53.9 months (95% CI, 36.7-67.3) in the placebo arm (HR, 0.893; 95% CI, 0.752-1.065; P = .207). The DFS rates at 18 months were 72.1% (95% CI, 68.8%-74.9%) vs 66.0% (95% CI, 60.9%-70.6%); at 24-months, they were 67.4% (95% CI, 64.0%-70.6%) vs 63.3% (95% CI, 58.1%-68.0%); and at 36-months, they were 60.4% (95% CI, 56.8%-63.8%) vs 56.4% (95% CI, 51.1%-61.3%).
"The outcomes of the BR.31 study suggest that the presence of primary disease and associated tumor antigens, as in the perioperative approach, may be required for optimal efficacy [in NSCLC]," Glenwood Goss, MB, BCh, FCPSA, FRCPC, a professor of medicine in the University of Ottawa Division of Medical Oncology, a chair of the Thoracic Oncology Site Committee, and director of Clinical and Translational Research at Ottawa Hospital Cancer Centre, said in a presentation on these data.
Patients with stage IB to IIIA NSCLC who had complete resection, an ECOG performance status of 0 to 1, and EGFR-mutated/ALK-positive disease were eligible to enroll. Patients received a platinum doublet followed by surgery and randomization at 3 weeks or more. Patients were randomly assigned 2:1 to durvalumab at 20 mg/kg every 4 weeks for 12 months or matched placebo.
The primary end point was investigator-assessed DFS in patients with PD-L1 expression of 25% or more and EGFR- or ALK-negative disease. Secondary end points included DFS in patients who had PD-L1 expression of 1% or more and EGFR- or ALK-negative disease, all patients with PD-L1 expression of 25% or more, all randomly assigned patients, PD-L1 all comers with EGFR- or ALK-negative disease, and all patients with PD-L1 expression of 1% or more; overall survival; adverse effects (AEs); and quality of life.
Overall, 1827 patients registered, with randomization of 1415 taking place between February 2015 and March 2020. There was a total of 1219 patients with EGFR- or ALK-negative disease. Of the 1415 patients who were randomly assigned, 944 and 471 were assigned to the durvalumab arm and the placebo arm, respectively. At data cutoff, 67.7% of patients in the durvalumab arm and 67.5% in the placebo arm were still receiving study treatment.
In the PD-L1 expression of 25% or more group, the median age was 65 years old vs 63 years old in the durvalumab vs placebo arms, 61.1% vs 64.6% were male, 47.5% vs 41.0% were White, and 81.6% vs 79.5% were former smokers. Additionally, the most common histology type was adenocarcinoma in 63.0% vs 59.0%, 54.4% vs 50.9% had stage II disease, and 65.8% vs 64.6% had PD-L1 expression of 50% or more.
In the PD-L1 expression of 1% or more group, the median age was 65 years old vs 63 years old in the durvalumab and placebo arms, with 62.5% vs 64.6% being male, 46.1% vs 42.1% were White, and 78.3% vs 77.5% were former smokers. The most common histology type was adenocarcinoma in 60.8% vs 58.8%, and 44.3% vs 43.3% had PD-L1 expression of 50% or more.
In the PD-L1 all-comers group, the median age was 64 years vs 64 years in each arm, respectively; 64.8% vs 66.8% were male, 46.1% vs 46.5% were White, and 78.4% vs 76.5% were formers smokers. The most common histology type was adenocarcinoma in 66.3% vs 60.6%, and 42.5% vs 40.6% had PD-L1 expression of less than 1%.
The safety analysis included all patients who had received at least 1 dose of treatment. Any AEs occurred in 93.8% in the durvalumab arm and 92.3% in the placebo arm. Grade 3/4 AEs occurred in 23.5% vs 19.6%, and AEs leading to death occurred in 0.7% vs 0.2% between either arm. Serious AEs were observed in 18.8% vs 15.4%, and AEs leading to discontinuation occurred in 14.0% vs 5.1% in the durvalumab and placebo arms, respectively.
Reference
Goss G. CCTG BR.31: a double-blind placebo-controlled randomized phase 3 trial of adjuvant durvalumab in completely resected non-small cell lung cancer. Presented at the 2024 European Society of Medical Oncology (ESMO) Congress, Barcelona, Spain; September 13-17, 2024. LBA48.
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