What Is ALK-Positive Lung Cancer?

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ALK-positive lung cancer is a non-small cell lung cancer (NSCLC) that harbors a mutation in a gene called anaplastic lymphoma kinase (ALK). More precisely, it's a gene rearrangement—a fusion of ALK and another gene, echinoderm microtubule-associated protein-like 4 (EML4). This abnormal fusion causes cell enzymes (proteins) to send signals to mutated cancer cells telling them to divide and multiply more quickly than usual. The result: the spread of lung cancer.

As with other types of lung cancer related to genetic mutations, ALK rearrangement can now be treated fairly effectively with targeted therapy drugs, allowing you to manage your cancer. This has led to better survival rates among patients at all stages of lung cancer.

ALK-Positive Lung Cancer Symptoms

The ALK mutation is, by far, most common in people with the type of non-small cell lung cancer called lung adenocarcinoma.

This type of cancer usually begins near the outer portion of the lungs away from the airways. This means that symptoms may not present until the cancer has spread toward the center of the lungs. When symptoms do appear, they usually manifest with a chronic cough and bloody sputum.

Because young women and non-smokers, who may never suspect that they have cancer, are at higher risks for developing ALK mutations, it is very common for this type of cancer to be missed until it is in an advanced stage.

Your doctor may not even be familiar with ALK-positive lung cancer and may never think to attribute minor respiratory symptoms to cancer. Being aware of the possibility of this type of cancer and discussing it with your doctor may help you get screened for the mutation or tested for NSCLC early, before the cancer spreads.

Causes

The ALK rearrangement is present in 3% to 5% percent of people with NSCLC. That may sound like a small number at first glance, but considering the number of people diagnosed with lung cancer annually, that means that there are around 10,000 newly diagnosed incidents of ALK each year in the United States.

The types of mutations present in lung cancers vary depending upon the type of lung cancer. While the ALK mutation is most common in people with lung adenocarcinoma, in rare cases, ALK lung cancer has been found in people with squamous cell carcinoma of the lungs (another type of non-small cell lung cancer) and small cell lung cancer.

This fusion gene isn’t a hereditary mutation like the BRCA mutations in some people with breast and some other cancers. People who have a lung cancer positive for the EML4-ALK fusion gene weren’t born with cells that had this mutation and didn’t inherit a tendency to have this mutation from their parents.

Instead, this is an acquired mutation that develops in some cells due to a variety of factors. For instance, exposure to environmental carcinogens may damage genes and chromosomes and result in mutated cells.

In addition, the EML4-ALK fusion gene is not exclusively related to lung cancer. It may also be found in people with neuroblastoma and anaplastic large cell lymphoma.

Risk Factors

Certain people are more likely to have the ALK fusion gene:

In studies, NSCLC patients younger than 40 tested positive for the EML4-ALK fusion gene 34% of the time compared to about 5% of people of all ages with NSCLC.

Diagnosis

An ALK rearrangement is diagnosed through genetic testing (also known as molecular profiling). Doctors obtain a sample of a lung tumor via a tissue biopsy and may examine a blood sample obtained via a liquid biopsy. These samples are checked for biomarkers that show that the ALK mutation is present.

Researchers are also looking at ways to determine if an ALK mutation is present before genetic testing is done, or if there is a substitute for molecular profiling.

A few things that suggest an ALK mutation may be present include:

  • Bloodwork: A test called carcinoembryonic antigen (CEA) tends to be negative or show low levels in people with ALK mutations.
  • Radiology: Imaging of ALK-positive lung cancer appears different than for other types of NSCLCs, which may help doctors identify the mutation early.

Who Should Be Tested for an ALK Mutation?

Several organizations have worked together to develop guidelines on this. The consensus is that all patients with advanced-stage adenocarcinoma should be tested for ALK and other treatable genetic mutations, regardless of sex, race, smoking history, and other risk factors.

These guidelines are somewhat flexible. Doctors may recommend that other people undergo testing as well, and some insist that everyone diagnosed with NSCLC undergo genetic testing.

Treatment

ALK rearrangement is treated with oral drugs that work to shrink advanced lung cancer tumors.

The drugs that have been approved by the U.S. Food and Drug Administration (FDA) to target ALK-positive lung cancer are called ALK inhibitors and include:

  • Alecensa (alectinib)
  • Alunbrig (brigatinib)
  • Lorbrena (lorlatinib)
  • Xalkori (crizotinib) 
  • Zykadia (ceritinib)

If you've tested positive for the ALK gene rearrangement, ALK inhibitors are usually used instead of chemotherapy as the first course of treatment. Although, doctors may sometimes start with chemo treatment and begin ALK medications only after the therapy has stopped working.

How ALK Inhibitors Work

Tyrosine kinases are elements of cells that allow signals to be sent from one cell to another. Tyrosine kinase receptors all the cells to receive these signals.

To understand how ALK targeted therapy medications work, think of the cell's tyrosine kinase receptor as a lock and the tyrosine kinase protein (which holds the message) as a key. If you have an ALK mutation, you have an abnormal key. When the mutated key is “inserted,” signals are sent to the cell's growth center telling cancer cells to divide without stopping.

Kinase inhibitor medications work by blocking the keyhole—as if you filled it in with concrete. As a result, the signal telling the cancer cells to divide and grow never gets communicated.

It’s important to keep in mind that tyrosine kinase inhibitors are not a cure for lung cancer, but rather something that allows a tumor to be kept in check (much like a medication for diabetes may control the disease, but will not cure it). It is hoped that in the future, lung cancer may be treated like other chronic diseases.

Tumors can be managed for years with these drugs, ensuring that the cells do not spread.

Resistance

Lung cancers may initially respond very well to targeted therapy medications. However, patients almost always become resistant to the medication over time.

Resistance may develop within nine weeks of beginning treatment, but for some people, medications can continue to be effective for many years.

If you develop resistance to an ALK inhibitor, your doctor will try a new medication or a combination of medications. New medications continue to be studied in clinical trials for people who develop resistance.

Medications may also need to be adjusted because cancers can further mutate over time. Sometimes a medication that targets another treatable mutation (such as EGFR) may work even though a tumor was not initially positive for an EGFR mutation. For instance, the drug Lorbrena (loratinib) was approved for people previously treated with other ALK inhibitors and was found to be effective in roughly half of people who had become resistant to other drugs in this class. The median duration of action was 12.5 months

Components of vitamin E can significantly interfere with some ALK inhibitors. Talk with your doctor before taking vitamin E or any supplements while undergoing cancer treatment.

Treatment Side Effects

Like other cancer medications, ALK inhibitors have side effects. These should be mild compared to the side effects of chemotherapy, but they still may be uncomfortable and disrupt everyday life.

Common adverse reactions to Xalkori (crizotinib) include:

  • Vision disorders
  • Nausea
  • Diarrhea
  • Vomiting
  • Edema
  • Constipation
  • Elevated transaminases (related to liver damage)
  • Fatigue
  • Decreased appetite
  • Upper respiratory infection
  • Dizziness
  • Neuropathy

Another rare but severe side effect that has been noted is the development of interstitial lung disease, which can be fatal.

Cost

The newer medications that target abnormalities in cancer cells like ALK mutations often come with a steep price tag. But there are options available.

For those who don’t have insurance, there are government as well as private programs that can help. For those with insurance, copay assistance programs may help defray costs.

In some cases, the manufacturer of the drug may be able to supply medications at a reduced cost. And, importantly, you may be able to receive free treatment if you participate in a clinical trial.

Prognosis

While the overall five-year survival rate for NSCLC is about 25%, which drops to 2% to 7% for advanced-stage lung cancer, researchers have found that the median survival for people with stage 4 ALK-positive lung cancer is 6.8 years with the right care. This survival rate held true even for those whose lung cancer had spread to the brain (brain metastases).

A study published in The New England Journal of Medicine found that treatment with Xalkori (crizotinib) results in a median progression-free survival of approximately 10 months. There is roughly a 50% to 60% response rate to the drug. This is a dramatic finding because the people in the test had already failed to show progress on chemotherapy and had an expected response rate of 10% with a projected average progression-free survival of around three months.

While studies don't show increases in overall survival for all ALK rearrangement treatments, there is clear improvement in the quality of life offered with these drugs and the possibility of living progression-free without serious side effects.

A Word From Verywell

The key to being able to take advantage of medications for ALK mutations is to undergo genetic testing. While many doctors recommend that everyone with NSCLC be evaluated in this way, many patients do not have molecular profiling done.

Discuss the option to test with your doctor. If possible, consider getting a second opinion at a cancer center that sees a large volume of lung cancer patients and may better support the decision to be tested.

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