Baltimore-Area Oncologists On How Next-Generation Sequencing Can Guide Lung Cancer Treatment

Next-generation sequencing (NGS) or molecular testing is a new testing technology that can help identify if your cancer has any of these targetable or actionable mutations by analyzing a sample of your tumor or blood. Targeted therapies are recommended if your doctor detects a tumor’s specific mutation in next-generation sequencing (NGS), which can identify if an already-approved drug exists that targets that mutation.

According to Dr. Valsamo Anagnostou, a thoracic oncologist and leader of the Johns Hopkins Molecular Tumor Board at The Sidney Kimmel Comprehensive Cancer Center, molecular testing or NGS is very important to ask your doctor about, especially when it comes to lung cancer treatment:  “Molecular testing should always be part of discussions between you and your healthcare team. It is important to make decisions on molecular testing together and come up with a plan.”

What is NGS Testing

Simply put, NGS testing is a super modern technology. Also frequently referred to as molecular testing or profiling, it looks for mutations in your tumor cells. Mutations are the errors in your genes that influence the tumor growth and spread. Your doctor uses NGS testing to look at multiple genes at once. Then, they identify any mutations that could be related to the growth of your lung cancer.

“Next-generation sequencing is a type of molecular testing that determines the sequence of DNA or RNA. By using these methods, we can pinpoint the kind of genetic information that is carried in a particular DNA molecule and highlight changes in the DNA sequence or structure. Again, we call these mutations, and these are the ones that may be used to match your cancer with a specific targeted therapy.” says Dr. Anagnostou.

Keep in mind that this is not a specific lung cancer test, rather it’s a test to search for genetic mutation in lung cancer cells. NGS testing broadens your treatment options based on the comprehensive results collected.

Who is Eligible for the NGS Testing

NGS has become the standard of care in lung cancer treatment. You may be a candidate for NGS testing if you have been diagnosed with:

• Advanced stage adenocarcinoma of the lung
• Advanced-stage squamous cell cancer of the lung
• Advanced-stage adenosquamous cancer of the lung

In early-stage lung cancer, you should discuss if NGS testing could be right for you, too.

How Does NGS Testing Work in Lung Cancer

For people with lung cancer, the goal of NGS is to find your tumor’s specific mutations; and then target those mutations with an already-approved therapy or a targeted therapy. NGS testing gives your doctor a more complete profile of your lung cancer to help identify proven, targeted treatments.

“Next-generation sequencing is our preferred approach, which is really a comprehensive panel that’s looking at many different changes within a patient’s tumor,” says Dr. Katherine A. Scilla, thoracic medical oncologist at the University of Maryland Greenebaum Comprehensive Cancer Center.

The gold standard to find an actionable mutation in lung cancer remains the tumor tissue itself (tissue biopsy). Also, newer technologies such as a liquid biopsy that looks at circulating tumor DNA (ctDNA) can be used for NGS testing. A liquid biopsy measures DNA that’s shed from dead tumor cells into your bloodstream. The test results from the liquid biopsy come back faster than the tissue biopsy. That’s why your doctor may send both the tissue-based NGS and a liquid biopsy simultaneously to find if the cancer is actionable and if so, to find it sooner.

Your doctor may need to obtain additional NGS testing if your cancer continues to grow and has become resistant to targeted therapy.

What are the Most Common Mutations in Lung Cancer

The following are the most common mutations that have FDA-approved targeted treatment options for you:

• EGFR
• ALK
• ROS1
• BRAF
• KRAS
• MET
• HER2
• RET
• NTRK

NGS Testing on Treatment Decisions and Prognosis

“Molecular testing or profiling has become a very important tool for medical oncologists to decide on the best treatment for a patient that has advanced non-small cell lung cancer. And this molecular profiling is looking at specific gene alterations within a patient’s tumor,” explains Dr. Scilla.

Looking at the broad list of mutation profiles by the NGS testing, your doctor can provide specific information on:

•  Whether you’re likely to benefit from a targeted agent
•  What targeted agent is available for you
• Whether the targeted agent makes you live longer and with better quality of life
• Finding a clinical trial that is right for you

“Several clinical trials include in their eligibility criteria, a specific mutation in a specific gene; your cancer molecular testing can identify these changes in the genetic makeup of cancer cells. And as such match your cancer and you as an individual with a clinical trial where an investigational targeted therapy is tested that may improve your outcome and overall survival,” explains Dr. Anagnostou.

You and your doctor will consider this information with other factors such as any contraindications of certain medications, interactions with other drugs, and side effects. Together you can make decisions about whether you should have targeted therapy.

Targeted Therapies in Lung Cancer

Targeted therapy has made the biggest impact on lung cancer. It is a type of treatment that works by identifying specific markers that directly target what is causing the tumor to grow. By doing so, they can reduce side effects while increasing the chances of a successful long-lasting response.

“Targeted therapy agents can be given orally. They (targeted agents) tend to be very efficacious, sometimes patients can respond to these treatments for many years, and also (can be) less toxic than traditional chemotherapy or other agents that we have,” added Dr. Scilla.

Newer Targeted Agents Made Possible Using NGS Testing

• EGFR Mutations: Present in about 10-15% of lung cancers in the United States. Tagrisso (Generic name: osimertinib), is an oral medication approved for EGFR gene mutation.
• Targeting EGFR exon20 mutation was a challenge for a long time and yet this is one of the most common mutations we find when we do NGS testing. Exkivity (Generic name: mobocertinib) and Rybrevant (Generic name: amivantamab) are the two drugs that target EGFR exon20 mutations.
• KRAS mutations occur in about 20% of patients with lung adenocarcinomas. Lumakras (Generic name: Sotorasib) and Krazati (Generic name: Adagrasib) can target KRAS G12C mutations.
• Targeted therapy may still be an option even if your cancer grows after being on first-line therapy.
• Also, if you do not test positive for any of the mutations with an approved targeted therapy, you may qualify for immunotherapy with or without traditional chemotherapy based on your PD-L1 testing.

Types of NGS Testing On The Market

There are a number of tests you may encounter, depending on where you are getting treatment and what you are getting treatment for. Here are some of the common ones currently on the market:

• FoundationOne®CDx looks at 324 genes in solid tumors and says it can takes up to 12 days for results. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB) to help inform immunotherapy decisions.
• OmniSeq Insight provides comprehensive genomic and immune profiling for all solid tumors. It looks for 523 different genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB), as well as PD-L1 by immunohistochemistry (IHC).
• Cobas EGFR Mutation Test v2 identifies 42 mutations in exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. It is designed to test both tissue and plasma specimens with a single kit, and allows labs to run tissue and plasma on the same plate simultaneously.

You should ask your healthcare team if the brand of molecular testing they are doing is optimal for your cancer type.

Questions to Ask Your Doctor

• How aggressively should we treat my cancer?
• Am I eligible to receive targeted therapy?
• Am I more, or less, likely to respond to this treatment?
• Do I have any genetic mutation that would change the course of my treatment?
• Is there a clinical trial that would be relevant for me?
• How long will it take to get my NGS testing results?

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