Understanding Mutation Testing for NSCLC Treatment

Elizabeth Waxman

Hello Whitney. Thank you for joining me in a conversation about EGFR in NSCLC, specifically about first-line treatment. It seems to me that there are more targets, or mutations, discovered and appropriate therapies developed every few years. I think it’s safe to say that the landscape of lung cancer treatment has dramatically changed and continues to change.

There are certainly more treatment options for NSCLC, and I defer to your expertise for this particular conversation. Before we discuss treatment options, I think it’s important to go over mutation testing.

Whitney Lewis

Liz, I completely agree. Patients are so much more empowered these days with much more information at their fingertips. Many times when I’m counseling patients the first thing out of their mouths relates to whether they are eligible for a “chemo pill” or any sort of oral targeted therapy so I think it’s a really important piece of the puzzle to share with patients up front to address these concerns. First, they want to know if their tumor is being tested for these things. And then would they be a candidate for any sort of alternative therapies to chemoimmunotherapy?

Elizabeth Waxman

Mutation testing has certainly changed over time. Early on we could test for just a few mutations, whereas now we can test for hundreds of mutations. Patient education on mutation testing is extremely important and an essential part of the patient’s understanding and ability to participate in their treatment.

Whitney Lewis

How do you explain testing to the patient?

Elizabeth Waxman

First and foremost, I explain to patients that the testing for mutations determines whether or not an oral (or immunotherapy) treatment for their cancer is indicated, and that mutation testing is part of the diagnostic workup. I also explain that these mutations are related to the cancer and are generally not hereditary. I try to keep the explanation and rationale of mutation testing uncomplicated and use language that is age appropriate for the patient. I also explain that there is a moderate percentage, about 12-15%, of positive results in mutation testing and that not every patient can be treated with an oral agent.

Whitney Lewis

In your experience, roughly how long does tissue mutation testing take?

Elizabeth Waxman

Timely results of tissue mutation testing vary. Results can take 1-2 weeks depending on the facility where the mutation testing is performed. When the mutation testing is performed at the same institution as the patient seeking treatment, so in-house, the results may come back sooner than when the tissue is sent to an external facility for testing. Occasionally, the results may take longer than 2 weeks. I stress to the patients to have patience, and they will be notified of the results as soon as the oncology team has them.

Whitney Lewis

Sometimes we may not have enough tissue to test for a broad panel of mutations and understandably patients are not always keen to have another biopsy, especially if there is a wait to get that scheduled. Can you speak on your experience with a liquid biopsy or circulating tumor DNA?

Elizabeth Waxman

Tissue mutation testing looks at the tumor cells and determines if there is a sufficient quantity of cells to do the testing. There are occasions when there is quantity not sufficient, or QNS, for mutation testing, which refers to there not being a sufficient quantity of cells. This can occur if the cell block is depleted. There is another method of mutation testing and that is liquid biopsy, where the patient’s blood is tested for mutations. In liquid biopsy, circulating free tumor, also known as CFT, DNA, or circulating tumor cells are analyzed for mutations. CftDNA is released into the bloodstream by the tumor cells.¹ Studies have shown that the amount of cftDNA correlates to disease stage, as patients with metastatic disease tend to have higher levels of cftDNA compared to patients with early stage disease.^2,3 However, patients with early-stage NSCLC shouldn’t be excluded from liquid biopsy as the tumor could be QNS for tissue mutation testing.

Whitney Lewis

Which is better, tissue mutation testing or liquid biopsy? If I were a patient I would certainly prefer a liquid biopsy, especially with later stage disease, as a higher tumor burden would likely have an increased chance for finding circulating tumor DNA.

Elizabeth Waxman

That is a very good question. Tissue mutation testing is the standard. As I mentioned earlier, hundreds of mutations can be tested based on sufficient material and next-generation sequencing, which we shorten to NGS. NGS is a molecular approach able to provide a comprehensive molecular profile of non-small cell lung cancer.⁴ One other important note about tissue mutation testing is that PD-L1, the marker used for immunotherapy treatment, is detected on tissue testing only. The problem arises if the tissue sample is QNS, or the cell block is depleted, then tissue mutation testing can’t be performed.

Liquid biopsy is also used for mutation testing. The benefits of liquid biopsy are that it is a blood test, so it’s minimally invasive. Liquid biopsy can be used if the patient has disease progression on targeted therapy, and the patient wouldn’t necessarily need to have a new tissue biopsy.  One issue with liquid biopsy is that PD-L1 is not detected

Whitney Lewis

Should the patient have a tissue biopsy or liquid biopsy if they progress on targeted therapy?

Elizabeth Waxman

Again Whitney, excellent question. Ultimately, this decision comes about from discussion with the oncology team, the patient, and the family. With repeat tissue biopsy, there may be resistant mechanisms discovered that led to the disease progression, think T790M in adenocarcinoma. Also, another very important consideration is the possibility of disease transformation from NSCLC to small cell lung cancer. This transformation has been seen in patients with EGFR mutation on targeted therapy (for example, osimertinib) and a histologic transformation cannot be detected with a liquid biopsy alone. I think the patient should have both a repeat tissue biopsy and liquid biopsy when there is disease progression, mainly for the reasons discussed above. 

Whitney Lewis

When should mutation testing be performed?

Elizabeth Waxman

The short answer is at the time of diagnosis. Now that targeted therapy has approvals for adjuvant treatment and first-line treatment, it’s important to have mutation testing results. Mutation testing should also be done at the time of disease progression. 

Whitney Lewis

I have also seen some early clinical trials looking at circulating tumor DNA after curative intent therapy and I think this will be very interesting as data evolves. Who knows, maybe one day we’ll base adjuvant therapy off of residual cell free DNA. I think the evidence is clear that in patients with a poorly sampled tumor or in cases where there may be mixed adenocarcinoma and squamous cell carcinoma that a best practice would be to test a patient’s tumor for mutations. But what about patients with tumors that are a pure squamous histology?

Elizabeth Waxman

The short answer is yes, mutation testing should be performed in patients with a pure squamous histology. Although small in number, there have been mutations identified as squamous cell carcinomas.

Whitney Lewis

So Liz, what do you think is really important for new oncology team members, new APPs, to know about mutation testing?

Elizabeth Waxman

Again, it’s part of the diagnostic workup and results have ramifications for treatment decisions. The testing is done on both tissue and blood. In terms of results and relevance, a predictive biomarker, like EGFR, is indicative of therapeutic effect due to the interaction between the biomarker and the therapy outcome, meaning the patient should have a good response to treatment based on appropriate targeted therapy for the mutation detected. EGFR and PD-L1 are predictive markers. A prognostic biomarker is indicative of patient survival independent of treatment as the biomarker is an indicator of the innate tumor behavior. KRAS, TP53, STK11, KEAP1 are prognostic biomarkers.⁵ 

Whitney Lewis

We’ve talked a lot about APs and what they should know. What do you think is important for the patient to know about mutation testing?

Elizabeth Waxman

It’s important for the patient and family to know and understand that mutation testing, both tissue and liquid biopsy, is part of the diagnostic process for NSCLC. The results help determine appropriate treatment. The mutation is not hereditary, with some exceptions for germline EGFR T790M, so the patient’s family members don’t need to be tested. If the tissue mutation or liquid biopsy reveals a mutation, then treatment with an oral targeted agent is recommended. It’s important for the patient and family to know that these oral treatments are quite expensive, and that is a conversation for another time. The patient and family should also know that if mutations are not found in the tissue or blood, there are other effective treatments for NSCLC. I also explain to patients that this is an ever-changing landscape with new targets and treatments on the horizon. Think of KRAS-G12C. KRAS was thought to be untargetable at one time, and now there are two FDA-approved oral treatments. This is a time for optimism.

Whitney Lewis

You’re so right, Liz. I love that this testing lets us really zero in on the best treatment for the patient. I’m glad that we could discuss this today.

Elizabeth Waxman

I am too. I look forward to our next discussion.