How Will the Availability of Liquid Biopsy Change the Paradigm of Genetic Testing in the Setting of Metastatic Lung Cancer?

Jonathan W. Riess, MD,MS: I think plasma tumor—DNA testing is changing the paradigm for how we look at resistance mechanisms in advanced non–small cell lung cancer, and also how we look at molecular aberrations in general. Right now, my general strategy is to use plasma cell–free DNA to look at resistance mechanisms to EGFR tyrosine kinase inhibitors. And if it’s T790M-positive, for example, it gives you enough evidence to proceed with matching the patient to giving them osimertinib, which is a great treatment option with high response rates and progression-free survival for these patients who are T790M-positive.

We know that the results for T790M-positive in plasma are comparable to the results for T790M positivity in tissue. Where EGFR T790M is negative in plasma, it does not substitute for tissue. That could be a false negative, so in those patients, I go for tissue. I generally do plasma first because they’re already in clinic, so it’s easy to draw a tube of blood and send it out, whereas obtaining a tissue biopsy is invasive. It takes time to set up the biopsy, it takes time for the pathology to send the specimen out, and for molecular testing and for those results to return. But, if the T790M is negative plasma, I proceed with getting a tissue biopsy because, often, you can detect positivity there if it’s a false negative and get them osimertinib if they’re T790M-positive. We’ll look for other treatments if they’re T790M-negative. So, I look at a strategy that gives me the best chance of finding a T790M-positive result because we have a great treatment in osimertinib for that. And, we know that if it’s plasma-positive, the results are comparable than if it’s tissue-positive.

In terms of the lesions to biopsy, I generally go for a) the safest lesion to biopsy in terms of minimizing potential complications, and b) what lesion seems to be the fastest growing. For example, if you have a scan on a patient where it’s getting larger and larger, but other lesions are in check, I generally go for the larger lesions. I generally don’t biopsy bone because the decalcification process can interfere with the molecular testing. For molecular testing, I don’t go for bone, although the soft tissue areas around the bone can sometimes be biopsied if you can see those. But, the bone itself, I do not biopsy. So, that’s another important thing to keep in mind.

In terms of plasma testing replacing tumor testing, I think that’s too early now to say. I think if you have a T790M-positive result, you could match to a targeted treatment in osimertinib. If it’s T790M-negative, we don’t have enough evidence yet that that could potentially be a false negative, and therefore tissue is required. At some point, the technology may evolve where that’s less of an issue, but we’re not there yet.

Riess case 1:

A 44-year-old female with relapsed stage IV adenocarcinoma.

• This is a 44-year-old female diagnosed with stage IV adenocarcinoma
• Tissue-based mutation testing showed an EGFR mutation with exon 19 deletion
• She was subsequently treated with afatinib
• After 11 months she became mildly symptomatic with small, nonspecific pulmonary nodules
• Follow up CT scan showed growth of the primary lesion
• The patient reported worsening of her cough
• Cell-free DNA testing was ordered and was negative for both the EGFR driver mutation and for T790M
• Subsequent tissue biopsy showed the presence of T790M
• The patient was switched to osimertinib and continues to respond well to therapy with minimal toxicity