The Evolving Landscape of Molecular Testing for NSCLC


Experts take a broad look at how molecular profiling has impacted the treatment landscape of non–small cell lung cancer.


Catherine Ann Shu, MD: The field of lung cancer has changed greatly in the last 20 years. We’ve really learned how to treat the disease, not as just 1 disease, like lung cancer, but as many separate diseases. The first type of personalized cancer treatment was when we separated the lung cancers into different histologies: small cell lung cancer and non–small cell lung cancer. Then under non–small cell lung cancer, it was squamous cell carcinoma and adenocarcinoma. Later, when we started to genetically profile the adenocarcinomas, we found out there were more targets that are important. Adenocarcinomas then became EGFR-mutant lung cancers and KRAS-mutant lung cancers. As the years have gone on, we’ve found more targets. Now we have things like ALKrearrangements, ROS1, BRAF, RET. Even for KRAS, we have the targeted agent. The field has changed so much in the last few years. We have not only particular molecular genotyping but also drugs that target those particular mutations. It’s a cool time to be in.

Erminia Massarelli, MD, MS, PhD: The molecular background starts in the early 2000s, when the first trials were done with gefitiniband erlotinib, which found that a proportion of patients were having higher responses to EGFR tyrosine kinase inhibitors. At that time patients weren’t included based on the molecular test because the EGFR mutations weren’t known. Then in 2005 there was a discovery of the EGFR-sensitizing mutations. In the last 16 years, there have been a lot of discoveries about what the responsible driver mutations for non–small cell lung cancer are. More recently we have multiple tyrosine kinase inhibitors and other kinds of molecular inhibitors. EGFR mutations represent 10% to 20% of tumors, and non–small cell lung cancer tumors have EGFR mutations. These are the data for Caucasian ethnicity. If we look at data for Asian ethnicity, the EGFR mutations are about 50% of non–small cell lung cancers. We’re talking about a significant number of patients, especially of Asian ethnicity. Among all these EGFR mutations, we do have some uncommon EGFR mutations that don’t have significant response to the appropriate EGFR tyrosine kinase inhibitors. Of these, the most frequent nonresponsive EGFR mutations are the exon 20 insertion mutations, which are present in 2% to 3% of EGFR-mutated non–small cell lung cancer.

Catherine Ann Shu, MD: Comprehensive genomic profiling in non–small cell lung cancer has changed the landscape of lung cancer. That means treating a patient with lung cancer today is so different from treating a patient with lung cancer 20 years ago, when you were just giving chemotherapy. In my clinical practice, every adenocarcinoma gets reflexive NGS [next-generation sequencing] testing. That’s just the way Columbia [University Herbert Irving Comprehensive Cancer Center] works. It’s not just stage IV; we do it for every lung adenocarcinoma. It’s reflexively tested, and if we want to do additional testing for squamous cell carcinomas, I send that out as a separate test.

I test every adenocarcinoma that comes through my clinic. They all get a reflexive next-generation sequencing lung cancer panel. I also test every never-smoker. Even if a never-smoker has a squamous cell carcinoma, I do NGS profiling because sometimes the cancer is heterogeneous, and maybe you’re not catching an important mutation. I try to dig deep for my never-smokers. I test at progression, especially for patients with EGFR or other mutations where we might be able to find some actionable acquired resistance mutation.

The advent of liquid-based assays or blood-based assays has been huge. In the past, we only had tissue, which takes a long time. For tissue, you have to get the biopsy, and then you have to send it to do the NGS panel. This probably takes 2 to 3 weeks. With some blood-based assays you’re able to get results in as few as 7 days, which is amazing. I try on all my new metastatic diagnoses to do an additional blood-based assay. You still need the tissue. The tissue is always important. Tissue is the gold standard. You need tissue for a diagnosis. I do the tissue, but at the same time, I’ll also send off for a blood-based assay, because if it comes back with an EGFR mutation, then you’re able to start them on treatment right away. It’s important to do that. Sometimes, before the patient even sees me, I’ll ask my office staff to draw a liquid biopsy, so that when I see them I’ll at least have the results of that.

Transcript edited for clarity.

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