KRAS Mutation Subtypes in Advanced NSCLC

Benjamin P. Levy, MD: You provided a nice overview of KRAS tumor biology and some downstream pathways that may be involved. Can you talk about the frequency of KRAS mutations in solid-tumor oncology? We know that they are important in lung cancer, and they’re seen in other cancers. Can you provide a brief overview of how common these are in lung cancer and other types of cancer?

David R. Gandara, MD: A KRAS mutation is 1 of the most common mutations in all solid tumors. For example, it’s in almost half—about 40%—of colorectal cancers, about 30% of lung adenocarcinomas, and essentially all patients with pancreatic cancers. But the type of KRAS mutation is different in different cancers. I mentioned earlier that KRAS G12C, which is the most common type in lung cancer and lung adenocarcinoma, is highly associated with tobacco carcinogenesis. Although it’s the most common type in lung cancer, it’s infrequent in colorectal cancer because that biology is different. We know now that the importance of KRAS in colorectal versus lung cancer directly relates to those subtypes. For example, in KRAS-mutated colorectal cancer, inhibitors of EGFR tend not to work as well. That is not the case in lung cancer, where it’s agnostic. Subtype is important, and it varies a great deal between tumor types.

Benjamin P. Levy, MD: Let’s talk specifically about lung adenocarcinoma KRAS mutations. There are multiple subtypes, as you mentioned. What are the most common subtypes that we see? We’ve talked about codon 12 and 13. Are there other subtypes of mutations that we see? It clearly matters now in terms of a therapeutic approach. Does it matter in terms of tumor biology or prognostication of these patients?

David R. Gandara, MD: The great majority in non–small cell lung cancer are codon 12 mutations, and of those, as I mentioned, G12C is the most common and the most actionable. There are some data we can talk about when we get to therapeutics. It’s not only finding the KRAS mutation and identifying what subtype it is that the oncologist has to worry about, but also who are the traveling partners. In other words, who’s going along with this KRAS? There are some bad actors, like TP53 and STK11, that are emerging as important partners. But we’ll come back to that when we talk more about therapeutics.

Benjamin P. Levy, MD: That’s such an important point. It gets to the complexity of KRAS—I agree with you wholeheartedly. Codon 12 and 13 are the most common, but it also includes the coalterations that may impact outcomes and therapeutic selection.

David R. Gandara, MD: Can I just add 1 thing, Ben?

Benjamin P. Levy, MD: Sure.

David R. Gandara, MD: One of the benefits of having a broad next-generation panel is you get a lot for free. What I mean by that is, it doesn’t matter whether you’re looking for 1 gene or 300 genes, you get all this other information. We get TP53 status. We get STK11 status. Regarding STK11, a tumor suppressor gene, there was nothing to be done about it. You would say, “Oh, that’s interesting.” Now it turns out these other things you find on next-generation sequencing may be important. If you were ordering tests 1 by 1, or if you were multiplexing, those would not be at the top of your list. You wouldn’t have that information. I’m a big fan of next-generation sequencing, whether it’s in tissue or blood.

Benjamin P. Levy, MD: I agree. We look for those “druggable or actionable” mutations, but we’re learning more and more that the coalterations may impact not just STK11 but also TP53 with EGFR, KEAP1. These are other mutations that start to tell a larger story about the tumor that may impact outcome and may impact what we do for these patients. I’m also a fan of doing comprehensive genomic profiling up front. Regarding nomenclature like KRAS G12C, what does this mean? Why do we say G12C? We’re going to hear a lot about G12C.

David R. Gandara, MD: These are named after the substitutions. G12C means “glycine for cysteine.” G12V is “valine,” and so forth. That’s not quite so important except that it alters the biology. In the case of G12C, glycine allows this protein to be constitutively activated, so your foot is on the gas all the time. Cancer cells, all they know is to grow and divide.

Benjamin P. Levy, MD: It’s important and helpful for the viewers to know that the names do mean something, and it helps delineate tumor biology. Specifically, it helps delineate therapeutic selection. That’s a nice overview.

Transcript edited for clarity.