Published on September 16, 2020
Understanding KRAS (Kirsten rat sarcoma viral oncogene homologue) Mutation in Lung Cancer
How many people with lung cancer have the KRAS mutation? How can knowing your mutation shape your treatment options? Terri Conneran, patient advocate and founder of the KRAS Kickers Support Group, gets the answers from lung cancer experts, Dr. Jyoti Patel from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Dr. Jessica Lin from Harvard Medical School.
This is Part 1 of a 3-part series. Watch all segments in the series below:
Transcript | What Is KRAS Lung Cancer?
The Most Prevalent Mutation in Lung Cancer
KRAS mutations were actually one of the oldest oncogenes known in lung cancer. They are the most prevalent mutation in lung cancer, they occur in about 25 to 30%. And for a long time, we've found KRAS mutant lung cancer to be really challenging to treat with what we call targeted therapies, which are therapies that are directly targeting the specific gene change present in the tumor. And I think that's where a lot of the excitement and the enthusiasm is coming in this past year as we'll talk about more during this session where we're seeing some of the challenges being overcome.
Just to kind of go over real high level what my story is, I was diagnosed three and a half years ago, and all I knew about was a PD-L1, marker. I didn't know anything about anything else. And then three years later found out it was KRAS, which was meaningless to me. And so now I'm learning all about, not that it's just a type of a treatment or it's just a type of a biomarker that there's a possibility for different types of treatments. And it has something to do with the subtypes.
So we know that KRAS mutations occur in 20% of people with lung cancer. But what we're finding is that there are particular types of KRAS. So that's an entire gene, and we're looking at specific changes at the DNA level that affect different places in that gene, the one of the many, many binding sites. And we know that particular mutations may be more associated with smoking behavior or never smoking behavior. We know that certain mutations have partners with them. When we think classically of KRAS mutations, there are certain ones that define or are more prevalent in lung cancer than in gastrointestinal cancers. We've been looking for KRAS mutations in colon cancer and the changed therapy based on KRAS mutations for quite some time. But these different subtypes, we think behave differently. They may have different genetic partners with them. They tend to be sort of distinct and sometimes they can be the main driver in a tumor based on their genetic subtypes. Sometimes they can have other drivers and not be the main reason that a cancer is growing. So when we're looking at these markers, you talked about PD-L1, so that's a stain that we see on a slide of cancer cells. How many cells harbor this protein, when we're talking about the subtype of a KRAS tumor, we're really talking about the genetic variation at the lowest level, sort of what those insertions and deletions look like.
What Experts Are Learning About Lung Cancer Biology
How the way we look at our patients' lung cancer is becoming more and more complex and more and more informed by what we are learning about lung cancer biology. And so 10, 20 years ago we might have said, okay, this patient has KRAS mutant lung cancer, and then stopped at that. But now that naturally leads to the next question of, okay, which KRAS mutation does the patient have, because that is relevant in thinking about treatment options. Is it KRAS G12C, or is it KRAS G12D or V? And then we also ask about, are there co mutations or alterations in other genes that are occurring together with the KRAS mutation? And so in the past few years, we've learned that the biology of KRAS mutant lung cancer can vary depending on the context in which the KRAS mutations occur. And so, just as an example, we know that when there's a STK11 or LKB1 one mutation that's co-occurring with a KRAS mutation, or perhaps a KEAP1 mutation that's occurring with a KRAS mutation that can confer a lower likelihood of benefit from immunotherapy treatments, which have really been a major breakthrough in lung cancer therapy.
And so we do think about does the patient have a KRAS mutation together with a STK11 or KEAP1 one or not? In some circumstances, I wouldn't say that it has changed our standard algorithm of how we choose between for example, immunotherapy or immunotherapy and chemotherapy. But if I have a patient in front of me who has high level of that marker, PD-L1 where the options are either using pembrolizumab (Keytruda) alone or pembrolizumab together with chemotherapy. If I know that there's also a STK11 or KEAP1 mutation present together with KRAS and the patient could tolerate chemotherapy, that may make me favor the latter option. And so now we're really looking at the whole kind of the genetic landscape of the tumor in trying to make these treatment decisions. And it really goes to emphasize the importance of having that appropriate genotype being performed when you're initially diagnosed with lung cancer, whether that is with a tumor biopsy or liquid biopsy.
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