Identifying PIK3CA Mutations in HR+ HER2- MBC

Joyce O’Shaughnessy, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “Updates in HR+/HER2- Advanced/Metastatic Breast Cancer.” I’m Joyce O’Shaughnessy, the chair of breast cancer research at Baylor University Medical Center, Texas Oncology [in Dallas, Texas] and US Oncology [Research Network]. I’m pleased to be joined by 3 esteemed colleagues who are very experienced clinicians and trialists. Let’s see if we can introduce ourselves, starting with Gabe.

Gabriel Hortobagyi, MD, MACP, FASCO: I’m Gabriel Hortobagyi. I’m a professor at The University of Texas MD Anderson Cancer Center [in Houston, Texas] in the department of breast medical oncology.

Joyce O’Shaughnessy, MD: Glad to be here with you, Gabe.

Neil M. Iyengar, MD: I’m Neil Iyengar. I’m an associate member and an attending medical oncologist in the breast medicine service at Memorial Sloan Kettering Cancer Center in New York, and I’m glad to be with you all tonight.

Joyce O’Shaughnessy, MD: Thanks, Neil. Sarah?

Sarah Sammons, MD: Hi, I’m Sarah Sammons. I’m an assistant professor of medicine at Duke University [School of Medicine] and a breast medical oncologist joining in from Durham, North Carolina. Thank you for having me.

Joyce O’Shaughnessy, MD: Glad you’re here. We just had an ESMO [European Society for Medical Oncology Congress] that was packed with new data. We’ll have a good conversation about some of the new data, particularly as it relates to HR+ [hormone receptor–positive] and HER2- [human epidermal growth factor receptor 2–negative] metastatic breast cancer. We’re going to discuss new data related to these patients from recent meetings and, most important, put it into perspective in terms of what we’re going to do with the information in practice. In addition, we’ll be discussing some other issues for which we’re still looking for answers. We’ll look at some of the evolving clinical trials and questions that we still need answered, and we’ll see what’s going to be coming in the near future. With that, let’s start by looking at the big picture in the HR+/HER- metastatic breast cancer landscape. Some questions might be how do we approach these patients? Is there particular molecular testing we need to obtain for these patients? What do we get at diagnosis? What do we get at progression? What are the standard approaches to ensuring the diagnosis? Gabe, start with what’s going on at MD Anderson.

Gabriel Hortobagyi, MD, MACP, FASCO: This is a work in progress, of course, in a rapidly moving field. When I face a patient with advanced breast cancer for the first time, in addition to staging and understanding the location and extent of metastatic disease and menopausal status, we routinely obtain either a new biopsy. That is our preference. We send it for mutation profiling, specifically looking at PI3 kinase and more recently with greater intensity for ESR1 mutations. If that patient hasn’t had germline mutation testing, if appropriate in the early stage, we will also do that at that time, but those are 2 separate steps. The PI3 kinase mutation is clearly relevant to choosing therapy for second-line today, as we’ll come to later.

Joyce O’Shaughnessy, MD: The timing on the PI3 kinase evaluation can be variable. We can get it either in the beginning when somebody is newly diagnosed, when we look at blood, when we look at tissue, when we look at it upon progression on first-line CDK4/6. What do you all think? What are some of the key caveats around this PI3 kinase testing?

Sarah Sammons, MD: I can start with the way I think about it. When I’m facing a new patient with metastatic breast cancer, I certainly do staging scans. I always want to get germline testing. I generally reserve next-generation sequencing to after they have progression on first-line therapy since it’s not going to help me determine their therapy in the first line, which would generally be endocrine therapy with the CDK4/6 inhibitor backbone. Once they progress on that, then I get into the next-generation sequencing. I try to go for tumor biopsy at that point if I can to look and make sure that their estrogen receptor hasn’t down-regulated during their time on first-line therapy. Of course, at that point, I want to know about the PI3 kinase mutation. I try to get tissue if I can, and if not, then I’d start with circulating tumor DNA [ctDNA].

Joyce O’Shaughnessy, MD: Thanks. How about you, Neil? How do you approach PI3KCA testing?

Neil M. Iyengar, MD: I’m more of an eagle-eye view guy. I like to know the landscape I’m dealing with right at the beginning, so I share Gabe’s approach, trying to do tumor sequencing up front. Certainly on a research basis. It’s helpful because we can do things like track clonal evolution and so forth. It’s useful clinically because it helps us prepare for subsequent lines of therapy and the presence of a PI3 kinase mutation. We’re going to talk about toxicity later, but if you have more time to optimize someone’s metabolic status in preparation for the hyperglycemia that goes on with a PI3 kinase inhibition, then that could be helpful. As we heard from Sarah, if you need to resort to liquid biopsies or ctDNA in the future, knowing the baseline mutational status of a tumor can improve the specificity and the sensitivity of ctDNA tracking throughout further lines of therapy, so I usually try to start with sequencing up front. Of course, there are insurance caveats, and being at a research institution does help with that but I do think it can be clinically helpful.

Gabriel Hortobagyi, MD, MACP, FASCO: There’s also the issue of the turnaround time. I hate to be placed in a situation where I have to tell a patient, “You’ve progressed in your first-line therapy. Now we’re going to start a biopsy and then do a mutation profiling. Three weeks from now we’ll have an answer to this, and we can sit down and talk about treatment.” For many of my patients, that’s too anxiety creating. I prefer to have that answer earlier. Because of that, I prefer to do that up front.

Joyce O’Shaughnessy, MD: I tend to do all the above. I love information. One thing, from a practical standpoint, if we check ctDNA for PI3K and we don’t find it, we definitely want to go to the tissue. It tends to be a truncal mutation. It tends to be in the primary breast cancer that you’ll find it. About 10% of the time, you can find it as a metastatic acquired mutation, but that’s a little more uncommon. If I don’t find it in the tissue and I don’t find it on ctDNA up front, then I’ll check it again after progression on CDK4/6. I’ll check again for the blood or if I biopsy, I’ll check it again. I just keep looking for it, but you can find it on tissue if you don’t find it in blood. That’s the main caveat that we all want to just be sure we look for and really try to find it because it’s helpful.

Transcript edited for clarity.