Novel Testing Methodologies in Breast Cancer Management
Key opinion leaders provide insight on testing strategies, primarily circulating tumor DNA, in patients diagnosed with HR+/HER2- metastatic breast cancer.
Transcript:
Joyce O'Shaughnessy, MD: But I would really love to hear from Komal and Pedram. Maybe we'll start with Komal; when do you test patients? And let's focus on metastatic breast cancer because I dare say that those circulating tumor DNA will be coming into early-stage breast cancer. Correct me if I'm wrong, it's just not ready for prime time at this time, so, it's mainly in metastatic breast cancer. We have tumor, we got ctDNA, when and how do you look for genomic alterations? And [are there] any others I think that came to your mind besides the list that I just showed you, for example?
Komal Jhaveri, MD, FACP: Thank you so much for that question. I agree with you, I think it's the metastatic setting really where we use this a whole lot more. And I think the most important role that we have for genomic testing [INAUDIBLE] from plasma is predominately in the hormone receptor positive subtype where we have approvals for drugs based on these findings. So, it's one thing to get a test and get a result, and it's another to apply those results to our patients so that we can offer a therapy or match a therapy based on the result we find. So, because we do a confirmation of metastatic disease by doing the biopsy for a patient on any site that might be suspicious, on imaging, whether it's genome metastatic disease, whether it's recurrent disease, we do get that tissue for confirmation of ER, PR, and HER2. I think those good old markers still are very, very relevant, and more relevant these days because of this entity called HER2-low, so we cannot forget those. And while we're getting that biopsy, I usually think about sending an NGS from that biopsy sample up front. I think 40%, roughly, of our PR patients harbor the PIK3CA mutations, which is really a truncal and a plural mutation. So, whether you test it in the primary tissue, whether you test it in the metastatic tissue, whether you test it in tissue or plasma, at least those truncal mutations can be identified from any of those archival specimens. And so, getting it from the metastatic site does not necessarily change my first-line recommendation of a CDK4/6 inhibitor. But, if there are clinical trials, and we did have that up until recently, we offered triplet therapy with a PI3K inhibitor and a CDK with endocrine therapy in the first-line metastatic setting to patients whose tumors are replicating the mutation. So, either I can use that information for a trial in the first line or I don't have to wait for that result upon progression on a CDK4/6 inhibitor, where I feel like it's more meaningful because that's where patients are now used to staying so long on CDK4/6 inhibitors. They're feeling good generally; it's well-tolerated therapy. And so when progression happens, the anxiety there is a little more, and so having this result really comes in handy because for those 40% of our patients, we do have PI3K inhibitors, and now very soon, we might probably even get approval for capivasertib, an AKT inhibitor regardless perhaps of alteration status. We'll see, we have to see that. And then when I think about plasma, I usually use plasma upon progression on a CDK4/6 inhibitor. And I predominately do that because we know that ESR1 mutations are, unlike PIK3CA mutations, more subclonal, developing under the selective pressure of therapies including aromatase inhibitors and also CDK4/6 inhibitors. So, that's where we have approval for elacestrant for ESR1 mutant tumors. And so getting that information at the time of progression on a CDK4/6 inhibitor with a good turnaround time these days, for example, Guardant, you can get the results within 7 days. I think that is where I predominantly use NGS for patients. And certainly, germline testing helps with PARP inhibitors for our patients, about 5% of our hormone receptor positive patients harbor the BRCA gene mutation. And so PARP inhibitors are a very appropriate treatment option in that setting, at least before we consider chemotherapy. So, post-CDK4/6, prechemotherapy is when I'm thinking about those. Those are the 3 most important ones. And then rarely we'll find a high tumor mutational burden where we can apply pembrolizumab perhaps, unless we're thinking this is all APOBEC mutation and not necessarily going to work. I think in breast cancer it's very, very rare. Very hard to justify sometimes. We have NTRK inhibitors for NTRK fusions. For RET fusions, we have RET inhibitors. So, we could apply those tiny little prevalent results to these small little subsets, small little biomarker-based assignments where we have tumor agnostic approvals already.
Joyce O’Shaughnessy, MD: Thank you very much for letting us know your algorithm there. And how about you, Pedram? How do you think about both tissue and ctDNA in the metastatic setting?
Pedram Razavi, MD, PhD: I follow a similar approach as Komal, but I would like to highlight that cell-free DNA and circulating tumor DNA (ctDNA) often provides complementary data to the tumor tissue. So, when it's feasible, even at the time of initial diagnosis, I send for both ctDNA and also for tumor sequencing; ctDNA results usually comes back much earlier and ctDNA has been shown to provide a much more comprehensive profile of the mutational landscape of the tumor because it's not subject to the sampling bias. When we put a needle in a part of a tumor and we sequence that part of a tumor, there's extensive spatial heterogeneity in the tumor. We might have missed some of these mutations that are coming from the other sides. For example, ESR1 mutations in tissue, after exposure to AI in the metastatic setting, are seen in around 18% [to] 20% of the cases. But when you go to ctDNA, it goes up to 35% of, or even a higher percentage, of the tumors. And these are subclonal mutations. These are the mutations that are coming from a small subset of cancers so that needle biopsy might have missed this. So overall, [it] provides more universal landscape. At the same time, tissue provides deep information that often is missed by ctDNA.,so these are complementary. For example, copy number alterations, fusions are sometimes better detected in the tumor tissue. Also, it provides much better information about the subclonal mutations when they are unique to that part, that site because the levels of mutation, the threshold of mutation can be better if that particular mutation is not represented in the ctDNA pool. So, I put this together. Another thing that you can use when you have a baseline ctDNA is looking at the dynamics of ctDNA. And that's something that in the research setting you see more and more being utilized. And in clinical setting you have to see what is the clinical utility of it. But after we start very effective treatment, ctDNA can have folds of change, can become even completely undetectable using the current type of assays that we are using in the metastatic setting. After a few weeks, a couple of weeks of treatment this was shown in the PALOMA-3 [NCT01942135] analysis of ctDNA and more recently we have multiple papers analyzing serial ctDNA testing showing that the dynamics of ctDNA can actually predict the progression free survival. So that's something that I have as baseline. Usually, in clinical practice outside clinical trials, we do not do serial ctDNA testing at this point. But if I have a question, for example, there is a questionable progression, if there is a… I see that this patient's imaging is inconclusive, I can go back and order a ctDNA and look at the levels of ctDNA, if it's going up and down. And it helps me clinically to decide whether this tumor—this patient is progressing or not. So, I think from that standpoint, I would like to do the joint approach. At the time of progression, especially post-CDK4/6 in the first-line setting, I think it's very, very important to get both ctDNA and biopsy feasible. We often get biopsy as the—obviously, biopsy tells us a lot about the receptor subtypes. This tumor is still ER-positive, it's expressing the ER or not, something has changed in the tumor. And sometimes even we see some receptor rare, receptor switch from HER2-negative to HER2-positive. We all have seen some of those rare cases. So when it's feasible, I offer it to the patient, but definitely offer the ctDNA testing. A lot of alterations can happen on CDK4/6 inhibition plus endocrine therapy that results in resistance to endocrine therapy or resistance to CDK4/6 inhibitors. And that can guide our next-line treatment. For example, RB1 loss of function mutations result in CDK4/6 resistance, regardless of the type of CKD4/6 that we use. So, if I see RB1 loss of function mutation after exposure to CDK4/6 inhibitors, I'm less likely to offer that patient another second-line CKD4/6 inhibitor, for example. Same thing goes with the PTEN alterations that known acquired mechanism of resistance to CDK4/6 inhibitors. And more importantly, better chance of finding ESR1 mutations now that there's an FDA-approved drug for it, and we are using it in clinical practice to change our backbone of endocrine therapies, so I do that as well.
Transcript is AI-generated and edited for clarity and readability.
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