Optimal ESR1 Testing Strategies in HR+/HER2- Metastatic Breast Cancer
In the context of ESR1 mutation in HR+/HER2- metastatic breast cancer, key opinion leaders consider ideal testing modalities and timing to improve patient outcomes.
Transcript:
Joyce O'Shaughnessy, MD: Pedram, how do you time your looking? And should we only look once, and if we don't find it we're done? Or should we think about it serially, or?...
Pedram Razavi, MD, PhD: Yeah, I think the more we look, obviously, the more likely we find it. ctDNA sensitivity very much affects, gets affected, by the amount of ctDNA that is in the bloodstream. So, if the patient doesn't have a lot of disease, for example, at the levels of ctDNA, the fraction of the cell-free DNA, normal cell-free DNA versus tumor cell-free DNA, the fraction that comes from the tumor is low, they might not have a good sensitivity to find these. I often test for, do the liquid biopsies at the time of progression, especially if the patient is exposed to certain therapies that are increasing the risk of ESR1 mutation. So, I definitely repeat the testing even if the patient has longtime negative, and that gives me the option of offering the patients oral SERDs or other clinical trials down the line for these patients. I would like to highlight what Komal just touched base on. I'd say it's very, very important: not all ESR1 mutations are the same. And I think I would like to give a shoutout to our colleague Sarat Chandarlapaty [MD, PhD], and others, [who] 10 years ago actually, discovered the association between these LBD domain ESR1 mutations that resistance to endocrine therapy, especially estrogen deprivation therapies. And now it's the celebration of 10 years of this discovery and finally it is becoming actionable in clinic. But what is important and what all of these studies in the lab and also in clinic has shown is that not all these mutations have the same level of activity of the downstream ER. For example, Y537 mutations are much more activating than the others. D538 is the next. And then we have all the other ESR1 mutations that are activating and result in resistance to endocrine therapy with an AI, but maybe not to the same extent. But all of these patients, regardless, will more or less benefit from SERDs. As Komal mentioned, 537 and some others might actually not be as sensitive to fulvestrant, and that might be one of the good reasons that elacestrant is working better than fulvestrant. Some of these alterations, some of these mutations do not respond to fulvestrant as much as they do to the oral SERDs. So, I think that's another reason to potentially explain why we see the benefit of these oral SERDs. Another class of ESR1 mutations that have been overlooked but now they are entering clinic more and more and I just want our listeners and viewers to know about them are the ESR1 fusions. Obviously, much more complex genomically, but the genetic testing, especially now that we do a lot of these next-gen sequencing testings, are becoming more and more complex, and we are more likely to pick up these complex alterations. And this is when a tumor, there has been a fusion. So, the ESR1 gene, the part of the ESR1 that results in activation of the downstream ER, binds to the DNA, so on and so forth, that is preserved. The tumor loses the LB [ligand-binding] domain, part of the ESR1, and fuses to another gene. So, this chimeric gene doesn't have the LBD domain, which is where all of our drugs work. So, the SERDs, everything, that's where the drugs work. So, these ESR1 mutations, if they are expressed and if the molecule and the protein is still active, they are resistant to almost all forms of endocrine therapy that we have, including some of the novel ones, like PROTACs, the current PROTACs that we have. Again, they target the LB domain. So, if a tumor has lost the LB domain, they're not going to be effective. I think that's another thing for us to consider and I think with the improved genetic testing, genomic testing that we're doing both in blood and also in tumor, we're going to pick them up more often, so I want all of us to be aware of them. And if you see 1 of these, and majority of the centers, they have molecular tumor boards or they can, if they're in community they can go and refer a patient or ask the question from one of the centers that have a molecular tumor board, does this particular fusion expected to result to resistance and activation of the downstream ER or not? So, I think that's something for us to consider. And also, we are finding some very rare ESR1 mutations. We have sequenced 10,000 breast cancers here at MSK and we are finding some new classes of ESR1 mutations that might actually result in resistant to fulvestrant and SERDs but not to AI. But those are extremely rare. There are resources for all of us to go and we are in the field and Komal and I review these genomic data on a daily basis, but still. And we also refer to this as well, to these online databases of the mutations, and I think we should refer to them. This OncoKB is one of the ones that is manually annotated. Every single gene, every single mutation is annotated over there for disease specific, in a disease specific manner. It also assigns a level of evidence: Is it FDA-approved? Is it NCCN-guideline endorsed? So on and so forth. It gives a level of evidence to particular mutation, for particular cancer type, and also provides some information: Is this mutation activating? Is this mutation loss of function? So on and so forth. I think when in doubt, it's very user-friendly, and I think all of us should feel comfortable using some of these databases quickly to understand and educate ourselves what is the effect of these mutations, because just the amount of information coming into clinic is overwhelming. It's hard to keep up with all of these.
Transcript is AI-generated and edited for clarity and readability.
