During a Case-Based Roundtable® event, Mark Pegram, MD, discussed the value of testing for UGT1A1 status in patients receiving sacituzumab govitecan for hormone receptor–positive breast cancer in the second article of a 2-part series.
CASE SUMMARY
A 62-year-old woman presented with a 6-cm mass in her right breast; it had been present for 1 year.
Targeted Oncology: How valuable is knowing the UGT1A1 status’s for anticipating the safety outcomes of patients in the TROPiCS-02 trial (NCT03901339)?
MARK PEGRAM, MD: The metabolism of SN-38, which is the active metabolite of irinotecan, is predicated by this enzyme UGT1A1. This gene has polymorphisms in humans; there are multiple, but there are some that impact the metabolism of SN-38 and can lead to more toxicity, particularly the *28/*28 patients who have the polymorphism in both alleles of this gene.
[Some institutions use] germline DNA sequence analysis to understand the UGT1A1 gene sequence before prescribing sacituzumab govitecan or irinotecan. We don’t…[and] I don’t know why that is—we probably should. We can do it. It’s expensive, and I assume that’s the main reason why we’re not doing it on everybody routinely. You could start at a lower dose; if you knew for a fact that you have a *28/*28 genotype, you wouldn’t want to give that patient a full dose on cycle 1. The same is true for irinotecan in colon cancer and other neoplasms. I’ve never tried to get reimbursed before; I don’t know the answer. But I would think if somebody got sick on the first cycle and then you get it, you can probably get reimbursed for [testing]. But at that point, you’re going to hold and then dose reduce anyway. [The test] would be just for the chart, but it’s not going to change anything. Even if you have to explain the cycle and toxicity. It’s satisfying because you have an explanation, but it’s not going to change your action. So some patients might be able to live without it. If a test result isn’t going to change what you’re going do, then do you need to do the test in any discipline?
But the pharmacologists in the world are [disappointed] when we don’t do these genotypes, because they spent their whole career developing this association and now clinicians are [less enthusiastic] about it. That will probably change in the next generation.
What is significant about the payload and composition of sacituzumab govitecan as an antibody-drug conjugate (ADC)?
The SN-38 payload is slightly different than the metabolite of irinotecan because the irinotecan metabolite is glucuronidated, and it’s more toxic than naked SN-38. The payload for sacituzumab govitecan was deliberately chosen to be SN-38 that isn’t glucuronidated because it’s only moderately toxic as payloads go. This is the first moderately toxic ADC of oncology. All the other payloads in hematologic malignancies and solid tumors have been [highly] toxic payloads for reasons that still mystify me. I think you could put probably any chemotherapy you want on an ADC and it would make that chemotherapy easier to give, safer, with much less toxicity and probably be more active.
I wrote my first ADC paper in 2003 and it was a taxane conjugated to [trastuzumab but] we couldn’t get into the clinic. There is a lot more to read about this SN-38 and its metabolism. If you’re interested in the genotyping, you can talk to your genetics clinic about it and see if they’re more enthusiastic than we are about it.
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