UGT1A1 Status Underutilized in Predicting Sacituzumab Toxicity in MBC

Mark Pegram, MD

Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology

Stanford University School of Medicine

Associate Director of Clinical Research

Stanford Comprehensive Cancer Institute

Stanford, CA

CASE SUMMARY

A 62-year-old woman presented with a 6-cm mass in her right breast; it had been present for 1 year​.

• Liver function tests: within normal limits​
• CT scan showed 2 liver nodules; the largest was 2 cm​.
• Bone scan showed extensive disease in her thoracic spine and ribs​.
• Biopsy: estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative ​grade 2 invasive ductal carcinoma
• Staging: T3N1M1 ​
• ECOG performance status: 0 ​
• She started treatment with letrozole (Femara) plus abemaciclib (Verzenio).
• Partial response was achieved​.
• Thirty months after treatment initiation:
• Follow-up imaging showed enlarged liver nodules and 2 new lung nodules (largest measuring 1.2 cm)​.
• ECOG performance status: 1​
• Liver function tests: normal​
• Hemoglobin A1c: normal​​
• Tissue sent for genomic testing did not show PIK3CA, ESR1, or other actionable mutations.
• Patient progressed after endocrine and CDK4/6i therapy. Received fulvestrant (Faslodex) plus everolimus (Afinitor) for progressive disease. ​
• Initial follow-up imaging post-treatment showed stable disease. Six-month post-treatment imaging showed liver and lung nodules enlarged from initial post-treatment scan.​
• Treated with capecitabine until progression of disease.
• The patient was then treated with sacituzumab govitecan (Trodelvy).

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.

REFERENCE:

1. Nelson RS, Seligson ND, Bottiglieri S, et al. UGT1A1 guided cancer therapy: Review of the evidence and considerations for clinical implementation. Cancers (Basel). 2021;13(7):1566. doi:10.3390/cancers13071566