UGT1A1 *28/*28 genotype and risk of toxicity and disease progression in breast cancer patients treated with sacituzumab govitecan-hziy.

Abstract

1033 Background: In metastatic and locally recurrent breast cancer the antibody drug conjugate, sacituzumab govitecan-hziy (SG), is approved as a second-line therapy in triple negative disease and a third-line therapy and beyond for ER+, endocrine resistant disease. UGT1A1 metabolizes the SN-38 payload of SG, and polymorphisms of the gene can lead to decreased enzyme activity and increased toxicity. We sought to determine if patients who were homozygous for the UGT1A1*28 allele polymorphism (*28/*28) experienced increased toxicity and a lower rate of disease progression when treated with SG. Methods: To evaluate the association of the *28/*28 genotype with the competing endpoints of Discontinuations for Disease Progression, Toxicity, and Futility, this pilot study undertook a single-center, retrospective chart review of breast cancer patients who received SG at City of Hope. Eligible subjects included breast cancer patients who received at least one dose of SG, had a known UGT1A1 status, and were followed for toxicity and disease progression. Data collection and analysis included reasons for discontinuing SG, onset of adverse effects, UGT1A1 status, age, gender, race and ethnicity, prior lines of therapy, and tumor receptor status. Results: Between July 2020 and September 2022, 67 women and 1 man underwent UGT1A1 testing prior to initiation of SG; the median age was 57.8 years, 75.0% had triple negative disease, and SG was given as a median third line of therapy. Seventeen (25%) patients were homozygous for *28 and 24 (35.3%) were heterozygous. Notably relating race and genotype, all 7 self-reported Black subjects were either carriers or homozygous for *28; there were no Black wildtype subjects. Most subjects were followed until Discontinuation for Disease Progression (55.9%), Toxicity (8.8%), or Futility (5.9%). Alternatively, 4.4% of subjects were lost to follow-up and 1 subject halted treatment due to cancer remission. The remaining 23.5% of subjects still took SG by the close of study in November 2022. On competing risk analysis comparing the wildtype group, *28/*28’s association with increased Discontinuation for Toxicity, was confirmed with a Hazards Ratio of 5.52 (95% confidence interval [CI] 1.15-26.49, p = 0.03). In contrast, Discontinuation for Disease Progression was unassociated to *28/*28 status in comparison to the wildtype group with a Hazards Ratio of 0.80 (95% CI 0.39-1.65, p = 0.54). Conclusions: Despite the relatively small sample size, 25% of patients had the *28/*28 genotype. We confirmed that *28/*28 is associated with a higher risk for discontinuation of SG for toxicity without an association to disease progression based on mutation status. Early UGT1A1 testing as standard practice may identify patients at risk for excess toxicity, who may undergo early dose reductions to prevent discontinuation of this important advanced breast cancer treatment.

Impact of Pharmacogenomics in Clinical Practice

“…In PMs, the administration of irinotecan has been found to be associated with higher systemic active metabolite concentrations with a higher risk of severe adverse events, such as profuse diarrhea and severe or life-threatening neutropenia [59]. Similar problems were found in PMs with the UGT1A1 *28/*28 genotype receiving sacituzumab govitecan-hziy [60]. Moreover, hyperbilirubinemia has been reported in patients with UGT polymorphisms receiving nilotinib [61] or pazopanib [62].…”