An exploratory study on prediction of risk for abemaciclib-induced interstitial lung disease or hepatotoxicity by specific human leukocyte antigen alleles.
Authors: Imamura Chiyo K. , Mushiroda Taisei , Hosonaga Mari , Tsurutani Junji , Tsuneizumi Michiko , Yanagawa Takehiro , Bando Hiroko , Fujimoto Yumi , Kojima Yasuyuki , Tamaki Kentaro , Iwamoto Takayuki , Sangai Takafumi , Ishikawa Takashi , Kikawa Yuichiro , Mukai Hirofumi 
Published: August 2024

3087

Background: Interstitial lung disease (ILD) and hepatotoxicity have been observed in a small population of patients treated with abemaciclib. It has been reported that the antitumor effect of cyclin-dependent kinases 4 and 6 inhibitors including abemaciclib is contributed by not only inducing tumor cell cycle arrest but also promoting antitumor immunity. Based on our experience of higher incidence of severe toxicities in the clinical study of abemaciclib combined with nivolumab, we speculated that abemaciclib-related toxicity might also be mediated by immune system. This study sought to identify specific human leukocyte antigen (HLA) alleles associated with abemaciclib-induced ILD or hepatotoxicity. Methods: Of 236 abemaciclib-treated patients with advanced breast cancer in the previous observational study, 83 patients were enrolled by obtaining additional informed consent for collecting blood and pharmacogenetic investigation. Genomic DNA was extracted from peripheral whole blood, and HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and -DPB1were genotyped to four-digit resolution by next generation sequencing method. Exploratory marker identification evaluated the HLA alleles with frequency of ≥ 10% in cases. The significance level was adjusted by Bonferroni’s correction for multiple testing. Results: One hundred seventeen alleles ( HLA-A,13 alleles; -B, 26 alleles; -C, 16alleles; -DRB1,24 alleles; -DQA1, 14 alleles; -DQB1, 13 alleles; -DPB1, 11 alleles) were detected. Of 28 alleles with frequency of ≥ 10% in cases with development of ILD [significance level = .00178 (0.05 divided by 28)], there was no significant association between HLA allele carriages and development of ILD in 16 cases and 67 controls. Of 28 alleles with frequency of ≥ 10% in cases with grade ≥ 2 alanine aminotransferase (ALT) elevation [significance level = .00178 (0.05 divided by 28)], HLA-DQA1*05:05 allele carriage was found to be significantly associated with ALT elevation in 13 cases with grade ≥ 2 and 47 controls with grade 0. HLA- DQA1*05:05 was present in 30.8% of cases and in 0.0% of controls ( P=.00147; odds ratio, 45.0; 95% CI, 2.23 to 907). Suggestive associations of ALT elevation were observed with HLA-DPB1*05:01 allele carriage ( P=.00930; odds ratio, 11.5; 95% CI, 1.38 to 95.7) and HLA-A*31:01 allele carriage ( P=.01522; odds ratio, 5.86; 95% CI, 1.46 to 23.4). Conclusions: Evaluated 28 HLA alleles were not associated with development of ILD. HLA-DQA1*05:05 allele was identified as a promising marker candidate that can predict patients with a higher risk of abemaciclib-induced hepatotoxicity. Further study is necessary to confirm the association in an independent population for managing liver safety risk during abemaciclib treatment. This result also implicates an immune-mediated mechanism for abemaciclib-related hepatotoxicity. Clinical trial information: UMIN000046611.