Abstract 2951: A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity

Chihiro Udagawa,Norie Abe,Tokiwa Motonari,Arata Shimo,Mari Hara,Masayuki Yoshida,Mikiko Unesoko,Yasuyuki Kojima,Kenji Tamura,Reiko Yoshie,Tatsunori Shimoi,Koichiro Tsugawa,Hiroshi Okamura,Hitoshi Zembutsu,Teruhiko Yoshida,Taisei Mushiroda,Hisamitsu Zaha

doi:10.1158/1538-7445.sabcs18-2951

Abstract

Purpose: Trastuzumab has been administered to HER2-positive breast or gastric cancer patients as an effective treatment, however, the cardiotoxicity is identified as one of the life-threatening side effects. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a genome-wide association study (GWAS). Experimental Design: We carried out a GWAS using 11 cases (with trastuzumab-induced cardiotoxicity) and 257 controls (showing no sign of trastuzumab-induced cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed smallest P value in GWAS ( P = 1.61 x 10 -7 -1.97 x 10 -4 ) were further examined using replication samples consisted of 14 cases and 199 controls. Results: The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (chromosome 13q14.3, 4q25, 15q26.3, 17q25.3 and another 15q26.3, P combined = 6.00 x 10 -6 , 8.60 x 10 -5 , 1.01 x 10 -4 , 1.07 x 10 -4 , 1.60 x 10 -4 , respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity, using five SNPs which revealed smallest P value at each locus. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was 42.5% ( P =8.69 x 10 -15 ) . This scoring system using five candidate loci could be used to predict the risk of the adverse event before administration of trastuzumab. Conclusion: We identified five novel loci, which could be associated with trastuzumab-induced cardiotoxicity. These findings provide new insights into personalized trastuzumab therapy for patients with HER2-positive cancer. Citation Format: Chihiro Udagawa, Mari Hara, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Hisamitsu Zaha, Norie Abe, Tokiwa Motonari, Mikiko Unesoko, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Taisei Mushiroda, Koichiro Tsugawa, Hitoshi Zembutsu. A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2951.

Full Text