Abstract P5-14-04: Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04)
Authors: Kim Min Hwan , Yang Yohan , Kim Eunyoung , Moon Yong Wha , Kim Gun Min , Kim Seul-Gi , Chae Yee Soo , Lee Jieun , Jeong Jae Ho , Lee Kyung-Hun , Kim Han Jo , Jung Joo Young , Koh Su-Jin , Lee Kyoung Eun , Kim Hee-Jun , Park Kyong Hwa , Lim Seungtaek , Park Yeon Hee , Kim Sangwoo , Sohn Joo Hyuk 
Published: March 2023

Background The hormone receptor (HR)-positive metastatic breast cancer (MBC) patients show a diverse range of tumor mutational burden (TMB), but its biological and clinical implication has been largely unrevealed. Here we report genomic landscape of 117 HR+ MBC patients who were included in the pre-screening tissue genomic analysis of MUTATION-1 study (SABCS 2021; Abs P1-19-03) according to TMB of tumors. Patients and method The MUTATION-1 study (NCT03608865) enrolled HR-positive MBC patients who received prior ≥ 1 line of systemic therapy, and performed prescreening with whole exome sequencing (WES) and RNA-seq of fresh-frozen tissue of metastatic or recurred tumors. Patients who met upper 30% of TMB were eligible for treatment phase and received durvalumab plus tremelimumab. This study analyzed 117 prescreening tissues of MUTATION-1 study patients for mutation and transcriptomic landscape analysis. (WES, n=117; RNA-seq, n=107) Results The 117 patients showed diverse TMB (range 0~21.7 mut/Mb, median 2.0 mut/Mb) and genomic alterations. The most frequently mutated gene included PIK3CA (29.1%), TP53 (27.4%), ESR1 (23.9%), GATA3 (19.7%), and MAP3K1 (12.0%). There was no association between patient survival and TMB. We estimated single base substitution (SBS) mutational signature of patients with SigMA algorithm. The patients were classified according to their dominant mutational signatures: APOBEC (25.6%), HRD (41.0%), clockwise (28.2%), SBS8, and SBS17. The APOBEC patients showed higher TMB (median 3.47 mut/Mb) and higher mutation prevalence in PIK3CA (63.3% vs. 29.1%), ARID1A (16.7% vs. 6.0%), and NF1 (16.7% vs. 6.8%) compared with other patients. The high TMB positively correlated with time from MBC diagnosis to biopsy. Tumors with TMB ≥ 5 mut/Mb were exclusively found in patients diagnosed as MBC ≥ 36 months before the timing of biopsy. In the matched RNA-seq analysis, TMB was higher in luminal B and HER2-enriched intrinsic subtype patients than basal or luminal A subtype. The high TMB (≥ 3.16 mut/Mb, cutoff used for treatment phase patient selection) patients showed upregulation of G2/M checkpoint, MYC, E2F1, and MTORC1 signature compared to low TMB patients. In the tumor microenvironment analysis by CIBESORT, PIK3CA mutant patients showed lower score of cytotoxic T cell than others. Conclusions The high TMB in HR+ breast cancer was associated with longer time duration from MBC diagnosis to biopsy, high APOBEC signature, and cell cycle/MYC signature gene upregulation. Further therapeutic targeting of high TMB patients is warranted based on their genomic and immunologic characteristics.

Citation Format: Min Hwan Kim, Yohan Yang, Eunyoung Kim, Yong Wha Moon, Gun Min Kim, Seul-Gi Kim, Yee Soo Chae, Jieun Lee, Jae Ho Jeong, Kyung-Hun Lee, Han Jo Kim, Joo Young Jung, Su-Jin Koh, Kyoung Eun Lee, Hee-Jun Kim, Kyong Hwa Park, Seungtaek Lim, Yeon Hee Park, Sangwoo Kim, Joo Hyuk Sohn. Genomic characterization of hormone receptor-positive advanced breast cancer with high tumor mutational burden: fresh-frozen tissue genomic analysis from MUTATION-1 study (KCSG BR17-04) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-04.