Actionable Gene Alterations in an Asian Population With Triple-Negative Breast Cancer

Abstract

Purpose It has been suggested that the biologic characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to occur at a higher incidence in Japan than in the United States. However, most genomic studies of these tumors are from Western countries, and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gathers data primarily from non-Asian patients. Materials and Methods We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes, among Japanese patients with TNBC (n = 53) and compared the results with independent data obtained from TCGA (n = 123). Results Driver alterations were identified in 51 (96%) of 53 Japanese patients. Although the overall alteration spectrum among Japanese patients was similar to that of TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutational burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35 of 53) of Japanese patients, as well as 66.7% (82 of 123) of TCGA cohort, had alterations in at least one actionable gene targetable by US Food and Drug Administration–approved drug. Conclusion Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer

“…Our data are consistent with previous evidence, i.e. that mutation of TP53 ( Cancer Genome Atlas Network, 2012 ; Jiang et al, 2019 ; Nagahashi et al, 2018 ) and amplification of MYC ( Cancer Genome Atlas Network, 2012 ; Jiang et al, 2019 ; Curtis et al, 2012 ) are the two most common genetic aberrations in TNBC, and frequently occur in combination ( Fig. 1 ).…”

“…Developing genetic models for TNBC is challenging. Most TNBCs contain mutations in TP53 , but some other genes are also commonly mutated ( Cancer Genome Atlas Network, 2012 ; Jiang et al, 2019 ; Nagahashi et al, 2018 ). However, computational work ( Cancer Genome Atlas Network, 2012 ; Jiang et al, 2019 ; Mermel et al, 2011 ; Sanchez-Garcia et al, 2014 ; Curtis et al, 2012 ) has identified extensive genomic copy number alterations (CNAs) that define regions that commonly overlap between different patients.…”

Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

“…Racial and ethnic population‐specific cancer driver alterations and single nucleotide polymorphisms (SNPs) may complicate the evaluation and interpretation of the results of genetic analyses. Several studies have reported obvious racial differences in cancer‐specific driver alterations among Japanese individuals . Furthermore, 15% of SNPs are reportedly specific to Japanese individuals, thus affecting the evaluation of the clinical significance of genetic alterations.…”

EGFR-to-Src family tyrosine kinase switching in proliferating-DTP TNBC cells creates a hyperphosphorylation-dependent vulnerability to EGFR TKI

“…Recently, a large single-cell RNA Sequencing analysis study on chemotherapy-treated patients by Kim et al (2018) demonstrates that resistance to chemotherapy is mainly adaptive in nature and NACT nongenetically selects residual tumor cells due to transcriptional and molecular reprogramming (Kim et al 2018). Few genomic studies on Asian TNBC cohorts from Japan and China detect actionable genetic vulnerabilities like alteration in MYC and PTK2 (Kovacevic et al 2016)(DOI: 10.1200/po.17.00211), while the top altered genes in recurrence in Chinese patients were TP53, PTEN, RB1, PIK3CA and BRCA1 (Nagahashi et al 2018(Nagahashi et al )(10.1080(Nagahashi et al /07853890.2021. These studies indicate that Asian TNBC tumors also exhibit genomic makeups not much different from the Western population, as reported in TCGA TNBC data.…”