Abstract P2-11-28: Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients
Authors: Nagahashi Masayuki , Toshikawa Chie , Ling YiWei , Hayashida Tetsu , Kitagawa Yuko , Futamura Manabu , Kuwayama Takashi , Nakamura Seigo , Yamauchi Hideko , Yamauchi Teruo , Kaneko Koji , Kanbayashi Chizuko , Sato Nobuaki , Tsuchida Junko , Moro Kazuki , Nakajima Masato , Shimada Yoshifumi , Ichikawa Hiroshi , Lyle Stephen , Miyoshi Yasuo , Takabe Kazuaki , Okuda Shujiro , Wakai Toshifumi 
Published: March 2023

Abstract
Background: Triple-negative breast cancer (TNBC) is the most fatal breast cancer subtype, which often shows aggressive progression, a high potential to metastasize, and resistance to chemotherapy. Comprehensive genomic profiling using next-generation sequencing (NGS) has been expected to identify gene alterations that are targetable by drugs. However, the significance of these genomic alterations in the cancer biology of TNBC patients has not yet been fully understood due to the lack of accurate clinical outcome data to compare with the genomic data. The aim of this study was to clarify the clinical impact of genomic profiling data, including copy number alterations (CNAs), in TNBC by comparing comprehensive genomic data with clinical outcomes. Methods: A total of 47 patients diagnosed with stage I-III TNBC (from the cohort reported in JCO Precis Oncol. 2018;2:PO.17.00211) were enrolled in this study. The genomic profiling of 435 known cancer genes by NGS with clinical outcomes were analyzed. Overall survival (OS) was evaluated for its association to gene alterations and distinctively CNAs. The cut-off values of CNA for OS were determined from the receiver operating characteristic curve using the Youden index for area under the curve (AUC). Kaplan-Meier plots and log-rank tests of OS were applied for each group. Univariate and multivariate analyses for OS were performed using a Cox proportional-hazards model to obtain the hazard ratio (HR) and 95% confidence intervals. Results: Utilizing NGS-based genomic profiling, at least one alteration was found in 82 of the 435 cancer-associated genes, and a total of 162 alterations were found in the 47 patients. Among the 82 genes with alterations, the presence or absence of TP53 and PTEN alterations was significantly associated with OS of TNBC patients; patients with TP53 alterations (n = 31) showed significantly shorter OS than those without TP53 alterations (n = 16, p = 0.023), and patients with PTEN alterations (n = 9) showed significantly shorter OS than those without PTEN alterations (n = 38, p = 0.023). The cut-off value of CNA for OS was set at 25 (AUC, 0.788; sensitivity, 0.727; specificity, 0.900). Interestingly, CNA-high patients (n = 20) showed significantly shorter OS than CNA-low patients (n = 27, p = 0.014). Univariate analysis revealed that TP53 alterations and CNAs were significant prognostic factors for OS (HR, 8.81; p = 0.008; and HR, 8.00; p = 0.014, respectively). Finally, multivariate analysis using background clinical data revealed that CNA was an independent prognostic factor for OS in TNBC patients (HR, 7.15; p = 0.044). Conclusion: Our data suggest that CNA is an independent prognostic marker in TNBC, and that can be estimated from comprehensive genomic profiling data by NGS. Further investigation is needed to clarify the mechanisms of how CNAs are associated with this lethal disease.
Citation Format: Masayuki Nagahashi, Chie Toshikawa, YiWei Ling, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Takashi Kuwayama, Seigo Nakamura, Hideko Yamauchi, Teruo Yamauchi, Koji Kaneko, Chizuko Kanbayashi, Nobuaki Sato, Junko Tsuchida, Kazuki Moro, Masato Nakajima, Yoshifumi Shimada, Hiroshi Ichikawa, Stephen Lyle, Yasuo Miyoshi, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai. Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients [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 P2-11-28.