Abstract P6-01-14: Genomic characterization and oncology outcomes of a locally advanced ER+/HER2- breast cancer cohort treated with neoadjuvant chemotherapy
Authors: Abreu Maira , Furlan Larissa , Ma Yutong , Chen Hanlin , Ferreira Carla , Fares Aline , Constantino Eduardo , Nora Gustavo R. , Lucio Gabriela , Colombo Tatiana , Liu Rui , Wu Xue , Ou Qiuxiang , Araujo Daniel V. 
Published: March 2023

Abstract
Background: Locally advanced ER+/HER2- breast cancer (LABC) is an aggressive condition often requiring multidisciplinary management. While early and metastatic breast cancer are well characterized, LABC is largely underrepresented in clinical trials and genomic studies. Herein we present comprehensive molecular profiling of an ER+/HER2- LABC cohort and their oncology outcomes. Method: The clinical records of locally advanced ER+/HER2- LABC (EC IIIA or higher) patients diagnosed and treated with neoadjuvant chemotherapy at Hospital de Base (Sao Jose do Rio Preto, Brazil) were reviewed. Comprehensive genomic profiling was performed on formalin-fixed paraffin-embedded (FFPE) tumor samples using capture-based hybrid next-generation sequencing (NGS) by targeting 425 cancer-related genes. The status of patients’ homologous recombination deficiency (HRD) and tumor mutation burden (TMB) were also measured. Survival outcomes were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed to assess the association between oncology outcomes with clinicopathological and molecular characteristics. A p-value of 0.05 was considered statistically significant. FDR was utilized for multiple comparisons adjustment. Result: From May 2010 and December 2019, after inclusion and exclusion criteria, 90 patients were included. The median age of the cohort was 54 (24 – 88) years old. There were 21 (23%), 65 (72%), and 4 (5%) patients with stage IIIA, IIIB, and IIIC, respectively. A majority of the patients had tumors Grade 2 (72%, 65/90), with 10 (11%) Grade 1, 12 (13%) Grade 3, and the remaining 3 (4%) being undetermined. Most patients were postmenopause, 58% (52/90). All patients received chemotherapy-based neoadjuvant treatment, and 6 (7%) achieved pathological complete response (pCR). After a median follow-up of 63 months, the median recurrence-free survival (RFS) of the entire cohort was 80.4 months and the median overall survival (OS) was not reached yet. . A lower tumor grade was strongly associated with better RFS (p = 0.00058) and OS (p = 0.00028), while the pCR subgroup did not show significantly better RFS or OS. In terms of genomic profiling, PICK3CA (32/90, 35.6%) and TP53 (27/90, 30.0%) were the most frequently mutated genes. The median TMB was 4.1 muts/Mb, ranging from 0 to 29.7 muts/Mb. Altered NOTCH pathway was a negative prognostic factor (HR: 2.6; 95%CI: 1.0 - 6.5, p = 0.042) while NRF2 pathway aberrations demonstrated poorer RFS compared to their wildtype counterparts (HR: 3.1; 95%CI: 1.1 - 8.9, p = 0.035). Of note, mutated CUL3, a key player of the NRF2 pathway, was correlated with poor RFS (HR: 42.8; 95%CI: 7.0 - 262.5, adjusted p = 0.0004) and OS (HR: 48.4; 95%CI: 8.0 - 294.0, adjusted p = 0.0003) although the sample size was restricted. Furthermore, patients carrying NOTCH2 mutations (N = 2) showed significantly shorter RFS (HR: 14.9; 95%CI: 3.0 - 74.2, adjusted p = 0.004) and OS (HR: 28.8; 95%CI: 5.2 - 160.2, adjusted p = 0.0008). TMB was not a predictor of either pCR or survival. Eight patients carried BRCA1/2 pathogenic mutations (8.9%), and ten out of 44 HRD evaluable patients (22.7%) were HRD-high (HRD score ≥ 38). However, neither BRCA1/2 mutations nor HRD-positivity was associated with pCR, RFS, or OS. Conclusion: Comprehensive genomic profiling of ER+/HER2- LABC patients revealed that altered NOTCH and NFR2 pathway genes were associated with poor survival outcomes. An analysis involving residual cancer burden (RCB) is currently ongoing.
Citation Format: Maira Abreu, Larissa Furlan, Yutong Ma, Hanlin Chen, Carla Ferreira, Aline Fares, Eduardo Constantino, Gustavo R. Nora, Gabriela Lucio, Tatiana Colombo, Rui Liu, Xue Wu, Qiuxiang Ou, Daniel V. Araujo. Genomic characterization and oncology outcomes of a locally advanced ER+/HER2- breast cancer cohort treated with neoadjuvant chemotherapy [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 P6-01-14.