Abstract P4-07-05: Tumor mutational profiles of extreme long-term survivors with metastatic breast cancer
Authors: Hu Yang , Shin Junha , Roy Sushmita , Burkard Mark E 
Published: March 2022

Background: Extreme population sampling can discover genomic characteristics with a high likelihood of functional significance. Here, we focus on people who live for many years or decades with metastatic breast cancer (MBC). Identification of genetic markers characteristic of this population may allow long-term survival to be predicted and enable de-escalation of treatment and improved care for this subgroup of breast cancer patients. . Methods: We identified women who have MBC and have lived greater than 10 years (HR+ breast cancer) or greater than 5 years (HR- breast cancer) from initial diagnosis. A total of 14 had archived FFPE metastatic tumor specimens and matched blood available for analysis. We performed whole-exome sequencing (WES) on FFPE tumor specimens (somatic) and blood samples (germline) pairs of 14 long term survivor patients. We used Illumina DRAGEN pipeline for the read alignment and base quality calibration and GATK MuTect2 pipeline for the somatic short variant identification. Common variants were filtered using 1000 Genomes Project, Exome Sequencing Project and gnomAD and annotated using Funcotator of the GATK pipeline. Results: A cohort of 53 patients, who met criteria, with biopsy proven MBC and long survival were identified in our institution. Among them, 14 patients had sufficient archived tumor for analysis, consisting of 7 HR+/HER2-, 5 HR+/HER2+, 1 HR+/HER2- and 1 TNBC specimens. Histological type was ductal in 9 patients and lobular in 4 patients. The median age of MBC diagnosis was 53 years with 11 patients diagnosed between ages 35-64 and 3 patients diagnosed after age 65. At the time of study, 13 of these 14 patients are still living. Median time to metastasis after diagnosis was 10.2 years with metastasis occurring in less than 1 year in 2 patients, less than 5 years in 10 patients and greater than 5 years in 2 patients. Metastases to bone were present in 9 patients, to visceral organs in 8 patients and to local and regional lymph nodes in 8 patients. The most common somatic variants identified were in PIK3CA, ARID1A, and TP53. When compared with prior analyses of MBC (INSERM, MBC Project), we found that ARID1A mutations were more commonly found, whereas PTEN and ESR1 mutations were never identified, suggesting a somatic mutational profile characteristic of extreme survivors. ARID1A mutations (2 nonsense - p.R1505* and p.Q944*, 1 missense - p.L1496V, 1 frameshift - p.P729fs) occurred in 4 patients, all with ER/PR+ and all HER2- breast cancer. Median survival to date since diagnosis was 30.1 years (range 21.4-39.0). Median survival to date after metastasis was 14.9 years (range 2.7-35.0). PIK3CA mutations (5 missense - p.H1047R x2, E545K, H1047L, E545K) occurred in 5 patients, all with ER/PR+ and 2 with HER2+ breast cancer. Median survival to date since diagnosis was 23.5 years (range 20.1-39.0). Median survival to date after metastasis was 15.97 years (range 3.4-35.0). TP53 mutations (1 nonsense - p.E285*, 1 missense - p.E285K, 1 frameshift - p.N200fs) occurred in 3 patients, all with ER/PR+ and 2 with HER2+ breast cancer. Median survival to date since diagnosis was 21.7 years (range 21.7-36.2). Median survival after metastasis was 16.0 years (range 2.7-21.4). Conclusions: ARID1A mutations are overrepresented and PTEN and ESR1 are underrepresented in metastatic tumors in extreme long-term survivors with MBC. Further analyses will determine if ARID1A mutations are present at tumor inception or are acquired in metastases in this cohort with indolent disease. Additionally, it is possible that germline genomic profiles may be relevant to long-term survival. Given the variability in this cohort, a larger sample of extreme survivors will be necessary to identify characteristic genetic profiles.

Citation Format: Yang Hu, Junha Shin, Sushmita Roy, Mark E Burkard. Tumor mutational profiles of extreme long-term survivors with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-05.