Abstract 3440: Genomic evolution of synchronous and metachronous breast cancer metastasis revealed from a prospective clinical trial
Authors: Driouch Keltouma , Tariq Zakia , Baulande Sylvain , Raynal Virginie , Bernard Virginie , Bidard Francois-Clement , Benhamo Vanessa , Bieche Ivan , Sigal Brigitte , Lidereau Rosette , Cottu Paul 
Published: August 2018

Abstract
Background: Tumor progression is an evolutionary process associated with the accumulation of somatic genomic alterations. Even though metastasis is a fundamental process and a challenging issue for the progress in targeted treatment, the molecular drivers of cancer metastasis remains poorly understood. Despite the advance in high throughput sequencing and the characterization of hundreds of breast tumor genomes, it is still unclear whether cancer genomes evolve by neutral processes or whether genetic alterations that favorable tumor progression are selected under pressures of cancer therapy or both.
To gain insights into the molecular processes driving breast cancer metastasis and to identify targetable genetic events associated with early and late stages of the disease, we studied the mutational profiles of a series of paired primary breast tumors and subsequent metastases collected as part of the ESOPE clinical Trial.
Methods: Matched primary breast tumors, first metastases and germline DNAs were obtained from 31 patients, divided in 10 therapy-naïve synchronous primary cancers and metastases and 21 metachronous primary tumors and metastases that undergone first line adjuvant treatments. On Illumina platform, WES was performed and three variant callers were used in parallel to predicted variations. After annotation, variants with low 1000Genome frequency and absent in germline samples, were validated by IGV visualization and then considered as somatic variants. To identify significantly mutated genes, we used the Mutation Significance (MutSigCV) tool and the Cancer Gene Census list of relevant genes. Analysis of mutational process signatures was also performed though DeconstructSigs R packages.
Results: Synchronous and metachronous metastases globally exhibited similar mutation rates, however a significant difference was observed in the number of accumulated private mutations in both types of metastases. With few exceptions, our data indicate that the genomic profiles of metastases mainly diverge late in breast cancer progression, with relatively few private mutations in the primary tumors. In contrast, an increase of somatic variants was found in the metachronous metastases as compared to their primary tumors of origin. Most of driver mutations were shared by primary tumors and metastases but additional drivers were highlighted in the metastatic lesions, such as variants of PIK3CA, IGF1R, CDH1, NF1 as well as ESR1. Moreover, recurrent mutated genes were also identified in metastases that have not been previously described (FDR&lt;0.1). Analyses of mutational signatures revealed a shift towards APOBEC, POLE, MMR and HR activity. In conclusion, synchronous and metachronous breast cancers differ in their genomic evolution and the characterization of driver mutations in metastases might open new avenues for novel therapeutic strategies in metastatic breast cancer.
Citation Format: Keltouma Driouch, Zakia Tariq, Sylvain Baulande, Virginie Raynal, Virginie Bernard, Francois-Clement Bidard, Vanessa Benhamo, Ivan Bieche, Brigitte Sigal, Rosette Lidereau, Paul Cottu. Genomic evolution of synchronous and metachronous breast cancer metastasis revealed from a prospective clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3440.