Abstract GS1-08: Genomic characterisation of metastatic breast cancer
Authors: Andre F , Filleron T , Ng C , Bertucci F , Letourneau C , Jacquet A , Piscuoglio S , Jimenez M , Bachelot T 
Published: May 2019

Rationale: while large efforts have been done to characterize early breast cancer, little is known about the genomic landscape of metastatic breast cancer. In the present study, we performed whole exome sequencing of 800 metastatic breast cancers, in order to identify new candidate targets and better stratify patients eligible for innovative therapies.

Patients and Methods: Patients were selected to present a metastatic breast cancer and to have received a biopsy in the context of precision medicine trials (SAFIR01, SAFIR02, PERMED, MOSCATO, SHIVA). Samples with &gt;30% cancer cells, and normal DNA, were sequenced using Hiseq and Novaseq. Drivers were identified using MutSigCV. Actionability of somatic genetic alterations was determined based on OncoKB. Decomposition of mutational signatures was performed using deconstructSigs. Prognostic value was assessed using a cox model. TCGA database was used as comparator to identify gene alterations enriched in metastatic samples.

Results: results presented in the current abstract are based on the first 629 patients analyzed.Sequencing was performed in 387 patients with HR+/Her2- breast cancer, 186 triple negative breast cancers, and 32 Her2-overexpressing breast cancers. only 9 patients received a pretreatment with a CDK4 inhibitor. 24 driver genes were significantly mutated. In patients with HR+/Her2- breast cancer, 11 genes were found more frequently mutated in the metastatic setting as compared to early stage breast cancer. This includes TP53 (29%), KMT2C (13%), NCOR1 (8%), NF1 (7%), RB1 (4%), C16orf3 (2%), FRG1 (6%), ESR1 (21%), RIC8A (4%), AKT1 (7%), PLSCR5 (2%). In addition, in the whole population, KRAS was found mutated in 3% of samples (G12A/C/R/V) while its frequency of mutation in early breast cancer is &lt;1%. No gene alteration was found enriched in metastatic Her2+++ and TNBC. Copy number alterations were compared between metastatic and early breast cancer. 18 amplicons were found more frequently in HR+/Her2- metastatic breast cancers as compared to eBC. Among the genes enriched in metastatic samples, mutations in RB1 or NF1 were associated with a poor outcome ( median OS 9 and 13 months respectively, p=0.0038 and 0.01 respectively). 73% of patients presenting HR+/Her2- mBC had an actionable alteration, as compared to 55% of patients presenting HR+/Her2- eBC (p&lt;0.01). Patients with HR+/Her2- mBC presented an enrichment of gene alterations in the MAPK/ERK pathway (37% vs 22%) and in the HRD pathway (22% vs 10%). When the analysis focuses on mTNBC; the proportion of patient presenting an actionable alteration was comparable to the eTNBC. 11 (6%) and 16 (9%) patients presented a somatic mutation or homozygous gene deletion on BRCA1 and PTEN respectively.

We further assessed the mutational signatures in order to better understand which mutational processes could drive cancer progression. Metastatic HR+/Her2- mBC presented an increase in APOBEC, S3 (HRD), S10 (POLE-associated signature), S17 signatures as compared to early HR+/Her2- BC.

Conclusion: the present study, based on 629 patients, identifies 11 driver gene alterations and four mutational processes enriched in HR+/Her2- metastatic breast cancers. Final results on 800 patients will be presented.

Citation Format: Andre F, Filleron T, Ng C, Bertucci F, Letourneau C, Jacquet A, Piscuoglio S, Jimenez M, Bachelot T. Genomic characterisation of metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-08.