Abstract CT135: Uncovering the genomic heterogeneity of multifocal breast cancer
Authors: Desmedt Christine , Fumagalli Debora , Pietri Elisabetta , Zoppoli Gabriele , Nik-Zainal Serena , Gundem Gunes , Brown David , Rothe Francois , Majjaj Samira , Garuti Anna , Carminati Enrico , Loi Sherene , Van Brussel Thomas , Maetens Marion , Mudie Laura , Vincent Delphine , Kheddoumi Naima , Serra Luigi , Massa Ilaria , Ballestrero Alberto , Amadori Dino , Salgado Roberto , de Wind Alexandre , Lambrechts Diether , Piccart Martine , Larsimont Denis , Campbell Peter J. , Sotiriou Christos 
Published: August 2015

Abstract
Background: Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histo-pathological parameters.Material and methods: The characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER and HER2 status. Mutations were classified as ‘oncogenic’ in case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep re-sequencing using an orthogonal platform. Whole genome rearrangement screen was further conducted in 8/36 patients.Results: Twenty-four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three-quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter-lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3 and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than the homogeneous ones. Genome-wide analysis of a limited number of MFBC nevertheless identified a common somatic background in all studied MFBC, including those with no mutation in common between the lesions.
Conclusion and perspectives: As the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings, based on the targeted sequencing of cancer genes in 36 MFBC tumors, highlight the presence of genomic inter-lesion heterogeneity in one-third of the cases despite similar pathological features. This implies that deeper molecular characterization of all MFBC lesions is warranted for the adequate management of those cancers.
[CD, DF, and EP contributed equally to this work. PJC and CS contributed equally to this work.]
Citation Format: Christine Desmedt, Debora Fumagalli, Elisabetta Pietri, Gabriele Zoppoli, Serena Nik-Zainal, Gunes Gundem, David Brown, Francois Rothe, Samira Majjaj, Anna Garuti, Enrico Carminati, Sherene Loi, Thomas Van Brussel, Marion Maetens, Laura Mudie, Delphine Vincent, Naima Kheddoumi, Luigi Serra, Ilaria Massa, Alberto Ballestrero, Dino Amadori, Roberto Salgado, Alexandre de Wind, Diether Lambrechts, Martine Piccart, Denis Larsimont, Peter J. Campbell, Christos Sotiriou. Uncovering the genomic heterogeneity of multifocal breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT135. doi:10.1158/1538-7445.AM2015-CT135