Abstract 4320: Genomic change in residual triple-negative breast cancers after neoadjuvant chemotherapy
Authors: Aguilar-Mahecha Adriana , Przybytkowski Ewa , Lafleur Josiane , Lan Cathy , Légaré Stephanie , Alirezaie Najmeh , Séguin Carole , Discepola Federico , Kovacina Bojan , Mihalcioiu Catalin , Robidoux André , Marcus Elizabeth , Roy Josée Anne , Pelmus Manuela , Aleynikova Olga , Nabavi Sheida , Majewski Jacek , Basik Mark 
Published: August 2015

Abstract
Background: Triple negative breast cancer (TNBC) is characterized by its aggressive phenotype and its genomic instability. TNBC patients who do not respond to neoadjuvant chemotherapy have a very poor prognosis. Currently, little is known about the mechanisms of drug resistance and how to overcome it in TNBC. Our study aims at identifying molecular factors enriched for in residual TNBC tumors after standard neoadjuvant chemotherapy.
Methods: We obtained specimens from 60 TNBC patients participating in a clinical trial (Q-CROC-03). Biopsies were collected prior to and after standard neoadjuvant chemotherapy and residual cancer was collected at the time of surgery. Matched tumor specimens (pre and post) from 9 patients were analyzed by array comparative genomic hybridization (CGH), gene expression microarrays and whole exome sequencing. All samples contained &gt;50% tumor cellularity.
Results: Gene expression data was used to identify the different TNBC subtypes (TNBCtype). Six of the 7 subtypes were represented in at least one sample from our cohort. In the post-chemo samples, we observed a change in TNBC subtype compared to the pre-chemo samples in 6 pairs. The most common switch was to the Immuno Modulatory subtype (IM). aCGH analysis showed relatively few differences in copy number variants (CNV) following chemotherapy in 3 out of 8 patients. Whole exome sequencing revealed increased allele frequency or appearance of de novo mutations in TP53 gene in the residual cancers of 2 of the 3 patients presenting differences in CNVs post treatment. Interestingly, pathway analyses revealed that genes involved in DNA binding, chromosomal organization and nucleosome organization were differentially expressed (&gt;2fold) in 2 of the patients with CNV changes. Our results suggest that increased levels of TP53 mutations and altered transcriptional expression of genes involved in chromosomal functions could be associated with the presence of CNV changes in drug resistant tumors.
Conclusion: In summary, the genome of TNBCs does not undergo major changes during neoadjuvant chemotherapy; however, enrichment for or de novo TP53 mutations is associated with the appearance of novel CNVs in drug resistant residual tumors.
Citation Format: Adriana Aguilar-Mahecha, Ewa Przybytkowski, Josiane Lafleur, Cathy Lan, Stephanie Légaré, Najmeh Alirezaie, Carole Séguin, Federico Discepola, Bojan Kovacina, Catalin Mihalcioiu, André Robidoux, Elizabeth Marcus, Josée Anne Roy, Manuela Pelmus, Olga Aleynikova, Sheida Nabavi, Jacek Majewski, Mark Basik. Genomic change in residual triple-negative breast cancers after neoadjuvant chemotherapy. [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 4320. doi:10.1158/1538-7445.AM2015-4320