Abstract P5-12-03: Genome copy number entropy as predictor of response for neoadjuvant therapy in early breast cancer

Abstract

Abstract Background Copy Number Alterations (CNAs) represent changes in the copy number of genomic segments of somatic cells due to chromosomal instability. CNAs include gene amplifications or deletions and can be involved in tumorigenesis. We analyzed CNAs data in pre- and post-treatment (ttm) tumors from patients (pts) with early breast cancer (BC) in the neoadjuvant trials GEICAM/2006-03 and GEICAM/2006-14, with the aim to identify CNAs in particular genomic regions (genetic entropy) associated with treatment response. Methods GEICAM/2006-03 (NCT00432172) HER2-negative pts were selectively treated according to clinical subtypes: triple negative (TN) pts were treated with standard anthracycline/taxane -based chemotherapy (AT-CT) +/- carboplatin, while luminal patients were randomized to AT-CT vs. hormonotherapy; GEICAM/2006-14 (NCT00841828) HER2+ pts received AT-CT plus anti-HER2 therapy.Shallow-whole genome Illumina sequencing DNA data from 204 paraffin-embedded tumors (100 pre- and 104 post-ttm) were segmented to obtain CNAs and recurrent altered genomic regions were defined. We used Wilcoxon test to analyze the frequency of altered regions and logistic regression analyses to explore their association with tumor response, in terms of pathological complete response (pCR) in breast and axilla. Validation of altered genes associated with therapy response was performed in the microarray gene expression-based Hatzis dataset (GSE25066) from pts receiving neoadjuvant AT-CT (1). Results A total of 672 regions covering the whole genome were identified upon analysis of CNAs data. Regions were categorized according to their alteration status as amplified, normal and lost. Comparative analysis of alterations revealed 11 regions significantly different (p<0.05) in pre- vs post-ttm tumors. Logistic regression analysis showed that in pre-ttm tumors specific alterations of 8 regions localized in 3 different genomic loci (11q12, 16q22 and 21q22) were significantly associated with pCR (p<0.05). Independent analyses of CNAs data with “CGH regions” and “GISTIC2.0” tools confirmed the special relevance of 2 of these 8 regions (#653 and #654), amplified in the locus 21q22.12. This locus contains 20 genes whose expression was tested in Hatzis dataset (1) (GSE25066): the analysis showed that overexpression of 5 of these 20 genes (CHAF1B, CBR1, CBR3, RCAN1 and SLC5A3) turned out to be significantly higher in the cohort of pts who reached pCR, in agreement with our findings. Some of these genes have already been described as proliferation markers (CHAF1B) or involved in treatment response (CBR1) in BC. Other genes related to BC in this genomic region are the transcription factor RUNX1 and the Lysine Methyltransferase SETD4. Conclusions According to our results, neoadjuvant therapy can modulate genomic aberrations landscape in BC. Our data suggest that amplification of specific genes in the genomic locus (21q22.12) is involved in the neoadjuvant therapy response in early BC. (1): Hatzis et al., JAMA 2011, 305(18) 1873-81 Citation Format: Alba E, Rueda OM, Lluch A, Albanell J, Chin S-F, Chacón JI, Calvo L, De la Haba-Rodriguez J, Bermejo B, Ribelles N, Sánchez-Rovira P, Plazaola A, Barnadas A, Cirauqul B, Ramos M, Arcusa A, Carrasco E, Herranz J, Chiesa M, Caballero R, Santonja A, Rojo F, Caldas C. Genome copy number entropy as predictor of response for neoadjuvant therapy in early 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 P5-12-03.