Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy - PubMed (original) (raw)

. 2007 Jan 29;96(2):341-51.

doi: 10.1038/sj.bjc.6603483. Epub 2006 Nov 28.

J S Reis-Filho, S J Cleator, T Dexter, A Mackay, P Simpson, K Fenwick, M Iravani, J Salter, M Hills, C Jones, A Ashworth, I E Smith, T Powles, M Dowsett

Affiliations

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

J-Y Pierga et al. Br J Cancer. 2007.

Abstract

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approximately 5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11-12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21-q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3-q4 and 18p11.31 and gains of 6p25.1-p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2-11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

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Figures

Figure 1

Figure 1

Frequency of copy number changes in 44 invasive breast carcinomas. (A) Overall frequency of DNA copy number alterations found in 44 invasive breast carcinomas as defined by aCGH. The proportion of tumours in which each clone is gained (green bars) or lost (red bars) is plotted (y axis) for each BAC clone according to genomic location (x axis). Vertical dotted lines represent chromosome centromeres. (B) – Pearson's correlation matrix of all thresholded aCGH data for 29 ER-positive, invasive breast carcinomas. Strong positive correlations are plotted as dark red, strong negative correlations as dark blue. Note the associations between chromosomes 1p/8p, 1p/12q, 4q/8p, 7p/22, 8q/12q and 11q/12q. Bacterial artificial chromosome clones are plotted in genome order. (C) Pearson's correlation matrix of all thresholded aCGH data for 15 ER-negative, invasive breast carcinomas. Strong direct plotted as dark red, strong negative correlations as dark blue. Note the associations between chromosomes 1p and 7q, 16p and 17q, and strong inverse correlations between 1q and 14q, 2q and 9q, 4q and 15q, 6q and 11q, 7p and 11q, 7p and 12q, 9p and 16p, and 13q and 15q. Bacterial artificial chromosome clones are plotted in genome order.

Figure 2

Figure 2

Categorical analysis of copy number gains and losses between non-responders (_N_=20) and responders (_N_=24). Fisher's exact tests are carried out on the segmented values for each clone, and those with a _P_-value of less than 0.01 are plotted (inverse log10, y axis) according to genomic location (x axis).

Figure 3

Figure 3

Hierarchical clustering analysis (Ward's method/Euclidean distance) of matched pre- and post-chemotherapy samples (17 patients) (A) and pre-chemotherapy, post-chemotherapy and surgical samples (12 patients) (B). (b – before chemotherapy; a – after chemotherapy (day 21); s – surgical biopsy).

Figure 4

Figure 4

Categorical analysis of copy number gains and losses between matched pre-chemotherapy and surgical tumour samples (21 patients). Fisher's exact tests are carried out on the segmented values for each clone, and those with a _P_-value of less than 0.01 are plotted (inverse log10, y axis) according to genomic location (x axis).

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