title: Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy.
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.
authors.affiliation: Breakthrough Breast Cancer Research Center, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Pierga
authors.forename: J S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: S J
authors.initials: SJ
authors.lastname: Cleator
authors.forename: T
authors.initials: T
authors.lastname: Dexter
authors.forename: A
authors.initials: A
authors.lastname: Mackay
authors.forename: P
authors.initials: P
authors.lastname: Simpson
authors.forename: K
authors.initials: K
authors.lastname: Fenwick
authors.forename: M
authors.initials: M
authors.lastname: Iravani
authors.forename: J
authors.initials: J
authors.lastname: Salter
authors.forename: M
authors.initials: M
authors.lastname: Hills
authors.forename: C
authors.initials: C
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Ashworth
authors.forename: I E
authors.initials: IE
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Powles
authors.forename: M
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype