Abstract PD3-3: Next generation sequencing shows clonal selection after treatment with anastrozole or fulvestrant in a randomized trial of postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 24_Supplement; p. PD3-3
• Main Authors: Iggo, RD, Wood, HM, Rabbitts, P, Quenel-Tueux, N, Mauriac, L, MacGrogan, G, Bonnefoi, H
• Format: Journal Article
• Language: English
• Published: 15-12-2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS13-PD3-3

Abstract
Background: Unlike chemotherapy, endocrine therapy is not clastogenic or mutagenic, so genetic changes arising during treatment are unlikely to be secondary events provoked by iatrogenic DNA damage. Endocrine therapy for breast cancer is thus a clean setting in which to explore the evolution of tumour genomes under treatment, and the changes seen are likely to be biologically meaningful. To identify such changes we have analysed pre and post treatment biopsies from a clinical trial that compared two endocrine therapies.
Patients and methods: DNA was extracted from pre and post treatment samples from 20 patients enrolled in the HORGEN trial. Postmenopausal patients with large operable or locally-advanced hormone-receptor-positive breast cancer were randomly assigned to receive either neoadjuvant anastrozole or fulvestrant for 6 months in this multicenter randomized phase II study. Low depth next generation sequencing was used to generate DNA copy number profiles for each sample.
Results: The copy number profiles were similar before and after treatment in 10 cases. In three cases new amplicons appeared. In one case the amplicon contained the ESR1 gene, in another the FOXA1 gene, and in the third the NCOA3 gene. In the remaining seven cases where the profiles changed after treatment, the differences affected whole chromosomal arms. In six of these cases the profiles became simpler, indicating that clones with gains and losses of chromosomal arms had been counterselected by the treatment.
Conclusions: Differences between the pre and post treatment biopsies were surprisingly frequent and informative. Genes directly implicated in estrogen signalling were amplified in three cases. This suggests that specific amplicons confer resistance to endocrine therapy. From a clinical perspective, their appearance in a post treatment biopsy probably indicates that the treatment should be changed. A possible explanation for the chromosomal arm changes after treatment, a phenomenon we have dubbed the “wandering arms” phenotype, is that endocrine therapy deprives tumour cells of signals that are necessary for the survival of clones with copy number changes affecting whole chromosomal arms.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-3.