Aromatase Inhibitors Reduce the Expression of a Hypoxia Metagene in Oestrogen Receptor Positive Breast Cancer in Postmenopausal Women.

Abstract

Abstract Aims: To (1) define the effect of oestrogen deprivation on genes related to hypoxia in oestrogen receptor positive (ER+) breast cancer and (2) identify any link between hypoxia and proliferation.Background: The majority of breast cancer patients are postmenopausal women with ER+ tumours and at some point receive an aromatase inhibitor (AI) as part of their treatment. Hypoxia and proliferation are important factors in the progression of ER+ tumours. Proliferation is profoundly reduced in most ER+ cancers after treatment with AIs[1], however little is known on the effects of AIs on hypoxia.Materials and methods: 81 pre- and 2-week post-treatment core-cut tumor biopsies were obtained from postmenopausal women with ER+ breast cancer who received single agent neoadjuvant anastrozole (AI)[2], and from 20 of these patients after 16 weeks of AI treatment. RNA was extracted and analysed on Illumina 48K microarrays. A hypoxia metagene (MG) was developed by identification of genes whose expression clustered with the expression of classical hypoxia-regulated genes[3]. Genes associated with proliferation were removed from the MG. A proliferation MG was derived by selecting the intersection of proliferation clusters from three public breast cancer datasets.Results: Spearman correlations revealed a strong relationship between the hypoxia and proliferation MGs prior to AI treatment (r =0.61, p<10-3), and persisted after 2 weeks (r =0.77, p<10-3) and after 16 weeks of treatment (r=0.72, p =0.002). Baseline expression of the hypoxia MG was (1) positively correlated with 2-week Ki67 (Spearman r =0.37, p =0.002), (2) showed a trend for a positive correlation with poor 2-week Ki67 change (Spearman r=0.22, p =0.06) and with poor reduction in the mean expression of four classical oestrogen dependant genes (TFF1/pS2, GREB1, PDZK1 and PGR) known as AVERG[4] (Spearman r =0.22, p=0.06). Expression of the hypoxia MG was significantly down-regulated after 2 weeks of oestrogen deprivation using AI treatment (p<10-3). The 2-week change in hypoxia showed a positive correlation with the 2-week change in proliferation (Spearman r=0.58, p<10-3), and with the 2-week change in Ki67 (Spearman r=0.35, p=0.005).Conclusions: The expression of a hypoxia MG decreases after oestrogen deprivation. The hypoxia MG is strongly associated with proliferation prior to and after AI treatment. The data are consistent with hypoxia being a secondary effect of proliferation in ER+ breast cancer and could contribute in understanding the need to combine anti-proliferative drugs with anti-angiogenic agents for these patients. There may be a weak effect of hypoxia on de-novo resistance to AIs.1. Dowsett M, et al., Clin Cancer Res 2006; 12(3): p.1024-302. Smith, I.E, et al., J Clin Oncol 2007; 25(25): p.3816-223. Winter, S.C, et al., Cancer Res 2007; 67(7): p.3441-94. Dunbier, A.K, et al., Cancer Res 2009; 69(Suppl.), 78sSupported by The Mary-Jean Mitchell Green Foundation and Breakthrough Breast Cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 408.