We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined.

HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II pre-menopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment (Cohort II). Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response.

HMG-CoAR protein and RNA expression was decreased in tamoxifen resistant MCF7-LCC9 cells compared to their tamoxifen sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumours that recurred following tamoxifen treatment (P<0.001) and was an independent predictor of RFS in Cohort I (HR 0.63, P=0.009). In Cohort II adjuvant tamoxifen increased RFS in HMG-CoAR positive tumours (P=0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in cohort II (HR = 0.67, P = 0.010) and subset analysis revealed that this was maintained in estrogen receptor (ER) positive patients (HR = 0.65, P =0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P=0.05). Analysis of tamoxifen response revealed that patients with ER positive/HMG-CoAR tumors had a significant response to tamoxifen (P=0.010) as well as patients with ER positive or HMG-CoAR positive tumors (P=0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER+/HMG-CoAR+ tumors had an improved RFS compared to ER+/HMG-CoAR- in the treatment arm (P=0.033) however this effect was lost in the control arm (P=0.138) suggesting that HMG-CoAR predicts tamoxifen response.

HMG-CoAR expression is a predictor of response to tamoxifen in both ER positive and negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen.

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