Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer

Abstract

Introduction: We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up.

Methods: The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS).

Results: In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours.

Conclusions: HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.

Figure 1

Immunohistochemical images of HMG-CoA reductase staining. Images (×400) representing tumours with (a) negative, (b) weak, (c) moderate and (d) strong immunohistochemical staining intensity for HMG-CoA reductase.

Figure 2

Recurrence-free survival according to HMG-CoA reductase expression. Kaplan-Meier estimates of recurrence-free survival according to HMG-CoA reductase expression, defined as negative (0) or positive (1 to 3), in all (a) patients, and in patients with (b) oestrogen receptor (ER) positive tumours and (c) ER-negative tumours.

Figure 3

Recurrence-free and breast cancer-specific survival according to combinations of oestrogen receptor (ER) status and HMG-CoA reductase expression. Kaplan-Meier estimates of (a) recurrence-free and (b) breast cancer-specific survival according to combinations of ER-status (negative/positive) and HMG-CoA reductase expression (negative [0]/positive [1 to 3]).