The aim of the present study was to evaluate HMG-CoAR expression as a predictive marker of tamoxifen response. Our results demonstrate a potentially important association with tamoxifen response both in vitro and using two independent breast cancer cohorts, one of which encompasses a randomized control trial of premenopausal stage II disease.
A wealth of evidence supports the role of tamoxifen in the treatment of breast cancer [25
]; however, resistance to tamoxifen is a significant clinical problem - and the Oxford meta-analysis reported a relapse rate of 15%, and an 8% incidence of breast-cancer-specific mortality within 5 years of the commencement of therapy [25
]. The introduction of aromatase inhibitors may lead to an improvement in postmenopausal women [26
], but resistance to aromatase inhibitors may become a problem over time. In premenopausal women, tamoxifen remains the endocrine drug of choice and both inherent and acquired resistance may be more prevalent in this population. Tamoxifen resistance in premenopausal women is quite hard to quantify accurately as the majority of premenopausal patients receive adjuvant cytotoxic chemotherapy; however, Ryden and colleagues reported a recurrence rate of 39.7% at 10 years in the absence of adjuvant chemotherapy in the trial from which Cohort II was derived [19
]. An ability to identify patients who will respond to endocrine therapy prior to commencing treatment would be extremely beneficial.
To that end, the data presented here are particularly interesting. Cox regression analysis confirmed HMG-CoAR was an independent prognostic marker in both cohorts. Cohort I was a nonrandomized cohort consisting of a mixture of premenopausal and postmenopausal patients and therefore cannot be used to validate a predictive biomarker; however, this cohort provides important information, particularly as HMG-CoAR mRNA expression was measured as a continuous variable. The relationship between HMG-CoAR protein expression and tamoxifen response was examined in Cohort II, a randomized exclusively premenopausal cohort, and a Cox interaction analysis revealed an interaction between tamoxifen treatment and HMG-CoAR expression. Subset analysis of Cohort II revealed that tumors expressing both ER and HMG-CoAR were particularly sensitive to tamoxifen, but tumors that expressed either ER or HMG-CoAR also responded to tamoxifen. In addition HMG-CoAR-positive/ER-positive patients had a significantly improved response to tamoxifen compared with HMG-CoAR-negative/ER-positive patients.
In contrast to previous studies by our group, none of the tumors expressed high levels (3+) of HMG-CoAR. This difference could potentially be explained by the fact that Cohort II was an exclusively premenopausal cohort with stage II breast cancer, which also explains the positive association with lymph node status seen in the present study. In our two previous breast cancer studies we demonstrated an inverse relationship between tumor size and HMG-CoAR [13
], and therefore the absence of small stage I tumors from Cohort II could explain the lack of tumors expressing high levels of HMG-CoAR in this study. This argument is further strengthened by the inverse relationship between HMG-CoAR mRNA expression and tumor size demonstrated in Cohort I in this study, as this cohort also included a significant number of small stage I tumors. We are unable to explain the positive association between Her2 and HMG-CoAR seen in Cohort II, but this could potentially be explained by the association with lymph-node-positivity.
Such findings raise the possibility of pharmacological interventions to increase tumor-specific HMG-CoAR expression as a potential therapeutic option for breast cancer. Statin-induced mevalonate depletion has been shown to result in an adaptive induction of HMG-CoAR expression in Chinese hamster ovary cells [28
] and MCF7 breast cancer cells [29
]. Treatment of MCF7 cells with mevastatin resulted in a 10-fold to 15-fold induction of HMG-CoAR activity in association with a 2.5-fold to 3.5-fold induction of HMG-CoA reductase mRNA expression [29
], suggesting that treatment with statins may increase tumor-specific HMG-CoAR expression in vivo
; however, this suggestion remains to be fully elucidated. Given our findings that increased levels of HMG-CoAR expression are associated with an improved response to tamoxifen in ER-positive tumors, a combination of tamoxifen and statins may be a new therapeutic option. Further studies, however, are required to investigate the value of HMG-CoAR expression as a predictive marker of response to statin treatment.
Despite an ever-growing body of literature describing the anti-neoplastic properties of statins, epidemiologic data regarding their preventive effect against cancer in general - and breast cancer in particular - remain inconclusive [7
]. In the adjuvant setting, a recent preoperative window trial of ductal carcinoma in situ
and stage I breast cancer was the first to demonstrate that statins can inhibit proliferation and increase apoptosis in vivo
], raising the possibility that the combination of statins and well-established chemotherapeutic and endocrine agents may be an option. A synergism between statins and trastuzumab, rapamycin and epirubicin has been demonstrated in breast cancer cell lines [34
]; however, a synergistic relationship between tamoxifen and statins has yet to be investigated.