Statins May Up Breast Cancer–Specific and Overall Survival

Pam Harrison

December 08, 2017

SAN ANTONIO — Overall survival and, more intriguingly, breast cancer–specific survival are significantly enhanced by statin therapy when used both in the prediagnostic and the postdiagnostic setting compared with no statin use, suggests a Swedish nationwide study reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017. 

"I don't think any of us were surprised that it was beneficial for women to be on a statin in terms of overall survival because statins have a lot of beneficial effects on  cardiovascular disease prevention," lead investigator, Signe Borgquist, MD, PhD, professor of oncology, Aarhus University Hospital, Denmark, told Medscape Medical News.

"But when we look at breast cancer–related death, which is a more interesting endpoint than overall survival when it comes to treatment as exposure, we see that both prediagnostic use and postdiagnostic use is beneficial for women in terms of breast cancer–related death, where we saw significantly lower hazard ratios if women were using a statin in either setting. If women were regular users, they had more benefit than if they were not regular users," she added.

Data were collected from a nationwide retrospective cohort study involving 20,559 Swedish women diagnosed with breast cancer from July 2005 through 2008. Statin use was identified through the Swedish Prescription Registry, while breast cancer–specific death was identified from the national cause-of-death registry through the end of 2012.

"During follow-up, a total of 4678 patients died, whereof 2669 were considered breast cancer–specific deaths," the investigators observed.

Compared with women not receiving statins at all, women who took a statin regularly before their diagnosis had a 23% lower relative risk of dying from breast cancer (hazard ratio [HR], 0.77; P = .014).

After their diagnosis, women who had been exposed to any statin use had a 17% lower relative risk of dying from breast cancer (HR, 0.83; P = .001).

The benefit of taking a statin before diagnosis also did not seem to be influenced by the statin dose, Dr Borgquist added. For example, women who took an intermediate statin dose had a 26% lower relative risk for a breast cancer–related death (HR, 0.74; P = .019).

In comparison, women who took high-dose statin therapy before diagnosis had a 16% lower risk of reaching the same endpoint, she added.

Nor did the type of statin taken in the postdiagnostic setting affect the risk of dying from breast cancer:  The relative risk was identical at an HR of 0.93 for both statin types (P < .001 and P = .002 for lipophilic and hydrophilic statins, respectively).

"The main take-home message from this study is that all the Scandinavian studies are showing more or less the same beneficial effect in breast cancer, even though studies from the United Kingdom have not depicted as good an effect as we have," Dr Borgquist observed.

"What we would like to do now is conduct a large adjuvant trial to show that this holds true in a trial setting, which would hopefully enable us to identify robust predictive markers as to which women might benefit from a statin and which might not, because I am sure that not all breast tumors are equally susceptible to statin treatment," she added.

HMG-CoA Reductase Target

As Dr Borgquist explained, extrahepatic function of the statins may affect the mevalonate pathway in cancer cells by targeting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

"HMG-CoA reductase is differentially expressed in breast tumors," she noted, with some tumors having high levels of HMG-CoA reductase expression and others, much lower levels of expression.

In early clinical work, Swedish investigators observed that high levels of HMG-CoA reductase expression was associated with better outcomes in breast cancer.

In a previous window-of-opportunity trial, Borgquist et al suggested that HMG-CoA reductase may serve as a predictive marker for statin response.

In this trial, they could also demonstrate that statins inhibit not just the HMG-CoA reductase enzyme but also decrease systemic levels of a cholesterol metabolite known as 27-hydroxycholesterol (27HC).

"This metabolite binds to the estrogen receptor," Dr Borgquist explained, "so you are not only inhibiting cholesterol production, you are also inhibiting the production of this cholesterol metabolite with estradiol-like capabilities," she added.

Because 27HC serves as an estrogen receptor agonist in breast cancer cells — stimulating growth and metastasis of tumors in models of breast cancer — it is possible that inhibition of the production of both cholesterol and its metabolite might have a mitigating effect on breast cancer progression and recurrence, as she suggested.

Indeed, in an analysis of the BIG 1-98 study published earlier this year, Borgquist and colleagues reported that the use of cholesterol-lowering medications — namely, the statins — during adjuvant endocrine therapy improved disease-free survival, breast cancer–free survival intervals, and distant recurrence–free intervals in postmenopausal women with early-stage, hormone receptor–positive breast cancer. These findings suggest that statins may have a role in preventing breast cancer recurrence in this patient population.

Dr. Borgquist and colleagues are now recruiting patients with metastatic breast cancer into the Advanced Breast Cancer-Statins and Endocrine Treatment (ABC-SE) trial, in which they will compare the efficacy and tolerability of atorvastatin, 40 mg, in addition to endocrine treatment in patients with estrogen receptor–positive advanced breast cancer.

The objective of the trial is to assess whether statin therapy can boost the effectiveness of endocrine therapy by modulating pathways of cholesterol production.

Asked by Medscape Medical News to comment on the findings, Thomas Ahern, PhD, assistant professor of epidemiology, University of Vermont, Burlington, noted that the current study is in fact concordant with many other studies and other independent course populations that have shown a protective association between statin use and breast cancer survival.

"I also think the protective effect seen with statin use is biologically very plausible," Dr Ahern said.

Indeed, a host of in vitro and animal model work provides compelling mechanisms by which statin treatment could affect pathways that lead to breast tumor survival and promotion, he pointed out.

"Some of these are mediated by cholesterol itself, the 27HC metabolite, which can interact with the estrogen receptor and potentiate growth, but there are also cholesterol-independent mechanisms as well and there are a variety of those," Dr Ahern explained.

"So there is a very strong biological rationale as well as strong epidemiologic evidence, but what we really need to do to answer this question now is a clinical trial in the adjuvant setting and get the experimental evidence that this question deserves," he said.

Dr Borgquist and Dr Ahern have disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2017. Poster P2-13=03. Presented December 7, 2017.

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