SAN ANTONIO – A definitive phase III randomized controlled trial of statin therapy during adjuvant endocrine therapy for breast cancer is warranted in light of recent encouraging evidence pointing to a protective effect against disease recurrence, Melissa L. Bondy, Ph.D., said at the San Antonio Breast Cancer Symposium.
“The next phase of research in this area is to learn whether we can improve survival in breast cancer patients by having them take cholesterol-lowering medication. We really need to have a phase III trial in the adjuvant setting that includes these cholesterol-lowering drugs,” said Dr. Bondy, professor of cancer prevention and population sciences at Baylor Medical College, Houston.
Her call for a formal, randomized trial came while serving as discussant for two positive reports of an apparent beneficial effect of statins on breast cancer recurrence-free survival: one from the BIG 1-98 trial of adjuvant endocrine therapy for early-stage breast cancer, the other a meta-analysis of 12 published studies totaling 72,774 breast cancer patients.
Dr. Signe Borgquist
Dr. Bondy found particularly compelling the Breast International Group (BIG) 1-98 study results presented by Dr. Signe Borgquist, an oncologist at Lund (Sweden) University. This secondary analysis of the impact of cholesterol-lowering medication included 7,963 postmenopausal women with early-stage, estrogen receptor–positive invasive breast cancer who were randomized to 5 years of tamoxifen, the aromatase inhibitor letrozole (Femara), or the two drugs in sequence. Serum total cholesterol levels and the use of cholesterol-lowering medications – a decision left up to individual physicians and patients – were assessed at baseline and again every 6 months for 5.5 years.
With a median 8 years of prospective follow-up, during which 1,432 patients experienced breast cancer recurrence, the disease-free survival rate was 18% higher in the 637 patients already on cholesterol-lowering medication – mainly statins – at enrollment, compared with those who were not. The distant recurrence-free interval was 19% better as well, with both analyses adjusted for their form of endocrine therapy, tumor size and grade, nodal status, local therapy, peritumoral vascular invasion, and other potential confounders.
Another 697 BIG 1-98 participants initiated cholesterol-lowering medication during their adjuvant endocrine therapy. In multivariate adjusted analyses, their disease-free survival rate was 21% greater and distant recurrence-free interval was 26% better than in participants not on a statin or other cholesterol-lowering medication during the trial.
As a possible mechanism by which statins might exert anticancer effects, Dr. Borgquist proposed that lowering cholesterol levels may deprive tumor cells of the ability to satisfy their increased demand for cholesterol uptake. This is a result of attenuated signaling through the estrogen receptor by the cholesterol metabolite 27-hydroxycholesterol, levels of which correlate with systemic total cholesterol.
Dr. Bondy offered another possible explanation for the reduced risk of breast cancer recurrence seen in women on cholesterol-lowering medication in BIG 1-98: “Many groups have shown that LDL affects the immune system by binding and inactivating all kinds of microorganisms and their toxic products. In other words, statins appear to affect the microbiome.”
She commented that, although the use of statins was nonrandomized in BIG 1-98, she was favorably impressed by the 8-year follow-up and careful monitoring of total cholesterol levels at 6-month intervals throughout the 5 years of adjuvant endocrine therapy.
Dr. Bondy noted that other studies – again, nonrandomized – suggest statins also interrupt the growth of colorectal cancer and other malignancies.
Dr. Sashidhar Manthravadi
Dr. Sashidhar Manthravadi presented a meta-analysis of the 12 published studies that have reported data on the association of statins with recurrence-free and/or overall survival in breast cancer patients. Statin use was associated with a significant 34% improvement in recurrence-free survival.
Moreover, this benefit was confined to breast cancer patients on the lipophilic statins atorvastatin and simvastatin; the use of hydrophilic statins was not associated with a significant improvement in recurrence-free survival, according to Dr. Manthravadi, an internal medicine resident at the University of Missouri, Kansas City.
The use of statins also was associated with a 27% improvement in breast cancer–specific survival and a 33% improvement in overall survival, compared with statin nonusers; however, neither of these results achieved statistical significance, he added.
Dr. Bondy cautioned against making too much of the apparent distinction between lipophilic and hydrophilic statin in terms of protection against breast cancer recurrence, given the inherent limitations of a meta-analysis.
“There’s always a lot of missing information, as well as a failure to adjust for comorbidities. And follow-up times in these 12 studies ranged from 2.5 to 11.5 years,” she noted.
The ongoing BIG 1-98 trial is sponsored by the International Breast Cancer Study Group. Dr. Borgquist, Dr. Bondy, and Dr. Manthravadi reported having no financial conflicts of interest.