Lipophilic Statins Lower ER-Negative Breast Ca Risk : No therapies were previously known to reduce the risk of estrogen receptor-negative breast cancer.


SAN ANTONIO — Women on a lipophilic statin have a markedly reduced likelihood of developing estrogen receptor-negative breast cancer, Dr. Anjali Kumar reported at a breast cancer symposium sponsored by the Cancer Therapy and Research Center.

That's extremely welcome news. Although tamoxifen is of well-established benefit for the chemoprevention of estrogen receptor-positive breast cancer, there are no therapies known to reduce the risk of developing estrogen receptor-negative (ER-negative) breast cancer, explained Dr. Kumar, a surgeon at the University of California, San Francisco.

She presented a retrospective cohort study involving 2,141 breast cancer patients in the Kaiser Permanente Northern California Cancer Registry. In addition to large patient numbers, the Kaiser registry offers the advantages of electronic pharmacy records along with more reliable centralized estrogen receptor staining, with confirmation by a team of five pathologists.

In addition, the only statins on the Kaiser formulary—atorvastatin, simvastatin, and lovastatin—are lipophilic. Being lipid soluble, these drugs can more readily permeate cell and nuclear membranes, which in theory should enhance full expression of the statins' pleotropic benefits.

And that's not just theory: In earlier mouse studies that laid the groundwork for the Kaiser study, Dr. Kumar and her San Francisco colleagues showed that lipophilic statins conferred protection against ER-negative murine breast carcinoma. They also showed in vitro that ER-negative human breast cancer cell lines were more sensitive to lipophilic statins than ER-positive cells, and that lipophobic statins—namely, pravastatin and rosuvastatin—didn't inhibit growth of the malignant cells.

Of the Kaiser breast cancer patients, 17% had used a lipophilic statin for longer than 1 year prior to diagnosis of their malignancy. Their tumor was ER negative in only 2% of cases, compared with a 17% ER-negative rate among women who had taken a statin for less than a year or never. The age-adjusted relative risk of developing an ER-negative tumor was reduced by 36% among women who had used a statin for more than 1 year. A significant reduction in the probability of ER-negative cancer associated with lipophilic statin use was observed across all age groups, Dr. Kumar noted.

Eleven prior studies have looked at the statin/breast cancer relationship. Five found a protective effect against ER-negative cancers, including the only three studies restricted to lipophilic statins or featuring results stratified by statin type. All six studies that found no benefit for statin therapy looked at statins globally without distinguishing lipophilic from lipophobic agents, she continued.

Because the Kaiser study was confined to women already diagnosed with breast cancer, it couldn't address whether statin use reduces the overall incidence of breast cancer. However, two prior studies by others did show significant reductions.

Based upon the encouraging results of the Kaiser study along with the statins' remarkably good safety profile, Dr. Kumar and coworkers are continuing to explore the role of lipophilic statins in breast cancer prevention.

Now underway is a pilot biomarker study at the University of California, San Francisco, Dana-Farber Cancer Institute in Boston, Memorial Sloan-Kettering Cancer Center in New York, and the University of Chicago, where women with newly diagnosed ductal carcinoma in situ or stage I invasive breast cancer by core biopsy are being randomized to 3-6 weeks of fluvastatin at either 20 or 80 mg/day before undergoing definitive surgery. The goal is to learn whether statin therapy improves circulating and tumor biomarkers and brings favorable early changes in breast MRI images.

The investigators are also planning a study of long-term lipophilic statin therapy in BRCA mutation carriers that will be aimed at reducing their very high breast cancer risk.

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