Lipid-Altering Drugs
Authors: Mark R. Goldstein
Journal: Cancer Research (2004)

The interesting paper by Cao et al. (1) exposes a disturbing paradox in preventive medicine that has significant implications. They demonstrated that expression of a mutant receptor for high-density lipoprotein (HDL) on breast cancer cell line MCF-7 inhibited the proliferation and attenuated the antiapoptotic effect of HDL on the breast cancer cells. This supports previous data suggesting that HDL is a growth stimulator for breast cancer cells (2), particularly estrogen receptor-positive cells (3). Raising HDL levels by lipid-altering drugs has been found to both prevent cardiovascular disease events (4, 5, 6) and decrease the angiographic progression of coronary artery disease (7, 8, 9). Therefore, therapeutically raising HDL may be a double-edged sword by decreasing cardiovascular disease at the expense of increasing breast cancer and possibly other malignancies. Recent literature suggests this may be true (10, 11, 12, 13).Several trials of cholesterol lowering with drugs to prevent cardiovascular disease events have demonstrated an increase in cancer incidents in the subjects treated with lipid-altering drugs (10, 11, 12, 13). The trials were randomized, double-blinded, and lasted an average of 5 years. The lipid-altering drugs were statins or fibrates, and the HDL cholesterol levels of the subjects randomized to the drug were raised by 5% or more for the duration of the trial period. A statistically significant excess of malignancy was seen in elderly subjects (12, 13) and women (11) randomized to the drug groups. Alarmingly, breast cancer was diagnosed in 1 of 290 women in the placebo group and 12 of 286 women in the pravastatin group during a 5-year trial (P = 0.002; ref. 11). In another randomized study, involving elderly subjects with a mean age of 75 years at entry (13), the significant decrease in coronary death in subjects randomized to pravastatin equaled the significant increase in cancer death in the same subjects, leaving total mortality unchanged.On balance, other trials of cholesterol lowering to prevent cardiovascular disease did not demonstrate an increase in cancer incidence or mortality (4, 5, 6, 14, 15, 16). However, these trials were severely underrepresented with women and the elderly.Unfortunately, there is a paucity of long-term data using lipid-altering drugs for the prevention of cardiovascular disease in women and the elderly. It is possible that women and the elderly are susceptible to cancer-promoting effects of HDL raising. Meanwhile, there is a push to put more individuals on lipid-altering drugs, particularly women and the elderly (17). I feel there is a need for caution in the widespread use of lipid-altering drugs in women and the elderly, and they should be used when the risk of imminent cardiovascular disease is very great. More long-term data are needed and can be obtained by well-designed clinical trials. By pharmacologically raising HDL in certain segments of the population, we may be decreasing cardiovascular disease at the expense of increasing cancer.We reply to Dr. Mark R. Goldstein’s comments prompted by our recent report (1). Dr. Goldstein points to a statistically significant excess of malignancies in several trials involving the use of statins to lower cholesterol. Several large-scale statin trials have shown that lowering cholesterol rapidly reduces the risk of major vascular events not only in middle-aged patients but also in older patients. These studies have also shown that statin therapy is well tolerated and safe, even among older patients, without evidence of any increases in cancer or other nonvascular morbidities or mortalities (2). In the PROSPER trial, patients randomized to pravastatin in PROSPER had a slightly higher diagnosis of cancer during the trial period. Much of the slight increase was observed early in the trial, soon after the start of therapy. In addition, there was no particular prevalence of cancer type, which suggests that it may have been due to chance. This conclusion is supported by the lack of any overall excess of cancer among patients of all ages randomized to pravastatin or other statins in the meta-analysis of previous large-scale trials as noted by investigators who participated in PROSPER. A nonsignificant trend toward more cancers among patients &gt;65 years was also noted in another statin trial, but again no particular site of the cancer predominated (3). Moreover, among more than 1,600 people with cancers recorded during Heart Protection Study, there was no significant excess among either young or old participants or at any particular site (4). The incidence of breast cancer was 0.2% in the pravastatin-treated group and 0.1% in those assigned to placebo. An imbalance in breast cancer had previously been noted in the CARE (Cholesterol and Recurrent Events) study (5). The LIPID study, compared with CARE, enrolled a larger number of women. In the LIPID study, there were 10 reported cases (1.3%) of breast cancer in pravastatin-treated women and 8 reports (1.1%) of breast cancer in placebo-treated women. In addition, 2 cases of breast cancer were reported in men; both were in the placebo group (3).Finally, Dr. Goldstein cautions clinicians regarding the widespread use of lipid-altering drugs in women and the elderly. Although our data show that high-density lipoprotein may contribute to the growth of breast cancer cells, these studies were done in vitro, and any attempt to extend these findings to clinical medicine is premature and unwarranted.