Cancer Chemoprevention: Hormones, Nonclassic Antioxidant Natural Agents, NSAIDs, and Other Agents

Introduction

Chemoprevention aims to directly modulate specific steps in the carcinogenic process, block mutagenic carcinogens, prevent DNA damage by free radicals, suppress epithelial cell hyperproliferation, and/or modulate epithelial cell differentiation and apoptosis (programmed cell death). Numerous chemopreventive agents are in various stages of development and testing.

Part 1 of this two-part series, published in last month’s issue, focused on the retinoids and carotenoids and other “classic” antioxidants. This second part will explore hormonally mediated chemopreventive agents, such as tamoxifen(Drug information on tamoxifen) (Nolvadex), finasteride(Drug information on finasteride) (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). A number of these agents have site-specific mechanisms of action and will be discussed as such. Part 2 will also discuss various nonclassic antioxidant natural agents, including calcium, the polyphenols, the isothiocyanates, and genistein, as well as the nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin(Drug information on aspirin) and sulindac(Drug information on sulindac); difluromethylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine. The proposed mechanisms of action of the various chemopreventive agents currently being investigated clinically and the specific disease sites in which they are being studied are listed in Table 1 and Table 2, respectively.

Hormones

A substantial body of epidemiologic, experimental, and clinical evidence indicates that hormones play an important role in the etiology of several human cancers.[112] Neoplasia of tissues that are responsive to hormones currently account for more than 40% of all newly diagnosed female cancers and 25% of all newly diagnosed male cancers in the United States.[112]

Since Bittner’s initial experimental work with estrogens(Drug information on estrogens) and mammary cancer in mice, the hormone responsiveness of carcinomas has been studied in numerous disease sites, including the breast, endometrium, prostate, ovary, thyroid, bone, and testis.[112,113] Of note, the activity of retinoids is governed by their interactions with receptors (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) that belong to the steroid receptor family.[31-35]

A key element of this hypothesis is that neoplasia results from hormonal stimulation of the target organ, accelerates cell division, and increases the likelihood that random genetic errors accumulate and lead to a neoplastic phenotype.[114,115] Epidemiologic findings are consistent with this multistep genetic damage model of carcinogenesis. Whereas the incidence of most non–hormone-dependent adult cancers rises continuously with age, investigators have noted that the age-incidence curves of endometrial, ovarian, and breast cancers rise with age at a rate similar to other cancers until menopause, at which time, there is a distinct slowing of the rate of rise.

The rise in incidence of endometrial, ovarian, and breast cancers prior to menopause is thought to result from sex steroid–driven cellular proliferation. Because genetic damage that accumulated during the premenopausal period is not lost after menopause, a continued increase in overall incidence is seen; however, the rate of rise decreases, presumably because cellular proliferation substantially decreases.[115,116]

The effects of the steroid hormones differ by organ site. The mitotic rate of the endometrial cells lining the uterus is stimulated by estrogen and inhibited by progestins. Breast tissue undergoes cell proliferation and loss in concert with the ovaries’ cyclic production of estrogen and progesterone(Drug information on progesterone).[115] The role of estrogen as a primary stimulant of breast cell proliferation, which contributes to the development of breast cancer, is supported by epidemiologic studies, animal studies, and clinical trials.[112,114] In addition, the simultaneous presence of progesterone probably further increases the rate of breast cell proliferation.[112]

Numerous epidemiologic findings support a role for gonadotropin exposure and ovulation in the pathogenesis of ovarian cancer. For example, the decreased risk of ovarian cancer seen with multiple pregnancies and prolonged lactation is proposed to be related to their direct suppressive effects on central gonadotropin release or the consequent inhibition of ovulation.[117]

Because of the evidence that endogenous hormones directly affect the risk of several cancers, chemoprevention through the manipulation of steroid hormones are an important focus of cancer prevention. The occurrence of key etiologic events during the premenopausal period supports the use of prevention strategies at this time. Under this model, prevention of cancer can be achieved by reducing the rate of cell division during proliferative periods in the relevant epithelial tissue.[115,118]

For example, oral contraceptives and progesterone in hormone replacement therapy have an antiproliferative, protective effect on the endometrium. The antiestrogenic effect of tamoxifen (Nolvadex) and related compounds in breast tissue and the antiandrogenic effects of finasteride (Proscar) on prostate tissue are classic examples of “antihormone” mechanisms. In addition, new agents, eg, dehydroepiandrosterone (DHEA) and its nonandrogenic structural analogs, are being evaluated for potential chemo- preventive activity.

Oral Contraceptives

Combination oral contraceptives include both estrogen and progestin components and, through gonadotropin suppression, inhibit ovulation to achieve many of their benefits.[119] The decrease in ovarian cancer that has been observed with oral contraceptive use is postulated to stem from either inhibition of ovulation or suppression of gonadotropins.

Hankinson et al reviewed 20 studies, including case-control as well as prospective cohort studies, and concluded that the summary relative risk of ovarian cancer associated with any use of combination oral contraceptives is 0.64 (95% confidence interval [CI], 0.57 to 0.73). They estimated that the risk of ovarian cancer decreases 11% with each year of oral contraceptive use.[119] This monotonic dose-response effect appears to be independent of parity.[118] In addition, the protective effect afforded by oral contraceptive use appears to persist for 10 or more years after their discontinuation.

Whereas the protective effects of oral contraceptives against ovarian cancer risk among the general population are well accepted, the possible benefits among high-risk groups are now being explored. A recent case-control study (involving 207 women with hereditary ovarian cancer and 161 of their sisters as controls) has suggested that oral contraceptives may reduce the risk of ovarian cancer in women carrying BRCA1 or BRCA2 mutations, resulting in an odds ratio of 0.5 (95% CI, 0.3 to 0.9) for BRCA1 mutation carriers and an odds ratio of 0.4 (95% CI, 0.2 to 1.1) for BRCA2 mutation carriers, as compared with the control group.[120] Questions have been raised, however, regarding: (1) potential biases in the study and (2) a possible increase in the risk of breast cancer with oral contraceptive use in women with a hereditary predisposition to this malignancy.[121,122]

Oral contraceptives minimize endometrial mitotic activity by limiting periods of exposure to estrogen unopposed by progestins. This leads to a decreased lifetime risk of endometrial cancer. Overall, case-control as well as prospective cohort studies show that endometrial cancer risk among oral contraceptive users is decreased by 40% to 50% relative to nonusers. The preventive effect lasts at least 15 years after the individual stops using oral contraceptives.[118,120-125] The protective effects of oral contraceptives may be modified by nulliparity or subsequent unopposed estrogen use.[118] Oral contraceptive use has also been suggested to protect against the development of malignant mixed müllerian tumors of the uterus.[126]

Although progesterone has inhibitory effects on the endometrium, evidence is accumulating that it increases the rate of cell division in breast tissue beyond that of estrogen alone.[118] Because the combined presence of estrogen and progesterone in oral contraceptives has stimulatory effects on breast cell proliferation, a protective effect against breast cancer is not anticipated, nor has such an effect been seen.[116,118]

Indeed, some studies have demonstrated a slight increase in the risk of breast cancer after oral contraceptive use; however, the risk does not appear to persist for more than 10 years after use.[118,127] Other studies have shown no increased risk of breast cancer with use of combination oral contraceptive formulations.[128,129]

Results from the Nurses’ Health Study suggest that oral contraceptive use protects against the development of colorectal cancer. In this prospectively followed cohort, women who used oral contraceptives for 96 months had a 40% lower risk of developing colorectal cancer (relative risk [RR], 0.60; 95% CI, 0.40 to 0.89 than those who never used oral contraceptives.[130] An Italian case-control study found that ever-use of oral contraceptive was inversely associated with colon cancer (odds ratio, 0.63; 95% CI, 0.45 to 0.87) and rectal cancer (odds ratio, 0.66; 95% CI, 0.43 to 1.01).[131]

Hormone Replacement Therapy

Hormone replacement therapy is advocated for both symptomatic and preventive health benefits unrelated to the development of malignancy. Since use of this therapy has become widespread, potential benefits, including the prevention of colonic malignancies, have been studied. Researchers for the Nurses’ Health Study have observed a decreased risk of colorectal cancer among current users of hormone replacement therapy (relative risk, 0.65; 95% CI, 0.50 to 0.83). However the apparent reduction in risk substantially diminished upon cessation of therapy.[132] Hormone use was also inversely associated with large (³ 1 cm) colorectal adenomas but not small ones.

A case-control study conducted by Italian researchers supported these findings. This study suggested an inverse relationship between ever-use of hormone replacement therapy and cancer of the colon (odds ratio, 0.64; 95% CI, 0.46 to 0.88) and cancer of the rectum (odds ratio, 0.46; 95% CI, 0.296 to 0.72). Increasing duration of use was related to decreasing risk of colon and rectal cancers (P value for the trend = .01).[133] In addition, researchers at the University of California, Los Angeles, have suggested a decreased risk of colorectal adenomatous polyps among recent users of hormone replacement therapy (odds ratio, 0.57; 95% CI, 0.35 to 0.94) with increasing duration of use.[134]

Consistent with the stimulatory effect of estrogen on the endometrial lining, the use of estrogen alone as postmenopausal hormone replacement therapy has shown a strong association with an increased incidence of endometrial cancer.[135,136] Recent work con-firms these findings, suggesting that even unopposed conjugated estrogen doses as low as 0.3 mg may be associated with an increased risk of endometrial cancer (risk relative to that of no replacement therapy, 5.4; 95% CI, 2.3 to 13), with risk increasing with increasing duration of use.[137] How-ever, the addition of progestin to estrogen-replacement regimens inhibits endometrial hyperplasia and may reduce the estrogen-enhanced risk of endometrial cancer.[138]

The effect of hormone replacement therapy on breast cancer risk remains unclear; variation in regimens and dosages, as well as in study design, are thought to contribute to the inconsistent results reported in the literature. A meta-analysis has shown no increased risk of breast cancer among women who had ever used hormone replacement therapy; in contrast, current users did demonstrate an increase in risk (RR, 1.40; 95% CI, 1.20 to 1.63).[139]

The Nurses’ Health Study showed an increased risk of breast cancer among women currently using unopposed estrogen (RR, 1.32; 95% CI, 1.14 to 1.54) or a combined estrogen- and progesterone-containing regimen (RR, 1.41; 95% CI, 1.15 to 1.74), as compared with those who had never received hormone replacement. This increased risk was limited largely to women who had used hormone therapy for ³ 5 years. For women who last used hormone replacement 5 or more years in the past, the relative risk was 0.95 (95% CI, 0.74 to 1.25).[118,140,141]

A population-based case-control study conducted in Washington state found that the use of an estrogen-progestin combination for hormone replacement was not associated with an increased risk of breast cancer in middle-aged women.[142] Also, a recent meta-analysis of 31 studies showed no increased risk of breast cancer among women who had ever used hormone replacement therapy.[129] Until more definitive studies have been completed, the potential risks and benefits for an individual patient must be weighed when deciding whether or not to use hormone replacement therapy.

A recent meta-analysis raises the possibility that hormone replacement therapy may be associated with an increased risk of developing epithelial ovarian cancer. In this analysis, ever-use of hormone replacement therapy was associated with an odds ratio of 1.15 (95% confidence interval, 1.05 to 1.27).[143] In contrast, a number of studies failed to demonstrate a significant association between the use of hormone replacement and the risk of developing epithelial ovarian cancer.[144]

Luteinizing Hormone–Releasing Hormone Agonists

The development of approaches that decrease exposure of the breast to the cyclic ovarian sex steroids of the premenopausal period should reduce breast cancer incidence. Among premenopausal women, a proposed strategy for retaining the benefits of combination oral contraceptives on endometrial and ovarian cancer while decreasing the risk of breast cancer is the use of luteinizing hormone–releasing hormone (LHRH) agonists.[115,118] Clinically, these drugs suppress gonadotropin secretion, leading to an inhibition of ovulation and ovarian steroidogenesis.[145]

Spicer, Pike, and colleagues have reported on a pilot study of a contraceptive regimen that utilizes monthly injections of leuprolide acetate depot (Lupron), an LHRH agonist, among patients with a fivefold or greater risk of breast cancer.[115] The adverse side effects of elimination of ovarian steroid production include hot flashes, bone loss, and an increased risk for cardiovascular disease associated with an alteration in cholesterol levels. To compensate for these effects, patients in this study received low-dose estrogen (ie, 0.625 mg of oral conjugated estrogens) for 6 out of every 7 days. Patients also were given intermittent progestin, in the form of medroxyprogesterone(Drug information on medroxyprogesterone) acetate (10 mg PO for 13 days of every fourth 28-day cycle) to avoid any increased risk of endometrial stimulation and resulting neoplasia.

Use of this contraceptive regimen for 10 years has been estimated to reduce lifetime breast cancer risk by 50%. In addition, the protection against ovarian cancer is projected to be identical to or greater than that afforded by combination oral contraceptives. Protection against endometrial cancer may also be seen, although not with the same magnitude as is seen with use of combination oral contraceptives.[115,116]

In the pilot study, 21 patients at fivefold or greater risk of breast cancer were randomized to the contraceptive regimen (14 patients) or a placebo (7 patients). At the end of the first year, symptom questionnaires revealed fewer complaints in the treated group, because of the elimination of premenstrual syndrome–related symptoms. Persistent hypoestrogenic effects of hot flashes and vaginal dryness were eliminated with an increase in the estrogen dose to 0.9 mg. A beneficial increase in high-density lipoprotein (HDL) cholesterol was also noted in treated patients.

Loss of bone mineral density in the subjects receiving the contraceptive regimen was addressed by the addition of a low dose of an androgen, similar to that produced by normally functioning ovaries. Preliminary results of this study suggest that no bone mineral density loss occurs with this modified regimen.

Finally, at the end of the first year, a substantial reduction in mammographic parenchymal density was seen in the contraceptive group, as measured by both expert examination and a computer-based method. This finding suggests reduced breast cell proliferation, which is hypothesized to lead to a reduction in long-term breast cancer risk.[115] Long-term follow-up of this study cohort is still pending.[115,146]