Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Published OnlineFirst February 24, 2012; DOI: 10.1158/1078-0432.CCR-11-1389

Clinical Cancer Molecular Pathways Research

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications

Robert J. Biggar

Abstract Digoxin, a phyto-estrogen, binds with estrogen receptors (ER) and can cause gynecomastia. Among women currently using digoxin, breast and uterus cancer incidences are signiﬁcantly increased (approximate risk ratios, 1.3–1.5). Both cancers are often estrogen sensitive. In contrast, ovary and cervix cancers are relatively estrogen insensitive, and incidence is unaffected by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in nonusers. These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal and/or acinar cells, accelerating the growth of nascent cancers. Also consistent with an estrogenic effect, men using digoxin have a small but signiﬁcant reduction in prostate cancer (risk ratio, 0.76). Other estrogen-like drugs, particularly spironolactone, should be investigated for similar effects. The effect of digoxin use in women being treated for breast cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy may take tamoxifen, which blocks ERs. However, postmenopausal patients may use aromatase inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in women with or at high risk of developing estrogen-sensitive cancers. Clin Cancer Res; 18(8); 2133–7. 2012 AACR.

Background estrogen receptors (ER), although with less affinity than Digitalis, a medicinal extract of the plant foxglove, has a estrogen itself (5, 6). Stimulation of ERs induces prolifer- powerful inotropic effect on cardiac muscle. Chemically, 2 ation of ductal and acinar tissue. Thus, it is not surprising forms are used as medications in patients with heart disease, that chronic use of digitalis induces gynecomastia in men digoxin and, less commonly, digitoxin. Both forms are (7, 8), just as estrogen excess does in men. The effect on phyto-estrogens, or plant estrogens. Recent studies have female breast tissue is likely similar, although enlargement shown that use of digoxin significantly increases the risk would be less noticeable. of breast and uterus cancer (1–3). Both cancers are often estrogen sensitive. In contrast, no changes in risk were seen Estrogen and cancer risk for 2 ovary and cervix (3) cancers, both relatively estrogen The vast literature on estrogen use and cancer risk in insensitive. women is beyond the scope of this review. Briefly, exogenous estrogens, given as menopausal hormone therapy, Chemistry and physiology have been documented to increase the incidence of breast The principal effect of digitalis drugs is to inhibit the cancer in many studies (9), particularly when given with sodium–potassium pump, which regulates the flux of ions progestins (10). Generally, breast cancer incidence across the cell membrane, calcium being of particular increases soon after initial exposure remained above importance in cardiac conditions (4). However, the basic expected levels for the duration of use, possibly increasing structure of digitalis compounds is similar to that of estra- slightly over time. However, when estrogen exposure ceases, diol, the principal estrogen (Fig. 1). Several studies have the incidence of breast cancer promptly declines as well. indicated that digitalis drugs have the capacity to bind to This pattern is consistent with a pathway in which current use of estrogen accelerates the growth of nascent breast cancers, rather than inducing them de novo (11). Similarly, Author's Affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark for the uterus, both hyperplasia (12) and endometrial cancer incidence (13) increase with estrogen use, an effect Corresponding Author: Robert J. Biggar, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Den- decreased by including progestins in the formulation of mark. Phone: 45-3268-3722; Fax: 45-3268-31-65; E-mail: hormone therapy. For ovary cancer, there seems to be a [email protected] slight increase in risk with estrogen use (14–16), but not to doi: 10.1158/1078-0432.CCR-11-1389 the risk ratios seen with breast cancer. Use seems not to have 2012 American Association for Cancer Research. an impact on cervical cancer risk (17).

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Figure 1. Speculation about the pathogenesis by which estrogen and estrogenic compounds might affect estrogen-sensitive tissues, including nascent cancer cells.

Digitalis and cancer risk adjusted nonusing women. Incidence increased within the The potential for digitalis to increase cancer risk was first year of digoxin use and continued for the duration of appreciated decades ago. Three studies specifically exam- exposure. Risk in continuing users was high in the first year ined this hypothesis, all concluding there was no significant of exposure and then dropped to a nadir at 3 years before þ increase in risk (18–20). However, in each study, the point rising again. Rate ratio for ER (1.35) and untested (1.51) estimate of incidence was increased about 30% above breast cancers were significantly increased, but for ER nonusers. With hindsight, there was inadequate power to breast cancers (1.20), CIs included unity. In former users, detect low risks with statistical confidence, given their incidence declined significantly below expected levels in the limited size. In 2 case–control studies, men with breast first year but increased to expected levels thereafter. cancer were significantly more likely (2-fold) to use digitalis The sodium–potassium pump regulates the transport of a than expected (21, 22). These studies ignored or dismissed variety of products across the cell membrane (4), providing the importance of these associations. alternative pathways by which digoxin might affect cancer Recently, 2 studies in Denmark reexamined breast cancer risk. To evaluate if the digoxin-associated risk was likely risk in women using digoxin (1, 2), the only digitalis drug in mediated through its effect on ERs, the incidences of cancers the Danish formulary. Using large data sets, both studies of corpus uteri (uterus), ovary, and uterine cervix were reached similar conclusions: The risk was significantly compared in digoxin-exposed and never-exposed women increased. In a regional case–control study (1), women (3). Uterus cancers are predominately estrogen-sensitive, þ with breast cancer (n ¼ 324 cases) had an OR of 1.30 ER endometrial cancers, whereas ovarian and cervix cancer [95% confidence interval (CI), 1.14–1.48] for being are relatively estrogen insensitive (with uncommon excep- current digoxin users, compared with nonusers (n ¼ tions). The incidence rate ratio of uterus cancers was 2,546). The association was robust even after adjustment increased 1.48-fold (95% CI, 1.32–1.65) in current digoxin for prior exposure to menopausal hormone therapy and was users. In contrast, risks of ovary and cervix cancers were not not confounded by indications for use of hormonal ther- increased in current digoxin users (1.06; 0.92–1.22 and apy. In a nationwide cohort, risk was examined in 2.1 1.00; 0.79–1.25, respectively). Furthermore, the higher risk million women (25.5 million person-years of follow-up of uterus cancer decreased when digoxin use ended. through 2008; n ¼ 49,016 breast cancers). Digoxin expo- Risk factors for uterus cancer include obesity (24), a sure was obtained through a national prescription database potentially confounding risk factor because it is shared (23) initiated in 1995. The breast cancer incidence rate ratio with cardiovascular disease. However, endometrial cancer was 1.39 (95% CI, 1.32–1.46) in women currently using risk is decreased in smokers (24), and furthermore, no digoxin, compared with exact age- and calendar-year– association was seen between uterus cancer and drugs used

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Digoxin and Estrogen-Sensitive Cancer Risk

for angina (3), which argues against the digoxin effect being pituitary-induced gynecomastia, galactorrhea may occur related to shared risk factors for cardiovascular disease. That (7), suggesting that ductal and/or acinar cells may differen- current digoxin increased the risk of only the estrogen- tiate further with hypothalamic and/or pituitary stimulation sensitive cancers of the breast and uterus, both approxi- than with estrogen, which might affect differentiation and mately 1.3- to 1.5-fold, but not ovary or cervix cancer, malignant potential. Finally, drugs such as cimetidine, a supports a mechanism mediated by its effect on the ERs. commonly used H2-receptor antagonist, and some (but not Estrogen retards the growth of prostate cancer; by anal- all) other antiulcer drugs used to control gastric acidity, may ogy, so might digoxin. In drug screening, digoxin was found interfere with estrogen metabolism (39), and chronic use to be among the most potent of commonly used drugs in has been associated with gynecomastia (40). However, 2 inhibiting growth of prostate cancer cell lines (25). In the studies found no association between cimetidine and breast same study, the investigators examined risk in men using cancer (41, 42). digoxin, finding a lower prostate cancer incidence (0.76; Dietary and over-the-counter phyto-estrogen formula- 95% CI, 0.61–0.95), compared with nonusers of digoxin tions are sometimes taken for menopausal symptoms. (25). Further studies are needed to confirm this result, but Compared with prescription medications, they are used in the result is consistent with digoxin exerting an estrogenic much weaker preparations and often taken only episodi- effect. cally. There is little evidence that they are effective as menopausal therapy (43), but also no evidence that they affect breast (44) or uterus cancer risk (45). Clinical–Translational Advances Other estrogen-mimicking drugs Public health impact Other common drugs resemble estrogen. Of most interest Despite concern about increasing the risk of breast cancer, is spironolactone, a synthetic 17-lactone steroid used as a digital drugs have important roles in patient care. Any potassium-sparing diuretic in patients with heart failure, reconsideration of their use would likely conclude that the cirrhosis, hypertension, and primary aldosteronism, often benefits of digoxin for heart disease outweigh the cancer for prolonged periods (26). Spironolactone binds to and risks. Digoxin use is primarily in the elderly, and hence, this inhibits aldosterone receptors, but also adheres to and discussion largely concerns postmenopausal breast cancer inhibits ERs (6). Functionally, it is an estrogen agonist risk in older women. In approximately 350,000 Danish (27), but it may also interfere with estrogen metabolism women 70 years old, breast and uterus cancer annual (28). Gynecomastia is a common side effect, occurring in incidences are approximately 350 and 90 per 100,000 per 10% with conventional doses and up to 50% with high year, respectively (data from the Danish Cancer Registry; doses (29, 30). In case reports, patients on spironolactone ref. 46). The higher rate ratios for breast and uterus cancers have been reported to have developed breast cancer (31– apply only to 2.2% of these women currently using digoxin 34), but with common cancers, case reports have limited (data from the Danish Register of Medicinal Products value. In one small case–control study (N ¼ 302 women Statistics; ref. 23). Thus, in 100,000 women 70 years old, with breast cancer), no significant association with spiro- 2,200 women would be current digoxin users, among nolactone use was observed (35). This finding should be whom approximately 11 breast (8 expected, based on reexamined in a study with more power. Both digoxin and nonusers) and 3 uterus (2 expected) cancers would be spironolactone may be used together in patients with heart observed. The net cancer increase is, therefore, about 3 disease, complicating analysis. However, this possibility breast and 1 uterus cancer cases per 100,000 elderly women also raises the prospect of overlapping stimulatory effects per year. Although this is only 1% of all breast cancers in this on breast tissue cells and perhaps even higher risks. age group, women using digoxin remain at increased risk for One clue to an estrogenic drug effect might be an associ- every year of digoxin use. ation of the drug with gynecomastia. However, gynecomastia may have different causes. Estrogen acts directly on ductal Digoxin use in women with cancer or acinar tissue. Presumably, digoxin and possibly spirono- The above presentation focused on cancer incidence. A lactone act similarly. However, gynecomastia may also further concern is the use of digoxin in women with a occur indirectly, via prolactin release from the pituitary history of estrogen-sensitive cancers. Most physicians (7). Antipsychotic and rauwolfia drugs can cause gyneco- consider exogenous estrogen contraindicated in such mastia by blocking dopamine and a-adrenergic receptor patients, but an absolute prohibition remains controver- sites in the hypothalamus (e.g., phenothiazine derivatives sial (e.g., refs. 47–48). Digoxin use in women with and opiate derivatives) or by depleting pituitary catechol- estrogen-sensitive cancers has not been rigorously exam- amine (e.g., reserpine; ref. 7). In the 1980s, considerable ined. Although incidence risk is increased with digoxin concern was raised about reserpine and breast cancer risk, exposure, this increase may not translate to risk of death but the association was inconclusive (e.g., ref. 36). In recent from breast cancer. Mortality from cancer is similar in years, the risk has been dismissed as unimportant (37), but women who develop breast cancer while on estrogens despite this, reserpine is no longer widely used. A review of and those not on estrogen (49, 50). Perhaps better med- neuroleptic drugs found no increase in breast cancer risk ical surveillance is provided or possibly the biology of the (38). Chemically, these drugs differ from estrogen. With cancers differs. If digoxin–cancer patterns of mortality

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Biggar

parallel those of estrogen, as might be predicted, there itself, at very high doses, can also inhibit breast cancer maybenodirectimpactonmortalityfrombreastcancer, cell lines in vitro (60). but even so, having both breast cancer and heart disease is likely to cause increased mortality overall. Similar con- Summary siderations likely apply to uterus cancer. Current digoxin use increases the incidence of estrogen- Complicating any analysis will be the use of adjuvant dependent breast and uterus cancers, with rate ratios revert- therapy, in particular tamoxifen. Tamoxifen and other drugs ing to the null when exposure stops. Because only current use of its type bind to the ER with complex results. They inhibit increases the incidence, the mechanism may be that of a attachment of estrogen on ductal and acinar cells (51) and, promoter, that is, digoxin enhancing proliferation of nascent thus, could also block digoxin effect on mammary tissue. tumors rather than inducing new tumors. On theoretical However, effects of different drugs within this class vary. grounds (and anecdotal data), other estrogen-mimicking In particular, tamoxifen increases the proliferation of drugs may have similar effects. Of particular concern are the endometrial cells and increases the risk of endometrial potassium-sparing diuretics. Despite cancer risks, the use of cancer and sarcomas of the uterus, whereas other drugs in digital drugs may be medically indicated because their car- the same class apparently do not (52, 53). In recent years, diac benefits likely exceed cancer risks. However, the impact aromatase inhibitors, a different class of drug, have of digoxin use on women with active estrogen-sensitive become widely used in the treatment of postmenopausal cancers has yet to be evaluated. It is possible that digoxin, patients. These agents block estrogen production but and perhaps other estrogen-mimicking drugs, could affect leave the ERs unaffected and without competition by extant breast and uterus cancers adversely. Physicians treating natural estrogens (54). Thus, digoxin would have full women with existing cancers may wish to consider using license to interact with the ER and stimulate proliferation, alternative therapies, when possible, and should be especial- assuming its effect is mediated through ER binding. If ly alert to possible breast or uterus cancer symptoms when digoxinuseisshowntoaffectbreastcancerprognosis digoxin use is clinically indicated. adversely, then use of tamoxifen as adjunct therapy might be considered. Disclosure of Potential Conflicts of Interest In conflict with concern about an increasing risk, No potential conflicts of interest were disclosed. some investigators hypothesize digoxin might benefit In vitro Acknowledgments women with breast cancer. ,itinhibitscelladhe- Dr. Louise Brinton, National Cancer Institute, Bethesda, MD and Prof. sion or proliferation in breast cancer cell cultures (55, Niels Kroman, Rigshospitalet, Copenhagen, Denmark provided helpful 56), and several different molecular pathways have been comments on this manuscript. proposed (e.g., refs. 57–58). One retrospective study (32 women on digoxin with mortality as the outcome) Grant Support Support for this article was provided by the Danish Cancer Society suggested it might be beneficial (59). For cell culture (KrI`ftens BekI`mpelse, grant number R40-A1857-11-S2) without restriction systems, drug doses may be well in excess of those of its contents or any role in the decision to submit. physiologically tolerated by human subjects and, hence, Received November 11, 2011; revised January 31, 2012; accepted February toxic both to cells and the patient. However, estrogen 1, 2012; published OnlineFirst February 24, 2012.

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www.aacrjournals.org Clin Cancer Res; 18(8) April 15, 2012 2137

Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers −−Risks and Possible Therapeutic Implications

Robert J. Biggar

Clin Cancer Res 2012;18:2133-2137. Published OnlineFirst February 24, 2012.

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