Digoxin Use and the Risk of Breast Cancer in Women

Biggar, Robert J.; Wohlfahrt, Jan; Oudin, Anna; Hjuler, Thomas; Melbye, Mads

doi:10.1200/jco.2010.32.8146

Cited by 65 publications

(68 citation statements)

References 29 publications

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“…Our analyses provide some reassurance that digoxin may be safe in women with breast cancer, despite the potential estrogenic effect of this drug and other observational evidence that it may increase breast cancer risk [1,[7][8][9]. Our analyses also did not show strong evidence of reductions in cancer-specific mortality in digoxin users and therefore does not support the findings of preclinical studies which suggest that digoxin has inhibitory effects on breast cancer cell growth [20][21][22][23].…”

Section: Discussioncontrasting

confidence: 63%

“…Consequently, a number of epidemiological studies have shown increases in breast cancer risk in digoxin users. For instance, two Danish studies have shown approximately 35 % increases in breast cancer risk in digoxin users versus non-users [8,10] and a US study observed a 45 % increase in breast cancer risk [7]. These observed increases in breast cancer risk in digoxin users raise questions about the safety of digoxin use in breast cancer patients.…”

Section: Introductionmentioning

confidence: 94%

“…Randomized controlled trials [5] and observational studies [6] have shown that exogenous estrogens can increase breast cancer risk, thus suggesting that the potential estrogenic effect of digoxin could influence breast cancer risk [1,[7][8][9]. Consequently, a number of epidemiological studies have shown increases in breast cancer risk in digoxin users.…”

Section: Introductionmentioning

confidence: 99%

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Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Karasneh

Murray

McMenamin

et al. 2015

Breast Cancer Res Treat

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Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify breast cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39-2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72-1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

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Section: Discussioncontrasting

confidence: 63%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Karasneh

Murray

McMenamin

et al. 2015

Breast Cancer Res Treat

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“…Recently, 2 studies in Denmark reexamined breast cancer risk in women using digoxin (1,2), the only digitalis drug in the Danish formulary. Using large data sets, both studies reached similar conclusions: The risk was significantly increased.…”

Section: Digitalis and Cancer Riskmentioning

confidence: 99%

“…Both forms are phyto-estrogens, or plant estrogens. Recent studies have shown that use of digoxin significantly increases the risk of breast and uterus cancer (1)(2)(3). Both cancers are often estrogen sensitive.…”

Section: Introductionmentioning

confidence: 99%

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

Biggar

2012

Clinical Cancer Research

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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.

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Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix

Biggar

Wohlfahrt

Melbye

2011

Intl Journal of Cancer

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Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age-and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N 5 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N 5 207) and 1.00 (95% CI: 0.79-1.25; N 5 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.Digoxin is an inotropic drug widely used in the management of cardiac problems, especially in the elderly. While its principal effect is on the Na þ K þ pump, 1 it is a phyto-estrogen capable of binding to estrogen receptors. 2,3 Recent studies in Denmark have found that breast cancer risk is increased about 30-40% in women currently using digoxin, 4,5 the effect being greatest on estrogen receptor positive cancers. 5 Risk of cancer of the corpus uteri (endometrium) is also increased by exogenous estrogen exposure when exposure is not opposed by progestins. [6][7][8] We hypothesized that the risk of this cancer would be increased in current digoxin users, analogous to its effects in breast cancer. Finding risk to be increased would have important clinical implications for the use of digoxin in women. It would also add further evidence that the mechanism by which digoxin affects cancer risk is likely attributable to the estrogenic effect of digoxin.To examine the hypothesis, we examined relative risks of three gynecological cancers in users of digoxin: cancer of the corpus uteri (hereafter called uterus cancer) to those of ovary and uterine cervix (hereafter called cervix) cancers. These three cancers were chosen as study end points because they are reasonably common and all are related to reproductive organs. In contrast to uterus cancer, neither ovary nor cervix cancer...

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Digoxin Use and the Risk of Breast Cancer in Women

Abstract: Women currently using digoxin had a significantly increased risk of breast cancer. Risk normalized when digoxin was stopped. No risk increases were observed in women using angina drugs only. The higher risk of developing ER-positive breast cancers supports an estrogen-mimicking mechanism.

Cited by 65 publications

References 29 publications

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

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

Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix

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