Statins may lower cardiotoxic effect of anthracyclines in early breast cancer treatment
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Older women who received early breast cancer treatment with anthracycline experienced fewer HF hospitalizations associated with the cardiotoxic effects of chemotherapy when also exposed to statin therapy, researchers reported.
According to data published in the Journal of American Heart Association, a similar trend was observed among women treated with trastuzumab (Herceptin, Genentech), but the association did not meet statistical significance.
“In this population-based, propensity score-matched cohort study, statin-exposed early breast cancer patients at high cardiovascular risk based on older age ( 65 years) had a significantly lower risk of HF hospital presentations following anthracycline-containing chemotherapy compared with matched women who were unexposed to statins,” Husam Abdel-Qadir, MD, PhD, scientist at Women’s College Research Institute, cardiologist at Women’s College Hospital and assistant professor in the department of medicine at the University of Toronto, and colleagues wrote. “There was a nonsignificant trend towards a lower risk of HF hospital presentations associated with statin exposure among trastuzumab-treated women compared with statin-unexposed women.”
Using linked administrative databases for this retrospective cohort study, researchers included 2,545 anthracycline-treated women (859 statin-exposed at baseline) and 1,371 trastuzumab-treated women (520 statin-exposed at baseline), without prior HF, matched 1:1 for the presence of statin exposure at baseline. Women treated with trastuzumab were also matched on anthracycline exposure. Overall, researchers matched 666 statin-discordant pairs of anthracycline-treated women (median age, 69 years) and 390 pairs of trastuzumab-treated women (median age, 71 years).
“Mounting evidence suggests that anthracycline-induced cardiotoxicity is mediated by topoisomerase-2 beta inhibition and oxidative stress secondary to reactive oxygen species generation by anthracyclines,” the researchers wrote. “Oxidative stress may also play a role in trastuzumab-induced cardiotoxicity.”
Researchers observed that the cumulative incidence of HF hospitalization among women treated with anthracyclines was lower among those who also received statin therapy compared with those who did not (P = .01).
Early breast cancer and anthracyclines
At 5 years, the incidence of HF hospitalization among women who received early breast cancer treatment with anthracycline and were statin-exposed was 1.2% (95% CI, 0.5-2.6) compared with 2.9% who were not statin-exposed (95% CI, 1.7-4.6; cause-specific HR = 0.45; 95% CI, 0.24-0.85; P = .01).
In a sensitivity analysis that censored women at time of interim acute MI hospitalization, the 5-year incidence of HF hospitalization in the anthracycline cohort was 1.2% among statin-exposed women (95% CI, 0.5-2.6) and 2.7% among unexposed patients (95% CI, 1.6-4.4; P = .02).
According to the study, the cause-specific HR associated with statin exposure within the anthracycline group was 0.44 (95% CI, 0.22-0.87; P = .02).
In women treated with trastuzumab, the cause-specific HR for HF associated with statin treatment was 0.51 in those without prior anthracyclines use (95% CI, 0.19-1.41; P = .19) and 0.39 in those with prior anthracyclines use (95% CI, 0.1-1.58; P = .19).
Early breast cancer and trastuzumab
Among women with early breast cancer treated with trastuzumab, researchers found a nonsignificant trend toward a lower risk for HF hospitalization among statin-exposed women compared with unexposed women at baseline.
At 5 years, the cumulative incidence of HF hospitalization among women in the trastuzumab group exposed to statin therapy at baseline was 2.7% (95% CI, 1.2-5.2) and 3.7% in the unexposed group (95% CI, 2-6.2; P = .09).
Moreover, among women treated with trastuzumab, the cause-specific HR for HF at 5 years was 0.46 among those exposed to statins (95% CI, 0.2-1.07; P = .07) compared with those with no prior statin use.
After censoring for interim acute MI, the 5-year incidence of HF hospitalization in the trastuzumab group was 2.7% among women exposed to statin therapy (95% CI, 1.2-5.2) and 3.7% among those who were unexposed (95% CI, 2-6.2; cause-specific HR = 0.41; 95% CI, 0.17-0.97: P = .04).
“The results of this study should be interpreted with caution given its retrospective design and dependence on administrative data,” the researchers wrote. “A key limitation is our inability to account for left ventricular ejection fraction, diastolic function, cardiac biomarkers or biohumoral data. Thus, we cannot determine if the HF events occurred with reduced or preserved LVEF. The study excluded women with established diagnoses of HF before chemotherapy but may have included women with asymptomatic cardiomyopathy, although this is not expected to occur more commonly in the nonstatin groups.”
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Ana Barac, MD, PhD, FACC, FAHA
The study is hypothesis-generating and suggests that statins may be cardioprotective and reduce the risk for HF associated with anthracyclines.
The results are not surprising, as prior basic science as well as smaller clinical studies have demonstrated the favorable effects of statins on attenuating cardiotoxic effects of anthracyclines. These epidemiological findings confirm prior observations and support the development of prospective clinical studies investigating the use of statins in patients with breast cancer.
This is a very dynamic area of investigation. A number of prospective randomized clinical studies investigating the effects of statins among patients with breast cancer are ongoing or have been recently completed. In the very near future, we should have more data on whether statins (including which statin and what dose) may provide protective effects on cardiac function during breast cancer treatment. I would love to point out arguably the most intriguing aspect of ongoing investigations: the effects of statins on cancer behavior and prevention of breast cancer recurrence. While in their early stages, they represent the true translational potential of cardio-oncology.
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This retrospective study conducted in Canada used propensity score matching — a statistical method for analysis of observational data — to match women aged older than 66 years with early-stage breast cancer who received anthracyclines with or without statins, or trastuzumab with or without statins.
The 5-year cumulative rate of HF hospital admission or ED visits served as the primary endpoint. Results showed a statistically significant difference among anthracycline-treated patients who received statins (1.2% vs 2.7%; HR = 0.45; 95% CI, 0.25-0.85), and a numerical difference among trastuzumab-treated patients who received statins (2.7% vs. 3.7%; HR = 0.45; 95% CI, 0.2-1.07).
Are statins used now for prevention of anthracycline toxicity based on these results? The answer is no, and the authors point out the limitations of this article.
Several points are worth mentioning.
The use of anthracyclines is likely to diminish — in this age group and in general — because of the development of effective nonanthracycline-containing regimens.
Also, HF from anthracyclines is very different than that associated with trastuzumab treatment. Anthracyclines cause myocardial cells to die and the damage is permanent, although often can be improved by cardiac medications. Trastuzumab causes “heart dysfunction,” with more than 50% of patients recovering their heart function and going on to be treated with trastuzumab again. This may explain the lack of statistically significant benefit with statins among women treated with trastuzumab.
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Marielle Scherrer-Crosbie, MD, PhD
This study confirmed some of the prior research that has been done in this particular field. This retrospective analysis compared older women with breast cancer treated with anthracyclines who were or were not simultaneously treated with statins. Women treated with statins usually have a worse CV profile than women not treated with statins, they have more CV risk factors and more prior CVDs. The women treated with statins were matched with women not treated with statins with a similar CV risk profile. When you adjust all these factors, it appears that women treated with statin have less hospitalizations for HF than women who are not treated with statins. That is the overall conclusion that when you are able to compare the two populations of women and match them for their clinical state, statins appear to have some protective effect against HF hospitalizations.
This finding was not surprising to me. There was a previous study that followed the same lines in 2013. There was also a small prospective study that showed statins may have a protective effect in patients treated with anthracyclines, but it was a very small study.
It is an interesting hypothesis and there are currently groups that are prospectively testing this hypothesis, including our own group.
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