Lisinopril may prevent cardiotoxicity of anthracycline, trastuzumab use in breast cancer
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A decrease in left ventricular ejection fraction to below normal levels occurred more frequently among women with HER2-positive early-stage breast cancer who received anthracyclines prior to trastuzumab, according to study results.
The findings of the prospective randomized study, presented at the virtual ASCO Annual Meeting, showed this decline in left ventricular ejection fraction (LVEF) appeared preventable with concurrent lisinopril.
“It would appear that anthracyclines have a more profound negative effect, even in a younger group of women, that we should take in consideration and we may be able to offer an intervention for those who will benefit from or need an anthracycline,” Pamela N. Munster, MD, professor in the department of medicine (hematology/oncology) at University of California, San Francisco, and director of the early-phase clinical trials unit, co-leader of the Center for BRCA Research and co-leader of the molecular oncology program at UCSF Helen Diller Family Comprehensive Cancer Center, told Healio.
Although trastuzumab (Herceptin, Genentech) is an effective treatment for HER2-positive breast cancer, it is associated with a decline in LVEF and clinical heart failure, leading to treatment interruption and discontinuation, according to study background.
Thus, Munster and colleagues sought to evaluate the impact of using an ACE inhibitor or beta blocker to prevent LVEF in this patient population.
“Patients in the community often have less access to more comprehensive care and we wanted to both determine the risks on the heart and whether a simple intervention could be meaningful,” Munster said.
The analysis included data of 468 women (mean age, 51 ± 10.7 years) with HER2-overexpressing early-stage breast cancer who received treatment at one of 127 community-based oncology practices. Of them, 189 received an anthracycline prior to trastuzumab, and 279 received trastuzumab alone.
Mean LVEF at baseline was 62.6%, mean BMI was 28.4 kg/m2, and 8.4% of the population had hypertension.
Researchers randomly assigned patients to receive 10 mg lisinopril, an ACE inhibitor; 10 mg carvedilol, a beta blocker; or placebo, starting on day 1 with trastuzumab for 1 year. Outcome measures assessed every 12 weeks included a decline in LVEF to below normal levels, defined as lower than 50%, or a 10% or greater decrease in LVEF that remained at normal levels.
At 12 months, a greater proportion of women treated with an anthracycline experienced a drop in LVEF to below normal levels than those treated with trastuzumab alone (21% vs. 4.1%).
In the group that received an anthracycline, significantly fewer women who received lisinopril than placebo experienced LVEF below 50% (10.8% vs. 30.5%; P = .045), but the 22.8% rate with carvedilol did not represent a significant difference from that of placebo.
“The findings of this study suggest that the drop in LVEF to below 50% was much larger than previously reported in the anthracycline group,” Munster said during her presentation.
In the group treated with trastuzumab alone, researchers observed no significant differences in those who showed LVEF below normal levels whether they received carvedilol (4.5%), lisinopril (1.3%) or placebo (6.4%).
An LVEF drop of 10% or greater at 12 months occurred among 14.4% of the trastuzumab-alone group and 5.5% of the anthracycline-trastuzumab group, with neither lisinopril nor carvedilol significantly affecting this manifestation of cardiotoxicity.
“Most importantly, we found a baseline elevated blood pressure in many of our patients,” Munster told Healio. “Maximizing overall health care including treating elevated blood pressure is important for overall cardiac health. Lisinopril is well-tolerated and we could have probably given a lower dose. The side effects of lisinopril are minimal compared with the benefits we saw, and this should be considered.
“In a curative breast cancer setting, preserving cardiac health is important and underlying risks factors should be addressed,” Munster added. “Breast cancer treatment should include maximized preservation of all health parameters.”
Future research should address how stress, environment, lack of exercise and obesity affect breast cancer treatment, Munster said.
Perspective
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Fatima Cardoso, MD
Although the researchers observed low numbers of patients and events in each of the subgroups, we also see that, overall, there is a low rate of an important decrease in LVEF, even with anthracycline-based chemotherapy. We also saw that lisinopril had the most important effect regarding prevention of a decrease in LVEF to below 50%. But, when looking at the outcomes for an LVEF drop of at least 10%, carvedilol seems to have a slightly bigger effect.
These results are in line with a previous study that also looked at using lisinopril or carvedilol and showed both could help improve cardiotoxicity-free survival among anthracycline-treated patients who received 1 year of trastuzumab (lisinopril vs. placebo, HR = 0.53; 95% CI, 0.3-0.94; carvedilol vs. placebo, HR = 0.49; 95% CI, 0.27-0.89).
We have escalating and de-escalating strategies for treatment of HER2-positive early breast cancer. Escalating strategies include treatment with anthracyclines plus taxanes and dual HER2 blockade, moving to the use of adjuvant ado-trastuzumab emtansine (Kadcyla, Genentech) and neratinib (Nerlynx, Puma Biotech) and, possibly in the near future, new drugs. We also have de-escalating strategies by omitting anthracyclines, pertuzumab (Perjeta/Phesgo; Genentech) or both, such as in the adjuvant paclitaxel and trastuzumab (APT) regimen and, perhaps in the future, with no use of chemotherapy.
But, the most important point is that this decision of escalating or de-escalating treatment should be based on the risk for relapse or death. We should not escalate just because we can, and we should also not de-escalate for fear of cardiotoxicity in the absence of important risk factors for cardiac disease, because severe cardiotoxicity is rare, especially with epirubicin. I believe we have sufficient data to try to use lisinopril or carvedilol as cardioprotective drugs — if they are well-tolerated by the patient —especially when anthracyclines and anti-HER2 agents are used.
Reference:
Guglin M, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2019.03.495.
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Munster PN, et al. Abstract 509. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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