1. Lisinopril or Carvedilol for Prevention of Trastuzumab Induced Cardiotoxicity
Maya Guglin, MD, PhD University of Kentucky, Lexington, KY
Jeffrey Krischer, PhD University of South Florida, Tampa, FL
Roy Tamura, PhD University of South Florida, Tampa, FL
Angelina Fink, MPH H. Lee Moffitt Cancer, Tampa, FL
Lauren Bello-Matricaria University of South Florida, Tampa, FL
Worta McCaskill-Stevens, MD National Cancer Institute, Rockville, MD
Pamela N. Munster, MD University of California San Francisco, San Francisco, CA
ClinicalTrials.gov Identifier: NCT
Sponsors and Collaborators:
University of South Florida
National Cancer Institute

2. Introduction: Incidence of Cardiotoxicity
Overall cardiac dysfunction
NYHA III/IV
Doxorubicin +
Cyclophosphamide 8% 4%
+Trastuzumab
27%
16%
Seidman et al. J Clin Oncol 2002; 20: :

3. HER2 positive breast cancer patients starting Trastuzumab
Hypothesis
HER2 positive breast cancer patients starting Trastuzumab
ACE-I
Placebo
β-blocker EF
↓ EF EF

4. Methods
Proportion of cardiotoxicity events at the end of trastuzumab therapy or week 52 was analyzed both by a chi-square test and by logistic regression with anthracycline strata and baseline LVEF as independent factors.
The significance of the coefficients was determined by the Wald test.
Long term cardiotoxicity effects, a secondary outcome, were analyzed by proportional hazards analyses of the time to first cardiotoxicity event were conducted with treatment group, anthracycline strata and baseline LVEF as independent factors of the model.

5. Design Trastuzumab + anthracyclines - anthracyclines ACE-I β-blocker
Enrollment
+ anthracyclines
- anthracyclines
Randomization
ACE-I
β-blocker
ACE-I
β-blocker
Placebo
Placebo

6. Primary Objective
to determine if administration of lisinopril or carvedilol results in decrease of the rate of cardiotoxicity in comparison with placebo

7. Secondary Objectives
to determine whether participants receiving lisinopril or carvedilol experienced fewer interruptions in trastuzumab therapy
to determine if treatment effects were consistent in anthracycline and non-anthracycline cohorts.

8. Inclusion Criteria Age ≥18 years old HER2 positive breast cancer
Scheduled to receive adjuvant trastuzumab therapy
LVEF ≥ 50% by MUGA scan or echocardiogram, based on institutional/clinician preference
Normal renal and hepatic function
Systolic blood pressure of > 90 mmHg
Heart rate ≥ 60 beats/minutes

9. Exclusion Criteria
Current treatment with ACE-inhibitors, ARBs, ß- blockers, digoxin
Patients with metastatic disease
Known cardiac history
History of asthma or related bronchospastic conditions
Hereditary or idiopathic angioedema
Severe hypersensitivity reaction to drugs or other causes
Pregnant or breastfeeding (must use effective birth control)

10. Definition of Cardiotoxicity
Decrease from baseline of ≥10% (LVEF) at study follow-up or
An absolute decrease ≥ 5% in LVEF if it is < 50% at study follow-up
The determination of LVEF was made locally at each site. LVEF testing was conducted at baseline, 3, 6, 9, and 12 months.

11. Results 468 patients 127 participating sites
86.3% Caucasian, 7.3% African American,
mean age 51±10.7
Baseline LVEF 63±6.29%
No difference between arms

12. Cardiotoxicity-free survival for the whole study cohort

13. Cardiotoxicity-free survival for the cohort with Trastuzumab and anthracycline exposure

14. Cardiotoxicity-free survival for the cohort with Trastuzumab exposure without anthracyclines

15. Conclusions
In patients with HER2 positive breast cancer treated with trastuzumab, the cardiotoxic events were similar on placebo, lisinopril or carvedilol with comparable treatment interruptions.
Both lisinopril and carvedilol were effective in preventing cardiotoxicity in patients who were treated with both trastuzumab and anthracyclines.
Cardiotoxicity associated with Trastuzumab superimposed on prior or current exposure to anthracyclines can be prevented with lisinopril or carvedilol.
In high risk patients who may benefit from an anthracycline- containing regimen, the use of lisinopril or carvedilol is justified and should be considered to off-set cardiotoxic events by the use of anthracyclines in combination with trastuzumab.

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