A 65-year-old woman with stage IIA left-sided breast cancer (ER/PR negative; HER2 positive) is referred to cardiology for cancer therapy-related cardiac dysfunction that developed on trastuzumab.
Her medical history is significant for coronary artery disease status-post coronary artery bypass grafting, hypertension, hyperlipidemia, and diabetes mellitus type 2. She is a nonsmoker. Her medications at cancer diagnosis follow:
Carvedilol 25 mg 2 times a day
Amlodipine 2.5 mg daily
Clonidine 0.2 mg 3 times a day
Furosemide 80 mg daily
Losartan 100 mg daily
Lovastatin 20 mg daily
Prior to initiating chemotherapy, her cardiovascular exam was unremarkable: blood pressure was 110/60 mmHg, she had regular and rhythmic heart sounds with no murmurs, her jugular venous pressure was normal, and she had no edema and no rales. Her baseline echocardiogram revealed a left ventricular ejection fraction (LVEF) of 58%, no wall motion abnormalities, and no valvular dysfunction. Her oncologist started her on paclitaxel and trastuzumab. After 8 doses of trastuzumab, she developed dyspnea and edema. A repeat echocardiogram revealed an LVEF of 47%. Trastuzumab was held, but there was no improvement in her LVEF after 5 weeks.
She now presents to cardiology for a second opinion regarding completing trastuzumab. Currently, she is asymptomatic. Her blood pressure is 120/76 mmHg, and her cardiovascular exam reveals no sign of decompensated heart failure. It has now been 8 weeks since her last dose of trastuzumab.
What is the most appropriate next step in this patient's treatment?
The correct answer is: B. Repeat the echocardiogram because it has now been 3 weeks since the last assessment.
Before making a recommendation regarding this patient's trastuzumab therapy, we wanted to make sure we were acting on recent data. In her case, repeating the echocardiogram simplified decision-making because her LVEF had normalized to 65%. Trastuzumab was resumed, and her LVEF was monitored every 3 months for the duration of her therapy. She was able to complete 12 months of trastuzumab with no recurrence of cancer therapy-related cardiac dysfunction.1
Answer A is not consistent with the US Food and Drug Administration (FDA) guidelines. Additionally, reassessment of her LVEF earlier than 3 months after resuming trastuzumab would be advisable if trastuzumab was resumed despite a persistently reduced LVEF. Answer C is consistent with the prescribing recommendations outlined by the FDA if the LVEF remains low after holding trastuzumab. However, there are data that this approach may deprive some people of lifesaving cancer therapy who may otherwise have tolerated it from a cardiovascular perspective despite a mildly reduced LVEF between 40% and 50%. Answer D may have been reasonable if her LVEF remained low. However, in this patient's case, it would have been premature because, given a bit more time, her LVEF normalized on her medical therapy that included carvedilol and losartan.
The HER2 gene is overexpressed in around 25% of breast cancers.2 Trastuzumab is a targeted antibody against the HER2 receptor tyrosine kinase that has significantly improved survival in HER2(+) breast cancer.2,3 However, it has also been associated with a risk of cardiomyopathy (4-10%) and heart failure (0-4%).2,3 These risks are even higher when the patient is first treated with a chemotherapy regimen containing an anthracycline.2
The FDA's prescribing guidelines for trastuzumab state that the LVEF should be assessed at baseline and regular intervals during treatment. If the LVEF decreases ≥16% from pretreatment values or if LVEF is less than normal according to institutional limits and has decreased ≥10% from pretreatment value, hold the trastuzumab for at least 4 weeks. Trastuzumab can be resumed if within 4-8 weeks the LVEF returns to normal limits and the absolute decrease is ≤15% from baseline. Finally, it recommends permanently discontinuing trastuzumab if the LVEF decline is persistent or if therapy has to be suspended for cardiomyopathy on more than 3 occasions.4
The standard treatment duration of trastuzumab for women with HER2 (+) early-stage breast cancer is 12 months. Shorter treatment durations have been studied; however, the results of a recent meta-analysis support the 12-month regimen, which was associated with improved overall survival (hazard ratio 1.16; 95% confidence interval [CI], 1.01-1.32). In this meta-analysis, a more significant benefit from 12 months of therapy was observed in patients with high-risk breast cancer. The 6-month regimen of trastuzumab was associated with fewer cardiac events (odds ratio 0.52; 95% CI, 0.43-0.62).5 From a cardiologist's perspective, these data suggest that when managing cancer therapy-related cardiac dysfunction in patients treated with trastuzumab, a discussion with their oncologists is warranted regarding how many months of treatment the patients have already completed, whether their breast cancer has high-risk features, and the oncologists' impression of the patients' likely benefit from ongoing trastuzumab therapy.
There are data to suggest that in patients who develop cardiotoxicity with a mild reduction in LVEF (40-49% range) on trastuzumab, trastuzumab may be resumed even if the LVEF does not normalize on cardiac therapy (beta-blocker and an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker) and that the majority of patients with a mildly reduced LVEF will tolerate ongoing trastuzumab therapy.6,7 In SAFE-HEART (Cardiac Safety Study in Patients With HER2 + Breast Cancer), patients were treated with beta-blockers and ACE inhibitors, and 90% were able to complete their planned therapy with trastuzumab despite an LVEF of 40-49%. However, in this study, 10% of patients had either symptomatic heart failure or an LVEF decline to less than 35%.6 Therefore, if a patient with a mildly reduced LVEF is treated with further trastuzumab therapy, they need close clinical monitoring for signs of heart failure and close cardiac imaging follow-up (first follow-up echocardiogram was after 6 weeks in SAFE-HEART).
In summary, cardiotoxicity is not an infrequent occurrence in patients receiving trastuzumab therapy. Holding trastuzumab therapy and initiating cardiac therapy with a beta-blocker and/or ACE inhibitor usually results in the recovery of left ventricular systolic function. After left ventricular systolic function recovers, trastuzumab can be resumed and is usually well-tolerated from a cardiac standpoint. If left ventricular systolic function does not recover, there are some data to suggest that many patients with a mildly reduced LVEF may tolerate trastuzumab therapy (LVEF 40-49%) with careful cardiac follow-up.6,7 This approach is worth considering for patients whose oncologists believe that additional trastuzumab therapy will significantly improve cancer outcomes.
Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39.
Jawa Z, Perez RM, Garlie L, et al. Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis. Medicine (Baltimore) 2016;95:e5195.
Mehta LS, Watson KE, Barac A, et al. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. Circulation 2018;137:e30-e66.
Chen L, Zhou W, Hu X, Yi M, Ye C, Yao G. Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials. Cancer Treat Rev 2019;75:12-9.
Lynce F, Barac A, Geng X, et al. Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study. Breast Cancer Res Treat 2019;175:595-603.
Nowsheen S, Aziz K, Park JY, Lerman A, Villarraga HR, Ruddy KJ, et al. Trastuzumab in Female Breast Cancer Patients With Reduced Left Ventricular Ejection Fraction. J Am Heart Assoc 2018;7:(e008637.