Cancer patients receiving HER-2 directed agents are at an increased risk of developing cardiotoxicity, typically manifesting as an asymptomatic decrease in the left ventricular ejection fraction (LVEF) and less commonly congestive heart failure (CHF).
Cardiotoxicity is a well recognised complication of trastuzumab therapy. However, this risk appears to be lower with the newer HER-2 directed agents (trastuzumab emtansine and pertuzumab), as well the mixed HER tyrosine kinase inhibitors (neratinib and lapatinib), although experience with these agents is limited. Mechanistically distinct from anthracycline-induced cardiotoxicity, it typically manifests as an asymptomatic decrease in the LVEF and less commonly as CHF.
HER-2 is an important mediator of unregulated cell growth and cell survival, with adult myocardium expressing HER-2 and HER-4, but not HER-3.rrr During periods of myocardial stress, neuregulin (released by endothelial cells) binds to HER-3 and HER-4, while recruiting HER-2 as a co-receptor, in order to increase expression of intracellular survival pathways. Blocking HER-2, HER-3 or HER-4 subsequently leads to increased cellular apoptosis and reduces myocardial proliferation.r
Cochrane systematic review for trastuzumabr
A systematic review from the Cochrane collaboration including 8 randomised controlled trials and 11,991 patients reported on the safety and efficacy of trastuzumab use in early breast cancer.
- CHF: Trastuzumab significantly increased the risk of CHF (RR 5.11; 90% CI 3.00 to 8.72). Definitions of CHF in these trials included NYHA class III-IV, severe CHF, symptomatic CHF and confirmed CHF. CHF was reported in 2.5% of 5471 patients receiving trastuzumab with chemotherapy and 0.4% of 4810 patients receiving chemotherapy alone.
- LVEF decline: Trastuzumab significantly increased the risk of LVEF decline (RR 1.83; 90% CI 1.36 to 2.47, p=0.0008). Definitions of LVEF decline varied across the trials. LVEF decline was seen in 11.2% of 4147 patients in the trastuzumab plus chemotherapy group and 5.6% of 3792 patients in the chemotherapy alone group.
The incidence of cardiac toxicities seemed higher in regimens where trastuzumab was given for more than 6 months than in those where trastuzumab was administered for less time. Cardiac toxicity was not significantly different in studies with concurrent administration of trastuzumab versus those with sequential administration. However subgroup analysis was limited by the small number of studies and further trials are required to confirm these results.
Of note, all 8 trials required normal heart function (many required LVEF >55%) for inclusion and patients with cardiovascular disease of any grade were excluded. Because of this the risks may be higher in routine clinical practice.
Elderly patients, usually underrepresented in clinical trials, have a higher prevalence of cardiovascular risk factors and are at a higher risk of cardiotoxicity. Two large population based studies in the older population have shown that the incidence of cardiotoxicity is substantially higher in older patients.rr In one study, of the 2203 patients receiving trastuzumab, the rate of CHF was 29.4% compared to 18.9% of the 7332 patients who did not receive trastuzumab (hazard ratio 1.95; 95% CI 1.75 to 2.17).r
With longer follow-up of patients treated with trastuzumab, there does not appear to be an increase in the incidence of cardiac events over time. This is demonstrated by the persisting low rates of cardiotoxicity reported in the updated analyses of the large adjuvant trials.rr
The Cleopatra trial of 808 patients randomly assigned to trastuzumab and docetaxel plus either pertuzumab or placebo revealed that the pertuzumab group was not at any increased risk of cardiotoxicity, with a rate of left ventricular (LV) dysfunction of 3.3% in the placebo arm versus 1.5% in the pertuzumab arm.r The TRYPHAENA study included 3 arms, with 2 different regimens of FEC + trastuzumab + pertuzumab followed by docetaxel, versus carboplatin + docetaxel + trastuzumab + pertuzumab. The incidence of symptomatic LV dysfunction occurred in up to 2.7%. Decline in LVEF ≤10% at baseline to <50% was between 3.9 and 5.6% across all 3 arms.r
Initial trials with trastuzumab emtansine have demonstrated similar results, however all these trials were after prior treatment with other potentially cardiotoxic agents including trastuzumab and docetaxel so cardiotoxicity associated with trastuzumab emtansine is unknown.r
The TH3RESA trial in metastatic breast cancer patients compared trastuzumab emtansine versus physician’s choice. It showed no increase in cardiac toxicity defined as LVEF ≥15% or absolute decrease in LVEF to <50%.r
Geyer et al. (2006) compared lapatinib + capecitabine versus capecitabine and placebo. It did not reveal a difference in the mean LVEF values between the two groups, with no symptomatic cardiac events.r A subsequent EMILIA trial of 991 patients compared T-DM1 to lapatinib with capecitabine, and showed no increase in mean LVEF between the two groups.r In the ALTTO trial, 8381 patients were randomly assigned to 1 year of adjuvant trastuzumab, lapatinib, sequential trastuzumab followed by lapatinib, or their combination (trastuzumab + lapatinib).r The incidence of primary and secondary cardiac events was low in all treatment arms – between 0.25% and 0.97% of patients developed primary cardiac endpoints with 3 fatal cardiac events in the sequential arm, and 1 in each of the other treatment arms.r
The cardiotoxicity profile of neratinib was favourable in the phase 3 NEfERT-T study in the first-line metastatic setting.r The only phase 3 trial exploring neratinib in the adjuvant setting reported a low rate of cardiac events.r
A careful risk benefit assessment should be made before deciding to treat with HER-2 directed agents and referral to a cardiologist may be required prior to initiating treatment.
Risk factors for development of cardiotoxicity include:rr
- previous or concurrent anthracycline use
- prior treatment with high dose cyclophosphamide
- radiotherapy to the chest area
- age over 60
- history of hypertension
- documented coronary artery disease (increased risk of impaired LV function).