Long-term cardiac outcomes of HER2+ breast cancer patients treated in the ALTTO trial
Authors: D. Eiger, N.F. Ponde, D. Agbor-Tarh, L.A. Korde, A. Moreno Aspitia, R.J. Rodeheffer, M. Ewer, T. Suter, M. Piccart, E. de Azambuja
Journal: Annals of Oncology (2019)

Background: Dual HER2 blockade with trastuzumab (T) and lapatinib (L) is approved for patients (pts) with T-resistant HER2+ metastatic breast cancer, although little is known regarding the cardiotoxicity of this combination. Thus, we report cardiac data on 4,190 pts treated with 1 year of adjuvant T or concomitant T+L in ALTTO (BIG 206/N063D/EGF106708) trial. Methods: ALTTO randomized 8,381 pts into 4 arms to investigate the benefit of L and T in early HER2+ breast cancer. Our dataset consists of pts randomized to the T arm and concomitant T+L arm. Eligible pts must have had a baseline left ventricular ejection fraction (LVEF) ≥50%, no serious cardiac illness and cumulative doses of doxorubicin ≤360mg/m2 or epirubicin ≤720mg/m2. Signs/symptoms of heart failure and LVEF were assessed tri-monthly during treatment, every 6 months until year 2, and yearly thereafter until year 10. Cardiac events (CEs) were defined as symptomatic heart failure NYHA class II, III and IV associated with a significant LVEF drop; asymptomatic CE (significant drop in LVEF without symptoms); and cardiac death. Acute recovery was defined as ≥ 2 consecutive LVEF assessments of ≥ 50% after a CE. The distribution of CEs and end-points are described by arm. A logistic regression model by arm was used to assess the odds of CEs and risk factors for its occurrence. Results: Pts characteristics were equally distributed among the 2 arms, except for diabetes (more common in T-arm; p = 0.024). With a median follow-up of 6.5 years (range 5.6-7.1 years), 197 (9.3%) CEs occurred in T vs 166 (7.9%) CEs in T+L arm. Median time to develop a CE was 6.4 months (range 3.6-11.7 months) in T vs 7.1 months (range 2.9-16.6 months) in T+L arm. Most CEs occurred during treatment (73.2%) and were asymptomatic (74%). Acute recovery was reached in 83.6% and 84.1% of pts in T and T+L arms, respectively. Time to recover from symptomatic CEs (T: 5.6 months; T+L: 4.2 months) was longer than for asymptomatic CEs (T: 3.1 months; T+L: 2.9 months). A 2nd LVEF drop to < 50% occurred in 29.9% of pts who recovered from a CE. T was completed by 84% and 82% of pts in T and T+L arms, respectively, while L was completed by 68% of pts in T+L arm. The main reason for discontinuation of L was safety (60%), especially non-cardiac safety (82%). Five cardiac risk factors were identified (see Table).Table199OCardiac Risk FactorMultivariate OR (95% CI)p-valuePre anti-HER2 LVEF 50-54% (vs > 64%)3.10 (1.54 to 6.25)0.002Presence of Diabetes Mellitus1.85 (1.25 to 2.75)0.002BMI >30kg/m2 (vs < 25kg/m2)2.21 (1.40 to 3.49)<0.001Doxorubicin dose ≥240mg/m21.36 (1.01 to 1.82)0.039Epirubicin dose ≥480mg/m22.33 (1.55 to 3.51)<0.001Age ≥65 years1.36 (0.98 to 1.88)0.064Left side radiotherapy0.92 (0.71 to 1.19)0.509Presence of Hypercholesterolemia0.90 (0.60 to 1.36)0.629Presence of Hypertension0.89 (0.67 to 1.17)0.402T+L vs T arm0.85 (0.68 to 1.05)0.139 Open table in a new tab Conclusions: Although dual HER2 blockade does not increase the rate of cardiotoxicity compared to T alone for 1 year, identification of risk factors prior to start of therapy and close collaboration with cardiologists is essential to ensure its proper management and treatment continuity. Clinical trial identification: NCT00490139, EudraCT Number: 2006-000562-36. Legal entity responsible for the study: Breast International Group (BIG). Funding: GSK/Novartis provided funding for the main trial. Disclosure: D. Eiger: Scholarship via ESMO`s clinical research fellowship program, made possible thanks to a sponsorship provided by Novartis. M. Piccart: Honoraria: Roche; Research funding to IJB: Roche, Novartis. E. de Azambuja: Honoraria, advisory board: Roche/GNE; Travel grants: Roche/GNE, GSK/Novartis; Research grant (my institution): Roche/GNE, Novartis, AstraZeneca. All other authors have declared no conflicts of interest.