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Long-term cardiac outcomes of HER2+ breast cancer patients treated in the ALTTO trial

Date

04 May 2019

Session

Mini oral session 2

Presenters

Daniel Eiger

Citation

Annals of Oncology (2019) 30 (suppl_3): iii65-iii71. 10.1093/annonc/mdz101

Authors

D. Eiger1, N.F. Ponde1, D. Agbor-Tarh2, L.A. Korde3, A. Moreno Aspitia4, R.J. Rodeheffer5, M. Ewer6, T. Suter7, M. Piccart8, E. de Azambuja1

Author affiliations

  • 1 Academic Promoting Team, Institute Jules Bordet, 1000 - Brussels/BE
  • 2 Statistic, Frontier Science, Kingussie/GB
  • 3 Head, Breast Cancer And Melanoma Therapeutics - Clinical Investigations Branch, CTEP, DCTD, NCI, Bethesda/US
  • 4 Medical Oncology, Mayo Clinic, Jacksonville/US
  • 5 Division Of Circulatory Failure, Department Of Cardiovascular Medicine, Mayo Clinic, Rochester/US
  • 6 Cardiology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 7 Internal Medicine, Inselspital - Universitätsspital Bern, 3010 - Bern/CH
  • 8 Director Of Medicine, Institute Jules Bordet, 1000 - Brussels/BE
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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).

Table: 199O

Cardiac Risk FactorMultivariate OR (95% CI)p-value
Pre anti-HER2 LVEF 50-54% (vs > 64%)3.10 (1.54 to 6.25)0.002
Presence of Diabetes Mellitus1.85 (1.25 to 2.75)0.002
BMI >30kg/m2 (vs < 25kg/m2)2.21 (1.40 to 3.49)<0.001
Doxorubicin dose ≥240mg/m21.36 (1.01 to 1.82)0.039
Epirubicin dose ≥480mg/m22.33 (1.55 to 3.51)<0.001
Age ≥65 years1.36 (0.98 to 1.88)0.064
Left side radiotherapy0.92 (0.71 to 1.19)0.509
Presence of Hypercholesterolemia0.90 (0.60 to 1.36)0.629
Presence of Hypertension0.89 (0.67 to 1.17)0.402
T+L vs T arm0.85 (0.68 to 1.05)0.139

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.

Editorial acknowledgement

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.

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