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J Natl Cancer Inst. 2019 Jan 1;111(1):86-94. doi: 10.1093/jnci/djy094.

Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients.

Author information

1
Department of Medical Oncology, Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium.
2
Frontier Science, Kingussie, UK.
3
Breast Cancer Therapeutics, National Cancer Institute, Bethesda, MD.
4
Novartis Pharma AG, Basel, Switzerland.
5
Breast International Group, Brussels, Belgium.
6
Department of Medical Oncology, U.O. Sviluppo Terapie Innovative, Policlinico San Martino-IRCCS per l'Oncologia, Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy.
7
Sunnybrook Odette Cancer Centre, the University of Toronto and the NCIC Clinical Trials Group, Toronto, Ontario, Canada.
8
Johns Hopkins School of Medicine, Baltimore, MD.
9
Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany.
10
National Institute of Oncology, Budapest, Hungary.
11
Helios Klinikum Berlin Buch, Multidisciplinary Breast Cancer Center, Berlin, Germany.
12
Breast Unit, Royal Marsden Hospital and The Institute of Cancer Research, London, UK.
13
Patricia Ritchie Centre for Cancer Care and Research, The University of Sydney, Mater Hospital, North Sydney, Australia.
14
Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
15
Department of Medicine, PUCRS, School of Medicine, Porto Alegre, Brazil.
16
Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
17
Memorial Sloan Kettering Cancer Center, New York, NY.
18
Mayo Clinic, Jacksonville, FL.
19
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health and Frontier Science and Technology Research Foundation, Boston, MA.

Abstract

Background:

In premenopausal patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown.

Methods:

In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor-positive and -negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided.

Results:

A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor-positive disease. Median age was 43 (interquartile range = 38-47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab→lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor-positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor-negative patients.

Conclusions:

In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor-positive/HER2-positive early breast cancer patients.

PMID:
29878225
PMCID:
PMC6335113
[Available on 2019-06-05]
DOI:
10.1093/jnci/djy094

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