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

Matteo Lambertini, Christine Campbell, José Bines, Larissa A. Korde, Miguel Izquierdo, Debora Fumagalli, Lucia Del Mastro, Michail Ignatiadis, Kathleen Pritchard, Antonio C. Wolff, Christian Jackisch, Istvan Lang, Michael Untch, Ian Smith, Frances Boyle, Binghe Xu, Carlos H. Barrios, José Baselga, Alvaro Moreno Aspitia, Martine PiccartRichard D. Gelber, Evandro de Azambuja

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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.

Original languageEnglish (US)
Pages (from-to)86-94
Number of pages9
JournalJournal of the National Cancer Institute
Volume111
Issue number1
DOIs
StatePublished - Jan 1 2019

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Amenorrhea
Breast Neoplasms
Survival
Hormones
Therapeutics
Disease-Free Survival
human ERBB2 protein
Confidence Intervals
lapatinib
Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients. / Lambertini, Matteo; Campbell, Christine; Bines, José; Korde, Larissa A.; Izquierdo, Miguel; Fumagalli, Debora; Del Mastro, Lucia; Ignatiadis, Michail; Pritchard, Kathleen; Wolff, Antonio C.; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Barrios, Carlos H.; Baselga, José; Moreno Aspitia, Alvaro; Piccart, Martine; Gelber, Richard D.; de Azambuja, Evandro.

In: Journal of the National Cancer Institute, Vol. 111, No. 1, 01.01.2019, p. 86-94.

Research output: Contribution to journalArticle

Lambertini, M, Campbell, C, Bines, J, Korde, LA, Izquierdo, M, Fumagalli, D, Del Mastro, L, Ignatiadis, M, Pritchard, K, Wolff, AC, Jackisch, C, Lang, I, Untch, M, Smith, I, Boyle, F, Xu, B, Barrios, CH, Baselga, J, Moreno Aspitia, A, Piccart, M, Gelber, RD & de Azambuja, E 2019, 'Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients', Journal of the National Cancer Institute, vol. 111, no. 1, pp. 86-94. https://doi.org/10.1093/jnci/djy094
Lambertini, Matteo ; Campbell, Christine ; Bines, José ; Korde, Larissa A. ; Izquierdo, Miguel ; Fumagalli, Debora ; Del Mastro, Lucia ; Ignatiadis, Michail ; Pritchard, Kathleen ; Wolff, Antonio C. ; Jackisch, Christian ; Lang, Istvan ; Untch, Michael ; Smith, Ian ; Boyle, Frances ; Xu, Binghe ; Barrios, Carlos H. ; Baselga, José ; Moreno Aspitia, Alvaro ; Piccart, Martine ; Gelber, Richard D. ; de Azambuja, Evandro. / Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients. In: Journal of the National Cancer Institute. 2019 ; Vol. 111, No. 1. pp. 86-94.
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title = "Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients",
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.",
author = "Matteo Lambertini and Christine Campbell and Jos{\'e} Bines and Korde, {Larissa A.} and Miguel Izquierdo and Debora Fumagalli and {Del Mastro}, Lucia and Michail Ignatiadis and Kathleen Pritchard and Wolff, {Antonio C.} and Christian Jackisch and Istvan Lang and Michael Untch and Ian Smith and Frances Boyle and Binghe Xu and Barrios, {Carlos H.} and Jos{\'e} Baselga and {Moreno Aspitia}, Alvaro and Martine Piccart and Gelber, {Richard D.} and {de Azambuja}, Evandro",
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T1 - Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients

AU - Lambertini, Matteo

AU - Campbell, Christine

AU - Bines, José

AU - Korde, Larissa A.

AU - Izquierdo, Miguel

AU - Fumagalli, Debora

AU - Del Mastro, Lucia

AU - Ignatiadis, Michail

AU - Pritchard, Kathleen

AU - Wolff, Antonio C.

AU - Jackisch, Christian

AU - Lang, Istvan

AU - Untch, Michael

AU - Smith, Ian

AU - Boyle, Frances

AU - Xu, Binghe

AU - Barrios, Carlos H.

AU - Baselga, José

AU - Moreno Aspitia, Alvaro

AU - Piccart, Martine

AU - Gelber, Richard D.

AU - de Azambuja, Evandro

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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