ReviewAromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo – Meta-analyses on efficacy and adverse events based on randomized clinical trials
Introduction
Hormonal therapy is the cornerstone of adjuvant systemic treatment for patients with ER- positive breast cancer. The efficacy of adjuvant tamoxifen (TAM) for 5 years, irrespective of menopausal status, compared to placebo has repeatedly been reported in terms of disease-free (DFS) and overall survival (OS) [1]. The side effects of TAM are well documented including increased risk of thromboembolic events and endometrial cancer [1]. For postmenopausal women, adjuvant endocrine therapy with TAM has been challenged during the last decade by third-generation AI showing improvement of DFS compared to TAM in ER-positive breast cancer [2], [3].
Trials comparing adjuvant aromatase inhibitors (AI) with TAM have used different schedules: 5 years of monotherapy; sequenced therapy, i.e. TAM for 2–3 years followed by AI to a total of 5 years or vice versa with either TAM or an AI as the comparator; and extended therapy with AI compared to placebo after 5 years of TAM (Fig. 1) [2], [3], [4], [5], [6], [7], [8], [9]. The adjuvant randomized controlled trials (RCT) of AI have included over 35,000 women worldwide and long-term follow-up data have been reported for some of the largest trials suggesting that AI also increases OS compared to TAM [2], [4]. AI has consistently been reported to increase the risk of fractures compared to TAM [10], [11], and to symptoms related to estrogen deprivation such as musculoskeletal- and genitourinary discomfort, whereas potentially negative effects on cardiovascular events are not fully elucidated.
In 2005 the Swedish Council on Health Technology Assessment and Assessment of Social Services (SBU) published a systematic review on the effects of AI in metastatic breast cancer together with data on adjuvant and neo-adjuvant treatment with AI in early breast cancer [12]. At that time point, no long-term data was available.
The aim of the present systematic review was to analyze long-term follow–up data from RCTs with AI (mono-, sequenced- and extended therapy) compared with TAM or placebo in order to provide a comprehensive update on efficacy (DFS and OS) and side effects including available data from on- and off-treatment.
Section snippets
Literature search and selection of articles
This article is based on a Health Technology Assessment reported by The Swedish Council of Health Technology Assessments and Assessment of Social Services, SBU [13], whose methods are in line with the Cochrane Collaboration Handbook for Systematic Reviews (http://handbook.cochrane.org/). The methods used in this review article are essentially the same as recommended in the Prisma Checklist (http://www.prisma-statement.org/statement.htm). The search strategy along with the text words (TW) and
Selection of studies
Seven-hundred-eighty-six abstracts met the search criteria; 559 of them were excluded due to: a) the PICO – criteria, b) available as abstract only and c) too short follow-up time, which left two-hundred-and-twenty-seven abstracts for further evaluation. An additional 12 articles were manually retrieved, resulting in 239 published full text articles that were assessed regarding scientific quality using the SBU checklist [13].
Two-hundred and seven were excluded due to low quality or not
Discussion
This systematic review shows that DFS and OS were improved with five years of AI monotherapy compared to five years of TAM with high and moderate quality of evidence respectively. However, the absolute differences in effects are relatively small, around 3% for DFS and 1% for OS. For sequenced AI therapy with TAM as comparator, DFS was superior with moderate level of evidence, whereas the effect on OS was non-significant. Sequenced therapy compared with AI monotherapy did not prove to be
Conclusions
AI monotherapy improves DFS and OS compared with TAM. Sequenced therapy with AI and extended therapy with 5 years of AI after 5 years of TAM improves DFS. Due to differences in toxicity profile, TAM is an appropriate option for some women. An elevated risk for cardiovascular events with AI treatment cannot be completely ruled out and therefore warrants further research in studies without TAM as comparator.
Ethical statement
An ethical approval has not been judged as necessary since this is a systematic review using only anonymous group level data that have been published before.
Conflict of interest statement
None of the authors declares any conflicts of interest.
Acknowledgment
The study was supported by the Swedish Council on Health Technology Assessment and Assessment of Social Services, SBU.
References (24)
- et al.
Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial
Lancet Oncol
(2010) - et al.
Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up
Lancet Oncol
(2011) - et al.
Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17
Ann Oncol
(2008) - et al.
Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial
Lancet
(2011) - et al.
Aromatase inhibitors versus tamoxifen as adjuvant hormonal therapy for oestrogen sensitive early breast cancer in post-menopausal women: meta-analyses of monotherapy, sequenced therapy and extended therapy
Breast
(2010) - et al.
Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial
Lancet
(2013) - et al.
Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12
Ann Oncol
(2015) - et al.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials
Lancet
(2011) - et al.
Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study
J Clin Oncol
(2012) - et al.
Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the austrian breast and colorectal cancer study group
J Clin Oncol
(2012)
Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial
Ann Oncol
Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study
J Clin Oncol
Cited by (0)
- 1
First authorship shared between Rydén L and Heibert Arnlind M.