Molecular and Cellular Endocrinology 382 (2014) 695–723
`
`Contents lists available at ScienceDirect
`
`Molecular and Cellular Endocrinology
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
`
`Review
`Breast cancer: Current and future endocrine therapies
`Carlo Palmieri a,b,c,⇑
`, Darren K. Patten d, Adam Januszewski e, Giorgia Zucchini f, Sacha J. Howell f
`a The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, Liverpool L69 3GA, UK
`b Liverpool & Merseyside Breast Academic Unit, The Linda McCartney Centre, Royal Liverpool University Hospital, Liverpool L7 8XP, UK
`c Academic Department of Medical Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, Wiral CH63 4JY, UK
`d Department of Surgery, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, UK
`e Department of Medical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, UK
`f The University of Manchester, Institute of Cancer Studies, Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Available online 7 August 2013
`
`Keywords:
`Breast cancer
`Endocrine therapy
`Targeted therapy
`
`Contents
`
`Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer.
`The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and
`more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal
`duration of adjuvant endocrine therapy remains an active area of clinical study with recent data support-
`ing 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the
`development of resistance, this can occur by a number of possible mechanisms and numerous studies
`have been performed which combine endocrine therapy with agents that modulate these mechanisms
`with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the com-
`bination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy
`have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review
`details the current endocrine therapy utilized in both early and advanced disease, as well as exploring
`potential new targets which modulate pathways of resistance, as well as agents which aim to modulate
`adrenal derived steroidogenic hormones.
`
`Ó 2013 Elsevier Ireland Ltd. All rights reserved.
`
`2.2.
`
`1.
`2.
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
`Adjuvant endocrine therapy for women with ER positive breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
`2.1.
`Premenopausal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
`Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
`2.1.1.
`Duration of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
`2.1.2.
`2.1.3.
`Ovarian suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
`2.1.4.
`Adjuvant ovarian suppression plus tamoxifen or aromatase inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
`Postmenopausal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
`Upfront aromatase inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
`2.2.1.
`Sequential and switch strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
`2.2.2.
`2.2.3.
`Extended aromatase inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
`2.2.4.
`Comparison of aromatase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
`2.2.5. Meta-analysis of adjuvant AI studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
`Neoadjuvant endocrine therapy for ER positive breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
`3.
`4. Metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`4.1.
`Ovarian suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`Aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`4.2.
`4.3.
`Switching between third generation aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`4.4.
`Fulvestrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`4.4.1.
`Single agent fulvestrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
`4.4.2.
`Combination anastrozole plus fulvestrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
`
`⇑ Corresponding author. Address: Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Duncan Building,
`
`Daulby Street, Liverpool, L69 3GA, UK. Tel.: +44 151 706 4875; fax: +44 151 706 5826.
`E-mail address: c.palmieri@liverpool.ac.uk (C. Palmieri).
`
`0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved.
`http://dx.doi.org/10.1016/j.mce.2013.08.001
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`4.5.
`4.6.
`4.7.
`4.8.
`
`Low dose estradiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
`Androgen receptor antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
`Progesterone receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
`Combination of endocrine therapy and signal transduction inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
`4.8.1.
`Inhibitors of Epidermal Growth Factor Receptor (EGFR) family members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
`Inhibitors of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway . . . . . . . . . . . . . . . . 708
`4.8.2.
`4.8.3.
`Inhibitors of cancer stem cell (CSC) activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
`On-going clinical studies combing endocrine therapy with a targeted agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
`5.1.
`Phosphatidylinositol 3-Kinase (P13K)/Akt/mammalian target of rapamycin (mTOR) pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
`Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
`5.2.
`5.3.
`Cyclin-dependent kinase (CDK) 4/6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
`5.4.
`Epidermal Growth Factor Receptor family. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
`5.5.
`Fıbroblast Growth Factor Receptor – (FGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
`5.6. Histone deacetylase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
`5.7.
`Insulin-Like Growth Factor (IGF) and insulin-like growth factor receptor 1 (IGF-1R) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
`5.8.
`Insulin receptor signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
`5.9.
`Src . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
`Novel enzymic targeted therapies: modulating adrenal derived steroidogenic hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
`Abiraterone acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
`6.1.
`Irosustat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
`6.2.
`Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
`
`5.
`
`6.
`
`7.
`
`1. Introduction
`
`Endocrine therapy (ET) is a key treatment modality in the man-
`agement of estrogen receptor alpha (ER)-positive breast cancer. ET
`can be given preoperatively (neoadjuvant), post-operatively (adju-
`vant), and in the metastatic/advanced disease setting (palliative
`treatment). Historically, ET is the oldest systemic therapy for the
`treatment of breast cancer, and the notable historical landmarks
`and studies are laid out in Fig. 1.
`Current ET constitutes treatments which modulate or disrupt
`the process of estrogen production or the function or presence of
`the ER in breast cancer cells. In pre-menopausal women the major-
`ity of estrogen production is from the ovarian follicles. This process
`is under the control of the anterior pituitary gland which produces
`luteinizing hormone (LH) and follicle stimulating hormone (FSH).
`LH acts upon thecal cells to stimulate androgen synthesis, while
`FSH acts upon granulosa cells to stimulate the production of the
`enzyme aromatase which then converts testosterone and andro-
`stenedione to estradiol and estrone respectively by aromatisation.
`The pituitary production of LH and FSH is in turn under the control
`of gonadotrophin releasing hormone (GnRH) (also known as
`luteinising-hormone-releasing hormone, LHRH) produced in the
`hypothalamus. In the postmenopausal setting estrogen production
`is dependent on peripheral aromatisation, predominantly in the li-
`ver, adrenal glands, and adipose tissue. Estrogen exerts its effect
`via binding to ER which in turn directly regulates the transcription
`of target genes. ET is aimed at modulating and disrupting this pro-
`cess by either blocking pituitary production of LH/FSH (GnRH ana-
`logues), blocking ER (tamoxifen), degrading ER (fulvestrant) or by
`inhibiting the peripheral production of estrogen (aromatase inhib-
`itors). Given their modes of action menopausal status is important
`in determining the potential endocrine treatment options that can
`be utilised.
`
`2. Adjuvant endocrine therapy for women with ER positive
`breast cancer
`
`2.1. Premenopausal
`
`2.1.1. Tamoxifen
`Tamoxifen has until recently been the gold standard for the
`adjuvant treatment of ER positive breast cancer in both pre- and
`
`postmenopausal women. The 2011 meta-analyses from the Early
`Breast Cancer Trialists’ Collaborative Group (EBCTCG), with a med-
`ian of 13 years follow up, has shown that 5 years of tamoxifen
`compared to none reduced recurrence rates by almost half
`throughout the first 10 years (Rate Ratio (RR) 0.53 [SE 0.03]). Fur-
`thermore, yearly breast-cancer mortality was reduced by about a
`third throughout the first 15 years (RR 0.70 [0.05], p < 0.00001).
`The EBCTCG data also showed that the proportional risk reductions
`produced by tamoxifen are little affected by age or chemotherapy
`(EBCTCG, 2011). This overview also explored the effect of ER level
`as measured by fmol/mg of cytosol protein, on outcome. ER levels
`were shown to predict for tamoxifen efficacy, with benefit only
`being shown with ER levels of 10 fmol/mg of cytosol protein and
`above (EBCTCG, 2011).
`
`2.1.2. Duration of treatment
`The EBCTCG meta-analysis also confirmed that 5 years of
`tamoxifen is superior to 1–2 years (EBCTCG, 2005). Whilst 5 years
`of tamoxifen has been the standard of care a number of studies
`have sought to explore whether further prolonging therapy may
`add additional benefit. These studies have include the Adjuvant
`Tamoxifen: Longer Against Shorter (ATLAS) trial (Davies et al.,
`2012) and adjuvant Tamoxifen—To offer more? (aTTom) trial (Gray
`et al., 2013). These studies both randomised women (pre- and
`postmenopausal) who had received 5 years of adjuvant tamoxifen
`to either no further treatment or an additional 5 years of tamoxi-
`fen. By randomising at least 20,000 women in total between the
`two studies the aim was to be able reliably identify a 2–3%
`improvement in survival with extended tamoxifen. In the ATLAS
`study, in which 12,894 women were randomised, those allocated
`to continued tamoxifen had a significantly reduced risk of recur-
`rence (RR: 0.84, 95% CI 0.76–0.94; p = 0.002), breast cancer mortal-
`ity (331 deaths with recurrence in women allocated to continue vs
`397 in controls, p = 0.01)), and all-cause mortality (639 deaths vs
`722 deaths, p = 0.01) compared to women who discontinued
`tamoxifen at 5 years. Of note, the reduction in recurrence rate
`was more pronounced in the years after completion of extended
`tamoxifen treatment (Davies et al., 2012).
`In the 10 years post-randomisation there were reductions of
`3.7% and 2.8% in recurrence and mortality respectively. As ex-
`pected rates of both pulmonary embolism and endometrial cancer
`were higher in those allocated to further tamoxifen, RR 1.87 (95%
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`697
`
`Fig. 1. Historical overview of the development of endocrine therapy and targeted therapy for breast cancer. AI: Aromatase Inhibitor; SERD: Selective Estrogen Receptor
`Downregulator; SERM; Selective Estrogen Receptor Modulator, EBCTCG; Early Breast Cancer Trialists’ Collaborative Group. (See above-mentioned references for further
`information.)
`
`CI 1.13–3.07, p = 0.01) and RR 1.74 (95% CI 1.30–2.34, p = 0.0002)
`respectively. Whilst no excess mortality was seen with regard to
`pulmonary embolus, there was a 0.2% absolute increase in death
`due to endometrial cancer (Davies et al., 2012). However, as with
`previous studies the increase in risk of uterine cancer with tamox-
`ifen was confined to post-menopausal women (EBCTCG, 2011).
`In the aTTom study which recruited 6953 women, those ran-
`domised to continue tamoxifen had a significant reduction in
`breast cancer recurrence (RR 0.85, 95% CI 0.76–0.95; p = 0.003),
`with an absolute difference of 4% at 15 years from randomization.
`There was a non-significant reduction in breast cancer mortality
`(RR 0.88, 95% CI 0.77–1.01; p = 0.06), with an absolute difference
`of 3% at 15 years from randomization. There was no obvious effect
`on non-breast-cancer mortality (RR: 0.95; 95% CI 0.84–1.08;
`p = 0.4). There was a significant excess of endometrial cancer in
`those who continued on tamoxifen 2.9% vs 1.3% (RR = 2.20 95%
`CI: 1.31–2.34, p < 0.0001), as well as deaths from endometrial can-
`cer 1.1% vs 0.6% (RR 1.83; 95% CI: 1.09–3.09, p = 0.02). (Gray et al.,
`2013). Combining the ATLAS and aTTom data (total of 17,477 pa-
`tients) there was a statistically significant reduction in breast can-
`cer mortality (RR 0.85; 95%CI 0.77–0.94; p = 0.001) and
`improvement
`in overall survival
`(RR 0.91 95%CI 0.84–0.94;
`p = 0.008) with 10 years of tamoxifen.
`Based on the results of ATLAS and aTTom it would be reasonable
`in women who remain premenopausal after 5 years of adjuvant
`tamoxifen to have a discussion regarding the potential benefits of
`extending treatment to 10 years. Any such discussion should
`weight the potential degree of benefit based on the clinico-patho-
`
`logical features of the original tumour, with the potential side ef-
`fects. In women who enter menopause during tamoxifen therapy,
`switching to an aromatase inhibitor or the use of an AI upon com-
`pletion of tamoxifen is a treatment option, these are discussed in
`more detail in the post-menopausal section below.
`
`2.1.3. Ovarian suppression
`In the premenopausal setting the efficacy of ovarian suppres-
`sion (OS) in addition to tamoxifen has been explored. OS may be
`achieved either surgically, by radiation or by the use of use of
`GnRH analogues.
`A meta-analysis of adjuvant use of GnRH analogues found that
`they did not significantly reduced the risk of recurrence (RR 28%;
`p = 0.08) when used as the only systemic therapy (LHRH-agonists
`in Early Breast Cancer Overview group, 2007). In contrast, the addi-
`tion of GnRH analogues in women treated with tamoxifen, chemo-
`therapy, or both reduced both recurrence and death after
`recurrence in the whole group, by 12.7%(2.4–21.9, p = 0.02); and
`15.1% (1.8–26.7, p = 0.03) respectively (LHRH-agonists in Early
`Breast Cancer Overview group, 2007). The effects of LHRH agonists
`were greater in younger women than in those 40 years or older.
`The overview also showed that LHRH agonists had a similar effi-
`cacy to chemotherapy, although, many of the chemotherapy regi-
`mens utilized would now be considered sub-optimal. At the time
`that these studies were performed there was not a full appreciation
`of the benefits of the use of adjuvant tamoxifen following chemo-
`therapy. Therefore, the effectiveness of LHRH analogue in compar-
`ison to chemotherapy when tamoxifen is utilized is unclear, as is
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`
`the additional benefit of ovarian suppression conferred to chemo-
`therapy if tamoxifen were used. The optimal duration of ovarian
`suppression also remains unanswered.
`The question of the benefit of OS plus tamoxifen as compared to
`current third generation adjuvant chemotherapy regimens followed
`by tamoxifen with or without OS remains unanswered. The ‘PERCHE’
`(Premenopausal Endocrine Responsive Chemotherapy Trial) trial
`which aimed to answer this question by randomizing pre-
`menopausal women with ER positive breast cancer to either OS plus
`contemporary chemotherapy followed by tamoxifen or OS and
`tamoxifen was closed before completion due to poor accrual (Price
`and Goldhirsch, 2005). In the absence of randomised trial data, OS
`and tamoxifen represents a reasonable treatment option in pre-
`menopausal women with border-line benefit from chemotherapy
`and for whom fertility preservation is a priority. To date, no studies
`are in place to explore the benefit of extended ovarian suppression in
`pre-menopausal women with early breast cancer (EBC).
`
`2.1.4. Adjuvant ovarian suppression plus tamoxifen or aromatase
`inhibition
`A number of studies have been established to explore the effi-
`cacy in the adjuvant setting of OS combined with either tamoxifen
`or an aromatase inhibitor (AI). The Austrian Breast and Colorectal
`Cancer Study Group trial 12 (ABCSG-12) study randomised 1803
`premenopausal women with ER positive breast cancer to OS (with
`the GnRH analogue goserelin) in combination with the AI anastroz-
`ole, vs the same OS in combination with tamoxifen for 3 years.
`After a median follow-up of 47.8 months, no difference in the pri-
`mary end point, disease-free survival (DFS) was seen between
`anastrozole and tamoxifen (hazard ratio (HR) for disease progres-
`sion in the anastrozole arm, 1.10; 95% CI, 0.78–1.53; p = 0.59)
`(Gnant et al., 2009). Two other trials are ongoing and yet to report.
`The Suppression of Ovarian Function Trial
`(SOFT) study is
`comparing 5 years of tamoxifen vs OS and tamoxifen vs OS and
`exemestane in premenopausal women who have not received che-
`motherapy, as well as premenopausal women that have retained
`ovarian function after chemotherapy (Regan et al., 2008). In addi-
`tion the Tamoxifen and Exemestane Trial (TEXT), is comparing
`OS (with triptorelin) plus tamoxifen vs OS plus exemestane with
`or without chemotherapy (Regan et al., 2008). Based on the results
`of ABCSG-12 AIs do not appear to add any additional benefits when
`compared to tamoxifen on the background of OS. However, further
`data from TEXT and SOFT should be awaited for a more definitive
`answer to this question.
`
`2.2. Postmenopausal
`
`Until recently tamoxifen was the gold standard adjuvant ET for
`ER positive breast cancer in postmenopausal women (EBCTCG,
`2011). The development of third generation AIs with their superior
`efficacy in the advanced disease setting, led to initiation of a series
`of adjuvant studies which compared AIs with tamoxifen. The de-
`sign of these studies differed and included upfront use of the AI,
`sequential use after a period on tamoxifen or following completion
`of tamoxifen. All studies bar one, Arimidex, Tamoxifen, Alone or in
`Combination (ATAC), compared tamoxifen and AIs as single agents.
`It should be noted that the definitions used for disease-free sur-
`vival (DFS) in these studies were not consistent and a common
`end-point definitions system (The STEEP system) has been sug-
`gested to standardise outcome definitions used in clinical trials
`(Hudis et al., 2007).
`
`2.2.1. Upfront aromatase inhibition
`The ATAC trial and The Breast International Group 1-98 study
`(BIG 1-98) compared 5 years of tamoxifen with 5 years of anastroz-
`ole or letrozole respectively. At the 100 month analysis of the ATAC
`
`study, the longest of any of the adjuvant AI studies, anastrozole
`was associated with a significantly improved DFS (HR 0.90,
`p = 0.25 in the intent-to-treat (ITT) population; HR 0.85, p = 0.003
`in the ER-positive population) but no improvement in overall sur-
`vival (OS) (HR 1.00, p = 0.99 in the ITT population; HR 0.97, p = 0.7
`in the ER-positive population). There was an absolute difference in
`DFS between the two arms in favour of anastrozole of 2.5% at
`5 years and 4.1% at 9 years (The ATAC Trialists’ Group, 2008). The
`combination arm was stopped at the first analysis due to a statis-
`tically non-significant trend towards inferiority compared to
`anastrazole alone (The ATAC Trialists’ Group, 2002).
`BIG 1-98 was the only study to compare upfront monotherapy
`as well as sequential treatment (both the tamoxifen-AI and AI-
`tamoxifen sequences were tested). At a median follow up of
`51 months an analysis of patients allocated to the monotherapy
`arms (Coates et al., 2007), found a significant improvement in
`DFS (HR, 0.82; 95% CI, 0.71–0.95; p = 0.007), similar to that in the
`ATAC study. A non-significant trend to improved overall survival
`with letrozole (HR 0.87, p = 0.08) was also seen in contrast with
`the lack of even a trend towards improved survival observed in
`ATAC (Coates et al., 2007). Following the initial publication of
`BIG 1-98, the trial was unblinded and women in the tamoxifen
`only arm were offered the option to cross-over to letrozole. Over
`600 chose to cross-over to letrozole. Subsequent ITT analysis has
`been influenced by this cross-over with attenuation in the benefits
`of letrozole (BIG 1-98, 2009). A later analysis employed inverse
`probability of censoring weighted (IPCW) Cox modelling, which
`aims to correct for the bias due to non-adherence to randomized
`treatment. IPCW at a median of 74 months estimated a significant
`survival benefit with letrozole compared with tamoxifen, esti-
`mates of 5 year OS were 91.8% and 90.4% respectively (HR 0.82,
`95% CI 0.71–0.95; p = <0.05) (Colleoni et al., 2011).
`The Tamoxifen, Exemestane Adjuvant Multicenter (TEAM) trial,
`was designed initially as an open label head to head study of
`5 years of tamoxifen vs exemestane. However, following publica-
`tion of the Intergroup Exemestane Study (IES) (Coombes et al.,
`2004) this was modified to a comparison of 5 years of exemestane
`monotherapy with sequential therapy comprising 2.5–3 years of
`tamoxifen followed by 2.5 years of exemestane. Initial results from
`the monotherapy arms comparing tamoxifen with exemestane
`(median follow-up 2.75 months) showed there was no significant
`difference in DFS, but it was acknowledged that the trial recorded
`a high rate of treatment discontinuation and unplanned crossover
`(Jones et al., 2009).
`Both the ATAC and BIG 1-98 groups undertook sub-group ana-
`lyse to determine if any sub-group derived particular benefit from
`upfront use of an AI. An initial report from the ATAC trial suggested
`that patients with progesterone receptor (PgR) negative tumours
`derived particular benefit from upfront use of an AI. However this
`was not seen in subsequent analysis (Dowsett et al., 2008), and no
`such effect was seen in BIG 1-98 (BIG 1-98 Collaborative Group,
`2005). There was a suggestion in BIG 1-98 that those patients with
`positive axillary lymph nodes as well as those who received adju-
`vant chemotherapy derived greater benefit from AI treatment (BIG
`1-98 Collaborative Group, 2005), however this was not borne out
`in subsequent analysis with longer follow up (Coates et al., 2007).
`
`2.2.2. Sequential and switch strategy
`Several trials have explored the efficacy of tamoxifen for 2–
`3 years followed by an AI to complete 5 years of treatment. The tri-
`als can be separated into those that randomised women prior to
`any adjuvant ET (sequencing studies) and those that randomised
`patients who were established relapse free on tamoxifen for 2–
`3 years to continuation of tamoxifen or switch to an AI (switch
`studies). Five studies have reported so far; three with anastrozole
`(Italian Tamoxifen Anastrozole (ITA); Austrian Breast and Colorec-
`
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`699
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`tal Cancer Study Group (ABCSG-8), and Arimidex–Nolvadex (ARNO
`95) (Boccardo et al., 2005; Jakesz et al., 2005) one with letrozole
`(including the reverse sequence (BIG 1-98) (BIG 1-98 Collaborative
`Group, 2009) and one with exemestane (Intergroup exemestane
`study (IES) (Coombes et al., 2007). Of these studies ABCSG-8 and
`BIG 1-98 randomised patients upfront, while ARNO 95, IES and
`ITA had a switch design. As discussed above, TEAM was modified
`from a monotherapy to a switch study during its recruitment.
`
`Switch studies
`The IES was a switch study with women randomised after 2–
`3 years of tamoxifen to further tamoxifen or 2–3 years of exemes-
`tane. At a median follow-up of 91 months the primary end-point
`DFS favoured the switch to exemestane (HR; 0.81; 95% CI, 0.72–
`0.91; p = 0.001), equating to an absolute difference of 4.5% (95%
`CI, 1.9–6.8%) in the numbers alive and disease-free at 8 years. An
`improvement in overall survival was also demonstrated again
`favouring the switch (HR, 0.86; 95% CI, 0.75–0.99; p = 0.04) (Bliss
`et al., 2012). In a combined analysis of the ARNO 95 and ABSG-8
`studies (Jakesz et al., 2005), at a median follow up of 28 months
`the switch was associated with improved event-free survival
`(EFS) (HR 0.60, 95% CI 0.44–0.81, p = 0.0009). A subsequent analy-
`sis of the ARNO 95 alone with a median follow up of 30 months
`found that switching to anastrozole resulted in a significant reduc-
`tion in the risk of disease recurrence (HR, 0.66; 95% CI, 0.44–1.00;
`p = 0.049), and improved overall survival (HR, 0.53; 95% CI, 0.28–
`0.99; p = 0.045) compared with continuing on tamoxifen (Kauf-
`mann et al., 2007). A meta-analysis combining ARNO 95 and
`ABSG-8 data with that derived from the small open label ITA trial,
`found significant improvement in both DFS (HR 0.61 95% CI 0.45–
`0.83; p = 0.002), and OS (HR 0.71 95% CI 0.52–0.98; p = 0.04)
`favouring the switch (Jonat et al., 2006).
`At a median follow up of 5.1 years the TEAM study found no dif-
`ference between the exemestane and sequential treatment arms
`(hazard ratio 0.97, 95% CI 0.88–1.08; p = 0.60 (van de Velde et al.,
`2011), theses data being consistent with those from BIG 1-98
`(letrozole vs tamoxifen-letrozole sequence). Of note at the time
`of reporting 20% remained on treatment and there were compli-
`ance issues, with 47% in the sequence group and 19% in the mono-
`therapy group having discontinued treatment before 5 years.
`
`Sequential studies
`BIG 1-98 as well as comparing the upfront use of AI also ex-
`plored the sequencing strategy, and included both a tamoxifen-
`letrozole and letrozole-tamoxifen sequence (Regan et al., 2011).
`Data from the sequencing as compared to letrozole monotherapy
`arms at a median follow-up of 8 years, showed no significant dif-
`ference in DFS with either sequential treatment as compared with
`letrozole alone (HR 1.07 95% CI, 0.92–1.25 for tamoxifen-letrozole;
`HR 1.06; 99% CI, 0.91–1.23 for letrozole-tamoxifen), (Regan et al.,
`2011). However, 2 years of tamoxifen upfront was associated with
`a non-significant increased risk of early relapse, consistent with
`data from ATAC and BIG 1-98 monotherapy arms.
`
`2.2.3. Extended aromatase inhibition
`Given that women with ER positive breast cancers remain at
`on-going, long term risk of relapse, a number of studies investigat-
`ing the role of extending AI therapy beyond 5 years have been con-
`ducted. To date three randomised studies have reported data on
`the use of an AI after 5 years of tamoxifen; MA.17, compared
`letrozole for 5 years in comparison with placebo (Goss et al.,
`2005), ABCSG-6a evaluated anastrozole for 3 years vs no treatment
`(Jakesz et al., 2005) and the NSABP B-33 compared 5 years of exe-
`mestane vs placebo (Mamounas et al., 2008).
`MA.17 was prematurely unblinded at 2.4 years of follow-up fol-
`lowing the first interim report that letrozole was associated with
`
`improved DFS (defined as recurrence or contralateral breast can-
`cer-HR 0.58, 95% CI 0.45–0.75, p > 0.001) and (in the node positive
`subgroup), overall survival (HR 0.61, 95% CI 0.38–0.98, p = 0.04)
`(Goss et al., 2005). Following unblinding, patients receiving pla-
`cebo were offered letrozole. In a subsequent cohort analysis, de-
`spite being a higher risk population and at a median time from
`tamoxifen treatment of 2.8 years, those patients switching to
`letrozole demo