The use of endocrine therapy to treat breast cancer began over one hundred years ago, long before identification of the target for such treatment, the estrogen receptor . Subsequently, the lack of expression of estrogen receptor by immunohistochemistry (IHC) has become widely accepted as a negative predictive factor for the efficacy of endocrine therapy [2,3]. In advanced breast cancer the optimal sequence of existing endocrine agents is not adequately defined. Meta-analyses suggest that, in postmenopausal women, there is a survival advantage with third-generation aromatase inhibitors compared with tamoxifen or progestagens [4,5]. This is reflected in clinical guidelines which recommend the use of a third-generation aromatase inhibitor as first-line therapy of advanced disease unless relapse occurred during or within 1 year of completion of adjuvant aromatase inhibitor therapy [6,7]. In the modern era, the majority of relapsed estrogen receptor-positive cancers will already have been exposed to endocrine therapy in the adjuvant setting, demonstrating a lack of complete sensitivity to therapy. Endocrine resistance will develop in the metastatic setting in all cases making endocrine resistant estrogen receptor-positive disease the commonest cause of breast cancer death. Strategies to overcome resistance are of great importance and several notable advances have recently been made. The most promising approach to date is the use of mammalian target of rapamycin (mTOR) inhibitors, although multiple alternative approaches are also in early clinical trials.
IDENTIFICATION OF ‘LUMINAL’ BREAST CANCERS
A significant proportion of breast cancers that express the estrogen receptor are insensitive to estrogen deprivation and estrogen receptor blockade. Quantitative analysis of estrogen receptor by IHC or ligand binding assays offers relatively little in terms of predictive power as shown in the latest 5 yearly meta-analysis of the Early Breast Cancer Trialists Collaborative Group . Substantial benefit with 5 years of tamoxifen was demonstrated for women with tumours expressing very low levels of estrogen receptor [recurrence risk (RR) 0.67 (standard error 0.08) for estrogen receptor 10–19 fmol/mg], with only slightly improved outcomes seen in those with maximal expression [RR 0.52 (standard error 0.07) for estrogen receptor ≥200 fmol/mg, trend in RR with estrogen receptor (if estrogen receptor ≥10 fmol/mg) P = 0.002]. However, the methods for detection of estrogen receptor have changed significantly. Specifically, the sensitivity of IHC assays has been driven up with advances in antigen retrieval and signal amplification techniques. Whereas 34% of tumours had estrogen receptor Quick (Allred) scores of 3–5 in the study first defining this scoring method, fewer than 10% score 3–5 in more recent studies [8▪,9,10]. Assessment of quantitative estrogen receptor mRNA levels may improve our ability to predict benefit of endocrine therapy. Retrospective analysis of the NSABP B14 trial showed quantitative estrogen receptor mRNA expression to be linearly related to the relative risk reduction of distant relapse by tamoxifen with increasing benefit seen with increasing estrogen receptor mRNA . Women with tumours in the lower tertile for estrogen receptor mRNA expression derived no benefit from adjuvant tamoxifen in contrast to the significant benefit seen in those with tumours in the higher two tertiles.
In a separate study, genomic profiling of breast tumours with 1–9% of cells estrogen receptor positive by IHC, revealed only 8% (2/25) to be luminal with the majority falling into basal (48%) and HER2 amplified (32%) cohorts [8▪]. Similarly, in the GEICAM/9906 study of anthracycline-based chemotherapy ± sequential taxane, gene expression of ESR1 and ERBB2 was of more prognostic value than assessment by central IHC . Furthermore, the standard IHC panel (estrogen receptor, progesterone receptor, and HER2) did not robustly identify the PAM50 gene expression subtypes. Taking this one step further to the prediction of benefit from endocrine therapy, Chia et al.  classified 398 of 672 assessable tumours from the MA.12 study of tamoxifen versus placebo into intrinsic subtypes using the PAM50 assay. Overall, the intrinsic classifier was prognostic for both disease-free survival (DFS) and overall survival (OS) and luminal subtype was predictive of tamoxifen benefit [DFS: hazard ratio (HR), 0.52; 95% confidence interval (CI) 0.32–0.86 versus. HR, 0.80; 95% CI 0.50–1.29 for nonluminal subtypes].
The Oncotype DX assay examines mRNA expression levels of 16 ‘active’ and five reference genes by real-time polymerase chain reaction in primary tumour blocks. The assay has previously been shown to be predictive for chemotherapy and endocrine therapy sensitivity in women with estrogen receptor-positive node-negative and node-positive disease [14,15]. Furthermore, a recent analysis of the NSABP-B28 study demonstrated no benefit in modern taxane-based chemotherapy in the low recurrence score cohort [16▪]. Low recurrence score has also been shown to correlate well with the luminal A intrinsic subtype in identifying a group of patients with low chance of relapse and little if any benefit from adjuvant chemotherapy [17,18]. It may also be possible to identify this cohort through quantitative assessment of four markers (estrogen receptor, progesterone receptor, Ki67 and HER2) by IHC and computation of the IHC4 recurrence score according to the algorithm defined by Cuzick et al. . Furthermore, in central analysis of the TEAM study, employing quantitative immunofluorescence in place of standard DAB-IHC resulted in enhanced prediction of recurrence . However, IHC assays are prone to significant variation in analytical practice between laboratories and the generalizability of IHC4 to the community setting represents a major challenge .
These data are encouraging and suggest that progress has recently been made in patient stratification based on the genomic analysis of primary breast tumours. However, even these approaches represent a simplification of the complexity and diversity of the breast cancer genetic landscape. Three recent studies in the journal Nature have reported the results of next-generation sequencing (NGS) in primary breast cancer samples [22▪,23▪,24▪]. Novel DNA copy number alterations and mutations were identified in multiple genes not previously associated with breast cancer. Although most recurrent mutations were infrequent, distinct patterns of pathway deregulation were evident. All studies identified novel potential therapeutic targets but highlighted the challenges for future clinical trial design. As the cost of NGS continues to fall rapidly this technology is certain to aid in the personalization of cancer treatments and it should now be mandatory to collect circulating and tumour DNA for biomarker analysis in all breast cancer clinical trials.
SEQUENCING ENDOCRINE THERAPIES IN ADVANCED BREAST CANCER
The use of third-generation aromatase inhibitors as first-line therapy has recently been challenged in women with endocrine-naive advanced disease. In the FIRST study, the estrogen receptor downregulator fulvestrant, at the newly approved and more efficacious dose of 500 mg every 4 weeks with an additional loading dose on day 15, demonstrated superior efficacy compared with anastrazole [25▪▪]. The updated results showed superior progression-free survival (PFS) with fulvestrant versus anastrazole (23.4 months versus 13.1 months, HR 0.66; 95% CI 0.47–0.92, P = 0.01) despite a lack of improvement in clinical benefit rate [72.5 versus 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72–2.38; P = 0.386)]. These are provocative and potentially practice changing phase II data and a randomized phase III study with OS as the primary endpoint is currently recruiting (http://www.ClinicalTrials.Gov NCT01602380 [Accessed 20 October 2012]). A total of 450 women will be recruited, with identical eligibility criteria, and results are expected in 2015.
Preclinical data in xenograft models have suggested that fulvestrant may be more efficacious in combination with an aromatase inhibitor . Three studies have recently reported on the addition of fulvestrant to anastrazole, with mixed results [27▪,28▪,29]. The SoFEA study randomized postmenopausal women previously treated with a nonsteroidal aromatase inhibitor (NSAI) to exemestane versus anastrazole versus fulvestrant plus anastrazole . The fulvestrant dose was 250 mg 4 weekly, which has now been shown to be significantly less effective than the 500 mg dose . The results, presented at EBCC in 2012, showed no significant differences between the groups in PFS, echoing the results of the EFECT study in which the outcome with fulvestrant 250 mg was identical to that with exemestane, after prior therapy with a NSAI .
In both the FACT and SWOG S0226 phase III studies postmenopausal women were randomized to an initial dose of fulvestrant at 500 mg followed by 250 mg 4 weekly thereafter with an additional 250mg loading dose on day 15, in combination with anastrazole versus anastrazole alone [27▪,28▪]. No prior endocrine therapy for advanced breast cancer was permitted in either trial. In SWOG S0226 fulvestrant in combination with anastrazole resulted in a significant improvement in the primary endpoint of PFS (15.0 versus 13.5 months; HR 0.80; 95% CI 0.68–0.94; P = 0.007) and a clinically meaningful improvement in OS (47.7 versus 41.3 months; HR 0.81; 95% CI, 0.65–1.0; P = 0.05). In contrast, the FACT study demonstrated no differences between the groups in time to progression (10.8 versus 10.2 months; HR 0.72 P = 0.91) or OS (37.8 versus 38.2 months; P = 1.00). It is difficult to explain the disparity in these results, although fewer women in the SWOG S0226 study had received adjuvant tamoxifen (40 versus 70%) adding further weight to the theory that fulvestrant may be best used early in the treatment pathway of women with estrogen receptor-positive metastatic breast cancer. It is unclear from these results whether the combination of fulvestrant with anastrazole in the SWOG S0226 study had any impact on the positive result but this seems relatively unlikely given the lack of benefit with the same approach in the other two trials.
Whether these trials, and indeed the SOFEA study would have shown a benefit for fulvestrant had the more efficacious dose of 500 mg been used remains an open question. Indirect evidence to support this was recently presented in an adjusted indirect comparison of meta-analysis data according to the Bucher method . The results suggested a significant improvement in PFS with fulvestrant 500 mg over anastrazole 1 mg, the latter population having had no prior aromatase inhibitor therapy but tamoxifen in 50–60% of cases. The increasing use of aromatase inhibitors in the adjuvant setting and the improved outcome with the increased dose of fulvestrant is likely to lead to increased fulvestrant use in the first-line therapy of postmenopausal women with advanced breast cancer.
RECENT ADVANCES IN OVERCOMING ENDOCRINE THERAPY RESISTANCE
Multiple mechanisms mediate endocrine therapy resistance in estrogen receptor-positive breast cancer . The most important clinical studies to report on endocrine resistance recently have investigated inhibitors of mTOR in reversing resistance. Although patients in these studies are frequently stratified by primary or acquired resistance, the definitions differ markedly between studies leading to difficulties in cross trial interpretation.
In the phase II TAMRAD study, 111 postmenopausal women with estrogen receptor-positive, HER2-negative and aromatase inhibitor-resistant advanced breast cancer were randomized to tamoxifen alone (n = 57) or tamoxifen and the mTOR inhibitor everolimus (10 mg per day, n = 54) [34▪▪]. There were some potentially important imbalances between the arms in that 24 of 57 (42%) in the tamoxifen alone arm versus 18 of 54 (33%) of the combination arm had received adjuvant tamoxifen and 23 of 57 (40%) versus 32 of 55 (59%), respectively, were of performance status zero. Notwithstanding these differences there was a significant improvement in the primary endpoint of clinical benefit rate from 42% (95% CI 29–56) with tamoxifen alone to 61% (95% CI 47–74; P = 0.045) with tamoxifen–everolimus. Time to progression increased from 4.5 months to 8.6 months with the combination, corresponding to a 46% reduction in the risk of progression (HR 0.54; 95% CI 0.36–0.81; exploratory P = 0.002). Remarkably for such a small study, the risk of death was also reduced significantly (HR, 0.45; 95% CI 0.24–0.81; exploratory P = 0.007). However, toxicity was increased significantly, although grade 3 or 4 events were relatively uncommon with the exception of stomatitis (0 versus 11% in tamoxifen versus combination arms, respectively).
Randomization in the trial was stratified by primary and secondary hormone resistance. Patients with primary resistance had relapsed during or within 6 months of adjuvant aromatase inhibitor treatment or progressed within 6 months of starting aromatase inhibitor treatment in the metastatic setting. Patients with secondary resistance had either relapsed more than 6 months after stopping adjuvant aromatase inhibitors or had responded for at least 6 months to aromatase inhibitors in the metastatic setting. The benefit of everolimus was seen largely in the cohort with secondary hormone resistance, with a HR for progression with the combination of 0.46 (95% CI 0.26–0.83). This compares with a nonsignificant HR of 0.70 (95% CI 0.40–1.21) in patients with primary resistance. A similar improvement in PFS was also seen with the addition of lapatinib to letrozole in women with advanced estrogen receptor-positive HER2-negative breast cancer and secondary endocrine resistance . Results with the epidermal growth factor receptor inhibitor gefitinib are less conclusive. In a small phase II trial improvements in PFS were seen in combination with anastrazole in women previously untreated for advanced breast cancer, with a trend for even better effect in those with endocrine-naive disease . However, no significant effect was seen in a larger phase II study when gefitinib was added to tamoxifen in either primary or secondary resistant settings .
In the phase III BOLERO2 trial, 724 postmenopausal women with estrogen receptor-positive advanced breast cancer with prior NSAI treatment were randomized 1 : 2 to exemstane alone or in combination with everolimus 10 mg per day [38▪▪]. The groups were well balanced and the protocol definition of prior endocrine sensitivity was at least 24 months of endocrine therapy before recurrence in the adjuvant setting or a response or stabilization for at least 24 weeks of endocrine therapy for advanced disease. The majority (84%) of patients fulfilled this definition of endocrine sensitivity. The primary endpoint was PFS and the addition of everolimus to exemestane increased the median PFS from 2.8 to 6.9 months (HR for progression or death, 0.43; 95% CI 0.35–0.54; P < 0.001). Overall survival data are currently immature. Grade 3 or 4 side effects more frequent in the combination arm were stomatitis (8 versus 1%), anaemia (6 versus <1%), dyspnoea (4 versus 1%), hyperglycaemia (4 versus <1%), fatigue (4 versus 1%) and pneumonitis (3 versus 0%). Everolimus was discontinued by 19% of women due to toxicity compared with 4% on placebo.
Similar positive results have also been presented for the mTOR inhibitor sirolimus (Rapamycin) in combination with tamoxifen . Median PFS improved from 3.3 to 11.7 months (HR 0.43; P = 0.0023) in women previously treated with an aromatase inhibitor and from 9.0 to 16.0 (HR 0.48; P = 0.0028) in women with no prior aromatase inhibitor treatment. However, a third mTOR inhibitor temsirolimus did not improve the outcome in women receiving letrozole for advanced breast cancer in a large phase III study . The reasons for this disparity are not entirely clear, although intermittent temsirolimus dosing (30 mg per day for 5 days out of 14) was used in contrast to continuous dosing with everolimus and sirolimus. Inhibitors of the upstream signalling elements PI3K and Akt are also now in early phase studies. One major challenge will be to develop predictive biomarkers for these agents and ask whether combination or sequential inhibition at different levels of the PI3k/Akt/mTOR pathway will be even more effective at inhibiting endocrine resistance.
In recent years there have been major changes in approaches to identify breast cancer patients who may benefit from endocrine manipulation. New technologies, in particular next-generation sequencing, will increase the complexity but also the capacity to personalize endocrine and other therapies. Further clinical studies of existing and novel endocrine agents and additive therapies to subvert resistance are ongoing. All such studies should collect and store tumour tissue, preferably from both primary and metastatic sites and the circulation, to aid in subsequent personalization of an ever enlarging pallet of treatment options.
Conflicts of interest
S.J.H. has received honoraria from AstraZeneca, Novartis and Genomic Health Inc.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 86–87).
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