Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women—a literature review and proposed guidelines

Multiple online electronic databases (PubMed, MEDLINE, and PREMEDLINE) were searched several times during the study period, the most recent being December 2019, using appropriate keywords and MeSH subheadings (Additional file 1, Table S1). The topic areas identified for the search were breast neoplasms, ER⁺/PgR⁺status, postmenopausal women, and neoadjuvant endocrine therapy. As pathological complete response is rare in ER⁺ breast cancer, there is often inconsistency in the outcome measures used in studies of NET. Consequently, an outcome measure was not included in the PICO search as this would have excluded a large number of relevant studies. This truncated PIC approach has been previously validated as preferable to the PICO model when conducting a systematic review search, to prevent excluding studies which do not use the specified outcome measure and consequently reducing the sensitivity of the search [31, 32]. The initial search produced 170 papers, of which the abstracts were reviewed to ensure the inclusion and exclusion criteria were met. The reference lists of relevant studies and reviews were used to identify further relevant literature.

Inclusion criteria include postmenopausal, female, and ER⁺ or PgR⁺ breast cancer.

Exclusion criteria include metastatic, inflammatory, triple negative, HER2⁺ or male breast cancer, prior breast cancer treatment, recent hormonal therapy, and articles published in a language other than English.

There was no cut-off date for literature inclusion, and no restriction on the type of study included in the review as this is a relatively small and under-investigated field and we did not want to limit the scope of the review.

A glossary of terms used and their definitions is given in Additional file 1, Table S2.

No conflict of interest was identified.

In order for neoadjuvant trials to be of value, reliable biomarkers for patient selection and treatment response must be available. It is known that NCT is less likely to result in a pathological complete response (pCR) in ER⁺ tumors compared to ER⁻ tumors, making NET a valuable alternative in these patients [33, 34]. Typically, patients with LABC who are treated with NET will receive post-surgical adjuvant treatment with endocrine therapy with or without chemotherapy. The adjuvant treatment recommendation is guided by the response of the tumor to NET and the estimated risk of recurrence based on the evaluation of the surgical specimen. The German Breast Group NCT trial showed a pCR rate of 22.8% in ER⁻ tumors, compared to only 6.2% in ER⁺ tumors [16, 35]. Rates of pCR for ER⁺ tumors treated with NET are typically as low as 3%; however, this figure may be increased with a longer treatment duration [29]. Consequently, pCR is rarely used as an outcome measure in studies of ER⁺ tumors. A number of different biomarkers exist which will be discussed in the following sections. Biomarkers currently in use for patient selection include high ER or PgR expression and gene expression profiling (low pre-treatment recurrence score (RS) or a high ER pathway activity score). Biomarkers with prognostic value include on-treatment and post-treatment Ki67, the preoperative endocrine prognostic index (PEPI) and P-PEPI, and post-treatment RS.

There have been three large randomized controlled trials comparing tamoxifen to aromatase inhibitors; each demonstrating either superiority or non-inferiority of aromatase inhibitors in the neoadjuvant setting [16, 19, 59, 60]. Tamoxifen is a long-standing treatment for breast cancer; however, it may lead to serious adverse effects including thromboembolism and endometrial cancer [59]. Additionally, tamoxifen resistance is not uncommon, yet approximately one-third of patients with resistance to tamoxifen will still benefit from aromatase inhibition [61]. Aromatase inhibitors block the peripheral conversion of androgen to estrogen, reducing circulating estrogen levels by up to 90% [62].

The P024 trial is the largest trial comparing neoadjuvant tamoxifen and letrozole in postmenopausal women with ER⁺ breast cancer who were ineligible for BCS [16, 59]. Letrozole led to a significantly greater objective response rate (ORR) and rate of BCS (Table 1) [59]. Response rates in the letrozole group were higher than for tamoxifen in all Allred Scores from 3 to 8, demonstrating letrozole’s superiority independently of ER expression level [36]. The most common adverse events in this trial were hot flushes and nausea, which occurred equally with tamoxifen and letrozole (57% of patients in each group) [59].

Two large trials compared neoadjuvant tamoxifen and anastrozole (Table 1). In terms of ORR, both the PROACT and IMPACT trials demonstrated non-inferiority of anastrozole to tamoxifen [19, 60]. In terms of BCS, the PROACT trial showed a significantly higher rate in patients taking anastrozole; however, this rate did not reach significance in the IMPACT trial (Table 1) [19, 60]. Hot flushes were the most common adverse event on both medications; however, anastrozole had a lower rate of vaginal discharge and thromboembolic events in the IMPACT trial [19]. Additional studies which demonstrate the superiority of aromatase inhibitors in comparison to tamoxifen are summarized in Table 1 [63, 64].

There have also been a number of trials comparing different aromatase inhibitors, or aromatase inhibitors with fulvestrant, a selective estrogen receptor degrader (Table 2) [26]. Overall, these studies have not been able to demonstrate superiority of one aromatase inhibitor over another. In terms of ORR, the largest trial (Z1031 trial) did not demonstrate a significant difference between exemestane (62.9%), letrozole (74.8%), and anastrozole (69.1%) (Table 2) [53, 54]. Other studies comparing aromatase inhibitors also did not demonstrate superiority of any one agent (Table 2) [28, 65, 66]. In terms of the BCS rate, there was no significant difference found between the types of aromatase inhibitors or fulvestrant (Table 2) [28, 53, 54, 65, 66].

Following the determination that all three aromatase inhibitors showed biological equivalence, the Z1031 trial created an extension study known as Z1031B [53, 54]. In the Z1031B trial, patients who had a Ki67 > 10% after 2 to 4 weeks of NET were switched to chemotherapy in an attempt to increase the rate of pCR [53]. Based on the IMPACT trial and Preoperative Letrozole study, patients with a Ki67 > 10% were found to have a < 2% chance of obtaining PEPI = 0 and, hence, avoiding adjuvant chemotherapy [19, 53, 67]. Of the patients who switched to NCT, only 5.7% (2 patients) went on to achieve a pCR [53]. In patients who had a 2-week Ki67 < 10% and received 16 weeks of NET, the pCR rate was 1.6% and the PEPI = 0 rate was 34.4% [53].

The ALTERNATE trial is a phase III trial currently in recruitment which aims to compare anastrozole, fulvestrant, or their combination and identify women at a low risk of recurrence based on the PEPI [26]. After 4 weeks of treatment, women with a Ki67 > 10% will be switched to NCT, and only women with a PEPI = 0 post-surgery will receive adjuvant endocrine therapy [26].

Despite the advantages of aromatase inhibitors being clearly highlighted in the P024 and Z1031A trials, there is continual limited use by physicians [68]. A study from the USA revealed only 3.1% of women with ER and/or PgR⁺ breast cancer received NET compared to 24.7% who received NCT [69]. However, this figure has slowly increased from 2.3% (2004) to 3.5% (2014), with women treated in academic rather than community centers more likely to receive NET [69]. In addition, this study found women were more likely to receive NET if they were > 60 years old and had tumors with a lower grade or stage III disease [69]. Potential barriers to widespread adoption of NET include the heterogenous nature of patient responses, and the long duration required to achieve a clinical response [53]. The reluctance to introduce NET into clinical practice may also represent the poor response rates seen when treatment is carried out for a duration of only 3 to 4 months [30]. In comparison to NCT, NET has more gradual effect on the tumor and an extended treatment period is usually required in order to appreciate the maximum clinical response [70].

The optimal duration of NET that should be administered to postmenopausal patients with ER⁺ breast cancer has not yet been determined or incorporated into clinical guidelines [18, 27, 71‐73]. The majority of NET randomized trials use a treatment duration of 3 to 4 months, which is largely arbitrary and related to historical studies of tamoxifen and chemotherapy [30, 73]. At the 2013 St. Gallen breast cancer conference, 62.2% of panelists supported NET being given until maximal response [74, 75]. An additional 26.7% of panelists supported a duration of 4 to 8 months, while only 11.1% supported the current duration of 3 to 4 months [75]. One of the major concerns of extending NET until maximal response is the risk of disease progression. A study by Carpenter et al. aiming to identify the optimal duration of letrozole therapy had a low progression rate of 6.5% [30]. Similarly, a study of neoadjuvant exemestane showed a 7.7% progression rate at 4 months, increasing to only 8% at 6 months of treatment [76]. Despite the evidence, 4 years on at the 2017 St. Gallen conference, uptake of NET remained suboptimal with the panel stating that “Neoadjuvant ET in postmenopausal women with ER⁺ stage II/III tumors is currently underused, although it shows low toxicity” [68]. Six years later at the 2019 St. Gallen International Breast Cancer Conference, there is extremely limited attention given to the neoadjuvant treatment of ER⁺ tumors and no clinical guidelines or recommendations are made [39].

Recently, there have been several small studies aiming to investigate the optimal duration of NET, only two of which were randomized trials. In the four studies where the duration of NET was extended to 12 months, the ORR’s ranged from 76.8 to 95%, and the rate of BCS was 45 to 87.5% (Table 3) [27, 29, 30, 73]. In contrast, the large PROACT and IMPACT trials, discussed previously, used a duration of 3 months and reported an ORR of only 49.7 and 37%, respectively, with BCS rates of 43 and 44% [19, 60]. A single-center study demonstrating the effectiveness of 12 months of letrozole found that in addition to the high ORR of 88%, 13% of patients achieved a pCR and less than 10% of patients progressed [29]. A second single-center study provided further evidence for increased duration of letrozole treatment, with a pCR rate of 2.5% at 4 months, 5% at 8 months, and 17.5% at 12 months [27]. This indicates that the short duration of conventional NET may be the reason behind the low pCR rate frequently observed [27]. A longitudinal phase IV study demonstrated that the median treatment time to allow BCS in previously ineligible patients was 7.5 months, suggesting the conventional duration of 4 months is not optimal [30]. The proportion of patients who became candidates for BCS increased with time, with 66% of patients suitable after 12 months of letrozole treatment [30]. This was an approximately twofold increase in eligibility for BCS when treatment was extended from 4 to 8 months [30]. An earlier phase II trial from 2012 studied letrozole administration over the period of 4 to 12 months and found that maximal response was achieved in a median time of 4.2 months [73]. However, 37% of patients continued to improve beyond 6 months and achieved a maximal response within 6 to 12 months, with the ORR increasing from 55% at 4 months to 76.8% at the conclusion of the study (Table 3) [73]. Other studies which demonstrate the benefit of extending NET are outlined in Table 3 [71, 72]. Interestingly, in the study by Krainick-Strobel et al., of 5 patients who had no change in clinical palpation at 4 months, 1 went on to achieve a complete response and 2 a partial response at 8 months of treatment with letrozole [72]. A retrospective analysis of data in the USA showed that in women who received NET for 1 to 3 months, 20.6% had their tumors down-staged, compared to down-staging in 34.9% of those who received NET for 12 to 24 months [69].

Two studies have investigated the optimal duration of NET using exemestane. Exemestane is an irreversible, steroidal aromatase inhibitor which may have fewer adverse effects on the metabolism of lipids and formation of bone when compared to letrozole or anastrozole [77, 78]. The PTEX46 randomized phase II trial found no significant difference in the ORR at 4 or 6 months and suggested the optimal duration of NET is around 4 months (Table 3) [76]. In contrast, the TEAM IIA trial found a significant increase in ORR from 3 to 6 months (Table 3) and concluded that in patients without progressive disease, extending exemestane treatment from 3 to 6 months improves clinical outcomes without increased toxicity [70].

A concern in recommending extended durations of NET is the challenge in evaluating treatment response, coupled with the possibility of disease progression. Although most studies evaluating primary endocrine treatment have generally compared surgery +/− adjuvant endocrine therapy, with endocrine treatment alone, and therefore represent a different paradigm to NET followed by surgery +/− adjuvant endocrine therapy, it is valuable to note that these studies generally support the safety of NET to at least 12 months if only ER⁺ cases are considered. Reviewed by Macaskill et al. [79] and Pepping et al. [80], it is important to note that most trials of primary endocrine treatment without surgery were not focused on LABC, and earlier trials did not select for ER positivity. Trials that selected on ER positivity found no difference in rates of recurrence and disease-specific outcome [79, 80]. The 20-year follow-up report of the Nottingham study of 153 fit elderly patients with ER⁺ breast cancer < 5 cm, randomized to primary tamoxifen or mastectomy with adjuvant tamoxifen [81], revealed no difference in regional recurrence, metastasis, disease-specific, or overall survival between groups. Moreover, while locoregional control was poorer long-term in the no surgery cohort, there was no difference between surgery and no surgery groups until at least 18 to 24 months [81]. This is in agreement with Willsher who reported a progression rate of 3% at 6 months of primary tamoxifen in a cohort selected for high ER, and just 16% requiring surgery after 3 years [82]. Moreover, partial or complete response at 6 months was a strong predictor of excellent control at 3 years. Mustacchi et al. compared outcomes after primary endocrine therapy with tamoxifen, to surgery followed by adjuvant tamoxifen, in 474 women aged 70 and older [83, 84]. No difference in disease-specific survival was observed between groups after 13 years, and although the progression rate was significantly greater in the tamoxifen only group at 80 months, there was no difference between groups at 12 months [83]. These studies suggest that NET for up to 12 months is safe with close monitoring of tumor burden. Treatment beyond 12 months should be considered with caution.

Recent studies looking at combining aromatase inhibitors with novel therapies to overcome endocrine resistance have been promising. Phosphatidylinositol 3-kinase (PI3K) inhibitors, including alpelisib and taselisib, have been combined with aromatase inhibitors in a number of recent trials due to the involvement of PI3K-AKT-mTOR pathway upregulation in endocrine resistance [85, 86]. The large randomized phase II LORELEI trial recruited 334 patients with early-stage ER⁺ breast cancer to letrozole plus taselisib or letrozole plus placebo and demonstrated a significant improvement in ORR in the letrozole plus taselisib group [86].

Of recent interest has been the testing of CDK4/6 inhibitors, as these agents have been shown to enhance the activity of aromatase inhibitors and fulvestrant in advanced disease. The randomized phase II PALLET trial investigated the addition of palbociclib, a CDK4/6 inhibitor, to neoadjuvant letrozole in postmenopausal women with ER⁺ breast cancer [87]. This study found that the addition of a CDK4/6 inhibitor led to a significant reduction in proliferation measured by Ki67, compared to letrozole alone, but no significant improvement in clinical response rates over the 14 week study period [87]. The NeoPAL trial demonstrated that this combination of palbociclib and letrozole produced an almost identical rate of clinical response and rate of BCS compared to patients receiving chemotherapy [88]. In the neoMONARCH study which combined abemaciclib with anastrozole, results have shown significantly reduced levels of Ki67 with the CDK4/6 inhibitor with or without anastrozole, compared to anastrozole alone over 14 weeks of therapy [89]. This study also observed an increase in gene expression associated with immune activation at 2 weeks, but only a modest increase in radiological response rates [89]. The CORALLEEN trial was a randomized phase II trial of 106 patients investigating ribociclib plus letrozole vs. chemotherapy in post-menopausal women with hormone receptor-positive breast cancer of the luminal B subtype [90]. At the end of the 6 months of the CORALLEEN trial the rate of patients achieving a PEPI of 0 was 17.3% with chemotherapy and 22.4% with ribociclib and letrozole [90]. Especially when combining with CDK4/6 inhibitors, NET can achieve high rates of clinical response, even in luminal B patients, as compared with chemotherapy [87, 88, 90]. This is in stark contrast to previous thoughts that NET should be for luminal A patients only. Therefore, the benefit of combination therapies is twofold; firstly, they can increase response in luminal A patients, and secondly, they have expanded the patient population to be considered for NET, sparing the toxicities of chemotherapy.

CDK4/6 inhibitors are approved, in Australia, Europe, and the USA, for treatment of ER⁺ metastatic disease in combination with endocrine therapies. While available for LABC, they are not broadly accessible. Currently, ribociclib and palbociclib are available for use in Australia for patients with LABC; however, they are restricted to patients with disease that is deemed inoperable from the outset. These agents are not options for other locally advanced breast cancers where the aim of NET might be to facilitate more restricted breast-conserving surgery or targeted axillary dissection. Investigational treatment strategies combining other targeted agents (including PI3K inhibitors, mTOR inhibitors, and EGFR inhibitors) with endocrine therapies are currently continuing in various clinical trials. In future trial designs, it would be of interest to study not only other novel drug combinations but also to test these combinations over varying treatment durations. Finally, the observation that adding CDK4/6 inhibitors to NET might stimulate anti-tumor immunity [89, 91], as has been observed with some chemotherapy agents [92, 93], suggests that patients with ER⁺ LABC could see improved benefit from second-line immunotherapy approaches, while avoiding cytotoxic chemotherapies. Future clinical trials combining NET and novel targeted agents would benefit from including this outcome measure.