Endocrine Therapy: From Ovarian Ablation to Individualized Therapy and Signal Inhibition Free

Endocrine therapy (ET) of breast cancer (BC) is established as the very first targeted therapy in all stages of BC long before the identification of steroid receptors and the interaction of estrogen (ER) and progesterone (PR) with their specific hormone response elements on a cellular level when Sir George Thomas Beatson first discovered the positive influence of a bilateral oophorectomy in women with advanced disease at the end of the 19th century [1]. By the 1980s, pharmacological inhibition of estrogen signaling started in MBC, first with diethystilbestrol, followed by tamoxifen (TAM), and lately supplanted by the increasing evidence of ovarian ablation in premenopausal women [2]. Lately, in a phase II trial, the optimal dose of estradiol was evaluated in endocrine-sensitive MBC resistant to aromatase inhibitors (AIs) [3]. ET is recognized as an effective adjuvant treatment for women with hormone receptor-positive (HR+) early-stage BC, now known as luminal BC subtypes. Antiestrogen therapy is targeting the estrogen-mediated signaling pathway as an essential component of treatment for both early and advanced-stage BC expressing ER and/or PR. The ER is a steroid hormone nuclear receptor consisting of a DNA-binding domain, ligand-binding domain, and transcriptional activation function domains 1 (AF1) and 2 (AF2). Activated ER can interact with estrogen-responsive elements within the DNA. ER expression occurs in the normal ductal epithelium and invasive BC, and immunohistochemistry can be used to semiquantitatively measure the degree of ER expression and/or PR expression and, therefore, potentially sensitive to agents targeting the estrogen signaling pathway, also commonly referred to as “endocrine therapy” (ET) [2, 3]. There is a substantial body of evidence from RCTs demonstrating the benefit of ovarian function suppression (OFS), TAM, and AIs alone, in combination with TAM, and in sequence, of different durations, and according to menopausal status. The composition of the ET is based on the individual risk of recurrence of an individual patient, solely. Thus, a minimum of 5 years of ET is recommended for women with stage I–III at presentation regardless of the menopausal status in HR+ EBC pre- and postmenopausal HR+ BC. In young premenopausal women with an increased risk of recurrence, combination therapy with TAM or AIs and OFS is regarded as standard of care that might be extended for up to 10 years in patients with higher stage/risk disease. AIs are favored for postmenopausal women [4‒6]. Lately, dual ET including CDK4/6 inhibitors such as abemaciclib or ribociclib are entering the adjuvant setting with evidence released from the MonarchE and NATALEE trial for those patients with intermediate and high risk of recurrence [7, 8].

The beginnings of evidence-based ET can be dated back to the late 1950s when Elwood Jensen discovered and started the characterization of an estrogen-binding protein, today recognized as ER [9]. In the following, the main substances that have been used for decades and still currently build the foundation of any endocrine-based therapy are based on these findings.

In fact, TAM was an unintentional discovery, and without any doubt, TAM has saved numerous lives since its introduction in cancer therapy; however, scientists had not originally intended its use in this field. The debut in the clinical setting was as a post-coital contraceptive in a trial led by Arthur L. Walpole in the early 1960s [10]. Since its introduction for the treatment of advanced BC, its indications have increased to include the treatment of early BC, ductal carcinoma in situ, and more recently for BC chemoprevention. TAM has a good tolerability profile, and moreover, unlike many other endocrine therapies, it is efficacious in both pre- and postmenopausal women. Further analyses showed a reduction in the risk of recurrence when TAM was given as adjuvant treatment. The optimal therapy duration was subject to several subsequent investigations, which showed a significant trend toward a greater effect with longer treatment, so for many years, an adjuvant therapy of 5 years of TAM was recommended [5, 11]. Later, the ATLAS and aTTom trials demonstrated that an extension from five to up to 10 years of treatment resulted in an absolute reduction in disease recurrence of approximately 3–4% and in BC mortality of 2.8%, with the benefit emerging mainly in the second decade, after the end of therapy, and a similar proportional risk reduction for various patients and tumor characteristics [12, 13].

In the 1970s, investigators also found that estrogen synthesis is not restricted to the ovaries and adrenal glands, but in postmenopausal women, also in muscle, liver, and adipose tissues by the catalysis of androgens to estrogens through aromatase, an enzyme of the cytochrome P450 family. This knowledge led to the development of the third-generation AIs such as anastrozole, letrozole, and exemestane to reduce estrogen levels in hormone receptor-positive BC patients [14]. The comparison between AIs and TAM in postmenopausal women with MBC demonstrated the superiority of AIs and resulted in their approval in this setting [15]. Regarding the adjuvant therapy of postmenopausal women presenting with hormone receptor-positive EBC and the improvement of DFS, AIs’ effect was found to be superior compared to TAM, resulting in an extension of the approval and incorporation in international treatment recommendations [5, 16, 17]. In our clinical practice, the majority of postmenopausal patients receive based on their individual risk of recurrence either upfront AIs or a sequence of TAM and AIs for the first 5 years of their adjuvant therapy. This sequence might start with an AI followed by TAM or vice versa.

For these patients, the benefit of extending AIs for an additional 5 years appears to be relatively small. In various trials investigating this approach, there was no significant difference in overall survival with longer AI treatment, but the effect on improving the disease-free survival revealed to be associated with a prevention of contralateral BC. Thus, it remains uncertain whether patients benefit after being exposed for at least 3 years to AIs in the adjuvant setting from an extension up to 10 years. According to this evidence, the optimal therapy duration of AIs seems to be at least 2 to 3 years followed by 2 to 3 years of TAM, resulting in a total duration of 5 years for postmenopausal women [5, 16‒18]. In conclusion, the latest ASCO update on six RCTs on the extension of endocrine adjuvant therapy summarized that the benefits in absolute risk of reduction were modest and that, for lower risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate [18]. The Early Breast Cancer Trialists’ Collaborative Group meta-analysis of 11 trials of extended adjuvant therapy revealed an absolute risk reduction of recurrences increased with the number of lymph nodes involved, with a 5-year gain that ranged from 1.1% for those with node-negative disease to 7.7% for those with node-positive disease. Based on these findings, 5–7 years of AI therapy can be reasonably considered the optimal treatment duration for patients at low-intermediate risk, with node-negative disease or limited nodal involvement (one to three involved lymph nodes), whereas patients with a greater tumor burden (≥ involved lymph nodes) are likely to benefit from a longer treatment duration of up to 10 years [19].

A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second BCs. Shared decision-making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of BC recurrence, the prevention of second BCs, and the impact of adverse effects of treatment [18].

A comprehensive discussion of challenges in adjuvant therapy for premenopausal women diagnosed with luminal BC is an ongoing debate to balance this treatment option against a chemoendocrine sequential treatment approach. It has been well demonstrated that OFS alone provides substantial benefit and that TAM adds further benefit to OFS [20, 21]. However, the open issue remains whether OFS adds benefit to TAM, and whether the use of an AI adds further benefit over use of TAM in premenopausal women undergoing OFS, has, until recently, been uncertain [22].

The largest evidence was derived from the TEXT (OFS plus TAM vs. OFS plus AI) and SOFT (TAM vs. OFS plus TAM vs. OFS plus AI) trials, presented 12-year OS updates [23, 24]. The results from SOFT at 12 years show an absolute reduction in distant recurrence of 1.4% and a reduction in deaths of 2.3% with the addition of OFS to TAM versus TAM alone. Benefits of AI plus OFS versus TAM were greater with 3.0% and 2.6% absolute reductions in distant recurrence and death, respectively.

Subgroup analysis revealed that in premenopausal women with low-risk clinical pathologic features (by patient/physician choice) not receiving chemotherapy, the 12-year OS was more than 95% in all three arms. In this group, 91% of participants had lymph node-negative disease, 86% had a tumor size ≤2 cm, and more than 90% had grade 1 or 2 histology. On the other hand, for those who received chemotherapy (by patient/physician choice), the addition of OFS to TAM produced an absolute reduction in distant recurrence/death of 2.6/4.7% at 12 years (OS improved from 78.9% to 83.6%). For those at yet greater clinical risk, such as those with HER2-negative disease who received neoadjuvant chemotherapy or were younger than age 35, absolute survival improvement was in the range of 10% for either oral endocrine agent combined with OFS compared with TAM alone [24].

Hence, the Early Breast Cancer Trialists’ Collaborative Group recently published a meta-analysis of four trials (ABCSG XII, SOFT, TEXT, and HOBOE) testing AIs versus TAM in premenopausal women with HR+ early-stage BC treated with OFS [25]. The rate of BC recurrence was less for women assigned to an AI (rate ratio, 0.79; p = 0.0005). Distant recurrence was also reduced (rate ratio, 0.83; p = 0.018). Benefits appeared greater in women with HER2-negative disease. There was no excess of noncancer deaths with either therapy. There was no significant difference in overall survival between therapies (rate ratio, 0.98; p = 0.89). However, median follow-up was only 8 years.

In summary, optimal distant disease-free outcomes for premenopausal women with higher risk estrogen receptor-positive, HER2-negative disease are achieved with the combination of AI and OFS. Although that randomized trials do not show that it increases noncancer deaths, use of OFS has important side effects – from reversible toxicities such as hot flushes, insomnia, and joint pain to long-lasting effects such as osteoporosis. Rates of adverse events are the highest with AI plus OFS [26]. Thus, the optimal combination and duration of endocrine adjuvant therapy should be discussed in those young women disclosing all aspects of efficacy and side effects of this effective therapy given the option of de-escalation to TAM and OFS if the side effect is jeopardizing the therapy adherence.

The addition of CDK4/6 inhibitors to ET has led to a dramatic improvement of survival outcomes in patients with HR+ metastatic BC and has paved the way for a new era in the treatment of luminal BC. Based on these major improvements in metastatic disease, a number of studies (PALLAS, PENELOPE-B, MonarchE) have recently explored the efficacy of CDK4/6 inhibitors in reducing the risk of recurrences among patients with HR+ EBC [27‒30].

The PALLAS trial randomly assigned 5,796 patients with stage II or III luminal BC to the addition of palbociclib for 2 years to standard adjuvant ET or standard et alone. At the final analysis, performed at a median follow-up of 31 months, there was no significant improvement in invasive DFS with the addition of palbociclib (HR, 0.96; 95% CI, 0.81–1.14), neither in the overall population nor in any of the predefined subgroups [29]. The PENELOPE-B trial explored the addition of placebo or palbociclib for 1 year to standard ET in a population with high-risk disease. High risk was defined as residual disease after neoadjuvant chemotherapy and a clinical pathologic staging-estrogen receptor grading score ≥3 or 2 points in the setting of positive lymph nodes. At a median follow-up of 42.8 months, the addition of palbociclib did not show a reduction in recurrence risk (invasive DFS stratified HR, 0.93; 95% CI, 0.74–1.17) [27].

Different results were reported for the MonarchE study, in which 2 years of abemaciclib were added to standard adjuvant ET. A total of 5,637 patients were included and assigned to either of two cohorts, according to clinicopathologic tumor characteristics at study entry. Cohort 1 included patients with four or more positive lymph nodes or one to three lymph nodes and a tumor size of ≥5 cm or grade 3; cohort 2 included patients with one to three positive lymph nodes and Ki-67 ≥20%. At a median follow-up of 19 months, the addition of abemaciclib to standard ET was associated with an absolute 3% improvement of 2-year invasive DFS (HR, 0.71; 95% CI, 0.58–0.87) in the overall population, with a greater absolute improvement in the population with high Ki-67 (4.5% absolute invasive DFS improvement) or with a higher tumor burden (5.2% absolute improvement). Importantly, the magnitude of effect was maintained beyond the 2-year treatment with abemaciclib [28, 31].

Based on the efficacy results of MonarchE, abemaciclib was approved on October 12, 2021, by the U.S. Food and Drug Administration as adjuvant treatment for patients with HR+ node-positive, early-stage BC with a high risk of recurrence, and recently, on February 24, 2022, the European Committee for Medicinal Products for Human Use approved an extension of abemaciclib indication for patients with early-stage BC at high risk of recurrence.

At ASCO 2023 interim findings from the NATALEE trial, evaluating ribociclib in combination with adjuvant therapy in patients with intermediate-risk disease were presenting. The trial included patients with earlier stage disease, normally considered lower risk than the high-risk population. In an effort to improve safety, the dose was reduced from the usual 600 mg–400 mg, based on findings from other trials with metastatic BC patients that showed when doses were reduced due to tolerability, efficacy was not lost. Patients were treated for 3 years instead of 2 years. The trial randomized 5,101 men and premenopausal and postmenopausal women with BC who were at risk of recurrence. Patients received either adjuvant ribociclib with hormonal therapy (2,549 patients) or hormonal therapy alone (2,552 patients). After a median follow-up of 34 months, 20.2% of those in the ribociclib group completed 3 years of therapy, and 56.8% completed 2 years of treatment. The results showed a 3-year iDFS rate of 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group. Adding ribociclib reduced the risk for recurrence by 25%. Overall, 74.7% of participants remained on treatment at the data cutoff, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone [8]. The different inclusion criteria of the two positive trials are displaced face to face (Table 1).

In daily routine of luminal EBC, it is still a controversial issue which patient needs ET versus chemoendocrine therapy. The introduction of multigene assays (MGA) is widely established and recommended in EBC (0–3 LN involved) [7]. Recently, the release of the ADAPT HR+/HER2− trial shed interesting light on the KI-67 dynamic derived from the core-needle biopsy and the surgical specimen after a short neoadjuvant ET in correlation with the MGA Oncotype DX [32]. This approach might be an easy to perform in vivo test for endocrine sensitivity once Ki-67 is decreased from baseline.

Antiestrogen therapy remains the key component of the treatment of both EBC and MBC in luminal BC subtypes. A recent review highlighted the new generation of drugs including selective estrogen receptor modulators, orally administered estrogen receptor degraders, as well as more unique agents such as complete estrogen receptor agonists, proteolysis targeting chimeric, and selective estrogen receptor covalent antagonists. All these drugs are currently in different stages of their development mostly in MBC but also in EBC (Fig. 1) [9].

Even more interesting than the adjuvant use of CDK4/6 inhibitors together with ET is the vision of this combination replacing neo-/adjuvant chemotherapy. The phase II CORALLEEN study compared neoadjuvant ET with six cycles of letrozole and ribociclib to four cycles of a chemotherapy regime containing anthracycline and taxanes. At the time of surgery, many of the tumors initially classified as luminal B were then measured to be luminal A tumors [33]. Neoadjuvant abemaciclib within the phase II neoMONARCH trial also demonstrated a certain potential for cell cycle arrest and immune activation [34], as did palbociclib in the neoadjuvant phase II trials NeoPAL [35] and NeoPalAna [36].

The phase III study ADAPTcycle with ribociclib will yield more information about the comparability of chemotherapy with a CDK4/6 inhibitor-based treatment with regard to efficacy and safety in and intermediate-risk group comparing an adjuvant chemotherapy versus a combined ET of ribociclib and ET [37].

The role of PI3K inhibitors in EBC remains unclear. LORELEI, a phase II trial, was initiated to investigate the efficacy of taselisib combined with letrozole in the neoadjuvant ET setting. An objective response due to the addition of this PI3K inhibitor was demonstrated, but it was not sufficient enough to be recommended [38]. Alpelisib, in contrast to its efficacy in MBC, did not show any benefit when added to neoadjuvant ET in the NEO-ORB trial [32]. The development of the newer PI3K inhibitors inavolisib, copanlisib, and gedatolisib will reveal more about their potential significance for EBC.

Oral selective estrogen receptor degraders (SERDs) evaluated in RCT subject of MBC and EBC as well. The phase III AMEERA-6 study, for instance, evaluates amcenestrant versus TAM for postmenopausal women, with hormone receptor-positive EBC unable to continue adjuvant AI therapy [39]. Giredestrant is being compared to physicians’ choices of ET in women with hormone receptor-positive, HER2-negative EBC within the phase III lidERA trial and in the coopERA phase II trial in the neoadjuvant setting [40, 41]. These trials will show whether oral SERDs can become established substances of (neo-)adjuvant ET.

In patients with hormone receptor-positive disease with a BRCA1/2 germline mutation (gBRCA1/2_mt), there is also evidence that PARP inhibitors may enhance ET efficacy through a synergistic effect since BRCA mutations have been linked to transcriptional function of hormone receptors. The OlympiA trial is the first to show a benefit in DFS in women with HER2-negative EBC and a BRCA1/2 mutation receiving 1 year of adjuvant olaparib. The 3-year DFS of the total population was 85.9% in the olaparib group and 77.1% in the placebo group (HR 0.58; 99.5% CI 0.41–0.82; and p < 0.001). However, a significant difference in OS rates could not be demonstrated. Looking only at hormone receptor-positive, HER2-negative EBC patients who received olaparib for 1 year in addition to ET, compared to those included after adjuvant chemotherapy on the basis of node positivity (HR 1.36; 95% CI 0.41–4.71), the subgroup of women who were enrolled due to residual disease after neoadjuvant chemotherapy benefitted the most (HR 0.52; 95% CI 0.25–1.04) [42, 43].

However, to be effective, each therapy requires patients’ adherence, especially in view of the cost-benefit ratio of novel substances and known unsatisfying adherence rates of standard ET. Therefore, to ensure women’s compliance and persistence and to improve their outcome with the help of expensive combinational regimens, the necessity of patients’ understanding of their recurrence risk, compliance programs, digital health solutions, continuous treatment and side effect monitoring, as well as a healthy patient-physician relationship will gain in importance with each novel therapy.

The hallmark of ET of both EBC and MBC is estrogen withdrawal on different levels introduced long before the evidence of hormones, receptors, and their pathways were discovered. The substantial benefit on improving survival is the biggest benefits in systemic therapy in BC and dominated in a carry-over effect even for a long period after cessation of the therapy. Prolonging survival in MBC and now also entering the EBC treatment setting, CDK4/6 inhibitors are after decades of clinical research first novel substances to revolutionize this therapy area over the coming decades [44, 45]. Global collaborative trialist’s networks are evaluating novel components in the neoadjuvant and adjuvant setting led by the motivation to overcome endocrine resistance and improving treatment adherence by minimizing treatment-associated comorbidity. Introducing MGAs and, to a certain degree, dynamic KI-67 measurement might help in reducing adjuvant chemotherapy and optimizing ET in the adjuvant and extended adjuvant setting. This remains an ongoing challenge in clinical practice for the global networking to allow new therapies in smart clinical trials for our patients on a global level to improve their outcome on a local and personal level by optimizing the local and international guidelines based on the results of those clinical trials.

The authors have no conflicts of interest to declare.

No funding was received.

Christian Jackisch and Athanasios Argyriadis contributed equally to this work.