Introduction
In the United States, approximately 60-70% of women with advanced breast cancer (aBC) are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) [
1‐
3]. Resistance to treatment, acquisition of novel mutations, and altered gene expression are the major challenges in the management of aBC [
4,
5]. There are established guidelines for first-line treatment of these patients, but a consensus has not yet been reached regarding the choice of second-line treatment [
6].
Endocrine therapy (ET), with either fulvestrant (Fulv) or aromatase inhibitors (AIs), plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the recommended first-line standard of care for patients with HR+/HER2- advanced breast cancer [
7]. Compared with endocrine monotherapy, the combination can obtain a higher response rate and progression-free survival benefit [
8‐
10]. However, the development of resistance to the treatment of aBC is frequent, and its treatment is primarily palliative [
11] In general, there are three main strategies after the failure of CDK4/6i treatment: diversion to chemotherapy, endocrine therapy alone, or combined targeted therapy [
12‐
14]. Currently, there are no recommended guidelines for the optimal ranking of these options. In any case, ET is still an important treatment strategy.
Estrogen receptor 1 mutations (ESR1m) are one of the common mechanisms of endocrine resistance, accounting for up to 36% of metastatic breast cancers [
15,
16]. Selective estrogen receptor degraders (SERDs) can bind to estrogen receptors and induce their degradation [
17,
18] and are considered one of the main ways to address endocrine resistance. Fulvestrant, as an intramuscular SERD, is not only the first-line or second-line treatment option for HR+/HER2- aBC [
19,
20] but is also a choice for patients with ESR1m, who are still sensitive to it [
15,
21,
22]. In recent years, oral SERDs, with their higher bioavailability and pharmacokinetics, have been continuously developed to address the limitations of fulvestrant intramuscular formulations [
23]. However, the value of oral SERDs in patients with HR+/HER2- advanced breast cancer remains controversial. EMERALD [
24] and SERENA-2 [
25] showed positive results, while the other two clinical trials, AMEERA-3 [
26] and acelERA [
27], failed the study endpoints.
In the present meta-analysis, we aimed to assess the value of oral SERDs in patients with HR+/HER2- advanced breast cancer after progression on ≥ 1 line of endocrine therapy.
Discussion
Our study showed that the oral SERD regimen was superior to standard-of-care ET in patients with HR+/HER2- advanced breast cancer after progression on ≥ 1 line of ET. However, the characteristics of these patients were complex, so it is crucial to select the characteristics of those patients who are likely to have sustained benefits.
Patients with ESR1m develop resistance to ET and exhibit worse overall survival [
32‐
34]. Our meta-analysis showed that for patients with ESR1 mutations, outcomes in the arms of oral SERDs were significantly better than those in the arms of standard-of-care ET. Surprisingly, in these four clinical trials, oral SERDs were able to provide PFS benefits in ESR1m patients. In addition, patients with ESR1m showed a trend of OS improvement in Elacestrant (HR = 0.59;
p = 0.03). AIs not only enhance the acquisition of ESR1 mutations in aBC, but patients with ESR1 mutations also showed a worse prognosis in AI treatment [
35]. However, patients with ESR1 mutations remained sensitive to fulvestrant [
15,
21,
22]. As an intramuscular SERD, fulvestrant binds to estrogen receptors and induces their degradation, [
17,
18] so it still plays a role in patients with ESR1 mutations. A pooled analysis of patients with ESR1 mutations in the EFECT and SoFEA trials (115/383) found no significant difference in PFS in the Fulv group (3.9 months versus 4.1 months) [
36‐
38]. However, the clinical utilization of Fulv is limited by its intramuscular formation. In the Elacestrant and SERENA-2 trials, the arms of oral SERDs were significantly better than the arms of fulvestrant (HR: 0.47, p < 0.00001). In addition, its better bioavailability and patient preference for oral medication may lead to better compliance. Patient tolerability of the drug also needs to be considered. The overall toxicity of oral SERDs was found to be greater in our analysis. However, considering that a proportion of patients in the control arms were on AI and tamoxifen regimens, the toxicity of AIs and tamoxifen was lower than that of Fulv [
39‐
41]. Therefore, this does not mean that oral SERDs are more toxic than Fulv. Moreover, treatment resistance to Fulv leading to disease progression remains a major concern for HR+/HER2- aBC. Therefore, both additional endocrine therapy and effective combination therapy are clinically necessary [
15,
16]. Data from the Elacestrant and acelELA trials also support oral SERD regimens for patients who failed Fulv therapy. Thus, oral SERDs are recommended in HR+/HER2- ESR1m aBC after ET ≥ 1 line progression, and oral SERDs could be a potential replacement for Fulv.
For HR+/HER2- aBC patients who progressed after first-line treatment with ET combined with CDK4/6i, the oral SERD regimen also had a statistically significant PFS benefit. In the event of disease progression during the use of CDK4/6is, ET-based regimens remain an appropriate option [
12,
13]. Patients' menopausal status, tolerance to drugs, and previous treatment regimens will affect the subsequent selection of endocrine agents [
42]. These enrolled patients had previously used one or two ET regimens, so it is still necessary to find new endocrine agents. Camizestrant therapy may be a new option for these patients. The median PFS in the oral SERDs group was 7.2 (75 mg) and 7.7 (150 mg) months, respectively, while that in the Fulv group was only 3.7 months. Even in the subgroup with previous use of CDK4/6i, there was a significant improvement in PFS [median PFS 5.5 (75 mg) and 3.8 (150 mg) months vs. 2.1 months]. However, the absolute benefit in Elacestrant was very small (median PFS 2.8 months vs. 1.9 months). In ESR1m aBC patients previously treated with CDK4/6i for ≥12 months, elacestrant had a median PFS of 8.6 months and SOC of 2.1 months, which was a clinically and statistically significant improvement. This suggests that a possible indication for elacestrant may be the duration of previous CDK4/6i [
43]. In addition, in those patients with visceral metastasis, oral SERDs also showed advantages (HR: 0.60,
P < 0.00001). Endocrine therapy is the preferred option for HR+ breast cancer patients even in the presence of visceral metastases [
44]. Compared with endocrine monotherapy, the combination can obtain a higher response rate and progression-free survival benefit [
45]. Chemotherapy is recommended for patients with visceral crisis. However, chemotherapy is more toxic and causes many side effects in patients [
46]. In contrast, oral SERDs show better efficacy in patients with visceral metastasis and can also reduce the serious side effects caused by chemotherapy.
EMERALD and SERENA-2 showed positive results in these four randomized controlled trials, while the other two trials, AMEERA-3 and acelERA, failed the study endpoints. Due to the heterogeneity of enrolled patients and differences in control settings, indirect cross-comparisons between different trials should be undertaken with caution. First, prior treatment regimens after disease progression varied across the four trials. In the SERENA-2 trial, 31.3% of patients had previously not received ET in the advanced setting, whereas in the other three trials, patients had previously received at least one or two lines of ET. Studies have shown that monotherapy with Fulv had advantages in PFS compared to aromatase inhibitors or tamoxifen monotherapy [
47,
48]. In the control arm of AMEERA-3 and acelERA, the proportion of patients treated with Fulv was higher (89.8% and 75%, respectively), which may have resulted in prolonged mPFS in the control group. In addition, all patients in the SERENA-2 control group received Fulv, but previous Fulv was not permitted for aBC patients. In EMERALD, however, 30.4% of patients had previously been treated with Fulv; in AMEERA-3, the corresponding value was 9.7%, and in acelERA, it was 26.19%.
Our study is the first to evaluate the value of oral SERDs in patients with HR+/HER2- aBC after progression on ≥ 1 line of endocrine therapy. The characteristics of the population that may benefit are also analysed. Especially for patients with ESR1m, oral SERDs are advantageous. Further screening of advantaged oral SERD groups for stratified treatment is the future development trend. The value of SERDs may not be limited to patients in advanced settings. Studies such as CAMBRIA-1 [
49] are being conducted to assess the potential of oral SERDs in early-stage breast cancer. In addition, oral dosage forms are more convenient. This can save manpower and material resources to a certain extent, and the compliance of patients will be better. It is believed that it will have good application prospects. There are several limitations to our study. First, this was not a network meta-analysis, and we could not directly compare all drugs or drug combinations with each other. As a result, a certain degree of precision was lost. In addition, we could not evaluate the overall survival (OS) benefit due to the unavailability of data. Although OS is the "gold standard" for efficacy evaluation in cancer clinical research, it has certain limitations in practical application. OS as the primary endpoint requires a large sample size, and clinical development is difficult. It is affected by death from nontumour causes. For tumour types with long survival, the duration of the study is extremely long. Therefore, alternative end points are often used for those patients with long survival, and the FDA currently supports the use of PFS as an end point. However, these limitations are unavoidable at present. At present, there are relatively few studies on oral SERDs, and it is hoped that more clinical trials will follow to confirm our experiments.
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