Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

Goals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.


Material and methods
This retrospective, observational study involved postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018. A total of 11 centers across Spain participated in the study. Inclusion criteria were: Informed consent written and signed prior to any specific study of procedures (in the case of patients who died at the time of inclusion, there were no signed informed consent, so the researcher assumed responsibility for data protection and confidentiality); postmenopausal women, according to NCCN definition, i.e. those who underwent a previous bilateral oophorectomy, aged ≥ 60 years, or aged < 60 years and amenorrhea for ≥ 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, as well as follicle-stimulating hormone and estradiol 14 ; diagnosis of MBC with histological/cytological confirmation; positive hormone receptor status (ER-positive and/or PgR-positive) from primary or metastatic tumor tissue receptors; Eastern Cooperative Oncology performance status (ECOG PS) score of 0, 1 or 2 at the time of starting fulvestrant 15 ; having experienced recurrence during or after completing the adjuvant anti-estrogenic therapy; and receiving fulvestrant 500 mg as first-line, i.e. subsequently to the recurrence. Exclusion criteria included: Patients who were not available for the signature date of informed consent (in the case of patients alive at the time of study inclusion) or later than the date of baseline study; having received fulvestrant previously; having received any other therapy (different to fulvestrant) after the recurrence; previous neoplasia (other than BC or treatment for basal or squamous cell carcinoma of the skin or cervical carcinoma in situ) unless it has been treated curatively with no evidence of disease in the last 5 years; and patients with HER2-positive BC (3-positive HER2 overexpression by immunohistochemistry or positive gene amplification by fluorescence in situ hybridization or similar techniques). The status of ER and PgR was evaluated by using an immunohistochemical analysis with antibodies against ER and PgR, respectively 16 . The classification of Luminal A and B was also established according to immunohistochemistry, i.e. luminal A (ER-positive, PgR-positive, HER2-neagtive, Ki67% ≤ 20), and luminal B (other cases) 16,17 . Patients were followed-up for a minimum period of 12 months were in accordance with Declaration of Helsinki and approved by the Ethics Committee of Hospital Universitario San Cecilio (Spain).
Studied variables. The effectiveness of fulvestrant was determined in terms of PFS. The PFS was defined as the elapsed time between start of treatment with fulvestrant and disease progression or death, by any cause. Secondary endpoints included: overall survival (OS), overall response rate (ORR), duration of the response, clinical benefit rate (CBR), duration of the clinical benefit (DoCB), response to subsequent treatments, progressionfree rate (PFR), safety, and tolerability. The OS was defined as the elapsed time between start of treatment with fulvestrant and death, by any cause. At the time of data collection, data from patients who were alive without progression were censored for the survival analysis on the date of their last follow-up. The ORR was calculated as the sum of complete response (CR) and partial response (PR); whereas CBR as CR, PR and stable disease (SD) persisting for ≥ 24 weeks. The PFR was defined as the proportion of patients who remained with no disease progression or death. The AEs were reported by using the Common Terminology Criteria for Adverse Events (CTCAE) V4.0. Primary endocrine resistance was defined as the relapse occurrence while on the first 2 years of adjuvant endocrine treatment; secondary endocrine resistance as the relapse occurrence while on adjuvant endocrine treatment but after the first 2 years; and hormone-sensitive patients as the relapse occurrence after 1 year of finishing 5 years on adjuvant endocrine treatment.
Statistical analysis. Quantitative variables were expressed as median, interquartile range (IQR) or 95% CI; whereas qualitative ones as absolute and relative frequencies. Survival analyses were carried out by following Kaplan-Meier methodology. Comparison of survival curves between subgroups was performed using Logrank tests. Comparison of variables between subgroups was carried out using parametric (T test or analysis of variance, ANOVA), or nonparametric (Mann-Whitney U or Kruskal-Wallis) tests, when appropriate. Statistical significance was established when p ≤ 0.05. All statistical procedures were performed using SAS software 9.4. Ethics approval. Procedures (7); asthenia (7); gastrointestinal disorders (6); musculoskeletal and connective tissue disorders (3); blood and lymphatic system disorders (2); respiratory-thoracic and mediastinal disorders (2); headache (1); fatigue (1); tachycardia (1); nail disorder (1); and decreased appetite (1) ( Table 3). One patient died because of a serious AE (grade 5 hemoptysis) not related with the fulvestrant. Metastatic information is from the same patients with early breast cancer. ***First n (%) for primary endocrine resistance, secondary endocrine resistance and hormone-sensitive patients calculated separately; second n (%) for the combination of primary with secondary endocrine resistance, and hormone-sensitive patients; and third n (%) for primary endocrine resistance, and the combination of secondary endocrine resistance with hormone-sensitive patients.   21 .
Results from our present real-world study are in concordance with pivotal trials 12,[18][19][20][21][22] : CBR (82.8%, slightly higher than 78% in FALCON trial) 12 , DoCB (19.2 months, slightly reduced than 22.1 months in FALCON trial); PFS (14.6 months, similar to 16.6 months in FALCON trial), and OS (43.1 months, slightly reduced than 54.1 months in FIRST trial 21 . The combination of a CDK4/6inhibitor (such as palbociclib, ribociclib or abemaciclib) with endocrine therapy is the standard treatment for ER-positive/HER2-negative MBC 10 . Recent studies have demonstrated that the combination of a CDK4/6 inhibitor and fulvestrant improves OS in patients with hormone receptor-positive, HER 2-negative MBC, either after failure of endocrine therapy (and irrespective of  www.nature.com/scientificreports/ menopausal status), and as first-or second-line therapy in postmenopausal women 23,24 . Our present study provides real-world efficacy data from fulvestrant (a high CBR and PFS of 14 months) that can be useful for patients who are not candidate for receiving a CDK4/6 inhibitor, due to possible added toxicity of the inhibitor, other comorbidities, elderly fragility, or that the patient is not able of undergoing the frequent clinical and hematologic controls required for CDK4/6 inhibitors. Indeed, ESMO has recommended for the management of MBC patients during the COVID-19 pandemic that, when combining CDK4/6 inhibitors with endocrine therapies, it is needed to consider risks of neutropenia, and that the patient requires close monitoring of symptoms of infection 25,26 . And so, considering the option of postponing a line of CDK4/6 inhibitors, for bone only, low burden, de novo metastatic disease, particularly in the elderly. Therefore, nowadays, the results from our study are relevant because an important group of patients could benefit from fulvestrant in first-line of MBC treatment.
On the other hand, there are no currently clinical tools that predict which patients may benefit from diverse endocrine therapies 27 . The CONFIRM and FIRST trials also evaluated PFS according to the characteristics of patients; however, the treatment efficacy was consistent across subgroups [19][20][21] . By contrast, FALCON study revealed that visceral involvement showed a significant differentiation in PFS (fulvestrant versus anastrozole) 12 . In patients receiving fulvestrant, PFS was 22.3 months (95% CI 16.6-32.8 months) for those with non-visceral disease, and 13.8 months (95% CI 11.0-16.5 months) with visceral involvement. In our real-world study, visceral disease was not associated with a differential effectiveness of fulvestrant. Nevertheless, ECOG PS 0 at the start of treatment was associated with greater CBR and OS, compared with ECOG 1-2.
Regarding the safety profile, reported AEs were in line with observed previously in clinical trials 12,[18][19][20][21][22] . Most frequent AEs included those concerning the musculoskeletal and connective tissue, administration site, and gastrointestinal disorders. The AEs did not raise any major concerns. The main limitation of the study derived from its retrospective design; providing only available data.

Conclusion
Results in real-world settings are in concordance with previously observed in randomized clinical trials. Moreover, fulvestrant continues to demonstrate clinical benefits in real-world settings, and appears well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.