For patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HR+/HER2– MBC), both endocrine therapy (ET) and chemotherapy (CT) are effective systemic treatments. International and domestic guidelines recommend ET and ET-based regimens as the preferred treatment options for patients with HR+/HER2– MBC,[1–4] while CT is commonly used as initial first-line treatment in many countries including China.[5–8]
The results from our previous real-world study using the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) database showed that 64.7% of patients with HR+/HER2– MBC received CT as initial first-line treatment. However, more than half of these patients discontinued CT, and most switched to ET as maintenance therapy. Which treatment option provides the greater benefits in terms of progression-free survival (PFS) and overall survival (OS) remains unclear. A few randomized controlled trials and meta-analyses indicated that ET-based regimens or ET provided a superior or similar clinical outcome to CT,[9–13] but studies evaluating the efficacy of CT and ET as first-line treatment are lacking. Furthermore, there are huge unmet medical needs in optimal first-line treatment strategy for patients with HR+/HER2– MBC, particularly for those without easy access to targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.
For patients with HR+/HER2– MBC, offering CT or ET as initial first-line treatment, continuing CT or switching to ET as maintenance therapy after initial CT remain major challenges in clinical practice. Thus, we performed a real-world study using CSCO BC database to evaluate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2– MBC (Research number: CSCO BC RWS2101).
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Affiliated Hospital of Qingdao University (No. QYFYKYLL 221311920). The informed consent was waived in accordance with the institutional requirements.
Study design and patients
Details of the study design and eligibility criteria were described previously. Briefly, this was a real-world study focusing on first-line treatment of patients with HR+/HER2– MBC. Patients diagnosed with HR+/HER2– MBC between January 1st, 1996 and September 30th, 2018 were screened from the CSCO BC database. The main inclusion criteria were primary or metastatic tumors with estrogen receptor (ER) and/or progesterone receptor (PR) expression ≥10% and HER2 negative expression, and patients that had received first-line systemic treatment. The exclusion criteria were as follows: patients with missing data in first-line treatment, regional recurrence or metastasis that had been removed by surgery or radiotherapy.
We collected patients' demographic, clinical and pathological data, efficacy and safety information of first-line treatment, and subsequent treatments from inpatient and outpatient medical records of the four research centers (The Fifth Medical Centre of Chinese People's Liberation Army General Hospital, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Jiangsu Province Hospital & The First Affiliated Hospital of Nanjing Medical University, and The Affiliated Hospital of Qingdao University). Survival data was obtained from medical records and telephone follow-up of patients or their families.
The initial therapy referred to the treatment after first diagnosis of metastatic disease, while maintenance therapy referred to the treatment after at least 3 months of initial therapy without evidence of disease progression. Clinical status without disease progression included documented complete response (CR), partial response (PR) and stable disease (SD).
Distant relapse-free interval (DRFI) was defined as the time from diagnosis to relapse at a distant site, and prior (neo)adjuvant ET disease-free interval was defined as the time from the end of (neo)adjuvant ET to relapse. Progression on (neo)adjuvant ET was defined as disease progression during (neo)adjuvant ET or prior (neo)adjuvant ET disease-free interval ≤12 months. Sensitive to prior ET was defined as the receipt of at least 24 months of adjuvant ET before relapse or prior (neo)adjuvant ET disease-free interval >12 months.
The primary objective was to evaluate PFS of groups with CT and ET as initial first-line treatment (initial CT group and initial ET group). PFS was defined as the time from the start of first-line treatment to the date of first disease progression or death from any cause, whichever occurred first.
The secondary objectives were to evaluate objective response rate (ORR) and clinical benefit rate (CBR) of initial CT regimen and initial ET regimen (maintenance therapy was not included), factors associated with PFS and OS benefits from initial CT and initial ET, PFS and OS in accordance with the four initial first-line regimens (taxane-based therapy, non-taxane-based chemotherapy, ET, and ET plus targeted drugs), PFS and OS in accordance with three treatment patterns (CT cohort, continuous schedule of CT, continued CT as maintenance therapy after initial CT; CT-ET cohort, which switched to ET as maintenance therapy after initial CT; ET cohort, continuous schedule of ET, continued ET as maintenance therapy after initial ET). OS was defined as the time from the start of first-line treatment to the date of death from any cause.
Patient demographic and clinicopathologic characteristics were summarized descriptively and described as frequency distribution. Pearson chi-squared test was used to compare the differences between groups for categorical variables. The Kaplan-Meier method was used to estimate median PFS and OS; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated using univariate and multivariate Cox regression. Survival analyses between groups were performed using log-rank test. Subgroup analyses of PFS and OS were performed on baseline characteristics and potential prognostic factors.
To assess the impact of first-line treatment choice on clinical outcome, multivariate Cox regression and propensity score matching were performed to balance confounding factors between patient groups at baseline. Factors adjusted in the multivariate Cox regression model included age, HR status, DRFI, visceral involvement, progression on prior (neo)adjuvant ET, and number of metastatic sites. Patients were matched (one to one) on the logit of the propensity score using a caliper width of 0.2 of the standard deviation of the logit of the propensity score. More details about propensity score matching are provided in the supplementary materials, https://links.lww.com/CM9/B521. Baseline characteristics compared before and after propensity score matching were applied. Statistical analysis of the data was performed using SAS 9.4 (SAS Institute Inc, Cary, NC, USA). P <0.05 indicated statistical significant difference.
Patient description and baseline characteristics
A total of 1877 patients with HR+/HER2– MBC were included in this study [Figure 1]. The follow-up ended on September 30th, 2019, and the median (range) follow-up time for the total population was 36.0 (12.0–220.0) months. Among the total 1877 patients, 1215 patients (64.7%) received CT and 662 patients (35.3%) received ET as initial first-line treatment [Figure 1].
The detailed baseline characteristics of the total population and distribution of initial first-line treatment have been reported previously. Briefly, the median age at first diagnosis of MBC was 48 years, and the most common site of metastasis was bone (52.9%, 993/1877), followed by lungs (32.6%, 611/1877) and liver (20.2%, 379/1877). The most commonly used initial ET and CT regimens were aromatase inhibitors (69.0% of ET, 457/662) and taxane-based (T-based) regimen (66.1% of CT, 803/1215), respectively.
Efficacy and clinical outcome of first-line treatment in accordance with initial therapy
In patients with measurable lesions, the ORR of initial CT regimen was higher than that of initial ET regimen (47.2% [374/793] vs. 21.6% [61/282], P <0.01). In the total population, the CBR of initial ET regimen was higher than that of initial CT regimen (68.6% [454/662] vs. 44.0% [534/1215], P <0.01) [Table 1].
Table 1 -
Best overall response to the initial CT regimen and the initial ET regimen*
in patients with HR+/HER2– MBC.
Initial CT regimen (n = 1215)
Initial ET regimen (n = 662)
|Best overall response
|SD ≥6 months
*The initial CT regimen and the initial ET regimen referred to the initial treatment regimen received after the first diagnosis of MBC; maintenance therapy was not included. †Calculated in 793 and 282 patients with measurable lesions in the initial CT and ET groups, respectively. ‡Defined as CR, PR, and SD for ≥6 months. CT: Chemotherapy; CR: Complete response; ET: Endocrine therapy; HR+/HER2– MBC: Hormone receptor-positive human epidermal growth factor receptor-negative metastatic breast cancer; MBC: Metastatic breast cancer; PD: Progressive disease; PR: Partial response; SD: Stable disease.
The median PFS was 12.0 (95% CI, 10.0–12.0) months in the initial ET group and 11.0 (95% CI, 10.0–11.0) months in the initial CT group (HR 0.94; 95% CI, 0.85–1.04; P = 0.22) [Figure 2A]. PFS did not differ statistically significantly between the two groups in the propensity score matched population (n = 614 in each group) [Supplementary Table 1 and Figure 1A, https://links.lww.com/CM9/B521]. The median OS was 54.0 (95% CI, 50.0–60.0) months in the initial ET group and 49.0 months (95% CI, 46.0–52.0) in the initial CT group (HR 0.90; 95% CI, 0.79–1.02; P =0.09) [Figure 2B]. There was also no statistically significant difference in OS between the two groups after propensity score matching [Supplementary Table 1 and Figure 1B, https://links.lww.com/CM9/B521].
Subgroup analyses of PFS using clinicopathologic factors demonstrated that patients who had a prior (neo)adjuvant ET disease-free interval >12 months were more likely to benefit from initial ET vs. initial CT (HR 0.72; 95% CI, 0.57–0.92; P = 0.01) [Figure 3A]. Additionally, a marginal PFS benefit was suggested for initial ET in patients with M0 disease at first diagnosis (HR 0.90; 95% CI, 0.81–1.00; P = 0.05). None of the tested factors were significantly associated with the PFS benefiting from initial CT compared with initial ET. Subgroup analyses of OS showed that patients with M0 disease at first diagnosis were more likely to benefit from initial ET rather than initial CT (HR 0.86; 95% CI, 0.76–0.99; P =0.03). A trend of OS benefit was suggested for initial ET in patients without visceral metastasis. No factors suggested the OS benefit from initial CT [Figure 3B].
The clinicopathologic characteristics of the four initial first-line regimen groups are presented in Supplementary Table 2, https://links.lww.com/CM9/B521. PFS did not differ significantly between the ET + targeted therapy group and ET group (15.0 vs. 11.0 months, HR 0.71, P = 0.05), and between the T-based group and ET group (12.0 vs. 11.0 months, HR 0.93, P = 0.20) [Figure 2C]. The PFS in the non-T-based CT group was significantly shorter than that in the ET group (8.0 vs. 11.0 months, HR 1.25, P <0.01). Similarly, there were no statistically significant differences in OS between the ET + targeted therapy group and ET group (52.0 months vs. 55.0 months, HR 1.16, P = 0.51), and between the T-based group and ET group (55.0 months vs. 55.0 months, HR 0.94, P = 0.39). The OS in the non-T-based CT group was significantly shorter than that in the ET group (38.0 months vs. 55.0 months, HR 1.26, P <0.01) [Figure 2D].
Clinical outcome of first-line treatment in accordance with treatment patterns
In the initial CT group and initial ET group, 360 (29.6%, 360/1215) and 135 (20.4%, 135/662) patients, respectively, showed disease progression or discontinued treatment within the first three months and did not receive maintenance therapy [Figure 1]. Among the remaining patients without disease progression after at least three months of initial therapy, 449 patients (37.0%, 449/1215) switched to ET as maintenance therapy after initial CT (CT-ET cohort), 406 patients (33.4%, 406/1215) continued CT as maintenance therapy until disease progression (CT cohort), and 527 patients (79.6%, 527/662) continued ET until disease progression (ET cohort).
The clinicopathologic characteristics of the CT-ET cohort, CT cohort, and ET cohort are presented in Supplementary Table 3, https://links.lww.com/CM9/B521. In the CT-ET cohort, maintenance ET regimens used were aromatase inhibitors (75.7%, 340/449), fulvestrant (4.0%, 18/449), ET + targeted therapy (2.0%, 9/449), and others (18.3%, 82/449) [Supplementary Table 4,https://links.lww.com/CM9/B521]. The median treatment time of initial CT was 5.0 months (approximately six cycles), while the median treatment time of maintenance ET was 10.0 months in the CT-ET cohort [Supplementary Table 5, https://links.lww.com/CM9/B521].
The median PFS was 17.0 (95% CI, 15.5–19.0) months in the CT-ET cohort, 14.0 (95% CI, 13.0–16.0) months in the ET cohort, and 8.5 (95% CI, 8.0–9.0) months in the CT cohort (CT-ET cohort vs. CT cohort, HR 0.43, P <0.01; ET cohort vs. CT cohort, HR 0.49; P <0.01) [Figure 4A]. After propensity score matching, significant differences were also observed between the CT-ET cohort and CT cohort [Supplementary Table 6 and Figure 2A, https://links.lww.com/CM9/B521], and between the ET cohort and CT cohort [Supplementary Table 7 and Figure 3A, https://links.lww.com/CM9/B521].
The median OS was 62.0 (95% CI, 56.0–67.0) months in the CT-ET cohort, 61.0 (95% CI, 56.0–66.0) months in the ET cohort, and 45.0 (95% CI, 40.0–50.0) months in the CT cohort (CT-ET cohort vs. CT cohort, HR 0.66, P <0.01; ET cohort vs. CT cohort, HR 0.74; P <0.01) [Figure 4B]. After propensity score matching, significant difference still existed between the CT-ET cohort and CT cohort [Supplementary Table 6 and Figure 2B, https://links.lww.com/CM9/B521], and between the ET cohort and CT cohort [Supplementary Table 7 and Figure 3B, https://links.lww.com/CM9/B521].
Subsequent lines of treatment
Of the total 1877 patients, 1329 patients (70.8%, 1329/1877) received second-line systemic therapy after disease progression on first-line treatment and 796 patients (42.4%, 796/1877) received third-line systemic therapy [Figure 5]. In both the initial CT and initial ET groups, approximately one-third of patients received ET as second-line treatment, while half of the patients received ET as third-line treatment. T-based and aromatase inhibitors were the most common CT and ET regimens, respectively, in both second-line and third-line settings [Supplementary Table 8, https://links.lww.com/CM9/B521].
This is a multicenter real-world study focusing on the efficacy and clinical outcome of CT and ET as first-line treatment in Chinese patients with HR+/HER2– MBC. We found that clinical outcome in terms of PFS and OS did not differ significantly between patients who received ET and CT as initial first-line treatment. Interestingly, maintenance ET following initial CT and continuous schedule of ET were associated with longer PFS and OS compared with continuous schedule of CT.
Initial CT regimen was associated with higher ORR, while initial ET regimen was associated with higher CBR, which may reflect the higher discontinuation rate of CT because of adverse events and inconvenience. There were no significant differences in PFS and OS with ET and CT as initial first-line treatment, which was consistent with findings of real-world studies in other countries.[6–8] Of note, approximately half of the patients receiving initial CT switched to ET as maintenance therapy, which may have contributed to the similar clinical outcome of the two groups. Additionally, the number of patients receiving ET plus targeted drugs, which is the most effective ET-based regimen, was small. Compared with other subtypes of breast cancer, HR+/HER2– breast cancer is less sensitive to CT.[16,17] While we observed a higher ORR with CT, the superiority did not translate into prolongation of PFS. The estrogen receptor signaling pathway is the main driver of cancer cell growth and survival in HR+/HER2– breast cancer.[13,17] Therefore, ET has a reasonable chance of providing considerable disease control for these patients.[2,18,19]
Subgroup analyses showed that factors indicating endocrine-sensitive and slow disease progression, such as prior (neo)adjuvant ET disease-free interval >12 months and M0 disease at first diagnosis, were predictors of PFS benefit from initial ET, while M0 disease at first diagnosis was the only predictor of OS benefiting from initial ET. Surprisingly, none of the factors tested, including multiple metastasis and visceral disease, were associated with OS benefiting from initial CT. These results indicated that ET and ET-based regimen should be recommended as the preferred first-line treatment, especially for patients with endocrine-sensitive tumor and slow disease progression.
There are many factors influencing the clinical outcome of MBC, including clinical and pathological features, sensitivity to treatment, first-line and subsequent lines of treatment, physical conditions, and other non-medical factors such as socioeconomic factors. In general, CT is associated with a rapid onset of action and increased frequency of adverse reactions, while ET is associated with less toxicity, greater satisfaction with treatment, and better quality of life.[12,20] The decrease in physical function and complications caused by CT may have negative effects on clinical outcome. In our study, there was no statistically significant difference in clinical outcome with ET and CT as initial first-line treatment, highlighting that clinical application of ET and ET-based regimen should be appropriately expanded in first-line treatment.
In our analysis of the four initial first-line regimens, there were no differences in PFS between patients treated with ET and ET plus targeted drugs, and between patients treated with ET and T-based regimen. The comparative analysis of OS in the four regimens yielded similar results as PFS. The PFS of the ET plus targeted drugs and ET groups did not differ significantly, probably because the number of patients receiving ET plus targeted drugs was too small. Of note, targeted drugs included CDK4/6 inhibitors, everolimus and tucidinostat, and among the 53 patients treated with ET plus targeted drugs, 39 had progressed on prior adjuvant ET. The non-T-based CT regimen was associated with the shortest PFS and OS among the four regimens. According to guidelines,[1,3] T-based regimen is recommended as the preferred CT for patients with MBC. Our study revealed that even after 2010, there was a considerable number of patients receiving non-T-based CT regimen as first-line treatment without evidence of taxane drug resistance. These inappropriate treatment options were inconsistent with guidelines and led to a worse clinical outcome.
In the efficacy analysis of first-line treatment pattern, which excluded patients with rapid disease progression and discontinuation within three months, the median PFS was longer in CT-ET cohort and ET cohort than that in CT cohort in both the total and propensity score matched populations, and the PFS benefit translated into a significant prolongation of OS. The inherent sensitivity of HR+/HER2– MBC to ET and the exclusion of patients with rapid disease progression may allow the efficacy of ET to be more clearly demonstrated, possibly explaining the improved survival observed in the ET cohort compared with the CT cohort.
Evidence for maintenance therapy after initial CT is scarce. Whether patients should switch to another regimen or choose one drug from the initial therapy as maintenance therapy is unclear. In the phase III AROBASE trial, the PFS of patients who received maintenance exemestane plus bevacizumab therapy did not improve compared with those who continued taxane and bevacizumab after first-line taxane and bevacizumab combination therapy. Wang et al reported in the randomized controlled trial OVERSTEP that maintenance ET was superior to maintenance CT in PFS after first-line CT (17.7 months vs.12.2 months, P = 0.01), especially in endocrine-sensitive and non-visceral metastasis populations. The single arm study FANCY showed that maintenance therapy with fulvestrant after first-line CT was effective and well tolerated in patients with HR+/HER2– MBC. The sequential use of maintenance ET after initial CT, a commonly used treatment pattern, combines the advantages of rapid response of initial CT, better tolerance and considerable effectiveness of maintenance ET, leading to a better clinical outcome.[2,12,20,25,26] In our study, more than half of patients with non-progressive disease switched to ET as maintenance therapy after a median of six cycles of CT, and the PFS benefit of CT-ET translated into prolongation of OS.
There are considerable medical needs for an optimal first-line treatment in patients with HR+/HER2– MBC, which is the most common type of MBC. In our previous study, single-agent ET was commonly used in patients with evidence of ET resistance. Several randomized controlled trials have proven the efficacy of ET plus targeted drugs such as CDK4/6 inhibitors and histone deacetylase inhibitor tucidinostat in patients with HR+/HER2– MBC.[14,27–30] However, these targeted drugs were not widely used because of high costs and inaccessibility during the study enrollment stage. CT is an option for patients requiring rapid remission, such as those with de novo stage IV disease and visceral crisis in some urgent cases.[2,26] If best overall response reaches objective response or stable disease during initial CT, switching to ET as maintenance therapy may offer a more favorable outcome than continuing CT until disease progression.
Our study was subject to the limitations inherent in retrospective and observational research. Clinical characteristics and treatment regimens varied over years because of the large time span of the study. Although propensity score matching was used to minimize bias when assessing differences in PFS and OS between the two groups, the results should be interpreted cautiously because of imbalances in baseline characteristics. Moreover, quality of life and health economics data, which may show advantages with ET, were not available. In our study, only 53 patients received ET plus targeted drugs, which is the preferred treatment for HR+/HER2– MBC. However, in the absence of randomized controlled studies comparing ET with CT as initial and maintenance therapy, this real-world study provides important information on the clinical outcome of CT and ET as first-line treatment for patients with HR+/HER2– MBC.
This real-world study offers an insight into the first-line treatment strategy for Chinese patients with HR+/HER2– MBC. Our study showed that there were no significant differences in PFS and OS between ET and CT as initial first-line treatment, which suggested that we should adhere to guidelines strictly and offer ET or ET-based regimen as the preferred first-line treatment for patients with HR+/HER2– MBC, especially for patients with endocrine-sensitive and slow disease progression. For patients without disease progression after initial CT, switching to maintenance ET provided superior clinical outcome to continuing CT until disease progression. Our findings may help clinicians make appropriate treatment recommendations for patients with HR+/HER2– MBC.
We thank doctors at the four research centers for their support and assistance. We would like to thank all patients and their family members for supporting our study. We thank Dr. Yingjian He from Beijing Cancer Hospital for reviewing the statistical analysis and Gabrielle White Wolf, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of this manuscript.
This study was supported by research and development project of medical data and artificial intelligence in Chinese PLA General Hospital (Grant No. 2019MBD-056).
Conflicts of interest
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