Although combining aromatase inhibitors (AI) with gonadotropin-releasing hormone agonists (GnRHa) is becoming more common, it is still not clear if GnRHa is as effective as bilateral salpingo-oophorectomy (BSO).
We retrospectively analyzed data of 66 premenopausal patients with hormone receptor– positive, human epidermal growth factor receptor 2–negative recurrent and metastatic breast cancer who had been treated with AIs in combination with GnRHa or BSO between 2002 and 2015.
The median patient age was 44 years. Overall, 24 (36%) received BSO and 42 (64%) received GnRHa. The clinical benefit rate was higher in the BSO group than in the GnRHa group (88% vs. 69%, p=0.092). Median progression-free survival (PFS) was longer in the BSO group, although statistical significance was not reached (17.2 months vs. 13.3 months, p=0.245). When propensity score matching was performed, the median PFS was 17.2 months for the BSO group and 8.2 months for the GnRHa group (p=0.137). Multivariate analyses revealed that the luminal B subtype (hazard ratio, 1.67; 95% confidence interval [CI], 1.08 to 2.60; p=0.022) and later-line treatment (≥ third line vs. first line; hazard ratio, 3.24; 95% CI, 1.59 to 6.59; p=0.001) were independent predictive factors for a shorter PFS. Incomplete ovarian suppression was observed in a subset of GnRHa-treated patients whose disease showed progression, with E2 levels higher than 21 pg/mL.
Both BSO and GnRHa were found to be effective in our AI-treated premenopausal metastatic breast cancer patient cohort. However, further studies in larger populations are needed to determine if BSO is superior to GnRHa.
Although bilateral salpingo-oophorectomy (BSO) has been used as a therapeutic option in hormone receptor (HR)–positive premenopausal women, this method has largely been replaced with suppression of ovarian function via gonadotropin-releasing hormone agonist (GnRHa). Combination therapy using the aromatase inhibitors (AI) and GnRHa is an increasingly common strategy in current clinical practice [
There are definite concerns associated with GnRHa and incomplete ovarian suppression. Furthermore, the addition of AIs may lead to an increase in estrogen synthesis and therefore have a negative impact on treatment outcomes. A study investigating the effects of the adjuvant leuprorelin in premenopausal patients revealed a hormonal escape rate of 7%, with the cutoff estradiol (E2) value being 30 pg/mL [
We retrospectively analyzed a database of consecutive recurrent/metastatic breast cancer patients who were treated with AIs and either GnRHa or BSO between January 2002 and December 2015 at Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH). The inclusion criteria was as follows: (1) pathologically confirmed breast cancer; (2) positive estrogen receptor (ER) and/or progesterone receptor (PR) expression; (3) premenopausal state; (4) initial stage IV or recurrence after curative surgery; (5) use of oral letrozole (2.5 mg/day) or oral anastrozole (1 mg/day) as palliative endocrine therapy; and (6) OFS with BSO or GnRHa injected subcutaneously every 4 weeks. Patients without evaluable disease were excluded. Premenopausal status was defined by regular menstruation periods or serum estradiol (E2) levels and/or follicle-stimulating hormone (FSH) levels within the premenopausal range. E2 and FSH levels were determined via chemiluminescent microparticle immunoassay, which was conducted using the ARCHITECT i2000 Immunoassay Analyzer (Abbott Diagnostics, Abbott Park, IL). The measurement range was 10 to 5,000 pg/mL for E2 and 0 to 750 mIU/mL for FSH. Premenopausal levels were defined (based on the assay reference ranges) as an FSH value less than 26.72 mIU/mL and an E2 value greater than 21 pg/mL. For patients who underwent BSO, premenopausal status before BSO was used as a surrogate.
Immunohistochemical staining for ER and PR expression was categorized as positive when ≥ 1% of the tumor cells were stained according to the 2010 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines [
Clinical data were retrieved from patient medical records. The Institutional Review Boards at SNUH and SNUBH approved this study (B-1603/338-108), and it was conducted in accordance with the Declaration of Helsinki.
Chest computed tomography scans (with or without the abdominopelvis) were performed every 8 to 12 weeks as a routine clinical procedure, and additionally when needed, to confirm patient response and assess disease progression. All responses were defined according to the revised Response Evaluation Criteria in Solid Tumors ver. 1.1. PFS was defined as the interval from the first day of AI treatment to either the date of disease progression or death. The objective tumor response rate (ORR) was defined as the total proportion of patients who achieved complete response (CR) or partial response (PR). CBR was defined as the percentage of patients with CR, PR, or stable disease (SD) after 6 months.
The chi-square test was used to evaluate associations between clinicopathological attributes based on OFS modality. PFS was calculated using the Kaplan-Meier method and the values were compared using the log-rank test. Univariate Cox proportional hazard regression (PHR) analyses were performed to evaluate the predictive value of each variable, and those found to be significant upon univariable analysis were introduced into the multivariable Cox PHR model for disease-free survival (DFS). Because of the retrospective nature of this study, we conducted propensity score matching to evaluate the efficacy of BSO and GnRHa. The propensity for each patient to undergo BSO or receive GnRHa was scored using multivariable logistic regression based on three variables that affected the PFS. All tests were two-sided, and a p-value of less than 0.05 was used to indicate statistical significance. All analyses were performed using SPSS ver. 21 (IBM Corp., Armonk, NY) and GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA) based on data collected through July 2016.
The database identified 66 premenopausal patients with HR-positive recurrent or metastatic breast cancer who had been treated by AI and GnRHa or BSO combination therapy. The clinical characteristics of the 66 patients are shown in
In the BSO group, six patients achieved PR (25%) and 16 reached SD (67%), with 15 (63%) having SD for a period longer than 6 months. In the GnRHa group, one patient achieved CR (2%), six reached PR (14%), and 29 patients experienced SD (69%), with 22 (50%) having SD for longer than 6 months. The ORR was similar between groups (25% for BSO vs. 16% for GnRHa, p=0.413), while the CBR was higher in the BSO group than in the GnRHa group (88% vs. 69%, p=0.092). Median PFS was shorter in the GnRHa group (median, 17.2 months vs. 13.3 months), although this difference was not statistically significant (p=0.245).
At the time of analysis, 39 patients in the GnRHa group experienced disease progression. Sixteen of these patients received cytotoxic chemotherapy, two were enrolled in clinical trials, and six had either died or were loss to follow-up. The remaining 16 patients underwent hormone therapy. Among them, eight patients (50%) underwent BSO and received letrozole (n=2; one patient experienced disease progression after 3.5 months of treatment, the other is still on treatment for 3 months), fulvestrant (n=2; one patient experienced disease progression after 12 months of treatment, the other is still on treatment for 8 months), and exemestane plus everolimus (n=4; patients experienced disease progression at 1.5, 10, 13, and 13 months, respectively). Additionally, three patients received GnRHa alone or in combination with fulvestrant or tamoxifen; however, all patients experienced disease progression within 2 months of treatment. Five patients became postmenopausal after receiving cytotoxic chemotherapy and then received endocrine treatment again (anastrozole [n=1], disease progressed after 4 months of treatment; exemestane [n=3], disease progressed after 2, 4, and 5 months, respectively; fulvestrant [n=1], disease progressed after 1.5 months of treatment).
In the 39 patients who were diagnosed with visceral metastasis, the median PFS was longer in the BSO group than in the GnRHa group, although this was not statistically significant (17.2 months vs. 12.9 months, p=0.261) (
In the 20 patients who received AI plus OFS as the first-line treatment, the median PFS was 22.4 months in the BSO group (n=9) and 14.3 months in the GnRHa group (p=0.741). In patients who received second-line AI treatment (n=26) the median PFS was 12.9 months in the BSO group (n=11) and 8.6 months in the GnRHa group (n=15) (p=0.288). For patients who received AIs as a third-line, or above, treatment (BSO, n=4; GnRHa, n=16), the median PFS was shorter in the BSO group than the GnRHa group (2.5 months vs. 8.2 months, p=0.047).
We conducted univariate and multivariate analyses to identify the predictive and prognostic importance of clinical characteristics. We also used these analyses to identify the OFS modality in premenopausal AI-treated breast cancer patients. Univariate Cox PHR analyses for PFS revealed no significant differences with respect to age, type of AI, pathological subtype, disease status, or the extent of disease at the time of AI treatment. However, PFS was shorter in luminal B subtype tumors (p=0.041), and in patients who received later-line AI treatments (p=0.002) (
Variables that were found to be significantly predictive in the univariate analyses were introduced into a multivariate Cox PHR model. Multivariate analyses revealed that luminal B subtype (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.08 to 2.60; p=0.022) and later-line AI treatment (≥ third line vs. first line; HR, 3.24; 95% CI, 1.59 to 6.59; p=0.001) were significant independent predictive factors for shorter PFS (
We used propensity score matching to compare the effects of BSO and GnRHa. To minimize the bias caused by nonrandom allocation of BSO and GnRHa, we developed a matching scheme that included variables shown to be associated with PFS in our analyses. We included the following domains: intrinsic subtype, the extent of disease at the time of AI treatment, and line of treatment. We then used propensity score matching to match the 18 patients (75% of the relevant group) who received BSO to the 18 patients (43% of the relevant group) who received GnRHa. With the exception of age, there were no significant differences in clinicopathological variables between groups (
Of the 42 patients who were treated with AI and GnRHa, 36 (86%) had at least one sample drawn for FSH and E2 measurement.
At the time of analysis, 39 patients in the GnRHa group experienced disease progression. Among these, 19 patients (49%) were assessed for FSH and E2 levels at the time of disease progression. The results revealed that 16 of these patients had baseline FSH and E2 levels, while 10 had postmenopausal E2 levels (range, < 10 to 17 pg/mL), and an increase in serum E2 levels (into the premenopausal range) was observed in the remaining nine patients (range, 25 to 209 pg/mL).
Three patients underwent combined AI/GnRHa treatment at the time of analysis. Of these patients, two showed postmenopausal E2 levels, and one patient, whose treatment lasted for 7.4 months, showed an elevated E2 level at 3 months (87 pg/mL at baseline to 105 pg/mL at 3 months).
We found that both BSO and GnRHa function as active treatments in AI-treated HR(+) premenopausal advanced breast cancer patients. Both also had a statistically similar PFS in such patients. However, BSO had a numerically higher CBR (88% vs. 69%, p=0.092) and longer PFS (17.2 months vs. 13.3 months, p=0.245), even after propensity score matching (median PFS, 17.2 months vs. 8.2 months; p=0.137). Assay of 19 of the 39 patients who showed disease progression in the GnRHa group for FSH and E2 expression at the time of disease progression revealed that approximately half of the tested GnRHa-treated patients (n=9) showed evidence of incomplete ovarian suppression, with E2 expression similar to premenopausal levels.
Since the 1990s, BSO has been largely replaced by GnRHa in premenopausal HR(+) breast cancer patients. Early studies indicated that medical castration with GnRHa was well-tolerated, and that the ORR for such a treatment ranged between 36.4% and 45.9% in premenopausal and perimenopausal metastatic breast cancer patients [
Because of its comparable efficacy, lack of operative morbidity, and avoidance of psychological trauma, GnRHa has mostly replaced BSO, and has even been adopted as the standard method of OFS in AI or fulvestrant-treated premenopausal patients. Despite this, no studies conducted to date have directly compared the efficacy of BSO and GnRHa when used in combination with AIs. Nevertheless, studies have gauged the effectiveness of AI and GnRHa combination treatment. For example, Carlson et al. [
Since AIs are contraindicated in premenopausal patients because of the possible reactivation of ovarian functions, the capacity of GnRHa to induce OFS has become a far more important issue. Recent trials combining adjuvant AIs with GnRHa in premenopausal patients have attempted to look into this matter. Both the Suppression of Ovarian Function Trial (SOFT) and the combined analysis of the SOFT and the Tamoxifen and Exemestane Trial (TEXT) reported that, when compared to a combination of tamoxifen and OFS, combined exemestane plus OFS therapy showed higher 5-year DFS rates. However, this did not translate into an increase in OS in the exemestane/OFS group [
There are multiple endocrine treatment options for postmenopausal advanced breast cancer patients, such as fulvestrant [
Information describing cost-effectiveness and quality-of-life (QoL) may allow physicians and patients to make more informed decisions regarding therapeutic approaches. However, there is limited data directly comparing the toxicity and QoL factors associated with surgical and medical ovarian suppression in premenopausal patients. Boccardo et al. [
Another important finding of our study is that later-line AI treatment and luminal B subtype were independent predictive factors for short PFS in premenopausal patients treated with AI. Since there are biological differences between the luminal A and B subtypes, a possibility of differences in their response to AI has been suggested. However, there is little data available regarding the relevance of biomarkers or breast cancer subtype to response to AIs. In a neoadjuvant study of AI in postmenopausal patients, there were no significant differences in AI response rates between luminal A and B subtypes [
It should be noted that our study had several limitations. First, our study only involved a small number of patients from two Korean institutions. Therefore, it does not provide a global, accurate, or complete perspective of the treatment outcomes of AI-treated premenopausal patients. Second, our data is limited due to the heterogeneous time points used to determine patient hormone levels. Third, patients were treated with AIs at heterogeneous time points, which resulted in a higher proportion of patients in the GnRHa group having later-line treatments (≥ 3rd line). However, this heterogeneity was adjusted for the propensity score matched cohort, and the difference in median PFS was even more accentuated, favoring BSO over GnRHa. Finally, toxicity and QoL assessment could not be conducted owing to the retrospective design of this study.
In conclusion, we demonstrated that both BSO and GnRHa were found to be effective in premenopausal HR(+) AI-treated advanced breast cancer patients. However, BSO patients had a higher CBR and a longer PFS. Evidence of incomplete ovarian suppression was also observed in a subset of patients treated with GnRHa. These results may be useful when selecting the OFS modality for premenopausal advanced breast cancer patients. However, further studies in a larger population are needed to determine if BSO is truly superior to GnRHa.
Supplementary materials are available at Cancer Research and Treatment website (
T.Y. Kim has received a speaker honorarium from Roche. S.A. Im received a research fund from AstraZeneca, and has uncompensated advisory roles for Novartis, Spectrum and Hanmi. None of the other authors have any potential conflicts of interest.
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (2015R1A2A2A01004655).
Kaplan-Meier plots of progression-free survival (PFS) based on ovarian function suppression modality. BSO, bilateral salpingo-oophorectomy; GnRHa, gonadotropin-releasing hormone agonists.
Kaplan-Meier plots of progression-free survival (PFS) with propensity score matching according to ovarian function suppression modality. BSO, bilateral salpingooophorectomy; GnRHa, gonadotropin-releasing hormone agonists.
The line charts show the individual changes in estradiol (E2) (A) and follicle-stimulating hormone (FSH) (B) between baseline and at progression in patients treated with aromatase inhibitors and gonadotropin-releasing hormone agonist. The value of same individuals on each graphs are marked with same symbols. Only patients with increased E2 levels compared to baseline are marked.
Patient characteristics
Variable | No. (n=66) | OFS modality |
p-value | |
---|---|---|---|---|
BSO (n=24) | GnRHa (n=42) | |||
47 (36-53) | 43 (29-56) | 0.019 | ||
IDC | 61 | 22 (92) | 39 (93) | 0.860 |
Others | 5 | 2 (8) | 3 (7) | |
Luminal A | 30 | 13 (54) | 17 (41) | 0.498 |
Luminal B, HER2 negative | 24 | 8 (33) | 16 (38) | |
Unknown | 12 | 3 (13) | 9 (21) | |
MBC at primary diagnosis | 26 | 8 (33) | 18 (43) | 0.446 |
Recurred | 40 | 16 (67) | 24 (57) | |
40 | 16 (67) | 24 (57) | 0.446 | |
38 | 14 (58) | 24 (57) | 0.400 | |
26 | 11 (69) | 15 (63) | 0.692 | |
37 | 15 (63) | 22 (52) | 0.714 | |
Tamoxifen | 28 | 12 (50) | 16 (38) | |
Tamoxifen+GnRHa | 8 | 3 (13) | 5 (12) | |
AI |
1 | 0 | 1 (2) | |
42.5 (16.8-102.0) | 45.0 (10.5-110.7) | 0.986 | ||
No | 35 | 16 (67) | 19 (45) | 0.093 |
Yes | 31 | 8 (33) | 23 (55) | |
No | 34 | 12 (50) | 22 (52) | 0.852 |
Yes | 32 | 12 (50) | 20 (48) | |
Tamoxifen | 12 | 3 (13) | 9 (21) | |
Tamoxifen+GnRHa | 15 | 5 (21) | 10 (24) | |
GnRHa | 3 | 3 (13) | 0 | |
AI |
2 | 1 (4) | 1 (2) | |
Letrozole | 61 | 24 (100) | 37 (88) | 0.150 |
Anastrozole | 5 | 0 | 5 (12) | |
Bone and soft tissue only | 27 | 10 (42) | 17 (41) | 0.925 |
Visceral metastasis | 39 | 14 (58) | 25 (59) | |
1st line | 20 | 9 (38) | 11 (26) | 0.187 |
2nd line | 26 | 11 (46) | 15 (36) | |
≥ 3rd line | 20 | 4 (17) | 16 (38) |
Values are presented as median (range) or number (%). OFS, ovarian function suppression; BSO, bilateral salpingoophorectomy; GnRHa, gonadotropin-releasing hormone agonist; AI, aromatase inhibitor; IDC, infiltrating ductal carcinoma; IHC, immunohistochemistry; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; RFI, relapse-free interval.
AI due to chemotherapy-induced amenorrhea.
Univariate and multivariate analysis on PFS
Variable | Univariate |
Multivariate |
||
---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | |
20-39 | 1 | - | ||
40-49 | 0.95 (0.50-1.77) | 0.859 | - | |
≥ 50 | 1.05 (0.42-2.62) | 0.918 | - | - |
BSO | 1 | - | ||
GnRHa | 1.41 (0.79-2.55) | 0.249 | - | - |
IDC | 1 | - | ||
Others | 0.64 (0.22-1.80) | 0.394 | - | - |
Luminal A | 1 | 1 | ||
Luminal B | 1.59 (1.02-2.49) | 0.041 | 1.67 (1.08-2.60) | 0.022 |
MBC at primary Dx | 1 | - | ||
Recurred | 0.82 (0.47-1.42) | 0.468 | - | - |
Bone/Soft tissue | 1 | - | ||
Visceral | 1.48 (0.85-2.58) | 0.168 | - | - |
Letrozole | 1 | - | ||
Anastrozole | 2.39 (0.83-6.88) | 0.107 | - | - |
1st line | 1 | 1 | ||
2nd line | 1.51 (0.77-2.98) | 0.232 | 1.73 (0.87-3.44) | 0.120 |
≥ 3rd line | 3.01 (1.48-6.13) | 0.002 | 3.24 (1.59-6.59) | 0.001 |
PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; AI, aromatase inhibitor; OFS, ovarian function suppression; BSO, bilateral salpingoophorectomy; GnRHa, gonadotropin-releasing hormone agonist; IDC, infiltrating ductal carcinoma; MBC, metastatic breast cancer; Dx, diagnosis.