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Introduction

Breast cancer is the most frequent cancer among women worldwide (1). The proportion of patients with breast cancer, who were younger than 50 years appears to be higher in Asian women compared with Western women (2). In Thailand, more than one-half of patients with breast cancer were diagnosed at an age younger than 50 years (3,4). In total, ~54% of breast cancer is hormone receptor-positive and the proportion is decreased in younger patients (3,5).

Endocrine therapy, either alone or after chemotherapy, is the most important treatment in hormone receptor-positive breast cancer. Blockage of the oestrogen receptor (ER) and its pathways is a key approach for the treatment of hormone receptor-positive breast cancer (6). Tamoxifen (TAM) is a standard endocrine therapy, especially in premenopausal women (7). In post-menopausal women, administration of aromatase inhibitors results in better survival compared with TAM (8,9). Ovarian ablation plus chemotherapy resulted in improved long-term survival in ER-positive early breast cancer (10). When comparing the cyclophosphamide, methotrexate and fluorouracil regimen (CMF) of chemotherapy with ovarian ablation/suppression, there was no difference in terms of survival in hormone receptor-positive early breast cancer (11–16). However, to the best of our knowledge, at present, there is no randomised controlled trial that has compared ovarian function suppression and TAM with the adriamycin and cyclophosphamide (AC) regimen of chemotherapy. The addition of ovarian function suppression to TAM in women who were premenopausal after chemotherapy resulted in a better disease outcome (17).

The present study aimed to compare disease-free survival (DFS) and overall survival (OS) in patients with early breast cancer who received gonadotropin-releasing hormone (GnRH) agonist-TAM (GnRH-TAM) alone compared with those who received chemotherapy followed by TAM (AC-TAM).

Patients and methods

Patients

Female patients with breast cancer who were treated at The Division of Head Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University (Bangkok, Thailand) between January 2005 and December 2015 were recruited. The inclusion criteria were premenopausal status, tumour size ≤3 cm, node-negative, no distant metastasis, hormone receptor-positive and did not receive neoadjuvant treatment. The patients who rejected adjuvant chemotherapy received GnRH-TAM were recruited in the GnRH-TAM group. The patients who received AC-TAM were recruited in the AC-TAM group. The patients with incomplete clinicopathological data were excluded. Medical records of the eligible patients were reviewed. Premenopausal status was defined as those who had menstruated within 1 year before surgery or had a follicle-stimulating hormone level <30 IU/ml. All of the patients who received GnRH-TAM without adjuvant chemotherapy were included. The patients who received standard AC-TAM with comparable demographic and clinicopathological parameters were recruited. The tumor grade was classified according to Elston/Nottingham modification of the Bloom-Richardson System (18,19). The follow-up time was 36–167 months with a median follow-up of 77 months. The sample size was calculated using the two proportions formula for a non-inferiority test (20). The parameters included in the formula were as follows: i) The expected survival was 0.98 and 0.96 for AC-TAM and GnRH-TAM, respectively; ii) one-sided significance level, 0.05; iii) the power of test, 0.8; iv) non-inferiority margin, 0.06; and v) the ratio of sample size, 3. This resulted in a calculated sample size of 120 patients who received AC-TAM and 40 patients who received GnRH-TAM. During the recruitment period, 130 patients who received AC-TAM and 40 patients who received GnRH-TAM met the inclusion criteria. All of the patients had complete follow-up data. The present study was approved by The Siriraj Institutional Review Board (certificate of approval no. Si 674/2016). No informed consent was obtained from the patients as the present study was retrospective in nature.

Treatment

In the GnRH-TAM group, the patients received subcutaneous injection of 10.8 mg goserelin every 3 months for 2–3 years and TAM (20 mg/day) for 5 years. In the AC-TAM group, AC was administered every 3 weeks for 4 cycles (60 mg/m2 adriamycin intravenously plus 60 mg/m2 cyclophosphamide intravenously every 21 days) followed by TAM (20 mg/day) for 5 years.

Statistical analysis

Continuous parameters are presented as the mean ± SD. Categorical parameters are presented as the frequency and percentage. The DFS period was defined as the time from the operation to disease recurrence or death (whichever occurred first) and the OS period was defined as the time from the operation to death from any cause. The categorical characteristics of the patients were compared between the two treatment groups using Pearson's χ2 test. The continuous parameters of the two treatment groups were compared using independent t-test. DFS and OS were assessed using Kaplan-Meier curves and compared using a log-rank test. The Cox proportional hazards model was used to calculate the adjusted hazard ratios. P<0.05 was considered to indicate a statistically significant difference. The statistical analysis was performed using SPSS software version 21 (IBM Corp.).

Results

Patients and tumour characteristics

The total number of the patients recruited was 170. The mean age at diagnosis was 44.4±6.3 years. In total, 40 patients received GnRH-TAM and 130 patients received AC-TAM. The baseline characteristics of the patients, tumours and treatments are presented in Table I. There was no significant difference in all pathological parameters. All patients with HER2 overexpression had a tumour size <2 cm and did not receive HER2-targeted therapy. In the GnRH-TAM group, a higher proportion of the patients underwent breast-conserving surgery followed by postoperative radiotherapy. All of the patients in the GnRH-TAM group experienced hot flashes but could tolerate and received complete treatment. Most of the patients in the AC-TAM group had common side effects of chemotherapy, including alopecia and nausea. No severe adverse effects, such as cardiotoxicity were observed in the AC-TAM group.

Table I. Characteristics of the patients.

Table I.

Characteristics of the patients.

Characteristics	GnRH-TAM, n=40 n (%)	AC-TAM, n=130 n (%)	P-value
Age, mean ± SD (years)	45.1±3.5	44.2±6.9	0.30a
Tumour size
≤20 mm	30 (75.0)	91 (70.0)	0.54
>20 mm	10 (25.0)	39 (30.0)
Histology
Invasive ductal carcinoma	40 (100.0)	123 (94.6)	0.13
Invasive lobular carcinoma	0	7 (5.4)
Tumour grade
Grade 1	13 (33.3)	23 (17.7)	0.11
Grade 2	23 (59.0)	97 (74.6)
Grade 3	3 (7.7)	10 (7.7)
Lymphovascular invasion
No	36 (90.0)	122 (93.8)	0.41
Yes	4 (10.0)	8 (6.2)
HER2
Negative	37 (92.5)	109 (83.8)	0.17
Positive	3 (7.5)	21 (16.2)
Type of surgery
Breast conserving surgery	27 (67.5)	56 (43.1)	0.01
Total mastectomy	13 (32.5)	74 (56.9)

a Independent t-test. HER2, human epidermal growth factor receptor 2; GnRH-TAM, gonadotropin-releasing hormone agonist plus tamoxifen; AC-TAM, adriamycin and cyclophosphamide plus tamoxifen.

Survival analysis

The median follow-up time was 77 (36–167) months. There was no death that occurred during the follow-up period. Only one local recurrence in the conserved breast occurred in the GnRH-TAM group at 48 months after surgery. In the AC-TAM group, there were 3 patients with loco-regional recurrence of the conserved breast, chest wall and axillary lymph nodes at 37, 47 and 120 months after surgery, respectively. Additionally, in the AC-TAM group, 1 patient had lung metastasis and another patient had lung and liver metastasis at 66 and 149 months, respectively. Survival analysis by Kaplan-Meier method revealed no difference in DFS for each parameter (Table II). OS analysis was not conducted in the present study as all patients survived and there was no death in the follow-up period. Multivariate analysis by Cox regression showed that lymphovascular invasion tended to be an independent prognostic factor for lower DFS; however, this was not significant. The survival curves of DFS by each treatment group showed no significant difference between the GnRH-TAM group and AC-TAM group (P=0.858; Fig. 1).

Figure 1. DFS of the treatment groups. There was no difference in DFS between the two groups. The GnRH-TAM group had slightly higher DFS than the AC-TAM group. DFS, disease-free survival; GnRH-TAM, gonadotropin-releasing hormone agonist plus tamoxifen; AC-TAM, adriamycin and cyclophosphamide plus tamoxifen.

Table II. Disease-free survival among different parameters and treatment groups.

Table II.

Disease-free survival among different parameters and treatment groups.

Parameters	Case	Event	5-year survival	10-year survival	P-valuea	Hazard ratio (95% CI)	P-valueb
Age at diagnosis
≤45 years	91	3	1.00	0.93	0.85	1.54 (0.27–8.82)	0.63
>45 years	79	3	0.96	0.96
Tumour size
≤20 mm	121	4	0.98	0.94	0.93	1.01 (0.17–5.88)	0.99
>20 mm	49	2	0.98	0.95
Tumour grade
Grade 1	36	0	1.00	1.00	0.19	N/A	0.98
Grade 2/3	133	6	0.98	0.93
Lymphovascular invasion
Absence	158	4	0.99	0.98	0.06	4.78 (0.84–27.29)	0.08
Presence	12	2	0.92	0.76
HER2 status
Negative	146	6	0.98	0.94	0.44	N/A	0.99
Positive	24	0	1.00	1.00
Surgery
Breast conserving	83	4	0.97	0.90	0.22	0.29 (0.04–1.89)	0.20
Total mastectomy	87	2	0.99	0.99
Systemic treatment
GnRH-TAM	40	1	0.97	0.97	0.86	1.90 (0.19–18.80)	0.58
AC-TAM	130	5	0.98	0.94

a Log rank test

b Cox regression. N/A, not available as very few events occurred. HER2, human epidermal growth factor receptor 2; GnRH-TAM, gonadotropin-releasing hormone agonist plus tamoxifen; AC-TAM, adriamycin and cyclophosphamide plus tamoxifen.

Discussion

Hormonal therapy after chemotherapy or hormonal therapy alone is the main treatment option in hormone receptor-positive, HER2-negative early breast cancer (7). The decision of treatment depends on the aggressiveness of the disease and the condition of the patients. In the present study, patients with breast cancer were recruited, who completely rejected chemotherapy due to concerns for quality of life. GnRH-TAM did not demonstrate inferior survival when compared with AC-TAM in hormone receptor-positive, HER2-negative early breast cancer.

Ovarian function suppression has been shown to improve the outcome of high-risk premenopausal patients when combined with TAM, but this benefit was not established in a low-risk group (17). Only a few previous studies, to the best of our knowledge, have illustrated that GnRH agonists are suitable substitutes for chemotherapy in hormone-responsive patients with breast cancer (21,22). Meta-analysis by Early Breast Cancer Trialist's Collaborative Group showed that patients with breast cancer under the age of 50 years who received ablation of ovarian function had better long-term survival regardless of hormone receptor status (10,23). In premenopausal women with hormone receptor-positive breast cancer, ovarian function suppression plus TAM resulted in increased 8-year DFS and OS rates (24). Subgroup analysis showed that in the patients who did not receive prior chemotherapy, the favourable outcome was more emphasized (24). The effect of ovarian ablation in the improvement of survival was more influential in the patients who did not receive chemotherapy; chemotherapy may itself suppress ovarian function in late premenopausal women.

Several previous randomised control trials compared ovarian function suppression/ovarian ablation to CMF alone in hormone receptor-positive premenopausal patients with early breast cancer there was no difference between the two treatment regimens in DFS and OS (22,25–31). The efficacy of ovarian function suppression or ovarian ablation is similar to that of chemotherapy and may replace chemotherapy as an alternative choice of treatment. Previous randomised control trials compared medical ovarian function ablation using a GnRH agonist with CMF in hormone receptor-positive premenopausal women, and found no difference in both DFS and OS (26–28,31). This finding was observed in both node-negative patients (27,31) and node-positive patients (26,28). However, patients who received GnRH agonist alone demonstrated better quality of life compared with those who received adjuvant chemotherapy (32–34). Several previous studies compared a combination of ovarian function suppression plus TAM to chemotherapy alone in hormone receptor positive, premenopausal early breast cancer. The results suggested that combined endocrine therapy is a reasonable alternative to chemotherapy (15,16,35,36). Furthermore, in hormone receptor-positive patients, administration of 3.6 mg goserelin every 4 weeks for 3 years plus TAM for 5 years was more effective than CMF (15). In terms of quality of life, the patients receiving GnRH analog had less deterioration in quality of life over the first 6 months when compared with those receiving the CMF regimen (37). In the present study, the patients who received GnRH-TAM had no adverse effects and were able to complete the course of treatment. In addition, the patients in the GnRH-TAM group could avoid the side-effects of chemotherapy, including alopecia, permanent infertility, chemotherapy-induced memory problems and febrile neutropenia (38).

To the best of our knowledge, at present, there is no randomised controlled trial that compared combined ovarian function suppression and TAM with sequential AC-TAM. The present retrospective study found comparable survival outcome between these two treatment regimens similar to other previous retrospective studies of a Korean population (39,40). There was only one local recurrence in the GnRH-TAM group while in the AC-TAM group, 2 patients with distant metastasis were identified. No mortality occurred in the enrolled patients. Further long-term follow-up might be required for luminal subtype breast cancer.

Cost-utility analysis of GnRH agonist and adjuvant chemotherapy showed that GnRH agonist is more cost-effective than the docetaxel cyclophosphamide (TC) regimen (41). However, in Thailand, TC is reserved for the patients who have a higher risk for cardiotoxicity when they receive the AC regimen due to cumulative dose-related and permanent cardiotoxicity of anthracycline (42), and the higher cost of a TC regimen. Administration of 10.8 mg goserelin every 3 months as in the present study is convenient, reduces costs, with no adverse effects. The efficacy of ovarian function suppression was comparable to 3.6 mg monthly doses (43). The present study indicated that 10.8 mg 3-monthly administration of goserelin does not result in a different outcome, and is safe and practical to use.

There are limitations to the present study; it is a retrospective study conducted in a single institute with a limited number of patients in GnRH-TAM group. This may cause selection bias in the analysis. According to The National Comprehensive Cancer Network Clinical Practice Guideline (version 3.2018) (7), this group of patients should be evaluated by a 21-gene reverse transcription-PCR assay to classify the risk of recurrence. Further studies including this assay might be beneficial and a multicentre-randomised controlled study is required for the prospective comparison of the efficacies of GnRH-TAM and AC-TAM regimens in premenopausal patients with early stage breast cancer.

In conclusion, it was demonstrated that in premenopausal women with hormone receptor-positive, node-negative early breast cancer, adjuvant treatment with GnRH-TAM had similar survival outcomes and improved the quality of life compared with patients who were treated with AC-TAM. This adjuvant treatment regimen represents a valid option in this group of patients.

Acknowledgements

The abstract was presented at The Primary Therapy of Early Breast Cancer 15th St. Gallen International Breast Cancer Conference 15–18 March 2017 in Vienna, Austria and published as abstract no. P007 in The Breast 32 (Suppl 1): 2017. The authors would like to thank Miss Surat Phumphuang (Division of Head Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University), for coordination of the research work.

Funding

No funding was received.

Availability of data and materials

The datasets generated and/or used during this study are available from the corresponding author on reasonable request.

Authors' contributions

DS performed the statistical analysis, manuscript preparation, revised and completed the manuscript for important content. TK collected the patient data, and performed the statistical analysis and manuscript preparation. WP helped with the study design, data acquisition and manuscript preparation, and revised the manuscript. PO was involved in the treatment of the patients, provided ideas, and contributed to the conception and design of the study, the critical point of discussion and the completion of the manuscript.

Ethics approval and consent to participate

The present study was approved by the Siriraj Institutional Review Board (certificate of approval no. Si 674/2016). No informed consent was obtained from the patients as the present study was retrospective in nature.

Patient consent for publication

Not applicable as the present study was retrospective in nature.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

References