Study design and treatment
This was a prospective, single-centre, randomized, controlled, and open-label clinical study. All participants were from Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine. Premenopausal patients with HR-positive early breast cancer who were scheduled to receive SERMs as adjuvant endocrine therapy after discussion by the multidisciplinary team (MDT) were recruited. A block randomization method with a block size of 6 was used to achieve balance between treatment groups by the investigator. There was no stratification for the study. Patients were enrolled by doctors in our centre. Sequentially numbered opaque sealed envelopes were used for allocation concealment and managed by the oncology nurse specialist.
After surgery, chemotherapy, and radiotherapy, patients were randomly assigned at a 1:1 ratio to the TOR group and the TAM group. Patients in the TOR group received TOR citrate tablets (60 mg/day), and patients in the TAM group received TAM citrate tablets (20 mg/day). All patients were followed up every 3 months in the first year from endocrine therapy initiation.
Patients were included if they met the following criteria: were premenopausal women; had histologically confirmed HR-positive breast cancer; underwent standard surgery for breast cancer; had completed other adjuvant therapy, such as chemotherapy and radiotherapy; had leukocyte counts ≥3.0 × 109/L and platelet counts ≥75 × 109/L; had serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels that were ≤ 2.5 times the upper limit of normal range (ULN); had serum creatinine levels less than the ULN; and had an Eastern Cooperative Oncology Group (ECOG) performance score of 0–2. The exclusion criteria were as follows: HR negative; previous neoadjuvant or adjuvant endocrine therapy administration; metastatic malignancies; family history of endometrial cancer or other gynaecologic malignant tumours; ovarian cysts (largest diameter ≥ 2 mm) by transvaginal ultrasound (TVU); hysterectomy or ovariectomy surgery; any complication that increased sex hormone secretion, such as thymic cancer, ovarian tumour or pituitary adenoma; any complication that decreased sex hormone secretion, such as hyperthyroidism, hypothyroidism, severe malnutrition, liver cirrhosis, sex hormone synthetase deficiency, Turner’s syndrome, intracranial tumour, or a pituitary condition; a severe non-malignant comorbidity that could influence long-term follow-up; severe cardiac dysfunction; severe hepatic dysfunction, Child-Pugh C; or a known severe hypersensitivity to any drug in this study.
The patients’ clinical information was collected from the case report forms of the study. Medical history data included age, menstrual status, ECOG score, past medical history, biochemical parameters and the parameters of routine blood tests. Other treatment information included chemotherapy, radiotherapy, and targeted therapy. Pathological results were reported by two different pathologists independently and included pathological type, tumour size, histological grade, lymph node involvement, ER expression, progesterone receptor (PR) expression, CerbB-2 status and the result of the fluorescence in situ hybridization (FISH) test. ER or PR positivity was defined as nuclear staining in more than 1% of tumour cells. Tumours with a CerbB-2 3+ status in the immunohistochemistry assay and/or human epidermal growth factor receptor-2 (HER-2) gene overexpression confirmed by FISH were defined as HER-2 positive.
Serum oestradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured at baseline and every 3 months after randomization by the gynecological clinical Lab in our hospital. Hormone levels were analyzed using commercially available kits from the Unicel DXI 800 Access immunoassay system (Beck-man Coulter).
Study end points
The primary end point of the study was the incidence of ovarian cysts, which were defined as pure liquid-filled structures that were equal to or greater than 2.0 cm at their largest diameters by TVU. The secondary end points were as follows: the incidence of endometrial thickening (endometrium ≥8.0 mm measured by TVU), changes in female hormones (E2, FSH and LH), the incidence of fatty liver (detected by abdominal ultrasound according to the criteria of the American Association for the Study of Liver Disease ), changes in the modified Kupperman Menopausal index (mKMI) and changes in quality of life.
Assessment of menopausal symptoms
The mKMI was used to evaluate menopausal symptoms . The mKMI consists of 13 items: hot flashes/sweats, palpitation, vertigo, headache, paraesthesia, formication, arthralgia, myalgia, fatigue, nervousness, melancholia, urinary infections and sexual complaints. Each item was divided into four grades (0–3 points) according to severity: 0, no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms. The total scores ranged from 0 to 63, and score ranges of 0–6, 7–15, 16–30 and > 30 represented the degrees of severity, namely, none, mild, moderate and severe, respectively . Patients were asked to complete the mKMI questionnaire at baseline and then every 3 months.
Quality of life assessment
Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0), which consists of 30 questions addressing five functional scales (cognitive, emotional, physical, social, and role), nine symptom scales (appetite loss, constipation, diarrhoea, dyspnoea, fatigue, financial difficulties, insomnia, nausea and vomiting, and pain) and one global health status scale . The EORTC-QLQ-C30 questionnaires were completed at baseline and then every 6 months.
The study was designed to have a power of 90% to detect an absolute reduction of 20% for the incidence of ovarian cysts in patients treated with toremifene compared to patients treated with tamoxifen (15% vs 35%), at a one-sided significance level of 0.05. Taking a withdrawal rate of 15% into consideration, the target enrolment was 52 eligible patients for each group based on the Simon 2-stage design.
Categorical variables between two groups are presented as frequencies and percentages and were compared using chi-square tests (the 2-sided Pearson) or Fisher’s exact test. Continuous data are presented as the mean ± standard deviation (SD) or mean ± standard error (SE) and were compared using a nonparametric test (Mann-Whitney U). The analysis was performed using SPSS (version 22.0) software (IBM Corporation, Armonk, NY, USA), and figures were generated by GraphPad Prism (version 5) (GraphPad Software, San Diego, CA, USA). A p value < 0.05 was considered to indicate statistical significance.