Bone Mineral Density after Oophorectomy and Tamoxifen in Premenopausal Breast Cancer
Abstract & Commentary
By Bindu Kanapuru, MD
Hematology/Oncology Division, IASIA-Falls Church, Falls Church, VA
Dr. Kanapuru reports no financial relationships relevant to this field of study.
Synopsis: In a study conducted as an adjunct to a randomized, Phase 3 investigation of optimal timing of oophorectomy for premenopausal breast cancer patients, Love and colleagues examined changes in bone mineral density (BMD) for patients receiving surgery (oophorectomy and mastectomy) plus tamoxifen. They observed a decline in lumbar spine BMD at a rate that lessened over 2 years, and no significant change in BMD at the femoral neck. The implications of this finding relate to the optimal management of premenopausal breast cancer, particularly in countries with limited health care resources.
Source: Love RR, et al. Bone mineral density following surgical oophorectomy and tamoxifen adjuvant therapy for breast cancer. Cancer 2013;119:3746-3752.
In premenopausal patients with hormone receptor-positive breast cancer, adjuvant ovarian ablation plus tamoxifen therapy has been shown to improve overall survival.1,2 A recent meta-analysis revealed an overall clinical trend toward ovarian ablation over hormonal treatment with luteinizing hormone-releasing hormone (LHRH).2 However, loss of ovarian function, and the subsequent menopausal state, is associated with loss of bone mineral density (BMD) and increase risk of fracture.3 In postmenopausal women with breast cancer, tamoxifen has been shown to preserve BMD.4,5 However, previous studies have demonstrated a loss of BMD in premenopausal women with breast cancer treated with tamoxifen alone.5 Additional studies have demonstrated loss of BMD in patients treated with LHRH agonists plus tamoxifen.6,7 However, to date, no studies have investigated the effect of oophorectomy plus tamoxifen on BMD in premenopausal women with breast cancer.
To evaluate the effect of surgical oophorectomy on BMD in premenopausal women with hormone receptor-positive breast cancer, Love and colleagues conducted a longitudinal ancillary study of women participating in a Phase 3 clinical trial investigating the timing of surgical oophorectomy. Initially, 740 Vietnamese and Filipino premenopausal women with hormone receptor-positive invasive breast cancer were enrolled in the parent Phase 3 trial. In this trial, patients were initially stratified based on likelihood of being in the luteal phase of the menstrual cycle. Patients in stratum 1 (not in the luteal phase) were randomized to either immediate surgical oophorectomy or delayed surgical oophorectomy during the estimated mid-luteal phase of the menstrual cycle. Patients in stratum 2 (in luteal phase) underwent immediate surgical oophorectomy. All patients underwent surgical oophorectomy and mastectomy on the same day, and all were started on tamoxifen 20 mg daily within 6 days of surgery.
The inclusion criteria for the parent study were as follows: age ≥ 18 years and ≤ 50 years, history of menstrual cycles for the last 3 months with a duration of 25-35 days each, last menstrual period < 35 days ago, no current oral contraceptive use, histologic diagnosis of invasive and hormone receptor-positive (estrogen receptor-positive and/or progesterone receptor-positive) breast cancer with clinical stage II-IIIB, no other underlying serious illnesses, negative chest x-ray, and negative urine pregnancy test.
Because this ancillary study was initiated late and several sites did not participate, BMD data on 270 patients (175 in stratum 1 and 90 in stratum 2) were available for analysis. BMD was evaluated in the lumbar spine (L1-L4) and the femoral neck at the time of study enrollment and randomization (baseline). All patients had between 1 and 3 follow-up evaluations, using the same equipment, within the first 30 months of treatment.
The average age of study participants was 42.7 years (SD 4.3), weight was 54.3 kg (SD 11.3), and body mass index (BMI) was 23.1 (SD 3.7). Of the 270 participants, 64.6% were diagnosed with stage I-II disease and 35.5% had stage III disease.
A non-linear regression model was used to assess changes in BMD over time. Significant changes were observed for lumbar spine BMD post-intervention. At 6 months, BMD had declined by 2.8% (95% confidence interval [CI], -3.5 to -2.1; P < 0.0001). At 12 months, BMD had declined by 4.7% (95% CI, -5.5 to -3.8; P < 0.0001), and at 24 months BMD had declined by 6.7% (95% CI, -7.7 to -5.6; P < 0.0001). However, there were no statistically significant changes in femoral neck BMD.
Data were also analyzed with respect to patient age, weight, and BMI. Patients ≥ 43 years of age had an average of 0.030 g/cm2 lower baseline femoral neck BMD than those < 43 years of age. However, the rate of decrease in BMD post-intervention was the same in both age groups. There was no difference in baseline lumbar spine BMD between the age groups. There were no significant changes in the rate of decline of BMD based on weight or BMI.
In this analysis, which represents the largest of its type examining BMD changes in premenopausal patients receiving adjuvant therapy, there was clearly defined evidence that surgical oophorectomy followed by immediate tamoxifen treatment was associated with loss of BMD at the lumbar spine, the rate of which declines over 2 years but, curiously, no significant change in BMD at the femoral neck.
These findings are particularly relevant to the management of hormone receptor-positive premenopausal breast cancer in countries where, for economic reasons, adjuvant treatment might not include expensive chemotherapy regimens such as those including taxanes and ancillary agents such as bisphosphonates or denosumab. Prior studies have shown surgical oophorectomy plus tamoxifen to be superior to LHRH plus tamoxifen and to be equivalent with chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil plus LHRH plus tamoxifen. Thus, the comparable lumbar spine BMD losses and absence of BMD loss in the femoral neck would speak in favor of oophorectomy and tamoxifen as the optimal adjuvant approach, with equivalency in breast cancer management and less dramatic negative consequences in terms of bone loss. n
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