DISCUSSION


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Tamoxifen was first reported by Cole et al for treating breast cancer in 1971,23 and approved in the UK in 1973 and in the USA in 1977.24 At the beginning, it was used as a treatment for late recurrent or metastatic breast cancer. Tamoxifen has since been used also as an adjuvant treatment and preventive measure for HR-positive breast cancer. Several studies have shown that 5 years of adjuvant tamoxifen treatment is associated with a reduction in breast cancer recurrence and death,25even at 15 years after diagnosis.26 A prolonged 10-year tamoxifen treatment appears to further reduce the risk of recurrence and mortality, as compared with a 5-year tamoxifen treatment.27,28 The ovaries are the primary source of estrogens, which may enhance the proliferation of HR-positive breast cancer. Oophorectomy was first recommended for treatment of breast cancer by Albert Schinzinger in 1889.29 Compared with no adjuvant therapy, OFS reduces the risk of recurrence by 31% and mortality by 28%.30 OFS and chemotherapy have demonstrated similar efficacy in premenopausal patients with early breast cancer if used alone.31 However, OFS did not significantly improve outcomes if added to adjuvant chemotherapy.32,33 For several years, it has been unclear to oncologists whether OFS provides any benefit beyond that offered by adjuvant tamoxifen treatment in premenopausal breast cancer. In the present study, we analyzed four studies published between 2006 and 2014, that comprised a total of 6,279 cases. The meta-analysis results showed an 8% reduction in recurrence after adding OFS, as compared with tamoxifen treatment alone, although this was not significant (RR 0.92; 95% CI 0.84–1.00; P=0.06). There was also a 9% reduction in death, but this also did not reach statistical significance (RR 0.91; 95% CI 0.80–1.03; P=0.15). The ZIPP trial and ABC (OAS) trial began enrolling patients in 1987 and 1993, respectively, when HR testing was not routinely performed. Consequently, both the ZIPP and ABC (OAS) trials enrolled patients regardless of HR status.8,9 We conducted another subgroup meta-analysis for the HR-positive patients, but no significant improvement was demonstrated in DFS or OS from addition of OFS. The results suggest that adding OFS should not be commonly recommended as an adjuvant treatment for premenopausal women because it offers no additional benefits.

It has been reported that patients with HR-positive breast cancer might benefit from chemotherapy-induced downregulation of estrogen, because of chemotherapy-induced ovarian suppression.34Further, the non-chemotherapy subgroup might obtain additional benefits from combining OFS with tamoxifen. However, the present meta-analysis results show that addition of OFS significantly improved OS in the chemotherapy subgroup (a mortality reduction of 24%; P=0.03). However, it did not provide any benefits in the non-chemotherapy subgroup. The reason might be that patients who were administered adjuvant chemotherapy were in a subgroup considered to be at a relatively higher risk for adverse outcomes.35 Adjuvant endocrine therapy with tamoxifen alone could not sufficiently reduce the risk of recurrence and death, and the addition of OFS might be helpful. However, in some of these studies, the chemotherapy regimens included a combination of cyclophosphamide, methotrexate, and fluorouracil or its equivalent, which would be considered insufficient today. This was also a limitation of the present study. However, patients who were administered chemotherapy have similar characteristics and a higher risk of recurrence. Distant recurrence results mainly from systemic treatment failure.36,37 Both the ABC (OSA) and SOFT trials provided a distant recurrence rate for the tamoxifen alone arm and the tamoxifen plus OFS arm.9,15 The meta-analysis results showed that addition of OFS did not reduce distant recurrence. Additionally, age is a factor that may influence the results of tamoxifen plus OFS therapy. The ABC (OSA) trial showed that only patients under the age of 40 years might benefit from addition of OFS. However, the authors did not provide the original survival data of the age subgroups.9 The ZIPP trial showed that the effect of tamoxifen alone and tamoxifen plus OFS was similar in women aged 40 years and over. The 5-year survival rate was 76.2% for patients assigned to tamoxifen alone and 82.6% for those assigned to tamoxifen plus OFS in women younger than 40 years, although the results were less conclusive because of the smaller number of events (one was contained within the 95% CIs which were somewhat wide).8 The SOFT trial showed that the freedom from breast cancer rate at 5 years was 67.7% for patients assigned to tamoxifen alone and 78.9% for those assigned to tamoxifen plus OFS in the very young subgroup (<35 years).15 The above results demonstrate that the young subgroup (<40 years) might benefit from addition of OFS. However, the included studies did not contain an adequate number of subgroups based on age. Further, the age groups were divided based on different cut-off points (40 years or 35 years) and did not provide adequate and specific survival data. We could not conduct a subgroup meta-analysis based on age. This topic may need further studies in future.

The present study includes the latest published trials, and subgroup analyses were performed to ensure that the results are reliable and valid. However, our meta-analysis had some limitations. First, the results of the subgroup analyses were calculated based on two to three studies with a relatively small sample size. Second, the concomitant anticancer treatments used in the four trials were not exactly the same because of advances in chemotherapy. Third, there were differences in the criteria used for determination of menopausal status among the four trials. In addition, the SOFT trial included more patients than any of the rest of the studies, and had a relatively higher impact on the statistical results, which may reduce the reliability of this study.

OFS was carried out to help premenopausal women to achieve an established postmenopausal state. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) and BIG (Breast International Group) 1-98 trials found that adjuvant therapy with an aromatase inhibitor was a better choice than tamoxifen in HR-positive postmenopausal breast cancer.38,39 The TEAM (Tamoxifen and Exemestane Adjuvant Multinational) trial found that exemestane monotherapy and sequential treatment (tamoxifen followed by exemestane) are two appropriate options for postmenopausal women with HR-positive early breast cancer.40 Further, analysis of data from TEXT (Tamoxifen and Exemestane Trial) and SOFT demonstrated that adjuvant exemestane plus OFS provided more benefits than adjuvant tamoxifen plus OFS,41 although the final results of TEXT have not been published. However, exemestane is more expensive than tamoxifen. Efficacy and cost should both be considered while planning treatment strategies. High costs might reduce patient compliance, which might lead to failure of endocrine therapy. Therefore, in low-income and middle-income countries, tamoxifen plus OFS might be an appropriate choice for patients at higher risk who require chemotherapy. Sequential treatment with tamoxifen plus OFS followed by exemestane plus OFS might be a new area of research.