| Objective:Now breast cancer still ranks the first in the women cancer incidence, and is also one of common cause of cancer-related death. The most frequent subtype of breast cancer is hormone receptor-positive subtypes, and premenopausal patient accounts for a large proportion. So a further of comprehensive breast cancer treatment for premenopausal patients has important clinical significance. Five years of tamoxifen (TAM) treatment is the cornerstone of current pre-menopausal hormone-receptor-positive breast cancer treatment. But there are some studies which have showed that in tamoxifen or aromatase inhibitors (AI) plus GnRHa induced ovarian suppression could produce more survival benefit. In these years, the st Gallen conference and ASCO guidelines have discussed GnRHa induced ovarian suppression for premenopausal breast cancer treatment. The main purpose of this study is to systematic evaluate the survival benefit of GnRHa induced ovarian suppression for premenopausal breast cancer patient, and to explore the optimal target population. In addition, using network meta-analysis, we can also evaluate the different drugcombination and course of treatment, and figure out the best drug combination of GnRHa induced ovarian suppression and the best course of treatment.Methods:We searched the English databases such as PubMed, EBSCO, Embase, Scopus, Cochrane library and Chinese databases such as CNKI, CQVIP and Wanfang. Relevant literature had also been retrievedmanually as a supplement. Search date ranges from 1980 to March 2016. Published randomized controlled trials and quasi-randomized controlled studies ware accepted. We used hazard ratio (HR) as efficacy analysis statistics, and a 95% confidence interval was needed. The primary out come to observe included overall survival (OS), disease-free survival (DFS), and response rate (RR). We used the software Stata to perform the normal Meta-analysis and subgroup analysis, and used the language R and the Netmeta package toper form net work Meta-analysis comparing different drug combination and course of treatment.Results:A total of 34 studies and 61,724 cases of patients included. Meta-analysis suggests that tamoxifen combined with ovarian suppression is superior to tamoxifen 5-year-monotherapy, the 5-year DFS HR was 0.89 (95% CI 0.80-0.98), and the 5-year OS HR was 0.87 (95% CI 0.77-1.00). In the hormone receptor positive subgroup, tamoxifen combined with ovarian suppression was significantly superior to tamoxifen 5-year-monotherapy, and the 5-year OS HR was 0.75 (95% CI 0.58-0.98). For the age subgroup older than 40 years, GnRHa plus tamoxifen yielded a 5-year OS HR 1.10 (95% CI 0.82-1.48), indicated that GnRHa induced ovarian suppression was detrimental to the survival of patients older than 40. For the age subgroup younger than 40 years, GnRHα plus tamoxifen yielded a 5-year OS HR 0.81 (95% CI 0.54-1.24), indicated that GnRHα induced ovarian suppression was benefit to the survival of patients younger than 40. Comparison of GnRHα plus AI and GnRHα plus tamoxifen, GnRHα plus AI was not superior to GnRHα plus tamoxifen, with a 5-year DFS HR 0.97 (95% CI 0.74-1.28). However, GnRHα plus exemestane was superior to GnRHα plus tamoxifen, with a 5-year DFS HR 0.63 (95% CI 0.46-1.86). For the Ki-67>20% subgroup, GnRHα plus AI was superior to GnRHα plus tamoxifen, with a treatment response rate (RR) HR 0.36 (95% CI 0.26-0.50). For the Ki-67<20% subgroup, GnRHα plus AI was not better than GnRHα plus tamoxifen, with a RR HR of 0.60 (95% CI 0.36-1.00). Network meta-analysis suggests that tamoxifen combined with Buserelin, Goserelin, Triptorelin could improve the survival rate, with a 5-year DFS HR 0.71 (95% CI 0.54-0.94),0.81 (95% CI 0.75-0.87),0.79 (95% CI 0.71-0.88) respectively. Anastrozole combined with Goserelin, Triptorelin could also improve the survival rate, with a 5-year DFS HR 0.84 (95% CI 0.73-0.96), and 0.89 (95% CI 0.75-1.05). Exemestane plus Triptorelin was better than any other drug combination, with a 5-year DFS HR 0.66 (95% CI 0.58-0.76). The 5-year OS HR for tamoxifen plus Buserelin, Goserelin, and Triptorelin were 0.69 (95% CI 0.50-0.94),0.82 (95% CI 0.75-0.90), and 0.74 (95% CI 0.63-0.86). The 5-year OS HR for Anastrozole plus Goserelin was 1.15 (95% CI 0.31-4.30). The advantage obtained in the 5-year DFS could not be converted to a 5-year OS benefit. the 5-year OS HR for GnRHα plus tamoxifen with 2 years,3 years,5 years were 0.81 (95% CI 0.74-0.88),0.74 (95% CI 0.62-0.89), and 0.76 (95% CI 0.57-1.02) respectively, indicating GnRHα plus tamoxifen therapy for 3 years was superior to 2 years and 5 years.Conclusion:This study shows that age less than 40 and Ki-67 expression is higher than 20% indicates that the patient may benefit from GnRHa induced ovarian suppression treatment. Taking all these factors together, the young Luminal B breast cancer patients may benefit from GnRHa induced ovarian suppression treatment. In terms of drug selection, Exemestane plus Triptorelin has certain advantagein 5-year DFS. But tamoxifen plus any GnRHa (Buserelin, goserelin or Triptorelin) has advantagein 5-year OS. Therefore, we recommended that tamoxifen plus any GnRHa for young premenopausal breast cancer patient. The treatment of tamoxifen plus any GnRHa for 3 years has more survival benefit comparing to the treatment of 2 or 5 years. Therefore, tamoxifen plus any GnRHa for 3 years treatment is recommended. Currently there is few trials on GnRHa plus aromatase inhibitor for premenopausal patients, more clinical trials are needed in the near future to support the existing clinical evidence. |
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