A protocol for systematic review and meta-analysis

Background: Breast cancer is the most common malignancy in women worldwide. Compared with other malignant tumors, breast cancer patients have a higher incidence of depression and other psychiatric symptoms. The purpose of this meta-analysis was to determine the association between long-term survival and depression in patients with breast cancer. Methods: This review will include cohort studies only. Multiple databases will be searched by 2 independent reviewers, including PubMed, EMBASE, the Cochrane Library, and PsycINFO. The language of studies should be English and Chinese, published from inception to the September 2020. Two independent reviewers will carry out literature screening, research selection and data extraction. Revman5.3 software will be used to generate funnel map, assess heterogeneity, make the subgroup analysis and complete sensitivity analysis. Results: This review will summarize the available evidence to determine the association between depression and survival in breast cancer patients. Conclusion:The results of this study will provide reference for the development of comprehensive treatment for breast cancer, and will promote further research. PROSPERO registration number: CRD42020202200 Abbreviations: 95% CI = 95% confidence interval, HR = hazard ratio, MST = median survival time.


Introduction
Breast cancer is the most common malignant tumor in women all over the world. According to the 2018 global cancer epidemic statistics, there are about 2.089 million new cases of female breast cancer every year, and about 627,000 deaths from breast cancer in the same period. [1] Even with advances in early screening and treatment, the death rate from breast cancer remains high. [2][3][4] In order to prolong the survival time and reduce the mortality of breast cancer patients, it is important to identify the risk factors affecting the survival of breast cancer patients. A study from Singapore showed that depression significantly shortened the survival time of cancer patients and could predict the prognosis. Depression was associated with an increased mortality rate among breast cancer survivors in women (Hazard Ratio [HR]: 11.6, 95% confidence interval [95% CI]: 0.69-194.1, P = .089). The risk of depression-related death was very high among cancer patients who lived over 5 years after cancer diagnosis (adjusted HR: 4.69, 95% CI: 1.76-12.5, P = .002). [5] After breast cancer diagnosed, the patients are worried about shortened survival time, recurrence and metastasis. Because most of them are female patients, they need to face impaired body image and decreased quality of sexual life caused by surgery and other treatments. Therefore, compared with other malignant tumors, the incidence of depression and other psychiatric symptoms in breast cancer patients are higher, [6][7][8] which is also closely related to the lack of female secondary characteristics and physical symptoms such as nausea, vomiting, fatigue, hair loss, and insomnia caused by chemotherapy. [9][10][11][12][13] Although the correlation between psychological factors and the survival of breast cancer patients has been extensively studied, the findings were not consistent. Some studies ZG and JL are co-first authors of this manuscript, contributing equally to the design and drafting the manuscript.
It is not necessary for ethical approval because it is based on published studies. The protocol will be disseminated in a peer-reviewed journal or presented at a topic-related conference.
This study will analyze data from published or unpublished trials, thus, ethical approval is unnecessary.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. This study was supported by the National Natural Science Foundation of China (81774289).
The funders had no influence on the study design in the collection, analysis, and interpretation of data.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. believed that depression was related to the shortened survival and increased mortality of breast cancer patients, [14,15] while some studies believed that there was no correlation between the 2. [16,17] A meta-analysis incorporating literature data found that depression was associated with a 30% increased risk of allcause death in breast cancer patients, a 29% increased risk of specific death, and a 24% increased risk of breast cancer recurrence. [18] However, the association between depression and breast cancer survival was not integrated.
Based on the above background, we designed this metaanalysis to collect and was to integrate data on survival, mortality, and risk of death in breast cancer patients with depression, in order to determine the correlation between longterm survival in patients with breast cancer and depression.

Method
This meta-analysis has been registered on PROSPERO (www. crd.york.ac.uk /prospero/) with number CRD42020202200, and referred to the guidance on conducting systematic reviews and meta-analyses of observational studies of a etiology. [19] It will follow the reporting guidelines and criteria set in the Preferred Reporting Items for Systematic Reviews and Meta-analyses [20] statement checklist and Meta-analysis Of Observational Studies in Epidemiology [21] checklist. Methods followed guidelines by the Cochrane Collaboration for the conduction of systematic reviews. [22] Ethical approval is unnecessary for this study. Two independent reviewers will carry out literature screening, research selection and data extraction. The obtained documents will be imported into EndnoteX8, and the duplicate files will be searched and deleted first. Then, the title and abstract are screened, and studies that do not meet the inclusion criteria are deleted. After reading the full text of the remaining studies, the final included studies were determined. If the full text is not found, the corresponding author will be contacted. If there is a disagreement between the 2, the third reviewer will decide. The research selection process is shown in the Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart (Fig. 1).

Extraction of data and information.
The main data extracted by the 2 independent reviewers will include: (1) The basic information included in the study, including the first author, publication time, area, published magazine, and impact factor. If the above data are not given directly in a study, the information in the study can be used to calculate. If the original data are not available or computable, this study will be excluded. A third senior author will help to reconcile any divergences between 2 authors.

Heterogeneity assessment.
Before the meta-analysis, the heterogeneity test was first performed using the I 2 test. If the Table 1 Search strategy for the PubMed.

No.
Search terms heterogeneity was small (P > .05 and I 2 < 50%), the fixed effect model was used for analysis. The random effect model would be used, when the heterogeneity was large (P .05 or I 2 ≥ 50%). [23] 2.2.4. Evaluation of studying quality. Two researchers independently adopted the Newcastle-Ottawa scale [24] to conduct a bias risk assessment on the included studies. Newcastle-Ottawa scale, with a total score of 9 stars, has a total of 8 items. If there was a disagreement, the 2 decided after a discussion; if it could not be resolved, a third researcher would assist.
2.2.5. Assessment of reporting deviations. If necessary, we will examine the reporting bias using funnel plot and Egger regression test, when >10 trials are included. [25,26] 2. 2.2.7. Subgroup analysis. The subgroup analysis of the metaanalysis results for each outcome was required. The subgroup only includes items related to the study design, for example, stage, location, and follow-up time. The evaluation subgroup analysis will be conducted in accordance with the guidelines for credibility assessment. [27] 2.2.8. Sensitivity analysis. The method of deleting studies one by one needed to be used to complete the sensitivity analysis of the results to ensure stability.
2.2.9. Quality of evidence. The system grading of recommendations assessment, development, and evaluation was used in evaluating the evidence level of outcomes. [28,29]

Discussion
People is with the mental disorders, which predict unhealthy lifestyles such as smoking, alcohol consumption, insomnia, and so on, which may lead to cardiovascular disease and increase the risk of death. [30] In addition, the treatment adherence of breast cancer patients diagnosed with depression is also one of the issues concerned by clinicians, such as difficulty in completing the full course of chemotherapy and endocrine therapy, leading to shortened survival time. [31] Suicide is also one of the factors leading to shortened survival of breast cancer patients. [32] Moreover, Kamiya A. et al found that chronic stress accelerated the growth and development of cancer by stimulating the sympathetic nerve in the tumor, affecting the survival of patients. [33] Through this meta-analysis, we hope to integrate current data related to depression and survival of breast cancer patients, so as to provide reference for the development of comprehensive treatment for breast cancer.

Amendments
If amendments are needed, we will update our protocol to include any changes in the whole process of research.