Abstract
Introduction:
Presently, there is a growing popularity of assisted reproductive technology (ART). Nevertheless, due to the significant fluctuations in reproductive hormone levels observed in patients receiving this novel technology, concerns have been raised regarding the potential increased risk of breast cancer associated with this treatment. The outcomes of pertinent clinical investigations exhibit significant disparities, leading to a lack of consensus regarding the association between ART and susceptibility to breast cancer. The primary objective of this study is to systematically evaluate the impact of ART on the risk of breast cancer.
Method and Analysis:
The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis Guidelines for Observational Studies in Epidemiology guidelines. Researchers conducted an extensive electronic search across databases including PubMed, Web of Science, Embase, and the Cochrane Library, encompassing all articles published over the last two decades (from January 2003 to December 2023). Two independent researchers meticulously examined the titles and abstracts of the literature based on predetermined inclusion criteria and research qualifications. Through collaborative deliberation, they identified the literature to be incorporated in the following analysis. Researchers will extract data in accordance with predetermined tables and perform quality assessments and implement bias control measures for each literature. Researchers will conduct a meta-analysis based on the extracted data to assess the overall risk and subgroup risks. The analysis will employ the odds ratio as the summary statistic and will use fixed or random effects models for estimation.
Ethics and Dissemination:
The findings of this systematic review will be disseminated through publication in peer-reviewed journals and presentation at international medical conferences, with the aim of reaching both medical professionals and the general public. As this study constitutes a systematic review, ethical approval is not required.
Keywords: assisted reproduction technology (ART), breast cancer, infertility, protocol, reproductive health, systematic review
Introduction
Breast cancer has become one of the most frequently diagnosed types of cancer globally. The latest global statistics on cancer incidence reveal that in 2020, there were 2.26 million new cases of breast cancer, establishing it as one of the primary contributors to cancer-related mortality in women on a global scale[1]. The detection and incidence rates of breast cancer have increased due to the development of economies and societies, advancements in medical care, and changes in lifestyle[2]. Hence, the prevention of breast cancer has emerged as a significant global concern. Epidemiological studies conducted in recent decades have identified numerous risk factors for breast cancer[3], offering valuable insights for promoting women’s breast health. Hence, investigating risk factors for breast cancer and providing thorough interpretations have emerged as primary areas of interest for epidemiologists and specialists in breast health.
HIGHLIGHTS
This study is anticipated to be the most recent and comprehensive systematic review and meta-analysis on the association between ART and the risk of breast cancer.
This review aims to offer a higher level of evidence to enhance the guidance of clinical practice.
This article provides a standardized process for systematic reviews on this topic, and following this protocol allows for the replication of related studies at any time.
As societal advancements progress swiftly, there is a noticeable trend of women marrying and having their first child at a later age[4]. The decline in female fertility will usually commence as early as age 30[5], thus postponing childbirth raises the probability of female infertility. This phenomenon has led to the rapid advancement of assisted reproductive technology (ART), which has become a significant component of contemporary reproductive medicine. According to the World Health Organization (WHO), in 2020, more than 8 million couples globally received ART treatments[6], resulting in successful pregnancies. In certain nations, the proportion of births resulting from ART even exceeded 5%[7].
It is certain that ART has been beneficial to numerous women and families; however, there have been raised concerns regarding the administration of ovarian-stimulating hormones during the procedure. ART refers to the procedures involved in in vitro fertilization (IVF) for reproductive purposes. The complete process encompasses ovarian stimulation treatments, which include ovarian stimulation and triggered ovulation, as well as the surgical retrieval of eggs from the ovaries, IVF, and embryo transfer. This entire sequence is generally referred to as an ART cycle[8]. Ovarian stimulation is a crucial therapeutic procedure for women undergoing ART, the primary goal of which is to stimulate the development of follicles and synchronize them to initiate the ovulatory cascade response using ovarian stimulants[9]. Various drugs have been utilized in ovarian stimulation therapy, with commonly associated medications including gonadotropin-releasing hormone agonists (GnRH-a) and GnRH antagonists, aromatase inhibitors like letrozole, selective Estrogen Receptor modulators such as clomiphene, and gonadotropins such as human menopause gonadotropin, recombinant follicle-stimulating hormone, and human chorionic gonadotropin[10-13]. During the process of ovarian stimulation, women experience significant alterations in hormone levels in addition to the physiological changes in the body. The levels of estrogen and progesterone increase significantly during ART as a result of the action of GnRH, gonadotropins, etc. The peak circulating estrogen level in an ART cycle is typically around 4000 pg/mL[14], whereas the peak estrogen level in a regular menstrual cycle is approximately 300 pg/mL[15]. Additionally, the peak progesterone exposure dose is at least double that of the peak level during a normal pregnancy[16]. The mammary gland, being a typical hormone-sensitive organ, exhibits hormone sensitivity in around 80% of breast cancers[17]. Numerous studies have identified high-dose estrogen and progesterone exposure as a risk factor for the development of breast cancer, which may impact cancer development by influencing mechanisms such as genotoxicity and oncogenic signaling pathways[18,19]. The abrupt and significant fluctuations in hormone levels resulting from ART treatment, and the possible oncogenic effects on the breast that may ensue, have inevitably received considerable attention. As a result, many patients and reproductive physicians have expressed concern regarding this matter[20].
Several reviews and meta-analyses have been conducted to investigate the relationship between ART and the risk of breast cancer, aiming to provide appropriate clinical guidance. Cullinane et al. suggested that fertility treatment was not significantly linked to breast cancer risk, and no elevated risk was observed in patients who underwent multiple cycles or were followed for more than 10 years[21]. However, a meta-analysis performed by Li et al. in 2013 demonstrated that fertility treatments had a protective effect against breast cancer[22]. Nevertheless, Sergentanis et al. did not observe a significant association between overall breast cancer risk and ART, while they reported an elevated risk of subsequent breast cancer among women over 30 years of age at the time of ART[23]. Additionally, a meta-analysis by Gennari et al. in 2015 revealed that patients undergoing fertility treatments had an increased risk of developing breast cancer when followed up for more than 10 years[24].
The current reviews and meta-analysis of the literature indicate an ongoing debate regarding the concerning issue of the association between ART and the risk of breast cancer. Meanwhile, the analysis of certain crucial subgroups, including age, treatment duration, parity, treatment method, and length of follow-up, remains incomplete. Researchers conducted a comprehensive analysis of previously published reviews and identified that the most recent review, which assessed the risk for the entire population, did not encompass all pertinent clinical studies up to the time of publication[21]. This deficiency may be attributed to limitations in the search strategy or inclusion criteria employed. Following the aforementioned review, several new clinical studies have since been published, introducing novel findings to this research topic[25-27]. Given the increasing prevalence of patients receiving ART and the substantial impact of breast cancer on women’s well-being, there is an urgent requirement for a fresh systematic review and meta-analysis. The primary objective of this research is to advance comprehension regarding the correlation between ART and the risk of breast cancer and to provide guidance and act as a foundational resource for the integration of ART clinical strategies and prospective investigative initiatives within this field.
Objectives
The aim of this systematic review and meta-analysis is to synthesize the studies investigating the association between ART and breast cancer risk and make quantitative study of their relationship.
Specifically, our aims include:
Synthesize the clinical research studies on the correlation between ART and the risk of breast cancer, extract crucial data and research findings from relevant studies, and conduct a systematic review.
Conduct a meta-analysis utilizing the risk data extracted from the studies to explore the correlation between ART and the overall risk of breast cancer, which will provide more robust evidence to guide clinical decision-making.
Assess the risks associated with specific subgroups. Subgroup analyses will be conducted to explore potential correlations between variables, including the type of fertility treatment medication, age, number of births, parity, duration of follow-up, cause of infertility, and the potential increase in the incidence of breast cancer.
Methods and analysis
The study will adhere to the guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and Meta-analysis Guidelines for Observational Studies in Epidemiology[28,29]. The PRISMA checklist is adhered in Supplemental Information http://links.lww.com/ISJP/A5. The PRISMA-P checklist is adhered in Supplemental Information http://links.lww.com/ISJP/A5.
Inclusion criteria and study eligibility
The research will focus on women who have undergone ART, with the control group consisting of women from the general population or infertile women who have not undergone ART treatment. The end point of the study will be the occurrence of breast cancer[23]. To maintain article quality and align with research language standards, specific inclusion criteria will be applied to all selected articles. These criteria include publication within the past 20 years (from 1 January 2003 to 31 December 2023), availability of complete full-text articles, utilization of the English language, inclusion of relevant keywords in the title or abstract, and provision of standardized risk scale data. The study will only consider case-control, retrospective, and prospective cohort studies, while excluding reviews, case studies, meta-analyses, syntheses, and articles related to animal or basic experiments.
Information sources and search strategy
In this study, a thorough electronic search will be carried out on prominent databases containing clinical research literature, including PubMed, Web of Science, Embase, and the Cochrane Library. To align with the most recent clinical trial findings and comply with contemporary clinical ART treatment methods[21], the search will encompass articles published within the last 20 years (from January 2003 to December 2023). The retrieved research will adhere strictly to pre-defined eligibility criteria. Upon verification with the PubMed Medical Subject Headings vocabulary, the search will incorporate keywords such as “cancer,” “breast cancer,” “breast carcinoma,” “assisted reproductive technology” or “ART,” “fertility treatment,” “ovarian stimulation,” and “in vitro fertilization” or “IVF,” and these terms will be systematically combined for the search process. We will utilize a comprehensive search strategy that encompasses searching literature titles, abstracts, keywords, and key points. The comprehensive search strategy tables for all databases will be provided in the subsequent full systematic review. The most recent search was conducted on 30 January 2024.
Data management
All articles identified through the aforementioned search strategy will be manually retrieved in full text from Google Scholar and pertinent publishing platforms. All acquired papers will be integrated into a database using Endnotes X9 software. Duplicate articles will be systematically eliminated. The remaining articles will be organized before being submitted to two independent reviewers for further evaluation and analysis.
Selection procedure
The selection procedure for the articles comprises two stages: screening of titles and abstracts, followed by screening of the full text. The screening process will entail two reviewers independently conducting a comprehensive review of the titles, abstracts, and full texts of the included studies, excluding literature that does not correspond with the research objectives. The two researchers will confirm the coherence of the articles selected for further analysis, and any inconsistencies will be deliberated with the co-investigators to achieve a consensus. The article screening process will adhere rigorously to the recommended PRISMA flow-diagram for systematic reviews, and a corresponding flow-diagram will be developed based on this selection procedure.
Outcomes and prioritization
The primary objective of this study is to assess potential alterations in the risk of breast cancer among patients undergoing ART treatment. Consequently, the primary outcome of the study is the odds ratio of breast cancer incidence in individuals undergoing ART compared to those who do not. The additional outcome of this study is to evaluate the risk of breast cancer among specific subgroups. Subgroup analyses will be conducted to explore potential correlations between variables such as the type of fertility treatment medication, age, number of births, parity, duration of follow-up, and cause of infertility and the incidence of breast cancer.
Data extraction and collection process
Two independent researchers will extract the following data from the article: general information (e.g. “Author,” “Publication year,” “district,” “periods of study”), study characteristics (e.g. “populations,” “following up years”), participant characteristics (e.g. “adjusting factors,” “Fertility treatment strategies,” “subgroups,” “cycles”), and “estimating data,” which includes risk scale types such as Standardized Incidence Ratio, hazard ratio, odds ratio, and relative risk[23]. In instances where data may be missing from the studies, we will reach out to the corresponding authors to request additional information. We will diligently document all correspondence with the authors. After data extraction, the two researchers will assess the consistency of the extracted data and address any disparities through consultation with the co-investigators. Finally, the researchers will compile the extracted data into an Excel spreadsheet to generate a comprehensive data extraction table for presentation.
Quality assessment and control of bias
All literature incorporated in the final analysis will undergo assessment for potential bias using suitable methodologies. Two distinct methodologies will be employed to evaluate the quality of the literature. Two researchers will evaluate the quality and risk of bias in the cohort studies and case-control studies included in the research independently. This assessment will be conducted using the standardized Robins-I tool for non-randomized intervention studies[30] and the Newcastle-Ottawa Quality Assessment Scale[31]. For studies with a low risk of bias, sensitivity analysis will also be taken into account. Any discrepancies will be addressed through consultation involving both researchers and the co-investigators in order to achieve a consensus.
Data synthesis
If feasible, a meta-analysis will be performed on the compiled literature for the primary and secondary outcomes. The meta-analysis will be conducted utilizing Review Manager 5.3 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark), with a predetermined statistical significance level of P < 0.05. We intend to utilize forest plots for assessing the outcomes of breast cancer risk, and for continuous variables, we will quantify variances using weighted mean differences. Heterogeneity among studies will be evaluated utilizing Cochrane’s Q test and the I2 statistic[32]. In instances where substantial heterogeneity is detected (i ≥ 50% in the Cochrane Q test), a random-effects (DerSimonian-Laird) model will be employed for the aggregated estimate; otherwise, a fixed-effects model will be utilized[33]. If there is limited literature pertaining to secondary outcome indicators and a high degree of heterogeneity among the studies, precluding the feasibility of performing subgroup meta-analysis, an alternative approach would involve conducting a narrative systematic review of the included publications.
Metabias
To address potential publication bias, two researchers will not only evaluate it by independently generating funnel plots but also conduct an Eggers test if appropriate[34].
Confidence in cumulative evidence
To evaluate the risk of bias within and between studies in the systematic review, an assessment will be conducted on the bias, limitations, accuracy, and other relevant factors of the literature included in the analysis, in accordance with the criteria outlined in the “Grades of Recommendation, Assessment, Development, and Evaluation (GRADE)” guidelines[35]. Based on the assessment findings, we will verify and lower the quality rating of the studies.
Discussion
This study aims to conduct a comprehensive systematic review and meta-analysis investigating the association between ART utilization and the risk of breast cancer. It will encompass a wide range of studies to provide a thorough analysis of the topic. Through a comprehensive systematic review, our objective is to synthesize the most recent literature concerning the correlation between ART and breast cancer and extract crucial data from pertinent studies and present it in visual tables. This approach aims to offer readers a more comprehensive and easily understandable overview of pertinent clinical research and, more importantly, provide more detailed references for both clinical practice and future research endeavors. The outcomes of the meta-analysis will aid in establishing the overall risk linked with ART treatment. Moreover, in cases where the studies under review offer comprehensive data on subgroup risks, our emphasis will be on performing meta-analyses on significant subgroups. This approach aims to enhance the comprehension of breast cancer risk factors within the particular cohort of patients receiving ART treatment. Consequently, it will facilitate the formulation of accurate and individualized medical and health care strategies in clinical settings. Moreover, this study aims to offer guidance for forthcoming research endeavors in this area, potentially enhancing the comprehensiveness and depth of future studies. One potential limitation of this study is the restricted number of studies or incomplete information reported in some studies, which may pose challenges in conducting meta-analyses on specific subgroups. This underscores the necessity for future clinical research to be more comprehensive and standardized.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Contributor Information
Zijie Guo, Email: 3200102805@zju.edu.cn.
Ziyu Zhu, Email: zhuziyu2001med@163.com.
Mingpeng Luo, Email: 872462051@qq.com.
Xixi Lin, Email: cicilin9012@163.com.
Linbo Wang, Email: linbowang@zju.edu.cn.
Jichun Zhou, Email: jichun-zhou@zju.edu.cn.
Ethics statement
Ethical approval is unnecessary as this study is a systematic review of previously published literature.
Missing consent comments
Not applicable.
Consent for publication
All authors have approved the manuscript and agreed with the publication.
Conflicts of interest disclosure
The authors declare that they have no competing interests.
Sources of funding
The work was supported by the National Natural Science Foundation of China (Nos. 82272855, 81972453, and 81972597), the Zhejiang Provincial Natural Science Foundation of China (under Grant Nos. LR22H160011, LY19H160055, LY19H160059, LY18H160005, and LY20H160026), and the Zhejiang Provincial Medical and Health Science and Technology (Youth Talent Program) Project No. 2021RC016. The work was sponsored by Zheng Shu Medical Elite Scholarship Fund.
Author contribution
Conceptualization: J.Z., L.W., and Z.G. Investigation: Z.G., Z.Z., and M.L. Writing—original draft preparation: Z.G. and Z.Z. Writing—protocol and editing: Z.G., Z.Z., X.L., S.W., M.L., Q.W., L.W., and J.Z. Funding acquisition: J.Z. All authors read and approved the manuscript.
Role of the funder/sponsor
The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Research registration unique identifying number (UIN)
This protocol has been registered with the PROSPERO (registration ID CRD42023494618). https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=494618.
Guarantor
Jichun Zhou, MD, PhD.
Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Provenance and peer review
Not commissioned; externally peer reviewed.
Acknowledgements
None.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.