Edited by: Maria Rosaria De Miglio, University of Sassari, Italy
Reviewed by: Tibor Tot, Falun Hospital, Sweden; Marco Fogante, Marche Polytechnic University, Italy; Min Yan, Henan Provincial Cancer Hospital, China
*Correspondence: Ailin Song,
†These authors have contributed equally to this work
This article was submitted to Breast Cancer, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This systematic review and meta-analysis compares the outcome between MMBC and unifocal breast cancer (UFBC), in order to provide a theoretical basis for the design of an appropriate clinical therapeutic strategy of MMBC patients.
PubMed, Embase, The Cochrane Library, Web of science, CNKI, WanFang Data, CBM and VIP database were searched from inception to July 2021, and observational studies reporting the outcome of patients with MMBC and UFBC were included. We extracted or calculated the mortality rates of MMBC and UFBC patients; and obtained the hazard ratios; odds ratios; relative risks; and the corresponding 95% confidence intervals from the eligible studies. All the meta-analyses were conducted by using the Stata 15.0 software.
31 eligible studies comprising a total of 15,703 individuals were included. The meta-analysis revealed that MMBC did not have a significant association with poor overall survival (
Patients with MMBC appeared to have a higher risk of death, however, it may not be independently associated with poorer outcomes. Considering the inter-study heterogeneity and other limitations, our results need to be validated by further multicenter prospective studies with a large sample size in the future.
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In 2020, the estimated number of new breast cancer cases was about 2.26 million and cancer deaths were projected to be around 0.68 million worldwide (
Breast cancer usually presents as a single lesion, but in unilateral breast cancer, multiple lesions may appear simultaneously or sequentially. To enable further study and differentiate it from the subtypes with only one separate lesion - unifocal breast cancer (UFBC), researchers have subdivided such cases into two categories. The first one is multicentric breast cancer (MCBC), wherein two or more tumors are present in more than one quadrant of the same breast, but some researchers suggest that regardless of whether the different lesions are present in multiple quadrants of the same breast, those separated by >4-5 cm from each other should be called MCBC (
At present, the prevalence of MMBC ranges between 6% - 77% (
Thus, the current study summarizes the studies related to the comparison of prognosis between MMBC and UFBC patients, and synthesizes a systematic review and meta-analysis to evaluate the differences in the prognosis, in order to provide a theoretical basis for the design of an appropriate therapeutic strategy for treating MMBC patients.
The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (
The inclusion criteria for the study were as follows: (1) Participants: female patients with pathologically proven stages I-III of unilateral invasive breast cancer, aged ≥18 years, without contralateral breast cancer, without distant metastases, without any previous or concomitant malignant disease, without any limitation due to race or nationality; (2) Exposure: patients with clinically or image-based or pathologically diagnosed MMBC or UFBC; (3) Outcomes: mortality rates of MMBC and UFBC, overall survival (OS), disease-free survival (DFS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), local recurrence-free survival (LRFS), risk of contralateral breast cancer (CBC); (5) Type of study: case-control and cohort studies.
The exclusion criteria were as follows: (1) articles without a clear definition of MMBC; (2) MFBC or MCBC only; (3) duplicate articles; (4) articles published in languages other than English or Chinese.
The following eight electronic databases were independently searched by two researchers (YLZ and FL) and the timeline was set at July 2021: PubMed; Embase; the Cochrane Library; Web of Science; CNKI; WanFang Data; CBM; and the VIP database. The references of the included studies and previous MMBC related systematic reviews were also checked, and the relevant literature was manually added if available. Before the final analyses, we re-searched the literature to ensure that any study meeting the inclusion criteria was included as far as possible. The detailed search strategies are showed in
Two researchers (YLZ and FL) checked all the collected studies independently and if there was any disagreement between them, a discussion or the third reviewer (QQG)’s decision was taken into account. All the retrieved literature were imported into Endnote X9 software. After removing the duplicates, we firstly screened the articles by the title and abstract and then identified the final included studies through the full-text reading of previously screened literature. Then, we recorded the reasons for excluding the literature in the last two steps.
Three researchers were involved in the data collection task. Two of them (YLZ and FL) independently collected the data from the included studies and recorded them in a pre-defined spreadsheet by using the Microsoft Excel 2021 software. The differences of opinion were discussed, and if they were still unresolved, a third Reviewer (QQG)’s opinion was taken into account. We extracted the following information from the included studies: (1) the first author’s name and the publication year, region where the study was conducted, study design, and recruitment period; (2) the sample size and age; (3) follow-up time; (4) definition of MMBC; (5) the AJCC edition used for the T-staging; (7) mortality rates of MMBC and UFBC patients. If the data needed further confirmation, the corresponding author of the article was contacted by email.
The risk of bias was assessed by using the Newcastle-Ottawa Scale (NOS) (
In this study, we extracted or calculated the mortality rates for MMBC and UFBC patients, and the
The eight databases were searched and a total of 15,703 articles were retrieved. After removing the duplicate articles, 10,027 were available for further screening. 9933 articles were excluded after browsing the titles and abstracts, and the full-text was examined for 94 studies. Lastly, 31 articles (
Flowchart of literature selection.
Among the included studies, four (
The quality of the included studies was evaluated using the NOS scale. Seventeen studies (
9 studies (
Forest plot of OS comparing MMBC and UFBC.
In total, four studies (
Forest plot of DFS comparing MMBC and UFBC.
Four studies (
Forest plot of BCSS comparing MMBC and UFBC.
The analysis of
Forest plot of RFS comparing MMBC and UFBC.
For LRFS, three studies (
Forest plot of LRFS comparing MMBC and UFBC.
10 studies (
Forest plot of the mortality rates of MMBC versus UFBC patients.
Only one study (
In this review, we pooled the data for MMBC and UFBC with regards to the OS, DFS, RFS, BCSS, LRFS, mortality, and CBC aspects and performed a meta-analysis. The final results showed that MMBC patients had a similar prognosis as the UFBC patients, except for a slightly higher mortality rate.
In this paper, we found that MMBC patients had a slightly higher mortality rate than the UFBC patients (
The findings from the current study showed that there were no significant differences between UFBC and MMBC patients in terms of the OS, DFS, RFS, BCSS, and LRFS in multivariate analysis, which may be due to the fact that MMBC per se is not associated with a worse prognosis. It was reported that the MMBC patients were younger, had larger tumors, had greater involvement of lymph nodes, and many of them were in pre-menopausal stage in comparison to the UFBC patients (
For the multivariate analysis of RFS, LRFS and BCSS, the general trend supported the finding that MMBC patients had a similar prognosis to that of UFBC patients. However, only few studies were included in these outcome indicators, which may affects the results reliability. A study on outcomes in 1163 MFBC/UFBC patients reported that MFBC was independently significantly associated with LRFS, DFS, and OS, but this study did not adjust for pathologic stage, T stage and nodal status (
Our meta-analysis results on DFS and BCSS indicated a significant and substantial heterogeneity among the included studies. And we think clinical factors cause heterogeneity mainly. With fewer studies included under each outcome indicators, the subgroup analysis may not produce meaningful results. But a decreased heterogeneity was also seen when we attempted to perform subgroup analysis based on some clinical factors (
Among the included studies, only one study (
Breast cancer is a heterogeneous group of diseases with regard to clinical manifestation, tumor morphology, and immunohistochemical differences within tumors (
In this systematic review and meta-analysis, several studies were included to assess the difference in the prognosis between MMBC and UFBC patients. Here, we searched eight databases using a relatively broad terminology and our search strategy ensured as far as possible, that none of the potentially relevant studies were excluded. However, the current study suffers from some limitations. First, most of the included studies were retrospective cohort studies which may existed selection bias and data analysis bias. Second, the definition and diagnostic criteria of MMBC was not completely consistent across all the included studies. These discrepancies affected the detection of MMBC, and it could have affected the reliability of the meta-analysis results. Third, as the heterogeneity among the included studies were significant and fewer studies were included under some of the outcome indicators, the source of heterogeneity was difficult to determine and limited the accuracy of our findings further. Finally, the limitation of the choice of language could have increased the publication or language bias.
In summary, patients with MMBC appeared to have a higher risk of death, however, it may be not independently associated with poor OS, DFS, RFS, BCSS, LRFS, and CBC risk. With appropriate surgical interventions and adjuvant therapies, the prognosis of patients with MMBC and UFBC was similar, but the prognostic impact of every lesion in MMBC still needs further investigation. Further multicenter prospective studies with larger sample size are needed for validating the findings from the current study.
The original contributions presented in the study are included in the article/
All authors contributed to the study conception and design. Study selection, data extraction and analysis were performed by YZ, FL and QG. The first draft of the manuscript was written by YZ and all authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.
This study was supported by Natural Science Foundation of Gansu Province, China (grant number: 20JR5RA342).
The authors would like to thank all the reviewers who participated in the review, as well as the Science and Technology Department of Gansu Province, the Center for Evidence-Based Medicine of Lanzhou University and the Second Hospital of Lanzhou University for their support.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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