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      Salivary biomarkers in breast cancer diagnosis: A systematic review and diagnostic meta‐analysis

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          Abstract

          Background

          Salivary diagnostics and their utility as a nonaggressive approach for breast cancer diagnosis have been extensively studied in recent years. This meta‐analysis assesses the diagnostic value of salivary biomarkers in differentiating between patients with breast cancer and controls.

          Methods

          We conducted a meta‐analysis and systematic review of studies related to salivary diagnostics published in PubMed, EMBASE, Scopus, Ovid, Science Direct, Web of Science (WOS), and Google Scholar. The articles were chosen utilizing inclusion and exclusion criteria, as well as assessing their quality. Specificity and sensitivity, along with negative and positive likelihood ratios (NLR and PLR) and diagnostic odds ratio (DOR), were calculated based on random‐ or fixed‐effects model. Area under the curve (AUC) and summary receiver‐operating characteristic (SROC) were plotted and evaluated, and Fagan's Nomogram was evaluated for clinical utility.

          Results

          Our systematic review and meta‐analysis included 14 papers containing 121 study units with 8639 adult subjects (4149 breast cancer patients and 4490 controls without cancer). The pooled specificity and sensitivity were 0.727 (95% CI: 0.713–0.740) and 0.717 (95% CI: 0.703–0.730), respectively. The pooled NLR and PLR were 0.396 (95% CI: 0.364–0.432) and 2.597 (95% CI: 2.389–2.824), respectively. The pooled DOR was 7.837 (95% CI: 6.624–9.277), with the AUC equal to 0.801. The Fagan's nomogram showed post‐test probabilities of 28% and 72% for negative and positive outcomes, respectively. We also conducted subgroup analyses to determine specificity, sensitivity, DOR, PLR, and NLR based on the mean age of patients (≤52 or >52 years old), saliva type (stimulated and unstimulated saliva), biomarker measurement method (mass spectrometry [MS] and non‐MS measurement methods), sample size (≤55 or >55), biomarker type (proteomics, metabolomics, transcriptomics and proteomics, and reagent‐free biophotonic), and nations.

          Conclusion

          Saliva, as a noninvasive biomarker, has the potential to accurately differentiate breast cancer patients from healthy controls.

          Abstract

          Our meta‐analysis showed that saliva might be a promising, efficient, and noninvasive biomarker with the potential to differentiate between patients with and without breast cancer. Subgroup analyses were done to determine sensitivity, specificity, PLR, NLR, and DOR based on the mean age of patients, saliva type (stimulated and unstimulated saliva), biomarker measurement method (mass spectrometry [MS] and non‐MS measurement methods), sample size, biomarker type (proteomics, metabolomics, transcriptomics and proteomics, and reagent‐free biophotonic), and nations. Unstimulated saliva has a more acceptable diagnostic value compared to stimulated saliva in breast cancer.

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          Most cited references81

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Bias in meta-analysis detected by a simple, graphical test

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              QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

              In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
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                Author and article information

                Contributors
                m_koopaie@tums.ac.ir , mariakoopaie@gmail.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                22 March 2022
                July 2022
                : 11
                : 13 ( doiID: 10.1002/cam4.v11.13 )
                : 2644-2661
                Affiliations
                [ 1 ] Tehran University of Medical Sciences Tehran Iran
                [ 2 ] USERN, Tehran University of Medical Sciences Tehran Iran
                [ 3 ] Department of Diagnostic Sciences Rutgers School of Dental Medicine Newark New Jersey USA
                [ 4 ] Cancer Research Center, Cancer Institute of Iran Tehran Iran
                Author notes
                [*] [* ] Correspondence

                Maryam Koopaie, Assistant Professor, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran.

                Email: m_koopaie@ 123456tums.ac.ir ; mariakoopaie@ 123456gmail.com

                Author information
                https://orcid.org/0000-0002-9999-1443
                Article
                CAM44640 CAM4-2021-11-4633.R2
                10.1002/cam4.4640
                9249990
                35315584
                b5f709ea-3012-4792-ad1a-1a1afcb7c4e7
                © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 December 2021
                : 15 November 2021
                : 02 January 2022
                Page count
                Figures: 11, Tables: 3, Pages: 18, Words: 7887
                Categories
                Review
                REVIEW
                Cancer Prevention
                Custom metadata
                2.0
                July 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:02.07.2022

                Oncology & Radiotherapy
                biomarker,breast cancer,diagnosis,meta‐analysis,saliva
                Oncology & Radiotherapy
                biomarker, breast cancer, diagnosis, meta‐analysis, saliva

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