Objective: This systematic review update synthesized recent evidence on the benefits and harms of breast cancer screening in women aged 40 years and older and aims to inform the Canadian Task Force on Preventive Health Care's (CTFPHC) guideline update. Methods: We searched Ovid MEDLINE ALL, Embase Classic+Embase, and Cochrane Central Register of Controlled Trials to update our searches to July 8, 2023. Search results for observational studies were limited to publication dates from 2014 to capture more relevant studies. Screening was performed independently and in duplicate by the review team. To expedite the screening process, machine learning was used to prioritize relevant references. Critical health outcomes, as outlined by the CTFPHC, included breast cancer and all-cause mortality, treatment-related morbidity, and overdiagnosis. Randomized controlled trials (RCTs), non/quasi RCTs, and observational studies were included. Data extraction and quality assessment were performed by one reviewer and verified by another. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool for RCTs and the Joanna Brigg's Institute (JBI) checklists for non-randomized and observational studies. When deemed appropriate, studies were pooled via random-effects models. The overall certainty of the evidence was assessed following GRADE guidance. Results: Three new papers reporting on existing RCT trial data and 26 observational studies were included. No new RCTs were identified in this update. No study reported results by ethnicity, race, proportion of study population with dense breasts, or socioeconomic status. For breast cancer mortality, RCT data from the prior review reported a significant relative reduction in the risk of breast cancer mortality with screening mammography for a general population of 15% (RR 0.85 95% CI 0.78 to 0.93). In this review update, the breast cancer mortality relative risk reduction based on RCT data remained the same, and absolute effects by age decade over 10 years were 0.27 fewer deaths per 1,000 in those aged 40 to 49; 0.50 fewer deaths per 1,000 in those aged 50 to 59; 0.65 fewer deaths per 1,000 in those aged 60 to 69; and 0.92 fewer deaths per 1,000 in those aged 70 to 74. For observational data, the relative mortality risk reduction ranged from 29% to 62%. Absolute effects from breast cancer mortality over 10 years ranged from 0.79 to 0.94 fewer deaths per 1,000 in those aged 40 to 49; 1.45 to 1.72 fewer deaths per 1,000 in those aged 50 to 59; 1.89 to 2.24 fewer deaths per 1,000 in those aged 60 to 69; and 2.68 to 3.17 fewer deaths per 1,000 in those aged 70 to 74. For all-cause mortality, RCT data from the prior review reported a non-significant relative reduction in the risk of all-cause mortality of screening mammography for a general population of 1% (RR 0.99, 95% CI 0.98 to 1.00). In this review update, the absolute effects for all-cause mortality over 10 years by age decade were 0.13 fewer deaths per 1,000 in those aged 40 to 49; 0.31 fewer deaths per 1,000 in those aged 50 to 59; 0.71 fewer deaths per 1,000 in those aged 60 to 69; and 1.41 fewer deaths per 1,000 in those aged 70 to 74. No observational data were found for all-cause mortality. For overdiagnosis, this review update found the absolute effects for RCT data (range of follow-up between 9 and 15 years) to be 1.95 more invasive and in situ cancers per 1,000, or 1 more invasive cancer per 1,000, for those aged 40 to 49 and 1.93 more invasive and in situ cancers per 1,000, or 1.18 more invasive cancers per 1,000, for those aged 50 to 59. A sensitivity analysis removing high risk of bias studies found 1.57 more invasive and in situ cancers, or 0.49 more invasive cancers, per 1,000 for those aged 40 to 49 and 3.95 more invasive and in situ cancers per 1,000, or 2.81 more invasive cancers per 1,000, in those aged 50 to 59. For observational data, one report (follow-up for 13 years) found 0.34 more invasive and in situ cancers per 1,000 in those aged 50 to 69. Overall, the GRADE certainty of evidence was assessed as low or very low, suggesting that the evidence is very uncertain about the effect of screening for breast cancer on the outcomes evaluated in this review. Conclusions: This systematic review update did not identify any new trials comparing breast cancer screening to no screening. Although 26 new observational studies were identified, the overall quality of evidence remains generally low or very low. Future research initiatives should prioritize studying screening in higher risk populations such as those from different ages, racial or ethnic groups, with dense breasts, or family history.

Competing interests: Dr. Anna Wilkinson is a consultant for Thrive Health, Survivor Advisor and has received honoraria from Cancer Care Ontario/The Ottawa Hospital: Regional Cancer Primary Care Lead. Dr. David Moher was previously Co-Editor-in-Chief with Systematic Reviews.

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Funding for this systematic review was provided by the Public Health Agency of Canada. This funding supported all phases of conduct of the evidence review, including the search and selection of the evidence, collection of the data, data management, analyses, and writing. The funder was involved in the development of the protocol and reviewed a draft version of the manuscript but did not take part in the conduct of the systematic review. Final decisions were made by the review team. The views expressed herein do not necessarily represent the views of the Government of Canada.

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