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Learn more: PMC Disclaimer | PMC Copyright Notice JAMA Netw Open . 2026 Apr 13;9(4):e265177. doi: 10.1001/jamanetworkopen.2026.5177 Search in PMC Search in PubMed View in NLM Catalog Add to search Tailored Exercise Strategies and Mortality Among Breast Cancer Survivors Jinani Jayasekera Jinani Jayasekera , MS, PhD 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland Find articles by Jinani Jayasekera 1, ✉ , Isaac J Ergas Isaac J Ergas , PhD, MPH 2 Division of Research, Kaiser Permanente Northern California, Pleasanton Find articles by Isaac J Ergas 2 , Jacob Schneider Jacob Schneider , MPH 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland Find articles by Jacob Schneider 1 , Emma Tian Emma Tian , MPH 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland Find articles by Emma Tian 1 , Kaitlyn M Wojcik Kaitlyn M Wojcik , MPH 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland Find articles by Kaitlyn M Wojcik 1 , Janise M Roh Janise M Roh , MPH 2 Division of Research, Kaiser Permanente Northern California, Pleasanton Find articles by Janise M Roh 2 , Jacqueline B Vo Jacqueline B Vo , PhD, RN, MPH 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland Find articles by Jacqueline B Vo 3 , Lawrence H Kushi Lawrence H Kushi , ScD 2 Division of Research, Kaiser Permanente Northern California, Pleasanton Find articles by Lawrence H Kushi 2 , Oliver WA Wilson Oliver WA Wilson , PhD 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland Find articles by Oliver WA Wilson 1 , Emma E McGee Emma E McGee , MS, PhD 4 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 5 Eric and Wendy Schmidt Center, Broad Institute, Massachusetts Institute of Technology and Harvard, Cambridge Find articles by Emma E McGee 4, 5 Author information Article notes Copyright and License information 1 Division of Intramural Research, National Institute on Minority Health and Health, Disparities, National Institutes of Health, Bethesda, Maryland 2 Division of Research, Kaiser Permanente Northern California, Pleasanton 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 4 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 5 Eric and Wendy Schmidt Center, Broad Institute, Massachusetts Institute of Technology and Harvard, Cambridge Accepted for Publication: February 6, 2026. Published: April 13, 2026. doi: 10.1001/jamanetworkopen.2026.5177 Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2026 Jayasekera J et al. JAMA Network Open . ✉ Corresponding Author: Jinani Jayasekera, MS, PhD, Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, Two White Flint, Bethesda, MD 20892 ( [email protected] ). Author Contributions: Drs Jayasekera and McGee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Jayasekera, Wojcik, Wilson, McGee. Acquisition, analysis, or interpretation of data: Jayasekera, Ergas, Schneider, Tian, Wojcik, Roh, Vo, Kushi, McGee. Drafting of the manuscript: Jayasekera, Schneider, Roh, Vo, McGee. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: Schneider, McGee. Obtained funding: Jayasekera, Kushi. Administrative, technical, or material support: Ergas, Schneider, Roh, Wilson. Supervision: Jayasekera, Kushi. Conflict of Interest Disclosures: None reported. Funding/Support: This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). This study was supported by grant ZIA MD000022 from the Division of Intramural Research, National Institute on Minority Health and Health Disparities, NIH (Drs Jayasekera, Wilson, and McGee, Mr Schneider, and Mss Wojcik and Tian). The Pathways Study was funded by grants R01 CA105274 and U01 CA195565 from the National Cancer Institute, NIH. 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 or review of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered works of the US government. However, the findings and conclusions presented in this article are those of the author(s) and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services. Data Sharing Statement: See Supplement 2 . Additional Contributions: We thank the Pathways Study participants for their contributions to this research. ✉ Corresponding author. Received 2025 Nov 3; Accepted 2026 Feb 6; Collection date 2026 Apr. Copyright 2026 Jayasekera J et al. JAMA Network Open . This is an open access article distributed under the terms of the CC-BY License. PMC Copyright notice PMCID: PMC13077521 PMID: 41973424 See commentary " Advancing Breast Cancer Survivorship Through Individualized Exercise Interventions. " on page e265184. Abstract Importance Guidelines recommend tailored (ie, individualized) exercise strategies for cancer survivors. However, there are limited data on the effects of these strategies on long-term mortality outcomes among breast cancer survivors. Objective To estimate the effect of tailored exercise strategies on mortality for breast cancer survivors. Design, Setting, and Participants In this cohort study, a target trial protocol was first specified to approximately mirror the Colon Health and Lifelong Exercise Change (CHALLENGE) trial among breast cancer survivors. Observational data from the Pathways Study were used to emulate this first target trial. These results were then extended by emulating a second target trial of more pragmatic, tailored exercise strategies applied to a broader population of breast cancer survivors. Women enrolled in the Kaiser Permanente Northern California health plan were recruited from January 2006 to December 2013, and were followed up through December 2021. Analyses were performed between September 2024 and September 2025. Exposures Tailored exercise strategies adaptively modified based on evolving characteristics. Main Outcomes and Measures All-cause and breast cancer–specific mortality. Results In the first target trial, there were 959 eligible women (mean [SD] age, 58.3 [12.5] years) and 183 deaths. Compared with a strategy similar to the health education intervention of the CHALLENGE trial, an aerobic exercise strategy was associated with an 8.0 (95% CI, 3.4-13.3)–percentage point lower 8-year all-cause mortality risk, which was compatible with the CHALLENGE trial (7.1 [95% CI, 1.8-12.3]–percentage point lower risk). In the second target trial, there were 2107 eligible women (mean [SD] age, 60.1 [12.1] years) and 321 deaths. Estimated 10-year all-cause mortality ranged from 18.1% to 21.2%. Breast cancer–specific mortality ranged from 7.6% to 10.0%. Compared with no intervention, engaging in a tailored strategy requiring an increase of 60 minutes of vigorous or 120 minutes of moderate aerobic exercise per week was associated with a 3.1 (95% CI, 2.0-4.6)–percentage point lower 10-year all-cause mortality risk and a 2.4 (95% CI, 1.2-3.5)–percentage point lower 10-year breast cancer–specific mortality risk. Conclusions and Relevance In this cohort study using a target trial emulation design, tailored exercise strategies were associated with reductions in 10-year mortality among breast cancer survivors. A randomized trial is warranted to confirm these findings. This cohort study estimates the association of pragmatic, tailored exercise strategies with long-term mortality outcomes in breast cancer survivors. Key Points Question How do tailored (ie, individualized) exercise strategies affect mortality among breast cancer survivors? Findings This cohort study with a target trial emulation design initially included 959 women and approximately replicated the results of the Colon Health and Lifelong Exercise Change randomized trial among breast cancer survivors. These findings were then extended to show that more pragmatic, tailored strategies requiring adaptive increases in exercise levels were associated with lower 10-year all-cause and breast cancer–specific mortality among a broader group of 2107 breast cancer survivors. Meaning These results suggest that clinicians may consider pragmatic, tailored strategies requiring increases in exercise levels that are adapted to the individual characteristics of breast cancer survivors. Introduction Guidelines recommend that clinicians offer individualized (ie, tailored) exercise prescriptions to individuals diagnosed with cancer (cancer survivors). 1 , 2 For instance, the American Cancer Society recommends exercise strategies that include “appropriate and tailored modifications” to accommodate diagnoses and treatment-related issues. 1 Although the Colon Health and Lifelong Exercise Change (CHALLENGE) randomized trial estimated a strong protective effect of a structured recreational exercise intervention on 8-year mortality among 889 colon cancer survivors, 3 to our knowledge, no randomized trial has evaluated the effects of tailored exercise strategies on long-term mortality outcomes among breast cancer survivors. Breast cancer survivors often encounter challenges due to fatigue, pain, lymphedema, and increased cardiovascular risk that may limit their ability to engage in high levels of exercise. 4 , 5 , 6 As a result, it is important to quantify the effects of pragmatic, tailored exercise strategies that require gradual increases in exercise levels and that allow for modifications based on evolving clinical characteristics. Furthermore, to inform clinical practice, it is also important to estimate the effects of these strategies in broad populations of breast cancer survivors. To address these gaps, we aimed to estimate the effects of pragmatic, tailored exercise strategies on long-term mortality outcomes for a broad population of breast cancer survivors. To accomplish this aim, we used observational data from the Pathways Study, 7 a prospective cohort of women diagnosed with breast cancer, to build on the findings of the CHALLENGE trial. 3 First, we specified the protocol of a hypothetical, pragmatic randomized trial that approximately mirrored the CHALLENGE trial but was conducted among breast cancer survivors. We refer to this hypothetical trial as a target trial. 8 Second, we used observational data from the Pathways Study to emulate this first target trial. Third, we used data from the Pathways Study to extend the results of the CHALLENGE trial by emulating a second target trial that aimed to estimate the effects of more pragmatic, tailored exercise strategies in a broader population of breast cancer survivors. 8 , 9 The overarching goal of this study was to provide novel data to support individualized exercise recommendations for breast cancer survivors in clinical settings. Methods This cohort study was approved by the National Institutes of Health Institutional Review Board and was considered exempt research based on use of deidentified preexisting data. This study follows the Transparent Reporting of Studies Emulating a Target Trial (TARGET) reporting guidelines (eMethods 2 in Supplement 1 ). 32 Target Trial 1 Specification Our initial step was to specify the protocol of a target trial among breast cancer survivors that mirrored, to the extent possible, the CHALLENGE trial. eTable 1 in Supplement 1 outlines the protocol of this target trial. Eligibility Criteria Briefly, individuals are eligible for the target trial if they meet the following criteria: (1) women 21 years or older who are members of the Kaiser Permanente Northern California (KPNC) health care system; (2) diagnosed with incident stage II or III invasive breast cancer between 2005 and 2013; (3) no substantial comorbid condition that could preclude participation in an exercise program, defined as a weighted Elixhauser Comorbidity Index of 14 or greater during the 12 months before diagnosis 10 or swelling that interfered with exercise within the past 6 months; (4) currently engaging in less than the equivalent of 150 minutes per week of moderate- to vigorous-intensity recreational aerobic exercise; and (5) no prior history of invasive cancer. Exercise Strategies Each eligible individual is randomly assigned to an exercise strategy that approximately mirrors the recreational aerobic exercise levels achieved under (1) the health education intervention and (2) the recreational aerobic exercise intervention of the CHALLENGE trial (eTable 1 in Supplement 1 ). 3 Interventions are discontinued if and when an individual experiences a disease event, defined as disease recurrence or second primary breast cancer. Women must also respond to follow-up questionnaires administered approximately every 2 years to update information on exercise and other clinical factors. Outcomes, Follow-Up, and Causal Contrasts The outcome of interest is all-cause mortality. Follow-up begins at assignment to an exercise strategy (baseline) and continues until the outcome, loss to follow-up (defined as questionnaire nonresponse), 10 years, or administrative end of follow-up (December 2021), whichever occurs first. The causal contrasts of interest are the intention-to-treat effect and the per-protocol effect of adhering to the strategies throughout the follow-up. Emulation Ideally, we would conduct the randomized target trial outlined in the previous section. However, in the absence of randomized trial data, we used observational data from the Pathways Study, a prospective cohort of women with breast cancer enrolled in the KPNC health plan, to emulate the design and analysis of this trial. Briefly, women in the Pathways Study completed a baseline questionnaire within a median (range) of approximately 2 (0.7-17.8) months after breast cancer diagnosis. 7 , 11 Women were recruited from January 2006 to March 2013, and have since been followed up via electronic health record linkage and periodic questionnaires. The Arizona Activity Frequency Questionnaire 12 was used to measure self-reported exercise at baseline and during follow-up (eTable 2 in Supplement 1 ). Self-reported race and ethnicity were obtained on the baseline questionnaire. 7 Deaths were ascertained from family members, medical records, and KPNC mortality files, which include data from KPNC, the state of California, the Social Security Administration, and the National Death Index. We assumed assignment to an exercise strategy within the Pathways Study was as if randomized conditional on covariates available on the baseline questionnaire or KPNC clinical records. We estimated an observational analogue only of the per-protocol effect because an analogue of the intention-to-treat effect would not be very informative if nonadherence to the exercise strategies was high, which is common in behavioral interventions. 13 Women in the Pathways Study provided informed consent to participate in data collection and longitudinal follow-up. The Pathways Study was approved by the KPNC Institutional Review Board. Target Trial 2 In the second target trial, we used the Pathways data to emulate a trial in which we considered several extensions that allowed us to assess the effects of more pragmatic exercise strategies in a broader population of breast cancer survivors (eTable 1 in Supplement 1 ). These extensions included (1) allowing eligible women to be diagnosed with stage I breast cancer; (2) allowing eligible women to have a prior history of cancer; (3) changing the strategies to consider tailored strategies that required women to increase total aerobic exercise beyond their normal levels for 8 years, unless they developed a serious comorbid condition (defined based on exercise guidelines for cancer survivors and the available observational data) 14 , 15 ; (3) estimating risks over 10 years; and (5) additionally estimating effects on breast cancer–specific mortality. To evaluate which, if any, of these modifications most strongly affected the estimates, we applied each extension sequentially in addition to evaluating them simultaneously. Statistical Analysis In both target trials, we conducted per-protocol analyses to estimate the risks that would have been observed had everyone followed each strategy throughout the entire follow-up with no loss to follow-up. We used the parametric g-formula, 16 , 17 a generalization of standardization that has previously been used to estimate per-protocol effects of lifestyle strategies. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 Risks estimated via the parametric g-formula were used to construct adjusted risk curves and were compared under different exercise strategies via risk differences and ratios at 8 years (target trial 1) or 10 years (target trial 2). In the first target trial, we also estimated hazard ratios over 8 years for comparison with the CHALLENGE trial. 3 Percentile-based 95% CIs were generated using a nonparametric bootstrap with 500 resamples. Details on the covariates and models are provided in eTable 3 in Supplement 1 . Additional information is provided in eMethods 1 in Supplement 1 . Sensitivity Analyses We conducted several sensitivity analyses to evaluate the robustness of our results to key assumptions (eMethods 1 and eTable 4 in Supplement 1 ). These analyses included changing the outcome to questionnaire nonresponse, a negative control outcome that we hypothesized would not be directly affected by exercise but could be similarly confounded. 31 Other Analyses We also estimated the effects of tailored strategies requiring increases in exercise levels among women with any baseline level of exercise. Finally, for comparison with prior observational studies, we estimated outcomes associated with aerobic exercise strategies that were not tailored to evolving characteristics and that required individuals to be insufficiently active, active, or highly active compared with minimally active (eMethods 1 in Supplement 1 ). Analyses were conducted using SAS software, version 9.4 (SAS Institute) with the GFORMULA macro and R software, version 4.4.0 (R Foundation for Statistical Computing). All analyses were performed between September 2024 and September 2025. Results Target Trial 1 A total of 959 women (mean [SD] age, 58.3 [12.5] years; 25 [2.6%] American Indian or Alaskan Native, 123 [12.8%] Asian, 136 [14.2%] Hispanic, 106 [11.3%] non-Hispanic Black, 561 [58.5%] non-Hispanic White, and 8 [0.8%] Pacific Islander) were eligible for the first target trial that approximately mirrored the CHALLENGE trial ( Table 1 ; eFigure 1 in Supplement 1 ). Most participants were postmenopausal (647 [67.5%]), college educated (745 [77.7%]) women with obesity (437 [45.6%]) and were diagnosed with hormone receptor–positive (759 [79.1%]), stage II (709 [73.9%]) breast cancer. Table 1. Baseline Characteristics of Eligible Individuals for the 2 Target Trial Emulations Using Observational Data From the Pathways Study (2005-2021). Characteristic No. (%) of participants a Target trial 1 (n = 959) Target trial 2 (n = 2107) Age, mean (SD), y 58.3 (12.5) 60.1 (12.1) Postmenopausal 647 (67.5) 1550 (73.5) Race and ethnicity American Indian or Alaskan Native 25 (2.6) 41 (1.9) Asian 123 (12.8) 287 (13.6) Hispanic 136 (14.2) 272 (12.9) Non-Hispanic Black 106 (11.3) 192 (9.1) Non-Hispanic White 561 (58.5) 1303 (61.8) Pacific Islander 8 (0.8) 12 (0.6) Educational attainment High school or less 214 (22.3) 445 (21.1) Some college 358 (37.3) 792 (37.6) College graduate 236 (24.6) 534 (25.3) Postcollege 151 (15.7) 336 (15.9) Annual income, $ <25 000 100 (10.4) 247 (11.7) 25 000 to <50 000 205 (21.4) 466 (22.1) 50 000 to <90 000 283 (29.5) 593 (28.1) ≥90 000 241 (25.1) 528 (25.1) Unknown 130 (13.6) 273 (13.0) Aerobic exercise, median (IQR) Moderate aerobic exercise, min/wk 90.0 (26.3-202.5) 90 (30.0-202.5) Vigorous aerobic exercise, min/wk 0.0 (0.0-33.8) 0.0 (0.0-33.8) Total moderate or vigorous aerobic exercise, MET-min/wk 1772.6 (1101.8-2729.3) 1771.9 (1125.0-2730.0) Recreational moderate or vigorous aerobic activity, MET-min/wk 135.0 (0.0-360.0) 135.0 (0.0-360.0) ≥1 Muscle strengthening activity per week 10 (1.0) 37 (1.8) BMI Underweight (<18.5) 11 (1.1) 25 (1.2) Normal weight (≥18.5 to <25) 224 (23.4) 519 (24.6) Overweight (≥25 to <30) 287 (29.9) 617 (29.3) Obese or morbidly obese (≥30) 437 (45.6) 946 (44.9) Smoking status Current smoker 539 (56.2) 1153 (54.7) Quit ≤1 y ago 349 (36.4) 811 (38.5) Never smoker or quit >1 y ago 71 (7.4) 143 (6.8) Weighted Elixhauser Comorbidity Index <0 281 (29.3) 603 (28.6) 0-1 510 (53.2) 1104 (52.4) ≥2 168 (17.5) 400 (19.0) AJCC stage Stage I NA 1117 (53.0) Stage II 709 (73.9) 728 (34.6) Stage III 250 (26.1) 262 (12.4) Lymph node positive 648 (67.6) 677 (32.1) Hormone receptor status ER and PR positive 570 (59.4) 1347 (63.9) ER or PR positive 189 (19.7) 413 (19.6) ER and PR negative 200 (20.9) 347 (16.5) ERBB2 (previously HER2/neu ) status Positive 160 (16.7) 274 (13.0) Negative 770 (80.3) 1752 (83.2) Unknown 29 (3.0) 81 (3.8) Year of diagnosis (calendar year) 2005-2007 367 (38.3) 811 (38.5) 2008-2010 400 (41.7) 857 (40.7) 2011-2013 192 (20.0) 439 (20.8) Treated with hormonal therapy b 686 (71.5) 1527 (72.4) Treated with chemotherapy b 704 (73.4) 972 (46.1) Treated with radiation therapy b 263 (27.4) 896 (42.5) Surgery type b No surgery 54 (5.6) 67 (3.2) Lumpectomy 422 (44.0) 1246 (59.1) Mastectomy 483 (50.4) 794 (37.7) Open in a new tab Abbreviations: AJCC, American Joint Committee on Cancer; BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); ER, estrogen receptor; MET, metabolic equivalent of task; NA, not applicable; PR, progesterone receptor. a Unless otherwise indicated. b Breast cancer treatment and surgery data include initial treatments received during the first 12 months after diagnosis. All-Cause Mortality During the 8-year follow-up, 183 deaths occurred (eTable 5 in Supplement 1 ). The observed risk of all-cause mortality was 24.2%. Using the parametric g-formula, the estimated 8-year risk of all-cause mortality under no intervention was 23.7% (95% CI, 20.1%-26.9%). The estimated 8-year all-cause mortality risk under a strategy that attempted to mirror the exercise levels achieved under the recreational aerobic exercise intervention of the CHALLENGE trial was 15.8% (95% CI, 9.6%-21.1%). Compared with a strategy that attempted to mirror exercise levels achieved under the health education intervention, this strategy was associated with an 8.0 (95% CI, 3.4-13.3)–percentage point lower 8-year risk of all-cause mortality ( Figure 1 and Table 2 ). A similar contrast in the CHALLENGE trial was compatible with these estimates (7.1 [95% CI, 1.8-12.3]–percentage point lower risk). Figure 1. Estimated Risk Curves for All-Cause Mortality Under Different Exercise Strategies in the First Target Trial Emulation, Pathways Study (2005-2021). Open in a new tab Under these strategies, eligible individuals were required to achieve exercise levels similar to those of the health education or recreational aerobic exercise interventions of the Colon Health and Lifelong Exercise Change (CHALLENGE) trial. 3 Table 2. Estimated 8-Year Risks of All-Cause Mortality Under Different Exercise Strategies in the CHALLENGE Trial and in the First Target Trial Emulation Using Observational Data From the Pathways Study (2005-2021) a . Exercise strategy b CHALLENGE trial (n = 889) Target trial 1 (n = 959) 8-y Risk, % (95% CI) Risk difference, % (95% CI) HR (95% CI) 8-y Risk, % (95% CI) Risk difference, % (95% CI) HR (95% CI) Health education intervention 16.8 (NR) 0 [Reference] 1 [Reference] 23.8 (20.0 to 26.9) 0 [Reference] 1 [Reference] Recreational aerobic exercise intervention 9.7 (NR) −7.1 (−12.3 to −1.8) 0.63 (0.43 to 0.94) 15.8 (9.6 to 21.1) −8.0 (−13.3 to −3.4) 0.63 (0.39 to 0.85) Open in a new tab Abbreviations: CHALLENGE, Colon Health and Lifelong Exercise Change; HR, hazard ratio; NR, not reported. a Estimates were obtained using the parametric g-formula, which included baseline covariates (age, race and ethnicity, educational attainment, smoking status, menopausal status, weighted Elixhauser Comorbidity Index, cancer stage, nodal status, hormone receptor status, year of diagnosis, initial treatment with hormonal therapy, initial treatment with chemotherapy, initial treatment with radiotherapy, and initial surgery type) and time-varying covariates (body mass index, muscle-strengthening exercise, recreational aerobic exercise, and development of disease recurrence or second primary breast cancer). b Under these strategies, eligible individuals in the target trial were required to achieve exercise levels similar to those of the health education or recreational aerobic exercise interventions of the CHALLENGE trial. 3 Target Trial 2 A total of 2107 women (mean [SD] age, 60.1 [12.1] years; 41 [1.9%] American Indian or Alaskan Native, 287 [13.6%] Asian, 272 [12.9%] Hispanic, 192 [9.1%] non-Hispanic Black, 1303 [61.8%] non-Hispanic White, and 12 [0.6%] Pacific Islander) were eligible for the second target trial (eFigure 2 in Supplement 1 ). Of these women, 1117 (53.0%) were diagnosed with stage I breast cancer ( Table 1 ). All-Cause Mortality During the 10-year follow-up, 321 deaths occurred (eTable 5 in Supplement 1 ). The observed risk of all-cause mortality was 21.9%. Using the parametric g-formula, the estimated 10-year risk of all-cause mortality under no intervention was 21.2% (95% CI, 18.7%-23.2%). The estimated 10-year all-cause mortality risks under different tailored exercise strategies ranged from 18.1% (95% CI, 15.5%-20.2%) to 20.2% (95% CI, 17.9%-22.1%). The proportion of individuals who would need to increase their exercise levels under these strategies ranged from 88.6% to 100%. Tailored strategies requiring increases in total aerobic exercise were associated with lower all-cause mortality ( Figure 2 and Table 3 ; eFigure 3 in Supplement 1 ). Compared with no intervention, a tailored strategy requiring women to increase their total weekly aerobic exercise by 60 minutes of vigorous or 120 minutes of moderate exercise was associated with a 3.1 (95% CI, 2.0-4.6)–percentage point lower 10-year risk of all-cause mortality. Figure 2. Estimated Risk Curves for All-Cause and Breast Cancer–Specific Mortality Under Different Exercise Strategies in the Second Target Trial Emulation, Pathways Study (2005-2021). Open in a new tab Strategies are tailored based on evolving individual characteristics. That is, individuals are no longer required to increase their aerobic exercise levels if and when they develop myocardial infarction, stroke, congestive heart failure, distant recurrence, or swelling that interferes with exercise. Table 3. Estimated 10-Year Risks of All-Cause and Breast Cancer–Specific Mortality Under Different Tailored Exercise Strategies in the Second Target Trial Emulation, Pathways Study (2005-2021) a . Exercise strategy b All-cause mortality Breast cancer–specific mortality 10-y Risk, % (95% CI) Risk difference, % (95% CI) Risk ratio (95% CI) 10-y Risk, % (95% CI) Risk difference, % (95% CI) Risk ratio (95% CI) No intervention 21.2 (18.7 to 23.2) 0 [Reference] 1.0 [Reference] 10.0 (8.0 to 11.5) 0 [Reference] 1.0 [Reference] Increase total weekly aerobic exercise by 15 min of vigorous or 30 min of moderate exercise 20.2 (17.9 to 22.1) −1.0 (−1.5 to −0.6) 0.95 (0.93 to 0.97) 9.1 (7.5 to 10.7) −0.9 (−1.2 to −0.4) 0.91 (0.88 to 0.96) Increase total weekly aerobic exercise by 30 min of vigorous or 60 min of moderate exercise 19.3 (17.0 to 21.2) −1.9 (−2.7 to −1.1) 0.91 (0.87 to 0.94) 8.5 (6.8 to 10.0) −1.5 (−2.2 to −0.7) 0.85 (0.79 to 0.92) Increase total weekly aerobic exercise by 45 min of vigorous or 90 min of moderate exercise 18.7 (16.3 to 20.6) −2.5 (−3.8 to −1.6) 0.88 (0.83 to 0.92) 8.0 (6.3 to 9.5) −2.0 (−2.9 to −1.0) 0.80 (0.72 to 0.89) Increase total weekly aerobic exercise by 60 min of vigorous or 120 min of moderate exercise 18.1 (15.5 to 20.2) −3.1 (−4.6 to −2.0) 0.86 (0.78 to 0.90) 7.6 (5.9 to 9.2) −2.4 (−3.5 to −1.2) 0.76 (0.66 to 0.87) Open in a new tab a Estimates were obtained using the parametric g-formula, which included baseline covariates (age, race and ethnicity, educational attainment, smoking status, menopausal status, weighted Elixhauser Comorbidity Index, cancer stage, nodal status, hormone receptor status, year of diagnosis, initial treatment with hormonal therapy, initial treatment with chemotherapy, initial treatment with radiotherapy, initial surgery type) and time-varying covariates (body mass index, muscle strengthening exercise, total aerobic exercise, and development of myocardial infarction, stroke, congestive heart failure, distant recurrence, or swelling that interferes with exercise). b Strategies are tailored based on evolving individual characteristics. That is, individuals are no longer required to increase their aerobic exercise levels if and when they develop myocardial infarction, stroke, congestive heart failure, distant recurrence, or swelling that interferes with exercise. Breast Cancer–Specific Mortality During the 10-year follow-up, 139 deaths due to breast cancer occurred. The observed 10-year risk of breast cancer–specific mortality was 10.6%. Using the parametric g-formula, the estimated 10-year risk of breast cancer–specific mortality under no intervention was 10.0% (95% CI, 8.0%-11.5%). Estimated 10-year breast cancer–specific mortality risks under tailored exercise strategies ranged from 7.6% (95% CI, 5.9%-9.2%) to 9.1% (95% CI, 7.5%-10.7%). Tailored strategies requiring increases in total aerobic exercise were associated with lower breast cancer–specific mortality ( Figure 2 and Table 3 ; eFigure 3 in Supplement 1 ). Compared with no intervention, a tailored strategy requiring women to increase their total weekly aerobic exercise by 60 minutes of vigorous or 120 minutes of moderate exercise was associated with a 2.4 (95% CI, 1.2-3.5)–percentage point lower 10-year risk of breast cancer–specific mortality. When we sequentially applied each extension, estimates changed the most when eligible women could be diagnosed with stage I breast cancer (8-year all-cause mortality risk for the recreational aerobic exercise strategy was 6.1 [95% CI, 3.3-9.0] percentage points lower than a strategy based on the health education strategy of the CHALLENGE trial) (eTable 6 in Supplement 1 ) and when the strategies required incremental increases in exercise (eg, 8-year all-cause mortality for an increase of 60 minutes of vigorous or 120 minutes of moderate exercise per week was 2.7 [95% CI, 1.6-3.6] percentage points lower than for no intervention) (eTable 6 in Supplement 1 ). Sensitivity Analyses Estimates for the negative outcome control of questionnaire nonresponse were null (eTable 7 in Supplement 1 ). Results were similar in other sensitivity analyses (eTable 8 and eFigure 4 in Supplement 1 ). Other Analyses Estimates were smaller among women with any baseline level of exercise (eg, 10-year all-cause mortality risk for an increase of 60 minutes of vigorous or 120 minutes of moderate exercise per week was 1.5 [95% CI, 0.9-2.5] percentage points lower than for no intervention) (eTable 9 in Supplement 1 ). Estimates were larger under strategies requiring women to be insufficiently active, active, or highly active compared with minimally active (eg, 10-year all-cause mortality risk for highly active was 16.2 [95% CI, 7.4-24.6] percentage points lower than for minimally active) (eTable 10 in Supplement 1 ). Discussion We used observational data to emulate a target trial that approximately replicated the results of the CHALLENGE trial 3 among breast cancer survivors. Next, we extended these findings to consider the effects of more pragmatic, tailored exercise strategies in a second target trial that was emulated in a broader population. We found that both all-cause and breast cancer–specific mortality risks were lower under tailored strategies that required women to increase their exercise levels only until they were diagnosed with a potentially serious condition. Estimated mortality risks were lowest under a strategy that required increases of 60 minutes of vigorous or 120 minutes of moderate exercise per week. However, meaningful risk reductions were also observed for strategies that required more modest increases in exercise. These findings are relevant for the clinical management of breast cancer because documentation of exercise recommendations by a medical oncologist is now required for the national accreditation of breast cancer centers in the US. 33 However, less than 40% of US health care professionals report having discussed exercise with cancer survivors, 34 in part due to lack of confidence in current research. 35 , 36 Previous research 37 also suggests that clinicians need to be better equipped to prescribe tailored exercise strategies to breast cancer survivors. Our findings could potentially support such discussions. Although no randomized trial has evaluated the long-term effects of exercise on mortality among breast cancer survivors, we used observational data to replicate the protective estimates of the CHALLENGE trial 3 among individuals newly diagnosed with breast cancer. These observational findings are important because, although randomized trials are the preferred option, they are difficult to conduct. For example, the CHALLENGE trial took 15 years to recruit 889 patients across 6 countries. Trials also often recruit a select group of cancer survivors (eg, individuals with stage II or III disease, as in the CHALLENGE trial, 3 or individuals with obesity, as in the Breast Cancer Weight Loss [BWEL] trial). 38 In contrast, we included a broad range of women, including women with stage I disease, who represent a large proportion of the breast cancer survivors in the US. 39 We were also able to estimate the effects of 5 different exercise strategies, sustained for up to 8 years, on 10-year mortality risks. Although it would be logistically challenging to estimate these effects in a randomized trial, our results highlight the need for a trial to confirm these findings. Several prior observational studies 30 , 40 , 41 , 42 , 43 have also reported that high levels of exercise are associated with lower mortality among breast cancer survivors. However, with few exceptions, 30 , 43 estimates from prior observational studies 40 , 41 , 42 are difficult to interpret because the analyses do not correspond to interventions that are currently used. For example, many prior studies 40 , 41 , 42 have relied on exercise categories that cannot be mapped to realistic recommendations for breast cancer survivors because the categories often imply hypothetical interventions that would require active, healthy women to decrease their exercise. When we emulated similar strategies, we found estimates that were larger than those reported in the CHALLENGE trial (eTable 10 in Supplement 1 ). Furthermore, prior studies frequently relied on a single measurement of exercise (which precludes the assessment of sustained exercise behaviors), assessed associations with prediagnostic exercise (which does not correspond to an actionable intervention because an individual with cancer cannot change their exercise before diagnosis), or did not consider strategies that are realistically tailored to evolving characteristics (which can introduce substantial bias if, as is expected, some individuals are unable to continuously sustain high levels of exercise due to comorbidities or other characteristics). 43 In contrast to these prior observational studies, we specified the protocols of 2 target trials with realistic, tailored exercise strategies that were sustained over time 43 and then emulated them using high-quality observational data. We leveraged a unique dataset that combined the strengths of electronic health records and questionnaire data to enhance the ascertainment of both clinical and exercise variables. Our target trial approach avoided common design-related biases and improved the interpretability of the estimates because they can be mapped to an intervention that can actually be implemented. We also used the parametric g-formula, a method that appropriately accounts for time-varying confounders that may be affected by prior exercise, facilitates the incorporation of competing events within a causal framework, and allows for the emulation of strategies that are tailored based on time-varying characteristics. Our results using these approaches were compatible with 2 previous studies 30 , 43 applying a similar causal inference framework to evaluate the effects of hypothetical interventions on exercise and other lifestyle factors. However, in contrast to these prior studies, 30 , 43 we began by approximately replicating the results of an existing randomized trial, which increased our confidence in the validity of the observational data. Furthermore, the strategies we emulated in the second target trial required incremental, individualized increases in exercise levels above a woman’s current levels, which may be an attainable goal for breast cancer survivors. Limitations Although our study has several strengths, it also has limitations. First, as in any observational analysis, we cannot rule out potential unmeasured confounding. For example, there could be unmeasured confounding due to other lifestyle factors (eg, sleep and alcohol use) or if women who were less likely to die were also more likely to engage in high levels of exercise (sometimes referred to as healthy adherer bias). However, we used several approaches to allay potential confounding concerns 44 : (1) we approximately replicated the results of a randomized trial in a different population, (2) we specified strategies that realistically allowed women to engage in as much exercise as they were able after the diagnosis of a serious condition, and (3) we carefully adjusted for a broad array of potential baseline and time-varying confounders, including demographic factors such as educational attainment, race, and ethnicity. We also illustrated similar results across several sensitivity analyses, including analyses that can be unbiased in the presence of unmeasured confounding. 27 Second, we were unable to replicate every aspect of the CHALLENGE trial due to irreconcilable differences between the observational data and the trial, which precluded a more formal benchmarking effort. 45 For example, the CHALLENGE trial was restricted to individuals who had recently completed adjuvant chemotherapy, which we were unable to replicate with the available observational data. Third, we cannot rule out other potential biases, such as measurement error, selection bias, or model misspecification. However, we used previously validated exercise data 12 and adjusted for potential selection bias due to loss to follow-up using the parametric g-formula and a rich set of covariates. Our results were also similar in multiple sensitivity analyses assessing these biases. Fourth, because women only reported exercise after diagnosis, we were unable to directly adjust for prediagnostic exercise. Nevertheless, in an auxiliary dataset with prediagnostic data, results were similar with vs without adjustment for prediagnostic behaviors. 43 Fifth, our strategies focused on increases in individual exercise levels. However, achieving and sustaining these individual increases may require changes in clinical, social, and environmental factors. Sixth, because we used as a comparator in the second target trial the risk under usual exercise among women with low baseline exercise levels in the Pathways Study (ie, no intervention) and specified strategies that required women to increase their exercise beyond what they were already doing, our estimates may not be transportable to populations with different exercise patterns or baseline risks of mortality. Specifically, women in the Pathways Study represent an insured population receiving care through an integrated health care system in California, which does not reflect the experience of all breast cancer survivors in the US. 46 , 47 Conclusions In this cohort study with a target trial emulation design, we used observational data to replicate the results of a randomized trial in a new population and then estimated meaningful decreases in mortality under more pragmatic, tailored exercise strategies that required women diagnosed with stage I to III breast cancer to increase their exercise levels. These findings could help inform decisions about tailored exercise strategies that are adapted to evolving individual characteristics. Supplement 1. eMethods 1. Supplemental methods eTable 1. Summary of the CHALLENGE randomized trial, specification of the target trial that approximately mirrored it, and two target trial emulations eTable 2. List of exercise activities included in the Arizona Activity Frequency Questionnaire eTable 3. Summary of covariates and models used in the two target trial emulations eTable 4. Summary of sensitivity analyses implemented in the second target trial emulation eTable 5. Number of individuals who were at risk, died and censored by follow-up interval in the first and second target trial emulations eTable 6. Sequential application of extensions to target trial 1 eTable 7. Sensitivity analysis changing the outcome to questionnaire non-responses (negative outcome control) eTable 8. Other sensitivity analyses eTable 9. Estimates among women with any baseline level of exercise eTable 10. Strategies requiring women to be insufficiently active, active, or highly active, as compared with minimally active eFigure 1. Flowchart of eligible individuals for the first target trial emulation eFigure 2. Flowchart of eligible individuals for the second target trial emulation eFigure 3. 10-year risk differences for all-cause and breast cancer-specific mortality comparing increases in aerobic exercise vs. no increase (i.e. usual aerobic exercise) in the second target trial emulation eFigure 4. Comparison of inverse probability weighted vs. parametric g-formula estimates of means of the time-varying covariates under no intervention (i.e., usual exercise levels) in the second target trial emulation eMethods 2. TARGET checklist eReferences jamanetwopen-e265177-s001.pdf (1,005.4KB, pdf) Supplement 2. Data Sharing Statement jamanetwopen-e265177-s002.pdf (16.9KB, pdf) References 1. Rock CL, Thomson CA, Sullivan KR, et al. American Cancer Society nutrition and physical activity guideline for cancer survivors. 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Summary of the CHALLENGE randomized trial, specification of the target trial that approximately mirrored it, and two target trial emulations eTable 2. List of exercise activities included in the Arizona Activity Frequency Questionnaire eTable 3. Summary of covariates and models used in the two target trial emulations eTable 4. Summary of sensitivity analyses implemented in the second target trial emulation eTable 5. Number of individuals who were at risk, died and censored by follow-up interval in the first and second target trial emulations eTable 6. Sequential application of extensions to target trial 1 eTable 7. Sensitivity analysis changing the outcome to questionnaire non-responses (negative outcome control) eTable 8. Other sensitivity analyses eTable 9. Estimates among women with any baseline level of exercise eTable 10. Strategies requiring women to be insufficiently active, active, or highly active, as compared with minimally active eFigure 1. Flowchart of eligible individuals for the first target trial emulation eFigure 2. Flowchart of eligible individuals for the second target trial emulation eFigure 3. 10-year risk differences for all-cause and breast cancer-specific mortality comparing increases in aerobic exercise vs. no increase (i.e. usual aerobic exercise) in the second target trial emulation eFigure 4. Comparison of inverse probability weighted vs. parametric g-formula estimates of means of the time-varying covariates under no intervention (i.e., usual exercise levels) in the second target trial emulation eMethods 2. TARGET checklist eReferences jamanetwopen-e265177-s001.pdf (1,005.4KB, pdf) Supplement 2. Data Sharing Statement jamanetwopen-e265177-s002.pdf (16.9KB, pdf) Articles from JAMA Network Open are provided here courtesy of American Medical Association ACTIONS View on publisher site Cite Collections Permalink PERMALINK Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Add to Collections Create a new collection Add to an existing collection Name your collection * Choose a collection Unable to load your collection due to an error Please try again Add Cancel Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top