Trajectories of Objectively Measured Physical Function Among Older Breast Cancer Survivors in Comparison With Cancer-Free Controls

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Carter, Elizabeth M Cespedes Feliciano, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-768755/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2022 Read the published version in Breast Cancer Research and Treatment → Version 1 posted 4 You are reading this latest preprint version Abstract PURPOSE: Aging associated with progressive declines in physical function is well-known; however, little is known about the trajectories of physical function before and after breast cancer diagnosis. The current study examined the trajectories in objective measures of physical function over 20 years for women with breast cancer and matched controls. METHODS: 2712 community-dwelling women (452 breast cancer cases and 1:5 matched cancer-free controls) aged 65 years or older at baseline (1986-1988) within the Study of Osteoporotic Fractures were followed for 20 years. Objective physical function was assessed up to 9 times, including hand-grip strength, timed chair stand, gait speed and quadriceps strength. Linear mixed models were used to model physical function changes in terms of secular time trend, group (cases or controls), period (pre-and post-diagnosis status), and their interaction terms. RESULTS: We observed all measures of physical function declined over time. While no differences in trends between cases and controls during the pre-diagnosis period were observed, after cancer diagnosis, grip strength and gait speed declined significantly faster in cases than controls. Quadriceps strength significantly decreased ~7 pounds shortly after breast cancer diagnosis, and then improved over time. CONCLUSION : Our prospective study revealed that older breast cancer survivors had significantly worse declines in grip strength and gait speed and a sharp, short-term drop followed by gradual improvement over time in quadriceps strength, compared to women without cancer. These findings suggest exercise training targeting muscle strength and mobility would be beneficial among older breast cancer survivors. Cancer Biology Breast cancer cancer survivors physical function trajectories physical function decline Figures Figure 1 Background Breast cancer is the most common cancer among women in the US and worldwide [1]. With advances in early detection and treatment, the 5-year survival rate for all stages combined has reached more than 90% in the United States (US) [2]. As a result, there are more than 3.8 million breast cancer survivors in the US with further increases projected due to an aging population. Despite improving survival, a growing body of evidence suggests that breast cancer survivors are uniquely confronted with an array of physical and psychosocial health problems after cancer treatment [3–8]. The contribution of cancer to objective physical function trajectory remains largely unknown. Several studies reported that women diagnosed with breast cancer experience a significant loss in physical function beyond the age-related decline observed in women without cancer diagnosis [9–12]. Other studies have indicated that the negative effects of breast cancer appeared to decrease with time [13–15]. However, the assessment of physical function in these studies employed self-report, known to be subject to bias. Alternatively, objectively measured physical function may include more accurate indicators of physical function better suited to reflect changes in function before problems are reported by an individual. Furthermore, objective measures of physical function can assess different components of status including gait speed and grip strength. To our knowledge, no prospective study has examined objectively measured physical function changes among older breast cancer survivors. Herein, secondary analyses were performed on the Study of Osteoporotic Fractures, a longitudinal investigation with more than 20 years of follow-up and repeated measures of objectively measured physical function to examine whether breast cancer occurrence contributes to a decline in physical function. Cancer-free women were also included to account for the attendant effects of usual aging. Given the accelerated aging may be attributed to the direct and indirect effects of cancer treatment, we hypothesized that the trajectory of age-related physical function declines would be greater among breast cancer survivors compared with women without cancer [16, 17]. Understanding the trajectory of breast cancer on objectively measured physical function can inform supportive interventions to improve specific components of health status among the growing population of older breast cancer survivors. Methods Study of Osteoporotic Fractures The Study of Osteoporotic Fractures (SOF) is a prospective study of risk factors for fractures and other health outcomes among community-dwelling older women. Details of the SOF cohort and study procedures have been published elsewhere [18]. Briefly, 9704 community-dwelling, ambulatory white women aged 65 years or older were recruited between 1986 and 1988 from population-based lists in Baltimore, Minneapolis, Pittsburgh and Portland. Those unable to walk without assistance or with bilateral hip replacements were excluded. Examination, interviews and questionnaires were performed at enrollment and at follow-up visits approximately every 2 years over 20 years of follow-up with a total of 9 measures. At each site, the institutional review boards approved the study, and all participants provided written informed consent. Study population For the purposes of our analysis, we considered all 9704 women who were initially recruited between 1986 and 1988 to ensure enough repeated measures. We excluded 31 women who had a non-released high value for age > 90 at baseline, 724 women who were lost to follow-up, 281 women who ever had a stroke or prevalent cancer at baseline, and 158 women with missing covariates. Of the remaining 8510, 452 women were diagnosed with an incident, invasive breast cancer during follow-up, confirmed through physician review of medical records. Each breast cancer case was matched with five cancer-free controls based on age at baseline and person-time of follow-up. Controls must have been followed at least as long as the case to be considered as a match [19]. A total of 2712 nested case-control individuals (452 breast cancer cases and 2260 controls) were included for further analysis. For each control, we assigned an index time as the date of breast cancer event for her matched case. Objectively measured physical function Hand-grip strength, gait speed and timed chair stand were measured during every visit with 9 repeated assessments. Grip strength was measured in both hands at each clinical site visit using a hand-held isometric dynamometer (Sparks Instruments and Academics, Coralville, Iowa) and a standard protocol. Both the max and the average of both hands (in kilograms) were used in the analysis. Timed chair stand (in seconds) was measured as the time to rise from a 16-inch height chair and sit down as quickly as possible five times without the use of arms according to a standard protocol. Gait speed (in meters per second) and step length (in meters) were assessed by a timed 6-meter walk according to a standard protocol. Participants were asked to walk at their usual pace and at their rapid pace, and the time and number of steps for both of their usual pace and their rapid pace were recorded. Quadriceps strength was measured at visit 2,3,4, 6 and 7, measured in pounds as the peak and the average force of the right and left limbs (Body Masters; Lafayette Instruments, Lafayette, Ind). All repeated measurements on physical function were used. For participants who were diagnosed with breast cancer during follow-up, measures preceding the cancer diagnosis were defined as pre-diagnosis measures, and measures following cancer diagnosis were defined as post-diagnosis measures. For the matched controls, we defined the pre- and post- diagnosis measures in the same way as their corresponding cases at their index date corresponding to cases. In addition, we also identified pre and post-diagnosis measures that were closest to the breast cancer diagnosis date for each individual to assess short-term change associated with cancer diagnosis. Covariates included age (in continuous years), education level (< 12 years, 12 years, 13–16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, < 10, 1–<30, 30-=50), history of hypertension (yes, no) and diabetes (yes, no). Age was assessed at cancer diagnosis. Other covariates were self-reported at baseline. Time-varying body mass index was measured by weight in kilograms divided by the square of height in meters. Waist circumference was measured in centimeters at baseline. Statistical Analysis First, t tests and chi-square tests were used to test differences of baseline characteristics between participants with and without breast cancer. Second, the difference-in-difference method (DID) [20] was used to assess the short-term impact of breast cancer diagnosis on physical function measures. Pre- and post- physical function assessments that were closest to the cancer diagnosis for women with breast cancer and the comparison group were analyzed using linear mixed models, with period (pre- or post-diagnosis), group (breast cancer or non-cancer controls) and their interaction term as fixed factors and individuals as random factors in the model. The mixed effects regression analysis takes account of the within-person correlation among the repeated measurements of our outcomes. The interaction term in the model was used to address the main question of whether the two groups (cases and controls) changed the same amount and in the same direction from pre to post-diagnosis of breast cancer. Third, generalized DID models [20] were used to assess the long-term impact of breast cancer diagnosis on physical function measures. All physical function measures were used in the model. In the models, a Time variable (measured in years since the breast cancer diagnosis, the index date), and Time interacting with other variables (pre-post diagnosis period, group and period*group) were added to the model to assess the secular time trends of physical function; whether the time trends differed between the two groups; and differed before and after breast cancer diagnosis using a formular as follows: $${Y} {it}={\beta } {0}+{\beta } {1}*Time+{\beta } {2}*Group+{\beta } {3}*Period+{\beta } {4} Group Period$$ $$+{\beta } {5} Group Time+{\beta } {6} Period Time+{\beta } {7} Group Period*Time+{\in } {it}$$ Where Y it – physical function; Time: years since breast cancer diagnosis (the index date); Group (cases or controls); Period (pre- or post- diagnosis period). β – coefficient. Statistical tests were evaluated at p < .05 for main effects and p < .10 for interactions. Results Table 1 presents the differences in basic characteristics between cases and matched controls. Compared with controls, cases were slightly higher in body mass index and waist circumference, and more likely to have higher education level and be never smokers. There were no significant baseline differences between cases and controls for other characteristics including age, total calories per week expended in past year, total number of alcoholic drinks over lifetime, and history of hypertension or diabetes. There are no significant differences between cases and controls for physical function measured at baseline or visit 2. More than 93% of cases were in breast cancer stage I-III (Table 1 ). Table 1 Baseline characteristics between breast cancer cases and their matched cancer-free controls * variable label Overall N = 2712 Controls (N = 2260) Cases (N = 452) P-value Age at baseline 70.5 ± 4.4 70.5 ± 4.4 70.5 ± 4.4 1.0000 Body mass index (kg/m 2 ) (mean, std) 26.5 ± 4.5 26.4 ± 4.4 27.1 ± 4.9 0.001 Waist circumference (cm) (mean, std) 83.3 ± 11.0 83.1 ± 11.0 84.5 ± 11.3 0.02 Education 0.01 <12 years 619 (22.8%) 524 (23.2%) 95 (21.0%) 12 years 1133 (41.8%) 953 (42.2%) 180 (39.8%) 13–16 years 719 (26.5%) 600 (26.5%) 119 (26.3%) 17 or more 241 (8.9%) 183 (8.1%) 58 (12.8%) Smoke packyear 0.02 Never smoker 1620 (59.7%) 1327 (58.7%) 293 (64.8%) <10 330 (12.2%) 285 (12.6%) 45 (10.0%) 10-<30 351 (12.9%) 302 (13.4%) 49 (10.8%) 30-<50 251 (9.3%) 203 (9.0%) 48 (10.6%) ≥ 50 160 (5.9%) 143 (6.3%) 17 (3.8%) Total kcal/wk expended in past year 1645 ± 1645 1628 ± 1644 1729 ± 1648 0.23 Total # alcoholic drinks over lifetime 5157 ± 12472 5151 ± 12967 5187 ± 9635 0.96 Hypertension 0.58 0 1751 (64.6%) 1454 (64.3%) 297 (65.7%) 1 961 (35.4%) 806 (35.7%) 155 (34.3%) Diabetes 0.66 0 2550 (94.0%) 2127 (94.1%) 423 (93.6%) 1 162 (6.0%) 133 (5.9%) 29 (6.4%) Objectively measured physical function Grip strength (kilograms) Average grip strength 21.3 ± 4.3 21.3 ± 4.4 21.5 ± 4.1 0.34 Max grip strength 22.6 ± 4.4 22.6 ± 4.4 22.8 ± 4.1 0.30 Timed chair stand (seconds) 12.1 ± 4.3 12.1 ± 4.4 12.0 ± 4.0 0.72 Gait speed/stride length Regular gait speed (meters per second) 1.0 ± 0.2 1.0 ± 0.2 1.0 ± 0.2 0.17 Rapid gait speed (meters per second) ** 1.3 ± 0.3 1.3 ± 0.3 1.3 ± 0.3 0.21 Regular stride length (meters) 0.6 ± 0.1 0.6 ± 0.1 0.6 ± 0.1 0.10 Rapid stride length (meters) ** 0.6 ± 0.1 0.6 ± 0.1 0.6 ± 0.1 0.81 Quadriceps strength (pounds) ** Average quadriceps strength 64.0 ± 27.0 63.7 ± 26.7 65.2 ± 28.1 0.33 Peak quadriceps strength 60.1 ± 25.8 59.9 ± 25.7 61.5 ± 26.5 0.27 Cancer stage I 290 (64.2%) II 56 (12.4%) III 59 (13.1%) IV 17 (3.8%) Unknown 30 (6.6%) *: Values expressed as n (%), mean ± standard deviation. P-value comparisons across breast categories are based on Chi-square test for categorical variables; T test for continuous variables. ** These physical functions were not measured at baseline. They were based on measurements at visit 2. Table 2 shows the coefficients of interest from the analysis for pre-and post- diagnosis (two time points that were closest to breast cancer diagnosis) of physical function. The results indicate no significant difference for most of the pre-diagnosis measures between cases and controls (Group) except for relative better gait speed in cases than controls. Physical function significantly declined for all physical function measures comparing post-diagnosis period to pre- diagnosis period except for rapid stride length in controls (Period), and the declines were significantly worse among breast cancer cases for gait speed and quadriceps strength (Group*Period) (Table 2 ). Table 2 Coefficients of the association between breast cancer diagnosis and changes in physical function between pre- and post-diagnosis Group (cases vs controls) Period (Post vs Pre) Group* Period Objectively measured physical Function Grip strength (kilograms) Average grip strength 0.14 -1.43 *** -0.18 Max grip strength 0.008 -1.45 *** 0.02 Timed chair stand (seconds) 0.002 0.77 *** 0.35 Gait speed/stride length Regular gait speed (meters per second) 0.03** -0.06 *** -0.03 * Rapid gait speed (meters per second) 0.04* -0.07 *** -0.05 * Regular stride length (meters) 0.008 -0.02 *** -0.01 Rapid stride length (meters) 0.01 -0.007 -0.02 Quadriceps strength (pounds) Average quadriceps strength 2.43 -8.43 *** -3.18 * Peak quadriceps strength 2.29 -8.44 *** -3.25 * *: P value < 0.05; ** p value < 0.01; *** p value < 0.0001. All the models were adjusted for age at diagnosis (in continuous years), education level (< 12 years, 12 years, 13–16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, < 10, 10–<30, 30-=50), history of hypertension (yes, no), diabetes (yes, no) and body mass index. In the analysis fitting all the repeated measurements of physical function over 20 years of follow-up, we did not observe significantly different patterns between cases and controls for timed chair stand, gait speed or stride length at regular pace. Rather, all the physical function components declined significantly over time in both case and control groups (Time). Table 3 only presents components that were statistically different over time between cases and controls. For average grip strength and rapid gait speed, there was no significant difference between cases and controls (Group) and time trend before cancer diagnosis (Group*Time). After cancer diagnosis, both grip strength and rapid gait speed among breast cancer cases exhibited a significantly greater decline compared to controls (Group*Period*Time). Figure 1 (a) and (b) illustrates the grip strength and rapid walking speed changes over time in cases and controls. Table 3 Coefficients of physical function trajectories in relation to breast cancer diagnosis * Average grip strength (kilograms) Rapid gait speed (meters per second) Average quadriceps strength (pounds) Estimate P-value Estimate P-value Estimate P-value Group (cases vs controls) 0.40 0.28 0.01 0.65 4.76 0.05 Period (Post vs Pre) -0.68 < 0.0001 -0.02 0.04 0.08 0.95 Group*Period -0.31 0.38 0.01 0.73 -6.90 0.04 Time (years) -0.39 < 0.0001 -0.02 < 0.0001 -1.62 < 0.0001 Group*Time 0.04 0.32 0.002 0.65 0.24 0.54 Period* Time 0.06 0.04 -0.002 0.56 -1.44 < 0.0001 Group*Period*Time -0.11 0.09 -0.01 0.04 1.54 0.07 *All the models were adjusted for age at diagnosis (in continuous years), education level (< 12 years, 12 years, 13–16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, < 10, 10–<30, 30-=50), history of hypertension (yes, no), diabetes (yes, no) and body mass index. For average quadriceps strength, there was a slightly better initial measurement in cases than controls (Period) but similar time trends during pre-diagnosis period (Group*Time) between cases and controls. However, after cancer diagnosis, there was a significant strength drop shortly after breast cancer diagnosis in cases (around 7 pounds drop for Group*Period) and then the strength recovered over time (coefficient = 1.54 pounds per year for Group*Period*Time) (Table 3 ). In other words, there was a precipitous drop around cancer diagnosis in cases, and then the slope continued to decline but less steeply compared to the controls. The patterns for the quadricep strength trajectories by group and period are illustrated in Fig. 1 (c). All the results remained similar after further adjusting for stage of breast cancer. Discussion Our prospective study using objectively measured physical function with 20 years of follow-up data revealed that breast cancer survivors aged 65 and over at baseline demonstrated worse decline in physical function compared to women without cancer and such changes varied depending on the physical function component examined. As expected, physical function significantly declined over time across all components measured for both cases and controls during the pre-diagnosis period. After cancer diagnosis, there was a significantly greater decline for grip strength and rapid walking speed among breast cancer survivors relative to cancer-free controls. For quadriceps strength, there was a sharp, short-term loss after breast cancer diagnosis followed by a gradual improvement over time. We did not observe significant differences in the rate of change for other measures (including timed chair stand, grip speed at regular pace or stride length) between cases and controls. Our study is the first to prospectively examine the impact of breast cancer on objectively measured physical function. When pre-/post- diagnosis measures from two time points closest to breast cancer diagnosis were analyzed, declines were significantly worse in breast cancer survivors than controls for gait speed and quadriceps strength. While not measured in this study, the short-term physical function declines between pre- and post-diagnosis may likely be due to the direct and indirect effects of cancer treatment. Indeed, such changes can precipitate sedentary physical activity patterns that can exacerbate mobility difficulties [21] and systemic deconditioning [22]. Moreover, breast cancer survivors are often treated with multiple aggressive therapies that are known to contribute to functional declines in older adults [23–26]. The short-term physical function decline we observed in older breast cancer survivors is consistent with findings from some studies [11, 12, 26, 27], while other studies reported non-significant differences in older breast cancer survivors compared with their cancer-free peers [9, 28–30]. However, all the previous studies were based on self-reported physical function and most did not include an appropriate cancer-free control group to represent ‘usual aging,’ such that it is hard to determine whether physical function changes are attributable to breast cancer and its treatments. This is especially problematic in studies of older women, given the high prevalence of aging symptoms. Among several studies that included pre-/post-breast cancer measures and cancer-free women, Satariano et al. [30] found that at 3 months after diagnosis, cases were approximately twice as likely as age-matched controls to report upper-body limitation, especially for women younger than 75 years. At one year after diagnosis, younger breast cancer patients showed the greatest improvement [30]. Kroenke et al. [9] reported a similar finding in the Nurses’ Health Study: younger (< 65 years) but not older (65 or older) breast cancer survivors experienced worse functional limitations compared with women without cancer. However, both studies were based on assessments conducted at two points in time without examining the long-term impacts of the disease on trajectories of functional aging. One longitudinal study based on 15 years of follow-up of self-reported physical function on both pre-/post-diagnosis measurements observed that breast cancer survivors had dramatic physical function declines one-year post-diagnosis and then began to return to levels of physical function similar to their pre- diagnosis status [31]. These findings are consistent with the long-term trends we observed for quadriceps strength. Although self-reported physical function has been used widely to monitor treatment-related symptoms and physical function decrements in cancer survivors, it is subjective and may be prone to bias. Furthermore, it cannot easily quantify and distinguish various physical components and thus it is hard to evaluate which aspects of function may be most affected by the cancer diagnosis and therefore which components are targets for interventions. Using objective measurements of physical function can overcome these limitations. However, we only identified one small cross-sectional study that examined objective measures of physical function in breast cancer survivors [32], and one cohort study based on older adults with any cancer [33]. The small cross-section study with one-time measurement reported that breast cancer survivors had significantly lower short Physical Performance Battery score, longer chair stand times, and lower handgrip strength than controls, but similar walk speed [32]. The cohort study observed that a steeper decline in gait speed prior to a cancer diagnosis and an accelerated declines in appendicular lean mass after a cancer diagnosis, compared with cancer-free controls [33]. Our study observed a worse decline in hand grip strength and rapid walking speed but not regular pace of gait speed in breast cancer survivors. This suggests that the maximum gait speed (walk as fast as safely possible) may be more sensitive to disease-related function decline than regular pace. Gait speed is a well-known indicator of functional decline and predictor of mortality in older adults and is frequently used in geriatric settings as a quick and reliable way of monitoring the functional capacity of older adults including cognitive ability [34–36]. Gait speed depends on the function and coordination of the musculoskeletal, visual, central nervous, and peripheral nervous systems [36]. It reflects mobility and dynamic balance, and quadriceps strength reflects lower body muscle function. Lower-limb muscle strength is linked to walking speed. Gait speed should be considered not only as a motor function but an integrative measure of health. Our findings indicate that the impacts of breast cancer on physical function may include both upper and lower body muscle function and mobility and dynamic balance. Our findings suggest that interventions to build skeletal muscle strength may improve physical function thereby positively affecting mobility among breast cancer survivors. Studies have suggested that structured training programs for older adults including resistance exercise can increase muscle strength and physical functioning [44]. Our study also highlights a need for routine assessment of physical function including grip strength, gait speed and leg strength by primary care physicians to help monitor and prevent physical function decline. As most individuals complete the intensive phase of cancer treatment during the first year after diagnosis, interventions to help them return to their pre-cancer status more quickly could be beneficial. Strengths of our study include use of age-matched cancer-free comparison groups, objective assessment of physical function and using multiple assessments of physical function over time to assess long term impact of breast cancer. Several limitations also deserve mention. First, we examined incident breast cancer during the follow-up; thus, the length of measurement of physical function between pre and post- diagnosis varied, which may affect assessment of physical function. Second, we were unable to adjust for information on cancer treatment. Third, our sample includes only older, non-Hispanic white women and thus may not generalize to other populations. Another limitation is there were no direct measures of cardiorespiratory fitness which is known to be linked to mobility and physical activity. In conclusion, our prospective study using objectively measured physical function with 20 years of follow-up data revealed that older breast cancer survivors had significantly worse declines in grip strength and rapid walking speed and a sharp short-term drop followed by gradual improvement over time in quadriceps strength compared to women without cancer. Our findings suggest that targeted exercise training among older breast cancer survivors focused on developing body muscle strength and mobility would improve physical functioning and thereby improve the healthy life span of this growing population. Further work is needed to understand how cancer treatments may impact the trajectories of specific physical function components in this growing population. Declarations Funding Dr. Luo is partially supported by the National Institutes of Health (R03CA256238). Dr. Cespedes is partially supported by K01CA226155; R01AG065334; R01CA240394; R01CA251589. Dr. Carter receives support from the National Cancer Institute (R01CA235598) and the Indiana Clinical and Translational Sciences Institute (UL1TR002529). Conflicts of Interest The authors declare no potential conflicts of interest. Availability of data and material The data are available from the National Institute on Aging (NIA) AgingResearchBiobank upon reasonable request ( https://agingresearchbiobank.nia.nih.gov/ ). Code availability: Not applicable. Acknowledgement We would like to acknowledge the contribution of the Study of Osteoporotic Fractures (SOF) Investigators and the National Institute on Aging (NIA) AgingResearchBiobank (https://agingresearchbiobank.nia.nih.gov/) where the SOF collection of biospecimens and data is maintained. Authors’ contributions J.L. contributed to the study concept and design, acquisition of data, data management, analysis and interpretation of data, and drafting of the manuscript. M.H. contributed to the study concept and design, interpretation of data, and critical review and revision of the manuscript. S.J.C. and E.M.C.F. contributed to interpretation of data and critical review and revision of the manuscript. J.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ethics approval This is a secondary data analysis. 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J Natl Cancer Inst 111:1245-1254. doi: 10.1093/jnci/djz136 Zhu J, Wang F, Shi L, Cai H, Zheng Y, Zheng W, Bao P, Shu XO (2020) Accelerated aging in breast cancer survivors and its association with mortality and cancer recurrence. Breast Cancer Res Treat 180:449-459. doi: 10.1007/s10549-020-05541-5 Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Mascioli SR, Scott JC, Seeley DG, Steiger P, et al. (1990) Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group. JAMA 263:665-668. Grandits G, Neuhaus J (2010) Using SAS® to Perform Individual Matching in Design of Case-Control Studies https://support.sas.com/resources/papers/proceedings10/061-2010.pdf . In: SAS Global Forum. Warton EM (2020) Time after time: difference-in-differences and interrupted time series models in SAS. In: SAS Global Forum 2020. Carter SJ, Hunter GR, Norian LA, Turan B, Rogers LQ (2018) Ease of walking associates with greater free-living physical activity and reduced depressive symptomology in breast cancer survivors: pilot randomized trial. Support Care Cancer 26:1675-1683. doi: 10.1007/s00520-017-4015-y Rogers LQ, Courneya KS, Carter SJ, Anton PM, Verhulst S, Vicari SK, Robbs RS, McAuley E (2016) Effects of a multicomponent physical activity behavior change intervention on breast cancer survivor health status outcomes in a randomized controlled trial. Breast Cancer Res Treat 159:283-291. doi: 10.1007/s10549-016-3945-2 Winters-Stone KM, Horak F, Jacobs PG, Trubowitz P, Dieckmann NF, Stoyles S, Faithfull S (2017) Falls, Functioning, and Disability Among Women With Persistent Symptoms of Chemotherapy-Induced Peripheral Neuropathy. Journal of Clinical Oncology 35:2604-+. doi: 10.1200/Jco.2016.71.3552 Sweeney C, Schmitz KH, Lazovich D, Virnig BA, Wallace RB, Folsom AR (2006) Functional limitations in elderly female cancer survivors. J Natl Cancer Inst 98:521-529. doi: 10.1093/jnci/djj130 Avis NE, Deimling GT (2008) Cancer survivorship and aging. Cancer 113:3519-3529. doi: 10.1002/cncr.23941 Hurria A, Soto-Perez-de-Celis E, Allred JB, Cohen HJ, Arsenyan A, Ballman K, Le-Rademacher J, Jatoi A, Filo J, Mandelblatt J, Lafky JM, Kimmick G, Klepin HD, Freedman RA, Burstein H, Gralow J, Wolff AC, Magrinat G, Barginear M, Muss H (2019) Functional Decline and Resilience in Older Women Receiving Adjuvant Chemotherapy for Breast Cancer. J Am Geriatr Soc 67:920-927. doi: 10.1111/jgs.15493 Euhus DM, Addae JK, Snyder CF, Canner JK (2019) Change in health-related quality of life in older women after diagnosis of a small breast cancer. Cancer 125:1807-1814. doi: 10.1002/cncr.31993 Cohen HJ, Lan L, Archer L, Kornblith AB (2012) Impact of age, comorbidity and symptoms on physical function in long-term breast cancer survivors (CALGB 70803). J Geriatr Oncol 3:82-89. doi: 10.1016/j.jgo.2012.01.005 Lazovich D, Robien K, Cutler G, Virnig B, Sweeney C (2009) Quality of Life in a Prospective Cohort of Elderly Women With and Without Cancer. Cancer 115:4283-4297. doi: 10.1002/cncr.24580 Satariano WA, Ragland DR (1996) Upper-body strength and breast cancer: a comparison of the effects of age and disease. J Gerontol A Biol Sci Med Sci 51:M215-219. doi: 10.1093/gerona/51a.5.m215 Petrick JL, Reeve BB, Kucharska-Newton AM, Foraker RE, Platz EA, Stearns SC, Han XS, Windham BG, Irwin DE (2014) Functional status declines among cancer survivors: Trajectory and contributing factors. J Geriatr Oncol 5:359-367. doi: 10.1016/j.jgo.2014.06.002 Winters-Stone KM, Medysky ME, Savin MA (2019) Patient-reported and objectively measured physical function in older breast cancer survivors and cancer-free controls. J Geriatr Oncol 10:311-316. doi: 10.1016/j.jgo.2018.10.006 Williams GR, Chen Y, Kenzik KM, McDonald A, Shachar SS, Klepin HD, Kritchevsky S, Bhatia S (2020) Assessment of Sarcopenia Measures, Survival, and Disability in Older Adults Before and After Diagnosis With Cancer. JAMA Netw Open 3:e204783. doi: 10.1001/jamanetworkopen.2020.4783 Peel NM, Kuys SS, Klein K (2013) Gait Speed as a Measure in Geriatric Assessment in Clinical Settings: A Systematic Review. J Gerontol a-Biol 68:39-46. doi: 10.1093/gerona/gls174 Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, Brach J, Chandler J, Cawthon P, Connor EB, Nevitt M, Visser M, Kritchevsky S, Badinelli S, Harris T, Newman AB, Cauley J, Ferrucci L, Guralnik J (2011) Gait speed and survival in older adults. JAMA 305:50-58. doi: 10.1001/jama.2010.1923 Yates T, Zaccardi F, Dhalwani NN, Davies MJ, Bakrania K, Celis-Morales CA, Gill JMR, Franks PW, Khunti K (2017) Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality: a UK Biobank observational study. Eur Heart J 38:3232-3240. doi: 10.1093/eurheartj/ehx449 Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2022 Read the published version in Breast Cancer Research and Treatment → Version 1 posted Reviews received at journal 06 Aug, 2021 Reviewers invited by journal 06 Aug, 2021 Editor assigned by journal 30 Jul, 2021 First submitted to journal 30 Jul, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-768755","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":44378063,"identity":"fff954c8-57d6-445c-8af3-81bad1048dca","order_by":0,"name":"Juhua Luo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACxgYexgMMDDY8DAyJDRChA4S1gNSkkaCFgQGs5TCQkcBAnBbmGbkHDvNUnJcxZ09u/FxQwyDHdyMBvxbGGXkJh3nO3Oax7HnYLD3jGIOxJGEtOQaHedtu8xjcSGyQ5mFjSNxApJZzIC3Nv3n+MdQTq+UASEubNG8bQ4IBQS09bwwOzjmTzGNw5mGbNW+fhOHMMw/wazFszzF88KbCzt7gePrj2zzfbOT5jhOwxbABlS+BXzkIyBNWMgpGwSgYBSMeAAAVSUizNqwzTAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8901-4462","institution":"Indiana University Bloomington","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Juhua","middleName":"","lastName":"Luo","suffix":""},{"id":44378064,"identity":"ba8a21e0-d5b6-4cbb-8915-187134a7ecc8","order_by":1,"name":"Stephen J. Carter","email":"","orcid":"","institution":"Indiana University Bloomington","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"J.","lastName":"Carter","suffix":""},{"id":44378065,"identity":"0127b7c8-eab4-4020-a643-25b4c049d3aa","order_by":2,"name":"Elizabeth M Cespedes Feliciano","email":"","orcid":"","institution":"Kaiser Permanente Northern California","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"M Cespedes","lastName":"Feliciano","suffix":""},{"id":44378066,"identity":"fdbb9f72-62e7-415d-bb2f-cfadf11b2992","order_by":3,"name":"Michael Hendryx","email":"","orcid":"","institution":"Indiana University Bloomington","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Hendryx","suffix":""}],"badges":[],"createdAt":"2021-07-31 04:33:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-768755/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-768755/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10549-022-06568-6","type":"published","date":"2022-03-26T02:56:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":12255641,"identity":"df27abb2-74a2-43c1-a6ea-e8603d79b93d","added_by":"auto","created_at":"2021-08-09 17:16:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41513,"visible":true,"origin":"","legend":"Physical function over time for cases and controls. ","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-768755/v1/3a7f70e95a7256a9b9111688.png"},{"id":19711962,"identity":"9bed0885-c5de-4be3-bb1c-98854c301585","added_by":"auto","created_at":"2022-03-29 02:56:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":436982,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-768755/v1/24612ac0-7aef-48fa-bf19-1ff2eac49009.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eTrajectories of Objectively Measured Physical Function Among Older Breast Cancer Survivors in Comparison With Cancer-Free Controls\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eBreast cancer is the most common cancer among women in the US and worldwide [1]. With advances in early detection and treatment, the 5-year survival rate for all stages combined has reached more than 90% in the United States (US) [2]. As a result, there are more than 3.8\u0026nbsp;million breast cancer survivors in the US with further increases projected due to an aging population. Despite improving survival, a growing body of evidence suggests that breast cancer survivors are uniquely confronted with an array of physical and psychosocial health problems after cancer treatment [3\u0026ndash;8].\u003c/p\u003e \u003cp\u003eThe contribution of cancer to objective physical function trajectory remains largely unknown. Several studies reported that women diagnosed with breast cancer experience a significant loss in physical function beyond the age-related decline observed in women without cancer diagnosis [9\u0026ndash;12]. Other studies have indicated that the negative effects of breast cancer appeared to decrease with time [13\u0026ndash;15]. However, the assessment of physical function in these studies employed self-report, known to be subject to bias. Alternatively, objectively measured physical function may include more accurate indicators of physical function better suited to reflect changes in function before problems are reported by an individual. Furthermore, objective measures of physical function can assess different components of status including gait speed and grip strength. To our knowledge, no prospective study has examined objectively measured physical function changes among older breast cancer survivors.\u003c/p\u003e \u003cp\u003eHerein, secondary analyses were performed on the Study of Osteoporotic Fractures, a longitudinal investigation with more than 20 years of follow-up and repeated measures of objectively measured physical function to examine whether breast cancer occurrence contributes to a decline in physical function. Cancer-free women were also included to account for the attendant effects of usual aging. Given the accelerated aging may be attributed to the direct and indirect effects of cancer treatment, we hypothesized that the trajectory of age-related physical function declines would be greater among breast cancer survivors compared with women without cancer [16, 17]. Understanding the trajectory of breast cancer on objectively measured physical function can inform supportive interventions to improve specific components of health status among the growing population of older breast cancer survivors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy of Osteoporotic Fractures\u003c/h2\u003e \u003cp\u003eThe Study of Osteoporotic Fractures (SOF) is a prospective study of risk factors for fractures and other health outcomes among community-dwelling older women. Details of the SOF cohort and study procedures have been published elsewhere [18]. Briefly, 9704 community-dwelling, ambulatory white women aged 65 years or older were recruited between 1986 and 1988 from population-based lists in Baltimore, Minneapolis, Pittsburgh and Portland. Those unable to walk without assistance or with bilateral hip replacements were excluded. Examination, interviews and questionnaires were performed at enrollment and at follow-up visits approximately every 2 years over 20 years of follow-up with a total of 9 measures. At each site, the institutional review boards approved the study, and all participants provided written informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eFor the purposes of our analysis, we considered all 9704 women who were initially recruited between 1986 and 1988 to ensure enough repeated measures. We excluded 31 women who had a non-released high value for age\u0026thinsp;\u0026gt;\u0026thinsp;90 at baseline, 724 women who were lost to follow-up, 281 women who ever had a stroke or prevalent cancer at baseline, and 158 women with missing covariates. Of the remaining 8510, 452 women were diagnosed with an incident, invasive breast cancer during follow-up, confirmed through physician review of medical records. Each breast cancer case was matched with five cancer-free controls based on age at baseline and person-time of follow-up. Controls must have been followed at least as long as the case to be considered as a match [19]. A total of 2712 nested case-control individuals (452 breast cancer cases and 2260 controls) were included for further analysis. For each control, we assigned an index time as the date of breast cancer event for her matched case.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eObjectively measured physical function\u003c/h2\u003e \u003cp\u003eHand-grip strength, gait speed and timed chair stand were measured during every visit with 9 repeated assessments. Grip strength was measured in both hands at each clinical site visit using a hand-held isometric dynamometer (Sparks Instruments and Academics, Coralville, Iowa) and a standard protocol. Both the max and the average of both hands (in kilograms) were used in the analysis. Timed chair stand (in seconds) was measured as the time to rise from a 16-inch height chair and sit down as quickly as possible five times without the use of arms according to a standard protocol. Gait speed (in meters per second) and step length (in meters) were assessed by a timed 6-meter walk according to a standard protocol. Participants were asked to walk at their usual pace and at their rapid pace, and the time and number of steps for both of their usual pace and their rapid pace were recorded. Quadriceps strength was measured at visit 2,3,4, 6 and 7, measured in pounds as the peak and the average force of the right and left limbs (Body Masters; Lafayette Instruments, Lafayette, Ind).\u003c/p\u003e \u003cp\u003eAll repeated measurements on physical function were used. For participants who were diagnosed with breast cancer during follow-up, measures preceding the cancer diagnosis were defined as pre-diagnosis measures, and measures following cancer diagnosis were defined as post-diagnosis measures. For the matched controls, we defined the pre- and post- diagnosis measures in the same way as their corresponding cases at their index date corresponding to cases.\u003c/p\u003e \u003cp\u003eIn addition, we also identified pre and post-diagnosis measures that were closest to the breast cancer diagnosis date for each individual to assess short-term change associated with cancer diagnosis.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eCovariates\u003c/span\u003e included age (in continuous years), education level (\u0026lt;\u0026thinsp;12 years, 12 years, 13\u0026ndash;16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, \u0026lt;\u0026thinsp;10, 1\u0026ndash;\u0026lt;30, 30-\u0026lt;50, \u0026gt;=50), history of hypertension (yes, no) and diabetes (yes, no). Age was assessed at cancer diagnosis. Other covariates were self-reported at baseline. Time-varying body mass index was measured by weight in kilograms divided by the square of height in meters. Waist circumference was measured in centimeters at baseline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eFirst, t tests and chi-square tests were used to test differences of baseline characteristics between participants with and without breast cancer.\u003c/p\u003e \u003cp\u003eSecond, the difference-in-difference method (DID) [20] was used to assess the short-term impact of breast cancer diagnosis on physical function measures. Pre- and post- physical function assessments that were closest to the cancer diagnosis for women with breast cancer and the comparison group were analyzed using linear mixed models, with period (pre- or post-diagnosis), group (breast cancer or non-cancer controls) and their interaction term as fixed factors and individuals as random factors in the model. The mixed effects regression analysis takes account of the within-person correlation among the repeated measurements of our outcomes. The interaction term in the model was used to address the main question of whether the two groups (cases and controls) changed the same amount and in the same direction from pre to post-diagnosis of breast cancer.\u003c/p\u003e \u003cp\u003eThird, generalized DID models [20] were used to assess the long-term impact of breast cancer diagnosis on physical function measures. All physical function measures were used in the model. In the models, a Time variable (measured in years since the breast cancer diagnosis, the index date), and Time interacting with other variables (pre-post diagnosis period, group and period*group) were added to the model to assess the secular time trends of physical function; whether the time trends differed between the two groups; and differed before and after breast cancer diagnosis using a formular as follows:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n\n$${Y}_{it}={\\beta }_{0}+{\\beta }_{1}*Time+{\\beta }_{2}*Group+{\\beta }_{3}*Period+{\\beta }_{4}*Group*Period$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n\n$$+{\\beta }_{5}*Group*Time+{\\beta }_{6}*Period*Time+{\\beta }_{7}*Group*Period*Time+{\\in }_{it}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eWhere Y\u003csub\u003eit\u003c/sub\u003e \u0026ndash; physical function; Time: years since breast cancer diagnosis (the index date); Group (cases or controls); Period (pre- or post- diagnosis period). β \u0026ndash; coefficient.\u003c/p\u003e \u003cp\u003eStatistical tests were evaluated at p\u0026thinsp;\u0026lt;\u0026thinsp;.05 for main effects and p\u0026thinsp;\u0026lt;\u0026thinsp;.10 for interactions.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the differences in basic characteristics between cases and matched controls. Compared with controls, cases were slightly higher in body mass index and waist circumference, and more likely to have higher education level and be never smokers. There were no significant baseline differences between cases and controls for other characteristics including age, total calories per week expended in past year, total number of alcoholic drinks over lifetime, and history of hypertension or diabetes. There are no significant differences between cases and controls for physical function measured at baseline or visit 2. More than 93% of cases were in breast cancer stage I-III (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics between breast cancer cases and their matched cancer-free controls *\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003evariable label\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;2712\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControls (N\u0026thinsp;=\u0026thinsp;2260)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;452)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.0000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e) (mean, std)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaist circumference (cm) (mean, std)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;12 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e619 (22.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e524 (23.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95 (21.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1133 (41.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e953 (42.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e180 (39.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u0026ndash;16 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e719 (26.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e600 (26.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119 (26.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17 or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e241 (8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (12.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoke packyear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1620 (59.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1327 (58.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e293 (64.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e330 (12.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e285 (12.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10-\u0026lt;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e351 (12.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e302 (13.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30-\u0026lt;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e251 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e203 (9.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal kcal/wk expended in past year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1645\u0026thinsp;\u0026plusmn;\u0026thinsp;1645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1628\u0026thinsp;\u0026plusmn;\u0026thinsp;1644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1729\u0026thinsp;\u0026plusmn;\u0026thinsp;1648\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal # alcoholic drinks over lifetime\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5157\u0026thinsp;\u0026plusmn;\u0026thinsp;12472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5151\u0026thinsp;\u0026plusmn;\u0026thinsp;12967\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5187\u0026thinsp;\u0026plusmn;\u0026thinsp;9635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1751 (64.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1454 (64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e297 (65.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e961 (35.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e806 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e155 (34.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2550 (94.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2127 (94.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e423 (93.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162 (6.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (6.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObjectively measured physical function\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrip strength (kilograms)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage grip strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMax grip strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTimed chair stand (seconds)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGait speed/stride length\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular gait speed (meters per second)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRapid gait speed (meters per second) **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular stride length (meters)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRapid stride length (meters) **\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eQuadriceps strength (pounds) **\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage quadriceps strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.0\u0026thinsp;\u0026plusmn;\u0026thinsp;27.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.7\u0026thinsp;\u0026plusmn;\u0026thinsp;26.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.2\u0026thinsp;\u0026plusmn;\u0026thinsp;28.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak quadriceps strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.1\u0026thinsp;\u0026plusmn;\u0026thinsp;25.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.9\u0026thinsp;\u0026plusmn;\u0026thinsp;25.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.5\u0026thinsp;\u0026plusmn;\u0026thinsp;26.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e290 (64.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (12.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59 (13.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*: Values expressed as n (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. P-value comparisons across breast categories are based on Chi-square test for categorical variables; T test for continuous variables.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e** These physical functions were not measured at baseline. They were based on measurements at visit 2.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the coefficients of interest from the analysis for pre-and post- diagnosis (two time points that were closest to breast cancer diagnosis) of physical function. The results indicate no significant difference for most of the pre-diagnosis measures between cases and controls (Group) except for relative better gait speed in cases than controls. Physical function significantly declined for all physical function measures comparing post-diagnosis period to pre- diagnosis period except for rapid stride length in controls (Period), and the declines were significantly worse among breast cancer cases for gait speed and quadriceps strength (Group*Period) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCoefficients of the association between breast cancer diagnosis and changes in physical function between pre- and post-diagnosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup (cases vs controls)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePeriod\u003c/p\u003e \u003cp\u003e(Post vs Pre)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup* Period\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObjectively measured physical Function\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrip strength (kilograms)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage grip strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.43 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMax grip strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.45 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTimed chair stand (seconds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.77 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGait speed/stride length\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular gait speed (meters per second)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.03**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.06 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.03 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRapid gait speed (meters per second)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.04*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.07 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.05 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegular stride length (meters)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.02 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRapid stride length (meters)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuadriceps strength (pounds)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage quadriceps strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-8.43 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.18 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak quadriceps strength\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-8.44 ***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-3.25 *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*: P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05; ** p value\u0026thinsp;\u0026lt;\u0026thinsp;0.01; *** p value\u0026thinsp;\u0026lt;\u0026thinsp;0.0001. All the models were adjusted for age at diagnosis (in continuous years), education level (\u0026lt;\u0026thinsp;12 years, 12 years, 13\u0026ndash;16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, \u0026lt;\u0026thinsp;10, 10\u0026ndash;\u0026lt;30, 30-\u0026lt;50, \u0026gt;=50), history of hypertension (yes, no), diabetes (yes, no) and body mass index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the analysis fitting all the repeated measurements of physical function over 20 years of follow-up, we did not observe significantly different patterns between cases and controls for timed chair stand, gait speed or stride length at regular pace. Rather, all the physical function components declined significantly over time in both case and control groups (Time). Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e only presents components that were statistically different over time between cases and controls. For average grip strength and rapid gait speed, there was no significant difference between cases and controls (Group) and time trend before cancer diagnosis (Group*Time). After cancer diagnosis, both grip strength and rapid gait speed among breast cancer cases exhibited a significantly greater decline compared to controls (Group*Period*Time). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (a) and (b) illustrates the grip strength and rapid walking speed changes over time in cases and controls.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCoefficients of physical function trajectories in relation to breast cancer diagnosis *\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAverage grip strength (kilograms)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eRapid gait speed (meters per second)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eAverage quadriceps strength (pounds)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003cp\u003e(cases vs controls)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod\u003c/p\u003e \u003cp\u003e(Post vs Pre)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup*Period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-6.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup*Time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod*\u003c/p\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup*Period*Time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*All the models were adjusted for age at diagnosis (in continuous years), education level (\u0026lt;\u0026thinsp;12 years, 12 years, 13\u0026ndash;16 years, 17 years or more), physical activity (measured in total calories per week expended in past year), alcohol consumption (measured in total number drinks over lifetime), smoking (measured in pack-years: never smoke, \u0026lt;\u0026thinsp;10, 10\u0026ndash;\u0026lt;30, 30-\u0026lt;50, \u0026gt;=50), history of hypertension (yes, no), diabetes (yes, no) and body mass index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor average quadriceps strength, there was a slightly better initial measurement in cases than controls (Period) but similar time trends during pre-diagnosis period (Group*Time) between cases and controls. However, after cancer diagnosis, there was a significant strength drop shortly after breast cancer diagnosis in cases (around 7 pounds drop for Group*Period) and then the strength recovered over time (coefficient\u0026thinsp;=\u0026thinsp;1.54 pounds per year for Group*Period*Time) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In other words, there was a precipitous drop around cancer diagnosis in cases, and then the slope continued to decline but less steeply compared to the controls. The patterns for the quadricep strength trajectories by group and period are illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (c). All the results remained similar after further adjusting for stage of breast cancer.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur prospective study using objectively measured physical function with 20 years of follow-up data revealed that breast cancer survivors aged 65 and over at baseline demonstrated worse decline in physical function compared to women without cancer and such changes varied depending on the physical function component examined. As expected, physical function significantly declined over time across all components measured for both cases and controls during the pre-diagnosis period. After cancer diagnosis, there was a significantly greater decline for grip strength and rapid walking speed among breast cancer survivors relative to cancer-free controls. For quadriceps strength, there was a sharp, short-term loss after breast cancer diagnosis followed by a gradual improvement over time. We did not observe significant differences in the rate of change for other measures (including timed chair stand, grip speed at regular pace or stride length) between cases and controls.\u003c/p\u003e \u003cp\u003eOur study is the first to prospectively examine the impact of breast cancer on objectively measured physical function. When pre-/post- diagnosis measures from two time points closest to breast cancer diagnosis were analyzed, declines were significantly worse in breast cancer survivors than controls for gait speed and quadriceps strength. While not measured in this study, the short-term physical function declines between pre- and post-diagnosis may likely be due to the direct and indirect effects of cancer treatment. Indeed, such changes can precipitate sedentary physical activity patterns that can exacerbate mobility difficulties [21] and systemic deconditioning [22]. Moreover, breast cancer survivors are often treated with multiple aggressive therapies that are known to contribute to functional declines in older adults [23\u0026ndash;26].\u003c/p\u003e \u003cp\u003eThe short-term physical function decline we observed in older breast cancer survivors is consistent with findings from some studies [11, 12, 26, 27], while other studies reported non-significant differences in older breast cancer survivors compared with their cancer-free peers [9, 28\u0026ndash;30]. However, all the previous studies were based on self-reported physical function and most did not include an appropriate cancer-free control group to represent \u0026lsquo;usual aging,\u0026rsquo; such that it is hard to determine whether physical function changes are attributable to breast cancer and its treatments. This is especially problematic in studies of older women, given the high prevalence of aging symptoms.\u003c/p\u003e \u003cp\u003eAmong several studies that included pre-/post-breast cancer measures and cancer-free women, Satariano et al. [30] found that at 3 months after diagnosis, cases were approximately twice as likely as age-matched controls to report upper-body limitation, especially for women younger than 75 years. At one year after diagnosis, younger breast cancer patients showed the greatest improvement [30]. Kroenke et al. [9] reported a similar finding in the Nurses\u0026rsquo; Health Study: younger (\u0026lt;\u0026thinsp;65 years) but not older (65 or older) breast cancer survivors experienced worse functional limitations compared with women without cancer. However, both studies were based on assessments conducted at two points in time without examining the long-term impacts of the disease on trajectories of functional aging. One longitudinal study based on 15 years of follow-up of self-reported physical function on both pre-/post-diagnosis measurements observed that breast cancer survivors had dramatic physical function declines one-year post-diagnosis and then began to return to levels of physical function similar to their pre- diagnosis status [31]. These findings are consistent with the long-term trends we observed for quadriceps strength.\u003c/p\u003e \u003cp\u003eAlthough self-reported physical function has been used widely to monitor treatment-related symptoms and physical function decrements in cancer survivors, it is subjective and may be prone to bias. Furthermore, it cannot easily quantify and distinguish various physical components and thus it is hard to evaluate which aspects of function may be most affected by the cancer diagnosis and therefore which components are targets for interventions. Using objective measurements of physical function can overcome these limitations. However, we only identified one small cross-sectional study that examined objective measures of physical function in breast cancer survivors [32], and one cohort study based on older adults with any cancer [33]. The small cross-section study with one-time measurement reported that breast cancer survivors had significantly lower short Physical Performance Battery score, longer chair stand times, and lower handgrip strength than controls, but similar walk speed [32]. The cohort study observed that a steeper decline in gait speed prior to a cancer diagnosis and an accelerated declines in appendicular lean mass after a cancer diagnosis, compared with cancer-free controls [33].\u003c/p\u003e \u003cp\u003eOur study observed a worse decline in hand grip strength and rapid walking speed but not regular pace of gait speed in breast cancer survivors. This suggests that the maximum gait speed (walk as fast as safely possible) may be more sensitive to disease-related function decline than regular pace. Gait speed is a well-known indicator of functional decline and predictor of mortality in older adults and is frequently used in geriatric settings as a quick and reliable way of monitoring the functional capacity of older adults including cognitive ability [34\u0026ndash;36]. Gait speed depends on the function and coordination of the musculoskeletal, visual, central nervous, and peripheral nervous systems [36]. It reflects mobility and dynamic balance, and quadriceps strength reflects lower body muscle function. Lower-limb muscle strength is linked to walking speed. Gait speed should be considered not only as a motor function but an integrative measure of health. Our findings indicate that the impacts of breast cancer on physical function may include both upper and lower body muscle function and mobility and dynamic balance. Our findings suggest that interventions to build skeletal muscle strength may improve physical function thereby positively affecting mobility among breast cancer survivors. Studies have suggested that structured training programs for older adults including resistance exercise can increase muscle strength and physical functioning [44]. Our study also highlights a need for routine assessment of physical function including grip strength, gait speed and leg strength by primary care physicians to help monitor and prevent physical function decline. As most individuals complete the intensive phase of cancer treatment during the first year after diagnosis, interventions to help them return to their pre-cancer status more quickly could be beneficial.\u003c/p\u003e \u003cp\u003eStrengths of our study include use of age-matched cancer-free comparison groups, objective assessment of physical function and using multiple assessments of physical function over time to assess long term impact of breast cancer. Several limitations also deserve mention. First, we examined incident breast cancer during the follow-up; thus, the length of measurement of physical function between pre and post- diagnosis varied, which may affect assessment of physical function. Second, we were unable to adjust for information on cancer treatment. Third, our sample includes only older, non-Hispanic white women and thus may not generalize to other populations. Another limitation is there were no direct measures of cardiorespiratory fitness which is known to be linked to mobility and physical activity.\u003c/p\u003e \u003cp\u003eIn conclusion, our prospective study using objectively measured physical function with 20 years of follow-up data revealed that older breast cancer survivors had significantly worse declines in grip strength and rapid walking speed and a sharp short-term drop followed by gradual improvement over time in quadriceps strength compared to women without cancer. Our findings suggest that targeted exercise training among older breast cancer survivors focused on developing body muscle strength and mobility would improve physical functioning and thereby improve the healthy life span of this growing population. Further work is needed to understand how cancer treatments may impact the trajectories of specific physical function components in this growing population.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Luo is partially supported by the National Institutes of Health (R03CA256238). Dr. Cespedes is partially supported by K01CA226155; R01AG065334; R01CA240394; R01CA251589. Dr. Carter receives support from the National Cancer Institute (R01CA235598) and the Indiana Clinical and Translational Sciences Institute (UL1TR002529).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no potential conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are available from the National Institute on Aging (NIA) AgingResearchBiobank upon reasonable request (\u003ca href=\"https://agingresearchbiobank.nia.nih.gov/\"\u003ehttps://agingresearchbiobank.nia.nih.gov/\u003c/a\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the contribution of the Study of Osteoporotic Fractures (SOF) Investigators and the National Institute on Aging (NIA) AgingResearchBiobank (https://agingresearchbiobank.nia.nih.gov/) where the SOF collection of biospecimens and data is maintained. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.L. contributed to the study concept and design, acquisition of data, data management, analysis and interpretation of data, and drafting of the manuscript. M.H. contributed to the study concept and design, interpretation of data, and critical review and revision of the manuscript. S.J.C. and E.M.C.F. contributed to interpretation of data and critical review and revision of the manuscript. J.L. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a secondary data analysis. In accordance with 45 CFR 46.101(b) and/or IU HRPP Policy, the study is granted exemption (category 4): Secondary research for which consent is not required\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209-249. doi: 10.3322/caac.21660\u003c/li\u003e\n\u003cli\u003eASC (2020) Survival Rates for Breast Cancer (\u003ca href=\"https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html\"\u003ehttps://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html\u003c/a\u003e). 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J Geriatr Oncol 3:82-89. doi: 10.1016/j.jgo.2012.01.005\u003c/li\u003e\n\u003cli\u003eLazovich D, Robien K, Cutler G, Virnig B, Sweeney C (2009) Quality of Life in a Prospective Cohort of Elderly Women With and Without Cancer. Cancer 115:4283-4297. doi: 10.1002/cncr.24580\u003c/li\u003e\n\u003cli\u003eSatariano WA, Ragland DR (1996) Upper-body strength and breast cancer: a comparison of the effects of age and disease. J Gerontol A Biol Sci Med Sci 51:M215-219. doi: 10.1093/gerona/51a.5.m215\u003c/li\u003e\n\u003cli\u003ePetrick JL, Reeve BB, Kucharska-Newton AM, Foraker RE, Platz EA, Stearns SC, Han XS, Windham BG, Irwin DE (2014) Functional status declines among cancer survivors: Trajectory and contributing factors. J Geriatr Oncol 5:359-367. doi: 10.1016/j.jgo.2014.06.002\u003c/li\u003e\n\u003cli\u003eWinters-Stone KM, Medysky ME, Savin MA (2019) Patient-reported and objectively measured physical function in older breast cancer survivors and cancer-free controls. J Geriatr Oncol 10:311-316. doi: 10.1016/j.jgo.2018.10.006\u003c/li\u003e\n\u003cli\u003eWilliams GR, Chen Y, Kenzik KM, McDonald A, Shachar SS, Klepin HD, Kritchevsky S, Bhatia S (2020) Assessment of Sarcopenia Measures, Survival, and Disability in Older Adults Before and After Diagnosis With Cancer. JAMA Netw Open 3:e204783. doi: 10.1001/jamanetworkopen.2020.4783\u003c/li\u003e\n\u003cli\u003ePeel NM, Kuys SS, Klein K (2013) Gait Speed as a Measure in Geriatric Assessment in Clinical Settings: A Systematic Review. J Gerontol a-Biol 68:39-46. doi: 10.1093/gerona/gls174\u003c/li\u003e\n\u003cli\u003eStudenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, Brach J, Chandler J, Cawthon P, Connor EB, Nevitt M, Visser M, Kritchevsky S, Badinelli S, Harris T, Newman AB, Cauley J, Ferrucci L, Guralnik J (2011) Gait speed and survival in older adults. JAMA 305:50-58. doi: 10.1001/jama.2010.1923\u003c/li\u003e\n\u003cli\u003eYates T, Zaccardi F, Dhalwani NN, Davies MJ, Bakrania K, Celis-Morales CA, Gill JMR, Franks PW, Khunti K (2017) Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality: a UK Biobank observational study. Eur Heart J 38:3232-3240. doi: 10.1093/eurheartj/ehx449\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Breast cancer, cancer survivors, physical function trajectories, physical function decline","lastPublishedDoi":"10.21203/rs.3.rs-768755/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-768755/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePURPOSE: \u003c/strong\u003eAging associated with progressive declines in physical function is well-known; however, little is known about the trajectories of physical function before and after breast cancer diagnosis. The current study examined the trajectories in objective measures of physical function over 20 years for women with breast cancer and matched controls. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMETHODS:\u003c/strong\u003e 2712 community-dwelling women (452 breast cancer cases and 1:5 matched cancer-free controls) aged 65 years or older at baseline (1986-1988) within the Study of Osteoporotic Fractures were followed for 20 years. Objective physical function was assessed up to 9 times, including hand-grip strength, timed chair stand, gait speed and quadriceps strength. Linear mixed models were used to model physical function changes in terms of secular time trend, group (cases or controls), period (pre-and post-diagnosis status), and their interaction terms. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eRESULTS:\u003c/strong\u003e We observed all measures of physical function declined over time. While no differences in trends between cases and controls during the pre-diagnosis period were observed, after cancer diagnosis, grip strength and gait speed declined significantly faster in cases than controls. Quadriceps strength significantly decreased ~7 pounds shortly after breast cancer diagnosis, and then improved over time. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCONCLUSION\u003c/strong\u003e: Our prospective study revealed that older breast cancer survivors had significantly worse declines in grip strength and gait speed and a sharp, short-term drop followed by gradual improvement over time in quadriceps strength, compared to women without cancer. These findings suggest exercise training targeting muscle strength and mobility would be beneficial among older breast cancer survivors.\u003c/p\u003e","manuscriptTitle":"Trajectories of Objectively Measured Physical Function Among Older Breast Cancer Survivors in Comparison With Cancer-Free Controls","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-09 17:16:25","doi":"10.21203/rs.3.rs-768755/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-08-06T16:46:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-08-06T16:39:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-07-30T15:28:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research and Treatment","date":"2021-07-30T09:47:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1b4f5741-5d01-4437-8fe3-bc43ecefee33","owner":[],"postedDate":"August 9th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":6321380,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2022-03-29T02:56:19+00:00","versionOfRecord":{"articleIdentity":"rs-768755","link":"https://doi.org/10.1007/s10549-022-06568-6","journal":{"identity":"breast-cancer-research-and-treatment","isVorOnly":false,"title":"Breast Cancer Research and Treatment"},"publishedOn":"2022-03-26 02:56:19","publishedOnDateReadable":"March 26th, 2022"},"versionCreatedAt":"2021-08-09 17:16:25","video":"","vorDoi":"10.1007/s10549-022-06568-6","vorDoiUrl":"https://doi.org/10.1007/s10549-022-06568-6","workflowStages":[]},"version":"v1","identity":"rs-768755","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-768755","identity":"rs-768755","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}