Long-term Prognostic Role of Functional Limitations Among Women With Breast Cancer

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1 JNCI Journal of the National Cancer Institute Advance Access published September 22, 2010 DOI: /jnci/djq344 ARTICLE The Author Published by Oxford University Press. All rights reserved. For Permissions, please Long-term Prognostic Role of Functional Limitations Among Women With Breast Cancer Dejana Braithwaite, William A. Satariano, Barbara Sternfeld, Robert A. Hiatt, Patricia A. Ganz, Karla Kerlikowske, Dan H. Moore, Martha L. Slattery, Martin Tammemagi, Adrienne Castillo, Michelle Melisko, Laura Esserman, Erin K. Weltzien, Bette J. Caan Manuscript received November 13, 2009; revised August 10, 2010; accepted August 10, Correspondence to: Dejana Braithwaite, Helen Diller Family Comprehensive Cancer Center and the Department of Epidemiology and Biostatistics, University of California, San Francisco, 185 Berry St, Ste 5700, San Francisco, CA ( Background Methods Results Conclusion The long-term prognostic role of functional limitations among women with breast cancer is poorly understood. We studied a cohort of 2202 women with breast cancer at two sites in the United States, who provided complete information on body functions involving endurance, strength, muscular range of motion, and small muscle dexterity following initial adjuvant treatment. Associations of baseline functional limitations with survival were evaluated in delayed entry Cox proportional hazards models, with adjustment for baseline sociodemographic factors, body mass index, smoking, physical activity, comorbidity, tumor characteristics, and treatment. Difference in covariates between women with and without limitations was assessed with Pearson x 2 and Student t tests. All statistical tests were two-sided. During the median follow-up of 9 years, 112 deaths were attributable to competing causes (5% of the cohort) and 157 were attributable to breast cancer causes (7% of the cohort). At least one functional limitation was present in 39% of study participants. Proportionately, more breast cancer patients with functional limitations after initial adjuvant treatment were older, less educated, and obese (P <.001). In multivariable models, functional limitations were associated with a statistically significantly increased risk of death from all causes (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.03 to 1.92) and from competing causes (HR = 2.60, 95% CI = 1.69 to 3.98) but not from breast cancer (HR = 0.90, 95% CI = 0.64 to 1.26). The relationship between functional limitations and overall survival differed by tumor stage (among women with stage I and stage III breast cancer, HR = 2.02, 95% CI = 1.23 to 3.32 and HR = 0.74, 95% CI = 0.42 to 1.30, respectively). In this prospective cohort study, functional limitations following initial breast cancer treatment were associated with an important reduction in all-cause and competing-cause survival, irrespective of clinical, lifestyle, and sociodemographic factors. J Natl Cancer Inst 2010;102:1 10 Breast cancer incidence is projected to increase in industrialized countries, but as a consequence of advances in early detection and adjuvant therapy, improvements in survival observed in the last two decades will likely continue (1,2). As is true for many other types of tumors, the number of breast cancer survivors is constantly increasing because of the gain in life expectancy (3). However, substantial disparities exist in the survival of cancer patients (4). In addition to classical prognostic and predictive factors that include the extent of disease (5), cancer patients have other characteristics that can affect outcomes (6). For example, functional limitations (reported difficulties in the completion of tasks of everyday life) at the time of breast cancer diagnosis and following initial treatment have been associated with multiple adverse outcomes (7 10). Overall survival is the most therapeutically relevant outcome for cancer patients (11). Although physical function domains of the geriatric assessment scale have been associated with poor treatment tolerance and survival in older breast cancer patients (12), it is unclear whether functional limitations affect risk of death from breast cancer or from competing (non-breast cancer) causes (13). Whereas the evidence generally points to an expanding prevalence of functional limitations among older women (9,12), overweight and/or obese breast cancer patients are also likely to experience a disproportionate burden of functional impairments. Indeed, obesity contributes to the burden of comorbid chronic disease and survival disparities among breast cancer patients (14) and is an important prognostic factor in postmenopausal women (15,16). The possibility that the association of jnci.oxfordjournals.org JNCI Articles 1

2 functional limitations with survival among breast cancer patients varies by age and body mass index (BMI) is yet to be examined. Moreover, functional limitations have been associated with tumor stage (17), but the extent to which the impact of functional limitations on survival may differ according to the extent of disease is not well defined. Evaluating such relationships may help to calculate the long-term human and economic costs of functional impairments and might justify and focus interventions that are intended to improve health and life span of breast cancer survivors. A recent Institute of Medicine report (3) emphasized the need to identify high-risk populations that could be targeted with interventions to promote quality and lengthy survival. In this study of the long-term prognostic role of functional limitations, we considered death from breast cancer, competing causes, and all causes for women in a population-based cohort of early-stage breast cancer survivors, Life After Cancer Epidemiology [LACE (18)]. Women with incident breast cancer in the LACE cohort were followed for a median of 9 years since diagnosis in two different geographic locations in the United States. By including both middle-aged and elderly women with breast cancer, this large cohort of breast cancer survivors was suitable for examining the consequences of functional limitations following initial breast cancer treatment while taking into account known prognostic factors in the clinical, lifestyle-related, and sociodemographic domains. We evaluated the extent to which the impact of functional limitations on survival differed as a function of age, BMI, and tumor stage. Methods Study Population The sampling frame consisted of women diagnosed with stage I ( 1 cm), II, or IIIa breast cancer from 1997 to 2000 in the Kaiser Permanente Northern California Cancer Registry or the Utah Cancer Registry; eligible women were diagnosed, on average, 21 months (range 9 39 months) before enrollment, had completed cancer treatment, and were free of any documented recurrence during that period. In addition to the Kaiser Permanente and Utah cancer registries, the sampling frame included women screened and eligible for the Women s Healthy Eating and Lifestyle study, a dietary intervention trial examining the prevention of breast cancer recurrence. These women had declined participation in the Women s Healthy Eating and Lifestyle study but met the eligibility requirements specified above. A total of 2586 women completed initial enrollment; subsequent review to confirm eligibility left 2270 women in the cohort. Of the cohort members, 82% came from Kaiser Permanente, 12% from Utah, and 6% from the Women s Healthy Eating and Lifestyle study. The upper age restriction for enrollment to the study was 79 years because one of the main goals of the study was to examine longterm effects and the role of lifestyle-related factors such as physical activity and diet in reducing the risk of recurrence. Of the 2270 women included in the cohort study, data on physical functioning were available from 2202 participants, who formed the final analytic cohort used in the present analysis (Figure 1). The institutional review boards at the University of California, CONTEXTS AND CAVEATS Prior knowledge With advances in treatment, more breast cancer survivors are living longer, but it is not known how physical limitations following initial treatment affect morbidity and mortality. Study design Women with incident breast cancer aged years in the Life After Cancer Epidemiology cohort were followed for up to 11 years after diagnosis. The impact of functional limitations on survival was assessed as a function of age; body mass index; tumor stage; and other clinical, lifestyle-related, and sociodemographic factors. Contribution Functional limitations following initial treatment have an adverse effect on overall and competing-cause survival, but not breast cancer specific survival of longer-term breast cancer survivors. Implications Failure to address physical functioning after initial diagnosis and treatment of breast cancer survivors may have adverse effects on their quality of life and longevity. Limitations Information on physical impairments was available only after initial treatment, so the effect of functional limitations before cancer diagnosis could not be evaluated. There was no control group, so the effect of physical limitations on mortality could not be compared between women with and without breast cancer. The study was not sufficiently statistically powered to determine effects on more specific causes of non-breast cancer death. Failed to meet eligibility criteria N = 316 Missing data on physical functioning N = 68 Completed initial enrollment N = 2586 Eligibility confirmed N = 2270 Completed assessments of physical functioning N = 2202 From the Editors San Francisco and the Kaiser Permanente Division of Research approved this study. Assessment of Functional Limitations On the baseline questionnaire that was completed, on average, 21 months after breast cancer diagnosis, women were asked whether they were able to perform certain daily activities in the past month. Figure 1. Flow diagram of participants in the cohort study. 2 Articles JNCI Vol. 102, Issue 19 October 6, 2010

3 These activities were pushing objects like a living room chair; stooping, crouching, or kneeling; getting up from stooping, crouching, or kneeling; lifting or carrying items lighter than 10 lbs (like a bag of potatoes); lifting or carrying items heavier than 10 lbs (like a heavy bag of groceries); reaching or extending the right arm above the shoulder; reaching or extending the left arm above the shoulder; writing or handling small objects; standing in place for 15 minutes or longer; sitting for long periods (eg, 1 hour); standing up after sitting in a chair; walking alone up and down a flight of stairs; and walking two to three city blocks. This questionnairebased measure of functional limitations was taken from the Framingham Disability Study (19) and the Established Populations for Epidemiologic Studies of the Elderly (20), and from Nagi (21) and Rosow and Breslau (22). Other studies have validated these measures of physical functioning among women with breast cancer (17,23). The items have been validated against direct measures of physical performance (24) and cover both upper and lower body functions involving endurance, strength, muscular range of motion, or small muscle dexterity. Individual functional limitations were weighted equally and categorized as a binary variable (ie, 1 vs 0 limitations). These definitions are consistent with those used in previous studies of functional limitations among breast cancer survivors (17,23). Outcome Ascertainment To monitor health outcomes in the LACE cohort, a health status update questionnaire was mailed to the participants semiannually until April 2006 and annually thereafter. The health status update asked women about any events that might have occurred in the preceding 6 months (or 12 months on the revised questionnaire), including recurrences or new primary breast cancer, other cancers, and hospitalizations. Women who reported an event were then telephoned to obtain details about that event. In addition, nonrespondents to the mailed health status update questionnaire were telephoned and asked about any new events. All reported deaths from any source, including date and cause, were confirmed by death certificate. Vital statistics files were matched to identifiers of women in the cohort using social security numbers. In situations where social security numbers were unavailable, matches were based on agreements between name and date of birth. The underlying cause of death was coded by nosologists who completed death certificate review. This information was then categorized as breast cancer death or non-breast cancer death. Outcome ascertainment was updated regularly by surveillance of electronic outpatient record, cancer registry, and mortality files for all participants, including those who dropped out (n = 90) or were lost to active follow-up (n = 15). In this analysis, the outcomes of interest were survival from competing causes, breast cancer specific causes, and all causes. Covariates The covariates in these analyses were sociodemographic, lifestylerelated, and clinical prognostic factors that, based on the existing literature and a priori hypotheses, could potentially confound or modify an association between functional status and survival. The sociodemographic covariates included age (calculated as the difference between date of enrollment and reported date of birth), race and/or ethnicity, and education, the last two being self-reported at baseline. Lifestyle-related factors included smoking status (never, former, and current) and BMI at enrollment (calculated as weight/height [kg/m 2 ] from self-reported weight and height). Three standard BMI categories (normal weight, <25; overweight, 25 30; and obese, 30) were used (25); we also separately evaluated underweight women (BMI 18.5). Physical activity was assessed in the LACE study with a questionnaire based on the Arizona Activity Frequency Questionnaire (26). Standard metabolic equivalent task values were assigned to each activity; then the frequency was multiplied by duration and metabolic equivalent task value and summed over all activities (other than the sedentary recreational and transportation activities), providing a summary measure of total activity in metabolic equivalent task hours per week (27). Medical factors were obtained from electronic databases for the LACE participants who were Kaiser Permanente members and from medical chart review for those who were not. Medical factors included tumor size; histology; lymph node involvement and distant metastasis; estrogen receptor (ER), progesterone receptor, and HER2 status; and treatments (type of surgery, radiation, chemotherapy, and use of adjuvant tamoxifen). Stage at diagnosis was classified according to the TNM system based on the criteria of the American Joint Committee on Cancer as stage 0, I, IIa, IIb, III, or IV (28). Patient-reported comorbid medical conditions were used as an indicator of the comorbidity burden; these conditions included thyroid disease, hypoglycemia, diabetes, hypertension, myocardial infarction, angina, peripheral arterial disease, gallbladder disease, diverticulitis, Crohn disease, pancreatitis, colorectal polyps, irritable bowel syndrome, kidney disease, arthritis, osteoporosis, cirrhosis, stroke, and lupus. The comorbidity burden was estimated using the following two methods: the comorbidity count (29) and the Charlson comorbidity index (CCI) (30,31). The CCI was derived from the number and type of underlying diseases present at study entry from patient questionnaire data. Both comorbidity count and CCI were categorized as binary variables (ie, 1 vs 0 comorbidities). In the absence of a standard comorbidity index and in light of the fact that the CCI omits important prognostic comorbidities in breast cancer (29,32), we compared the effects of using the comorbidity count vs the CCI in functional limitation models. Statistical Analyses Differences in means and proportions of each potential covariate between women with and without limitations (ie, 1 vs 0 limitations) were compared using Student t tests for continuous variables and Pearson x 2 tests for categorical variables. Univariate and multivariable associations between functional limitations and survival were examined using Kaplan Meier plots and Cox proportional hazards models. Guided by a priori considerations (33), separate delayed entry Cox proportional hazards models (34,35) with time since diagnosis as the time scale were used to estimate the risk of each outcome associated with functional status, accounting for varying times of enrollment into the cohort and adjusting for covariates. Risk was expressed as a hazard ratio (HR) and 95% confidence interval jnci.oxfordjournals.org JNCI Articles 3

4 (CI). The level of significance was set at.05 and all reported P values are two-sided. Follow-up time ended at date of first confirmed date of death, depending on the specific analysis. Individuals who were alive were censored at date of last contact (either most recent questionnaire on health status update or electronic surveillance). When death due to competing causes was analyzed, breast cancer specific deaths were censored. After computing age-adjusted Cox proportional hazards models for functional limitations, known prognostic variables and those that showed statistically significant relations with either the independent or dependent variable were added to the model (with P <.10 level of significance). All Cox proportional hazards models were tested for proportionality of hazards using Schoenfeld residuals (36). When this assumption was violated, stratified proportional hazards models were fitted; no material differences in hazard ratios were observed. In multivariable models, interaction terms were considered. To avoid collinearity in modeling, tamoxifen use and ER status were entered into the same model by creating variables, ER positive/no tamoxifen and ER positive/tamoxifen. Stata version 11.0 software (StataCorp LP, College Station, TX) was used to conduct statistical analyses. Results Characteristics of Study Participants by Functional Status Thirty-nine percent of the study participants reported at least one limitation following initial adjuvant treatment at study entry. The majority of the women were early-stage breast cancer survivors with 81% in stages I or IIa at the time of diagnosis (Table 1). The median age was 57 years (SD = 13.2 years; range years) at the time of entrance to the study. The sample was ethnically and socioeconomically diverse: 20% of participants were nonwhite, and nearly 30% were educated at the high school level or below (Table 1). The proportion of functional limitations generally increased with age; 39.2% of women with one or more functional limitations were aged vs 23.8% of women without limitations (P <.001; Table 1). Women with limitations were more likely to be overweight or obese; 35.7% had a BMI of at least 30 vs 21.4% of women without limitations (P <.001; Table 1). Impaired women were disproportionately less educated; 33.2% had been educated at the high school level or below compared with 23.6% of nonimpaired women (P <.001). Women with limitations were less physically active compared with women without limitations (metabolic equivalent task hours per week: mean = 45.8 vs 55.7, respectively; P =.01). There were also differences in breast cancer treatment by physical functioning; patients with functional limitations were less likely to receive chemotherapy (51.1% vs 61.2%, respectively, P <.001), radiotherapy (58.7% vs 65.3%, respectively, P =.002), and breast-conserving surgery (47.8% vs 52.2%, respectively; P =.05). However, the proportion of functional limitations did not differ by tumor stage, nodal status, or ER or progesterone receptor or HER2 status (Table 1). Women with functional limitations were also proportionately more likely to have at least one comorbid condition compared with those without limitations (78.6% vs 60.4%, respectively; P <.001) and a CCI score of at least 1.0 (69.7% vs 44.1%, respectively, P <.001; Table 1). Comorbid conditions associated with at least one functional limitation were arthritis (51% vs 25% for women with and without limitations, respectively; P <.001), hypertension (40% vs 26%, P <.001), gallbladder disease (17% vs 10%, P <.001), diverticulitis (11% vs 6%, P <.001), irritable bowel syndrome (11% vs 7%; P <.001), osteoporosis (10% vs 5%, P <.001), ulcer (10% vs 5%, P <.001), diabetes mellitus (5% vs 1%, P <.002), angina (6% vs 2%, P <.001), and stroke (4% vs 1%, P <.001). Proportionately more women with functional limitations than those without limitations died of competing causes (8.9% vs 2.7% respectively, P <.001). In contrast, similar proportions of patients with and without functional limitations died of breast cancer (P =.99; Table 1). Survival Data The median follow-up in the entire LACE cohort of 2270 women was 9 years (SD = 1.5 years, range = 1 11 years); 95% of the women were followed for a minimum of 6.3 years. During this period, there were 284 deaths in the entire cohort, 120 of these were attributable to competing causes and 164 to breast cancer. Among the 2202 women in our final analytic cohort who completed functional assessments after initial adjuvant treatment, there were 269 deaths, 112 due to competing causes (5% of the cohort) and 157 to breast cancer (7% of the cohort) (Table 2). Functional Limitations and Survival Women with functional limitations had statistically significantly shorter all-cause and competing-cause survival but not breast cancer specific survival (Figure 2 and Table 2). The ageadjusted hazard ratio for association of functional limitations with overall survival was 1.56 (95% CI = 1.22 to 1.98). In the fully adjusted model that also included race and/or ethnicity, education, BMI, smoking, physical activity, comorbidity, tumor characteristics, and treatment, the effect estimate was attenuated but remained statistically significant (HR = 1.40, 95% CI = 1.03 to 1.92; Table 2). When data were reanalyzed using the CCI instead of the comorbidity count and with further adjustment for surgery, similar results were obtained (data not shown). We also examined whether treatment modified the effect of functional limitations on survival. The adjusted hazard ratio for women who received tamoxifen but not chemotherapy was statistically significant at 1.39 (95% CI = 1.12 to 1.71, P =.002) but not for those who received both (HR = 1.15, 95% CI = 0.93 to 1.43, P =.19). Furthermore, women who received chemotherapy were more likely to have higher-stage disease (P <.001). Functional limitations were strongly associated with competingcause survival in the age-adjusted model (HR = 2.82, 95% CI = 1.89 to 4.21) and were only slightly attenuated in the fully adjusted model (HR= 2.60, 95% CI = 1.69 to 3.98; Table 2). Current results do not support an association of functional limitations with survival from breast cancer specifically (adjusted HR = 0.90, 95% CI = 0.64 to 1.26; Table 2). 4 Articles JNCI Vol. 102, Issue 19 October 6, 2010

5 Table 1. Characteristics of the study population by functional limitations* Characteristic Without limitations (n = 1345) With limitations (n = 857) P Age at diagnosis, No. (%), y <.001 < (29.0) 153 (17.9) (47.2) 368 (42.9) (23.8) 336 (39.2) Education, No. (%) < y high school 316 (23.6) 284 (33.2) College 487 (36.3) 331 (38.7) Graduate degree 539 (40.2) 240 (28.1) Race and/or ethnicity, No. (%).83 White 1080 (80.3) 684 (80.0) Black 60 (4.5) 43 (5.0) Hispanic 82 (6.1) 57 (6.7) Asian 82 (6.1) 44 (5.2) Other 41 (3.5) 27 (3.2) Body mass index, No. (%), kg/m 2 <.001 < (44.6) 213 (30.2) (34.0) 241 (34.1) > (21.4) 252 (35.7) Cigarette smoking, No. (%).14 Former 729 (54.3) 438 (51.1) Past 522 (38.9) 343 (40.0) Current 92 (6.9) 76 (8.9) Comorbidity count, No. (%) < (39.5) 160 (21.3) (60.4) 590 (78.6) Charlson comorbidity, No. (%) < (55.9) 236 (30.3) (44.1) 544 (69.7) Adjuvant tamoxifen, No. (%).02 No 302 (22.6) 184 (21.6) Past 78 (5.8) 76 (8.9) Current 959 (71.6) 591 (69.5) Chemotherapy, No. (%) <.001 No 522 (38.8) 418 (48.9) Yes 823 (61.2) 437 (51.1) Radiotherapy, No. (%).002 No 466 (34.7) 353 (41.3) Yes 879 (65.3) 502 (58.7) Surgery, No. (%).05 Conserving 702 (52.2) 410 (7.8) Mastectomy 643 (47.8) 447 (52.2) Stage, No. (%).72 I 634 (47.2) 393 (45.9) IIA 436 (32.5) 298 (34.8) IIB 229 (17.1) 140 (16.4) III 43 (3.2) 25 (2.9) Lymph node positivity, No. (%).46 No 789 (62.5) 521 (64.1) Yes 474 (37.5) 292 (35.9) ER positivity, No. (%).82 No 236 (17.8) 141 (16.7) Yes 1089 (82) 701 (83.1) PR positivity, No. (%).07 No 395 (29.8) 245 (29.0) Yes 930 (70.1) 597 (70.7 HER2 positivity, No. (%).10 No 919 (72.1) 569 (71.9) Yes 175 (13.7) 107 (13.5) All-cause death, No. (%) 132 (9.8) 137 (15.9) <.001 (Table continues) Table 1. Continued Characteristic Breast cancer death, No. (%) Competing-cause death, No. (%) Total number of physical activity, mean (SD), MET-h/wk Without limitations (n = 1345) With limitations (n = 857) P 96 (7.1) 61 (7.1) (2.7) 76 (8.9) < , 55.7 (32.4) 725, 45.9 (29.8).01 * Numbers may not equal the sample size of the final analytic cohort (n = 2202) because of missing data on some of the covariates. The study population consisted of women diagnosed with breast cancer from the Life After Cancer Epidemiology study in the United States, , who provided complete information on functional limitations. ER = estrogen receptor; PR = progesterone receptor; MET = metabolic equivalent task. Differences in means and proportions of each potential covariate between women with and without limitations ( 1 vs 0 limitations) were compared using Student t tests for continuous variables and Pearson s x 2 tests for categorical variables. P values were computed using two-sided tests. Breast-conserving surgery included lumpectomy, wide excision, partial mastectomy, segmental mastectomy or quadrantectomy; mastectomy included modified radical mastectomy (simple mastectomy with lymph node dissection), total mastectomy without axillary lymph node dissection, and radical mastectomy with pectoral muscle dissection. Functional Limitations and Survival by Age Strata We next examined the possible disproportionate impact of functional limitations on survival in different age groups (Table 3). Although the proportion of functional limitations increased with age (Table 1), the effect of functional limitations on survival did not statistically significantly differ by age (P interaction =.16; adjusted HR = 1.01, 95% CI = 0.99 to 1.03). The direction of the effect estimates across age strata supports an association of functional limitations with decreased survival. After adjustment for race and/or ethnicity, education, BMI, smoking, physical activity, comorbidity, tumor characteristics (stage, lymph node status, and ER or progesterone receptor and HER2 status), and treatment (chemotherapy and radiation therapy), we found that the adverse impact of functional limitations on all-cause survival increased only among women aged years (adjusted HR = 1.55, 95% CI = 1.01 to 2.40) and among those aged years (adjusted HR = 1.19, 95% CI = 0.74 to 1.92; Table 3). In multivariable models adjusted for race and/or ethnicity, education, BMI, smoking, physical activity, and comorbidity, hazard ratios for the association of functional limitations with competing-cause survival were most increased in the two older age groups, thus mirroring the results obtained with all-cause survival. Specifically, for 50- to 65-year-old women, the adjusted hazard ratio was 2.49 (95% CI = 1.06 to 5.88), whereas the corresponding value in the oldest group was 2.65 (95% CI = 1.39 to 5.04; Table 3). Although the hazard ratio among women aged 50 years or less also increased, it was of smaller magnitude because of wide confidence intervals resulting from a very small number of events (n = 6). When the association of functional limitations with breast cancer specific survival was stratified across the three levels of age, the magnitude of effect jnci.oxfordjournals.org JNCI Articles 5

6 estimates suggested no strong effect in any of the three age groups (Table 3). Functional Limitations and Survival by BMI Strata Because functional limitations were more prevalent among obese patients (Table 1), we next investigated whether the impact of functional limitations on survival varied across BMI strata (Table 3). When we evaluated whether excluding the underweight (BMI 18.5) group (n = 19) affected the estimates among women of normal weight (BMI <25), similar results were obtained (data not shown). Interaction testing revealed that the effect of functional limitations on survival did not differ by BMI (P interaction =.15, adjusted HR = 0.96, 95% CI = 0.91 to 1.01). After adjustment for age, race and/or ethnicity, education, BMI, smoking, physical activity, comorbidity, tumor characteristics, and treatment, the hazard ratio for association of functional limitations with allcause survival was the highest among normal weight women (HR = 1.99, 95% CI = 1.20 to 3.32; Table 3). The corresponding hazard ratios among overweight and obese women were 0.98 (95% CI = 0.58 to 1.64) and 1.29 (95% CI =.70 to 2.37), respectively (Table 3). Functional limitations were associated with competing-cause survival across BMI levels. The adjusted hazard ratios were 2.53 (95% CI = 1.16 to 5.51), 3.40 (95% CI = 1.21 to 9.49), and 2.69 (95% CI = 1.05 to 6.90), respectively, in the lowest, middle, and highest BMI groups (Table 3). When the association of functional limitations with breast cancer specific survival was stratified across the three levels of BMI, the magnitude of effect estimates suggested no strong effect in any of the three BMI groups (Table 3). Functional Limitations and Survival by Tumor Stage Strata To better understand the relationships among functional limitations, extent of disease, and survival, we next performed analyses stratified by tumor stage (Table 3). The effect of functional limitations on survival differed by stage (P interaction =.02, HR = 0.48, 95% CI = 0.26 to 0.87). With respect to all-cause survival, adjusted for age, race and/or ethnicity, education, BMI, smoking, physical activity and comorbidity, tumor characteristics, and treatment, there was a twofold increase in the risk of death among women with functional limitations and stage I disease (HR = 2.02, 95% CI = 1.23 to 3.32; Table 3); corresponding hazard ratios among stage IIa patients were of lower magnitude than those of women with stage I disease but still elevated at 1.41 (95% CI = 0.86 to 2.29). In the stage IIb and III groups, the hazard ratios were 1.00 (95% CI = 0.57 to 1.73) and 0.74 (95% CI = 0.42 to 1.30), respectively (Table 3). Paralleling the results of all-cause survival, the adjusted hazard ratio for competing-cause survival was highest in the stage I group (HR = 4.30, 95% CI = 2.06 to 8.98; Table 3). In the stage IIa and IIb groups, hazard ratios were still elevated but with lower magnitude at 1.57 (95% CI = 0.73 to 3.40) and 2.15 (95% CI = 0.66 to 7.08), respectively (Table 3). Among women with stage III disease, only one death occurred, precluding the computation of effect estimates. Functional limitations were unrelated to breast cancer survival across stage strata (Table 3). Discussion This large multiethnic cohort study of breast cancer survivors followed for a median of 9 years after diagnosis is, to our knowledge, the first to provide prospective evidence of the long-term prognostic impact of functional capacity on survival, following initial breast cancer treatment, while taking into account clinical, sociodemographic, and lifestyle-related factors. The importance of functional status as a prognostic factor for survival has been well established in older noncancer populations (37,38). A new finding from this analysis among longer-term breast cancer survivors is that functional limitations following initial adjuvant treatment primarily affect overall and competing-cause survival, but not breast cancer specific survival. The pattern of the relationships between functional limitations and survival supports the view that functional limitations have prognostic value for breast cancer independently of known prognostic factors, including comorbidity (8,12). Although the prevalence of functional limitations in this study was generally greater among older and overweight or obese individuals, the impact of functional limitations on survival did not statistically significantly differ according to age and BMI. Our results are consistent with previous studies indicating that functional limitations are common among breast cancer survivors (10,39); as many as 39% of the patients in this study reported at least one limitation following initial breast cancer treatment at study entry. Table 2. Hazard ratios for the association of functional limitations with survival* Model All-cause survival (deaths = 269), HR Competing-cause survival (deaths = 112), HR Breast cancer survival (deaths = 157), HR Age adjusted 1.56 (1.22 to 1.98) 2.82 (1.89 to 4.21) 1.03 (0.74 to 1.42) Fully adjusted 1.40 (1.03 to 1.92) 2.60 (1.69 to 3.98) 0.90 (0.64 to 1.26) * The study population consisted of women diagnosed with breast cancer from the Life After Cancer Epidemiology study in the United States, , who provided complete information on functional limitations. n = 2202; CI = confidence interval; HR = hazard ratio. Statistical tests are based on delayed entry Cox proportional hazards models. Fully adjusted models included age, race and/or ethnicity, education, BMI, smoking, physical activity, and comorbidity using the cut points in Table 1. In models examining overall and breast cancer specific survival, additional adjustments for tumor characteristics (stage, lymph node status, and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor status) and treatment (chemotherapy and radiation therapy) were performed using the cut points in Table 1. 6 Articles JNCI Vol. 102, Issue 19 October 6, 2010

7 Figure 2. Kaplan Meier survival curves according to functional limitations. A) Overall survival for breast cancer patients with and without functional limitations. B) Competing-cause (non-breast cancer) survival for women with and without functional limitations. C) Breast cancer specific survival for women with and without functional limitations. In each graph, the solid line indicates the proportion of breast cancer patients surviving without functional limitations and The impact of functional limitations on the course of breast cancer and outcomes among breast cancer patients has been studied to a limited extent. Satariano et al. (17) showed that the stage of disease was strongly associated with functional limitations, after taking into account breast cancer treatment, financial adequacy, education, marital status, and comorbidity. To our knowledge, this study represents an advancement over previous research because of our ability to determine that functional limitations exert the greatest impact among women with localized disease. In that subgroup, deaths were more likely attributable to causes other than breast cancer. Our finding that women with functional limitations were least likely to have received chemotherapy and radiation corroborates previous research linking functional impairments with poor treatment tolerance in older breast cancer survivors (12). Whereas the dotted line indicates the proportion of breast cancer patients surviving with functional limitations. At 0, 5, and 10 years after breast cancer diagnosis, the numbers of patients at risk of death from all causes are shown. Plots were computed with baseline data on functional limitations obtained following initial adjuvant treatment. Hazard ratios and 95% confidence intervals are given in Table 2. functional limitations played a statistically significant role in the survival of the whole cohort, subgroup analyses revealed that this was not the case among women who received adjuvant chemotherapy. Because chemotherapy was associated with advanced disease stage, it appears that advanced disease that led to chemotherapeutic treatment overrode the prognostic impact of functional capacity. Indeed, the all-cause survival hazard ratio was higher in stages I and IIa but was near null for stages IIb and III. Generally, the impact of functional limitations decreased with increasing stage. The functional limitations found to affect survival in our study make biological and clinical sense because they may reflect chronic inflammation and commensurately diminished function of vital organs or systems (40). As biological models and molecular tools jnci.oxfordjournals.org JNCI Articles 7

8 Table 3. Hazard ratios for the association of functional limitations with survival stratified by age, body mass index (BMI), and tumor stage* All-cause survival Competing-cause survival Breast cancer survival Adjusted HR Unadjusted HR No. of patients/ No. of deaths Adjusted HR Unadjusted HR No. of patients/ No. of deaths Adjusted HR Unadjusted HR No. of patients/ No. of deaths Variable Age, y <50 543/ (0.81 to 2.99) 0.85 (0.31 to 2.35) 543/ (0.70 to 3.86) 1.86 (0.30 to 11.5) 543/ (0.67 to 2.85) 1.04 (0.55 to 1.95) / (0.80 to 1.77) 1.19 (0.74 to 1.92) 1002/ (1.0 to 2.60) 2.49 (1.06 to 5.88) 1003/ (0.53 to 1.42) 0.99 (0.89 to 1.10) / (1.34 to 2.79) 1.55 (1.01 to 2.40) 656/ (1.74 to 5.18) 2.65 (1.39 to 5.04) 656/ (0.63 to 1.86) 0.86 (0.44 to 1.68) BMI, kg/m 2 <25 730/ (1.59 to 3.90) 1.99 (1.20 to 3.32) 730/ (1.83 to 6.73) 2.53 (1.16 to 5.51) 730/ (0.87 to 2.90) 1.72 (0.90 to 3.30) / (0.91 to 2.19) 0.98 (0.58 to 1.64) 635/ (2.21 to 11.06) 3.40 (1.21 to 9.49) 635/ (0.38 to 1.28) 0.57 (0.30 to 1.08) >30 500/ (0.88 to 2.45) 1.29 (0.70 to 2.37) 500/ (1.24 to 5.81) 2.69 (1.05 to 6.90) 500/ (0.54 to 2.12) 0.72 (0.34 to 1.53) Tumor stage I 1027/ (1.60 to 3.76) 2.02 (1.23 to 3.32) 1027/ (2.65 to 9.45) 4.30 (2.06 to 8.98) 1027/ (0.54 to 2.03) 1.06 (0.51 to 2.19) IIa 734/ (1.39 to 3.23) 1.41 (0.86 to 2.29) 734/ (1.57 to 5.99) 1.57 (0.73 to 3.40) 734/ (0.94 to 2.83) 1.25 (0.69 to 2.29) IIb 369/ (0.77 to 1.95) 1.00 (0.57 to 1.73) 369/ (1.19 to 6.38) 2.15 (0.66 to 7.08) 369/ (0.45 to 1.49) 0.66 (0.34 to 1.26) III 68/20 52 (0.19 to 1.44) 0.74 (0.42 to 1.30) 68/1 68/ (0.20 to 1.55) 0.75 (0.22 to 2.64) * The study population consisted of women diagnosed with breast cancer from the Life After Cancer Epidemiology study in the United States, , who provided complete information on functional limitations. CI = confidence interval; HR = hazard ratio. Statistical tests are based on delayed entry Cox proportional hazards models. Adjusted models included age, race and/or ethnicity, education, BMI, smoking, physical activity, and comorbidity using the cut points in Table 1. In models examining overall and breast cancer specific survival, additional adjustments for tumor characteristics (stage, lymph node status, and estrogen receptor, progesterone receptor, and HER2 status) and treatment (chemotherapy and radiation therapy) were performed using the cut points in Table 1. Tumor stage at diagnosis was classified according to the TNM system based on the criteria of the American Joint Committee on Cancer as stage 0, I, IIa, IIb, III or IV. Insufficient number of deaths to compute hazard ratios in this subgroup. increasingly help us uncover new opportunities to decrease risk of breast cancer recurrence and breast cancer specific mortality, it is equally important to intervene to improve survival from competing causes of death (13). The findings of this study underscore the need to track long-term effects and explore whether they are amenable to interventions. Targeting functional limitations for future interventions among cancer survivors is particularly compelling (41). Our findings suggest that functional status may be an important addition to clinical screening among breast cancer patients to identify groups that are at high risk of poor prognosis, allowing the targeting of functionally impaired patients to improve quality and length of life. This study included a large cohort of breast cancer patients from a Northern California health maintenance organization whose members were representative of the general population with respect to most socioeconomic categories (42) and the Utah Cancer Registry, with a long follow-up and broad range of current ages and ages at diagnosis. We used a reliable and valid measure of physical functioning that is consistent with previous studies among breast cancer patients (17,23). Alternative measurement strategies are, nevertheless, needed to understand whether differential weighting of individual limitations may improve their prognostic value and clinical use. This study had several limitations. Although we established the effect of functional limitations on competing-cause survival, the current study was not statistically powered to determine effects on more specific causes of non-breast cancer death. More detailed knowledge of the impact of functional status on cause-specific mortality (eg, cardiovascular disease or diabetes) may reveal mechanisms by which functional impairments exert their effects. Functional assessments were obtained after initial breast cancer treatment; thus, information on impairments before breast cancer diagnosis was unavailable. Because this study did not include a control group of women without breast cancer, we were unable to determine whether the mortality increase due to functional limitations was higher in women with breast cancer than in their counterparts without the disease. Another limitation relates to response bias that may have resulted in a sample not fully representative of this survivor population. For example, the lack of the association of functional limitations with mortality due to breast cancer may have been specific to this early-stage patient population, which is characterized by a more indolent tumor pattern and a higher likelihood of ER-positive breast cancer (43). Moreover, the impact of functional limitations was greatest in early-stage disease, which suggests that functional limitations would have a modest impact on breast cancer specific death in patients with advanced disease. However, further validation of the effects of physical functioning is warranted in more geographically, demographically, and clinically diverse samples, including survivors of other cancers, and over longer follow-up periods. In conclusion, functional limitations observed following initial breast cancer treatment were associated with an important reduction in all-cause and competing-cause survival and one or more of these limitations were present in 39% of patients. Although the impact of functional limitations on survival did not differ by age and BMI, it differed by disease stage, as reflected by the modest impact among women with advanced disease and remarkably strong effects among women with localized disease. Importantly, women with 8 Articles JNCI Vol. 102, Issue 19 October 6, 2010

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