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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1849-1856 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.04.173 Functional Impact of Breast Cancer by Age at DiagnosisFrom the Channing Laboratory, Department of Medicine, Brigham & Women's Hospital, and Harvard Medical School; Department of Medical Oncology, Dana Farber Cancer Institute; and Department of Health and Social Behavior and Department of Epidemiology, Harvard School of Public Health, Boston, MA Address reprint requests to Candyce Kroenke, Channing Laboratory, 181 Longwood Ave, 3rd floor, Boston, MA 02115; e-mail: candyce.kroenke{at}channing.harvard.edu
PURPOSE: To explore changes in physical and psychosocial function before and after breast cancer by age at diagnosis.
PATIENTS AND METHODS: A total of 122,969 women from the Nurses' Health Study (NHS) and NHS 2, ages 29 to 71 years, who responded to pre- and postfunctional status assessments were included; 1,082 women were diagnosed with breast cancer between 1992 and 1997. Functional status was measured using the Medical Outcomes Study Short Form 36 (SF-36). Mean change in health-related quality of life (HRQoL) scores was computed across categories representing the combination of incident breast cancer (yes or no) and age at diagnosis (
RESULTS: Compared with women CONCLUSION: Young women may fare worse than middle-aged or elderly women in both physical and psychosocial dimensions after breast cancer diagnosis. The needs of women facing breast cancer may be better understood within a life stage framework.
Previous studies suggest that elderly women experience more persistent problems with physical function after breast cancer diagnosis, compared with young women.1-7 Comorbid conditions in older women may compound the physical effects of breast cancer diagnosis and treatment. Conversely, young women appear to have more problems with psychological adjustment than elderly women.2,3,6,8-15 They may have greater life stage challenges in adapting to the unexpectedness of breast cancer diagnosis, including possible losses in their careers, family life, and fertility.9 Unfortunately, much previous research has been limited by lack of control groups, cross-sectional designs, lack of adjustment for age-related differences in treatment, and small sample sizes. These limitations have made it impossible to account for age-related declines when comparing older and younger women. Furthermore, the failure to adjust for baseline function may lead to an overestimation of the physical and underestimation of the mental health impact of breast cancer on older women, who have lower baseline levels of physical function but higher levels of mental health than younger women.
In a preliminary analysis of data from the Nurses' Health Study (NHS), Michael et al16 analyzed 4-year change in functional health status in older women, comparing 759 women diagnosed with breast cancer to a group that remained healthy over the same time period. They found that women who developed breast cancer were more likely to have experienced reduced physical function, physical role function, emotional role function, vitality, and social function, and increased bodily pain over time, compared with women who remained free of breast cancer. In their preliminary analysis, they found no difference in changes in functional status by age (< 65 v This study extends their prior analysis and adds women from the NHS 2, a younger cohort than NHS, and thereby enables a prospective, longitudinal exploration of functional change among breast cancer patients by age group over a wider age range.
Study Population The NHS includes 121,700 female, married, registered nurses living in one of 11 US states who completed an initial baseline questionnaire in 1976. In 1989, a group of 116,671 younger female nurses from 15 US states, who were free of diagnosed cancer, were recruited into the NHS 2 cohort. The age range of women in the NHS 2 cohort is nonoverlapping with NHS. Investigators have followed each of the cohorts with biennial mailed questionnaires. The study population consisted of women aged 29 to 71 years in 1992, from both the NHS (ages 46 to 71 years) and NHS 2 (ages 29 to 45) who responded to pre- and post-health-related quality of life (HRQoL) assessments 4 years apart. A total of 67,300 nurses from the NHS cohort completed assessments in 1992 and 1996 and 71,877 nurses from the NHS 2 cohort responded to assessments in 1993 and 1997. Women with any prior cancer, except skin cancer other than melanoma, were excluded, leaving 122,969 women in the analyses.
Data Collection Instruments. The Medical Outcomes Study Short Form (SF-36)17 is a self-administered questionnaire that measures eight domains of HRQoL, including physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), mental health (MH), and general health perceptions. We included the seven specific functional domains in our study but not general health perceptions or global scores. Subscales were scored on a scale of 0 (lowest) to 100 (highest). In longitudinal data collected by Ware,18 patients 18 to 97 years old who declined more than 6.5 points in the physical or 7.9 points in the mental health summary scores during a 4-year period were nearly 10 times more likely (0.9% to 8.1%; P < .001) to die during the subsequent 3 years. Although changes in summary scores are not directly comparable to changes in function represented by the SF-36 subscales, they help provide context for Ware's suggestion that subscale differences of 5 to 10 points are clinically and socially relevant.19 This instrument has been tested extensively and validated.20-26 To supplement the assessment of generic quality of life, in the year 2000 (3 to 8 years after diagnosis), women with breast cancer were administered the widely used 59-item Cancer Rehabilitation Evaluation System–Short Form (CARES-SF) to supplement the SF-36 data by assessing cancer-specific quality of life. In this study, we included medical interaction, marital interaction, and sexual function. Scores ranged from 0 to 4, with higher scores indicating greater problems.27-29 Assessment of age and other covariates. In 1976 (NHS) and 1989 (NHS 2), women were asked their date of birth. Data on biomedical and lifestyle factors including hormone use, body mass index, menopausal status, smoking, physical activity, alcohol consumption, and comorbidity (defined here as presence of hypertension, diabetes, arthritis, osteoporosis, and cardiovascular disease) have been assessed biennially.
Statistical Analyses
The full cohort was then categorized into one of six groups according to both diagnosis of invasive breast cancer between 1992 and 1997 (yes or no) and age group ( Using linear regression methods (SAS PROC GLM; 2000, SAS Institute, Cary, NC), we regressed potential confounding variables against age group categories (Table 1). We further evaluated changes in the SF-36 subscales between baseline and follow-up for each exposure group. Outcomes are represented as the change in function for each exposure group compared with the reference group. To account for age-related declines in HRQoL when evaluating the effect of breast cancer diagnosis, we computed relative declines as the within-age group differences, employing the variance-covariance matrix to determine whether relative declines by age group differed from zero and from each other.
Initial analyses were adjusted for baseline functional status (mean centered). Subsequent models were adjusted for factors listed in Table 2. Because results did not substantially differ by level of adjustment, only results from multivariate-adjusted models are presented.
Because of the potential for ceiling effects for five of the SF-36 subscales (PF, RP, BP, SF, RE), we also used logistic regression to analyze subscales. For each subscale, if there was no change in function or function increased (change in function  0), women were considered to have no new limitation. If women declined in function (change in function < 0), they were considered to have a new limitation. The odds ratio was interpreted as the increased odds of any new limitation. To evaluate the impact of breast cancer within an age group, relative odds were computed by dividing the increased odds of a new limitation for women with breast cancer by the increased odds of any new limitation for similar-age women without breast cancer (Table 3).
A second set of analyses included women with breast cancer only. Time since diagnosis was computed as months between diagnosis and postfunctional assessment. To determine whether disease severity or treatment differentially influenced prospective change in functional status by age, we ran models with interactions of each of these variables by age group, adjusting for other disease and severity factors.
Finally, we examined cross-sectional differences in cancer-specific function by age group. Of the 1,082 women with breast cancer in this sample, 975 responded to the CARES-SF. Because of variable missing outcome data for each of the subscores (n = 695 to 865), we included variable numbers of women in analyses to maximize power. Young women
Description of the Study Population Among the 122,969 women in the study, 1,082 primary invasive breast cancers were diagnosed between 1992 and 1997; 783 were from the NHS, and 299, from the NHS 2 cohorts. Compared with women who remained free of breast cancer, women with breast cancer drank larger amounts of alcohol per day and were more likely to be current postmenopausal hormone users and have any comorbidity at baseline. Among women with breast cancer, those 65 years and older were less likely than younger women to receive chemotherapy or radiation and more likely to receive tamoxifen. Middle-aged women were most likely to receive lumpectomy. Older women were less likely to be node-positive, had smaller tumor size, and at the time of the postfunctional assessment, tended to be further out from diagnosis than the younger women (Table 1).
Change in Functional Status by Age at Diagnosis Logistic regression analyses confirmed the above results. Relative to similar-age women free of breast cancer, young women with breast cancer were more likely to experience a functional limitation because of a diagnosis of breast cancer than women in other age groups. The relative odds of any limitation generally decreased with increasing age group (Table 4).
In analyses of main effects, including women with breast cancer only, having four or more positive nodes (v no nodes) and diagnosis within the past 12 months (v
Cancer-Specific Function by Age at Diagnosis
In our study, young women who developed invasive breast cancer experienced greater absolute and relative functional losses in physical role function, bodily pain, social function, and mental health, compared with middle-aged or elderly women with incident breast cancer. Overall, HRQoL declines in young women with breast cancer were twice as large as cancer-related losses in middle-aged or elderly women. With the exception of physical role function, which seemed sensitive to the cumulative effects of age, young women comprised a distinct population that differed in their response to breast cancer than did women who were middle-aged or older. These results stress the importance of life stage in evaluating the impact of breast cancer on functional status.30 Our study findings further highlight the need for age-appropriate comparison groups and prospective data collection in studies of cancer and HRQoL. Past literature has generally indicated that elderly women do more poorly than young women with regard to physical function after diagnosis of breast cancer.1,3,5-7,10,31 However, nearly all these studies have failed to use appropriate control groups or examine changes from baseline. We found substantial physical declines in elderly women both with and without breast cancer over time, suggesting that much of the decline in elderly women with breast cancer was related to age, rather than to disease or treatment. Satariano et al,32 in the only other prospective study in addition to the NHS that included disease-free subjects, had similar findings to ours. It is interesting that without the information on prediagnosis functional status and change in status among similar-age women without breast cancer for comparison, we also would have concluded that elderly women fare worse physically after diagnosis, compared with younger women. Not every study has reported physical differences by age.10,15,16,32,33 This could be due to where age group cut points were drawn and the range of ages studied. We found limited variability in the physical impact of breast cancer among women ages 40 to 75 years. Studies with little variability across the age range may find few differences in functional change by age. Larger declines in young women in our study for physical role function and pain were not due to more severe disease or aggressive treatment; we found no evidence of interactions of age with disease severity or treatment factors for these outcomes. In fact, the difference in R2 between models with and without these factors was less than 10% (3% for pain and 6% for physical role function), indicating that less than 10% of the variation in physical function was explained by these factors. This suggests that other factors (eg, social networks, marital status, education33,34) may be more important in predicting physical outcomes. However, we did not include lymph node dissection in the analysis, which may have a more pronounced impact on function.35 The areas in which young women experienced the greatest declines (RP, BP, SF) may reflect higher levels of responsibilities in which physical effort is required, including greater work hours and childcare responsibilities.36 This is consistent with a study by Ganz et al37 showing that cancer influenced young women (< 50 years) more than older women in the areas of educational plans, career, family plans, and ability to provide care for children or others. Mor et al9 also reported significantly higher unmet needs across QoL domains among younger breast cancer patients in the areas of administrative and childcare tasks. Breast cancer and associated treatments may be particularly disruptive in young women's lives, especially in the short term. In terms of psychological function, studies typically report that older women adjust more easily than younger women,2,6,9-11,14,15 both immediately after surgery11,38,39 and 1 or more years postdiagnosis.2,10-13 However, studies are mixed with regard to social function,31 with some indicating greater social disruption among younger women3,8 and others showing no differences by age.9,10,15 Our results are consistent with prior research indicating worse psychosocial function in younger women. Possible age-related reasons for greater emotional problems among younger women include greater fear of death, greater issues with the return to work, nonnormative timing for disease, concerns about the impact on their families, and lost opportunities for childbearing.9,40 Treatments such as tamoxifen and chemotherapy that adversely influence sexual function in young women may contribute to poorer psychological function. It is also possible that young women have fewer adaptive coping skills.41-45 Young women might have faced fewer life issues, may be at a different stage in the life course, and have grown up in a different historic and social context than middle-aged and older women.46 Study limitations include the lack of complete information on treatment and severity because of the inclusion of women in the analysis for whom we were unable to obtain medical records, the lack of information on lymph node dissection, and the lack of specific information on type of chemotherapy and hormonal treatment. In addition, the number of older women receiving chemotherapy was small so it was difficult to evaluate age differences for this treatment. Nevertheless, other studies have been considerably smaller in size. A final issue is the potential lack of generalizability given our study population of nurses. Nurses may be better able to navigate medical systems and gain the help they need in dealing with breast cancer diagnosis. This could in part explain the small declines in mental health seen in our sample, although one study of nurses as patients in an acute setting found they were not immune to feelings of lack of control and difficulties with gaining assistance. There was no comparison with nonnurses.47 Socioeconomic status and baseline SF-36 HRQoL scores in our cohorts were also slightly higher than the general population.48 However, the influence of socioeconomic status on health outcomes can be seen across the life course and is unlikely to explain differences by age. In addition, cancer patients typically score better on QoL measures than the general population.49,50 Postdiagnosis SF-36 physical function scores in young and elderly women in our study were comparable to those of similar-age breast cancer survivors drawn from hospital tumor registries,1,2 although mental health scores were slightly higher among elderly women in our study. Age-comparable CARES-SF scores in our study were similar to those in other samples of breast cancer survivors.1,51,52 Our study represents an advancement over the prior literature because of the use of prospective data and age-appropriate, disease-free comparison groups. Other strengths included a large study population with adequate statistical power to look at interactions with disease severity and treatment factors, expansive data on potential confounding factors, and validation of cancer diagnosis. Adjusted for disease severity and treatment factors, younger women in our study fared worse after breast cancer diagnosis than older women, both in terms of physical and psychosocial function. Clinicians addressing the needs of patients undergoing breast cancer treatment might find it useful to consider that women's needs after breast cancer may vary by life stage and that younger women may be at greater risk for significant declines in HRQoL compared with older women.
The authors indicated no potential conflicts of interest.
Supported by grants AG14742, CA87969, and CA50385 from the National Institutes of Health. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40, 41 to 64, or 65+ years). 
