Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: pooled results from three countries.

INTRODUCTION: Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer. METHODS: We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P < 0.0001), International Federation of Gynaecology and Obstetrics staging system for gynecological malignancy (FIGO) stage (P < 0.0001) and age (P < 0.0001). No overall association was observed between tamoxifen treatment and endometrial cancer mortality (HR = 1.17 (95% CI: (0.89 to 1.55)). Tamoxifen use for at least five years was associated with increased endometrial cancer mortality (HR = 1.59 (1.13 to 2.25)). This association appeared to be due primarily to the excess of unfavorable histologies and advanced stage in women using tamoxifen for five or more years since the association with mortality was no longer significant after adjustment for morphological type and FIGO stage (HR = 1.37 (0.97 to 1.93)). Those patients with endometrioid tumors, who stopped tamoxifen use at least five years before their endometrial cancer diagnosis, had a greater mortality risk from endometrial cancer than endometrioid patients with no tamoxifen exposure (HR = 2.11 (1.13 to 3.94)). The explanation for this latter observation is not apparent. CONCLUSIONS: Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This can be attributed to non-endometrioid histological subtypes with poorer prognosis among long term tamoxifen users.

Genomic profile of endometrial tumors depends on morphological subtype, not on tamoxifen exposure.

Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Array CGH was used on archival formalin-fixed paraffin embedded endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>or=2 years) tamoxifen use (endometrioid adenocarcinomas, n = 26; carcinosarcomas, n = 14; and serous adenocarcinomas, n = 12) with endometrial tumors from unexposed breast cancer patients (n = 45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes, and histopathological characteristics of the endometrial tumors. The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations; however, they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Thus, endometrial carcinomas that develop after prolonged tamoxifen use cannot be distinguished from nonusers on basis of their tumor genomic profile.

Prognosis of uterine corpus cancer after tamoxifen treatment for breast cancer.

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P=0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P=0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P=0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ERalpha, PRA and PRB, P<0.05) and P53-positive (P=0.015). Three-year uterine corpus cancer-specific survival was worse for long-term tamoxifen users than for non-users (82% vs. 93% P=0.0001). The survival difference remained after adjustment for histopathologic and immunohistochemical characteristics (hazard ratio (HR) for >or=2 years tamoxifen=2.4; 95% CI=1.2-4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer.

Psychosocial work characteristics in relation to neck and upper limb symptoms.

The aim of this study was to investigate the relationship between psychosocial work characteristics and neck and upper limb symptoms and to examine to what extent this relationship could be explained by other risk factors. Data were used from a prospective cohort study in a working population, with a follow-up period of 3 years. The 3-year cumulative incidence rates of neck or upper limb symptoms, neck/shoulder symptoms and elbow/wrist/hand symptoms were 32, 24 and 15%, respectively. After adjustment for potential confounders high job demands was identified as a risk factor for neck/shoulder symptoms (RR: 2.1; CI: 1.2-3.6) and elbow/wrist/hand symptoms (RR: 1.9; CI: 1.0-3.7), and low social support of co-workers was identified as a risk factor for elbow/wrist/hand symptoms (RR: 2.2; CI: 1.0-4.9). Partly, but not exclusively, these relationships were intermediated by an increased exposure to physical risk factors and increased stress symptoms. Personal characteristics did not considerably influence the main effects of the identified risk factors.

Working with a chronic disorder--the development of the Work and Handicap Questionnaire.

The Work and Handicap Questionnaire (WHQ) was developed to improve the vocational perspectives of patients with a chronic disorder. The WHQ differs from similar instruments in its explicit linkage between disabilities in daily life and job demands. This is an important feature, which allows for the development of specific strategies to counter work problems of people with a chronic disorder. The WHQ makes an inventory of possibly harmful working conditions and of possible strategies to counter health-related work problems by means of the work adjustments. Results of the application of the WHQ are shown for three patient groups (neuromuscular disorders, multiple sclerosis and asthma) and a group of colleagues with no chronic disorder. Results show similarities and differences between labour conditions and labour experiences between the three patient groups. It also shows differences and similarities between those working with a chronic disorder and those without such a disorder. Acceptance of the consequences of a chronic disorder for the job performance and a focus on health-related work problems would prolong career opportunities for workers with a chronic disorder. The use of the Work and Handicap Questionnaire will hopefully further these aims in determining health-related work problems and offer solutions by means of adequate work adjustment.

Prognostic factors related to recurrent low-back pain and sickness absence.

OBJECTIVES: This study aimed at determining the prognostic factors related to the recurrence of low-back pain and future sickness absence due to low-back pain. METHODS: Data were used from a prospective cohort study in a working population with a 3-year follow-up period. They were collected with annual questionnaires. A generalized estimating equation model was used to study the relation between pain characteristics, individual characteristics, and work-related factors and the recurrence of low-back pain or sickness absence due to low-back pain in the following year. Adjustments were made for potential confounders. RESULTS: All the pain characteristics [odds ratios (OR) varying from 1.4 to 2.4], flexion and rotation of the upper part of the body [OR 1.6, 95% confidence interval (95% CI) 1.1-2.5], low decision authority (OR 1.6, 95% CI 1.0-2.6), and low job satisfaction (OR 1.5, 95% CI 1.0-2.3), increased the risk of recurrent low-back pain. High disability due to low-back pain (OR 2.6, 95% CI 1.2-5.7), low co-worker support (OR 4.1, 95% CI 1.6-10.5), and low job satisfaction (OR 2.4, 95% CI 1.3-4.5) were predictors of sickness absence due to low-back pain. Lifting weights did not influence the risk of recurrences or sick leave. CONCLUSIONS: According to this study, high disability due to low-back pain is a prognostic factor for recurrent low-back pain and future sickness absence due to low-back pain. In addition, the following work-related factors predict a poor prognosis of low-back pain: flexion or rotation of the trunk, low job satisfaction, low decision authority, and low social support.

High physical and psychosocial load at work and sickness absence due to neck pain.

OBJECTIVES: This study investigates the relationship between physical and psychosocial load at work and sickness absence due to neck pain. METHODS: A prospective cohort study with a follow-up period of 3 years (1994-1998) was performed among a working population. At the beginning of the study, physical load at work was quantified by means of video recordings. Work-related psychosocial variables were measured by means of the Job Content Questionnaire. The frequency of sickness absence due to neck pain with a minimal duration of 3 days was assessed on the basis of company registrations during the follow-up period. Altogether 758 workers were included in the analyses. Possible confounding by individual characteristics, physical load, and psychosocial load was studied. RESULTS: Work-related neck flexion and neck rotation, low decision authority, and medium skill discretion showed statistically significant increased risks for sickness absence due to neck pain (adjusted rate ratios ranging from 1.6 to 4.2). High quantitative job demands, low skill discretion, and low job security showed nonsignificant increased risks for sickness absence due to neck pain (adjusted rate ratios of 2.0, 1.6 and 1.7, respectively). Work-related sitting, conflicting job demands, supervisor support, and co-worker support did not increase sickness absence due to neck pain. CONCLUSION: Work-related neck flexion, neck rotation, low decision authority, and medium skill discretion are risk factors for sickness absence due to neck pain. There are indications that high job demands, low skill discretion, and low job security are also risk factors for sickness absence due to neck pain.