This analysis of TEAM trial data focuses on the effects of comorbidities and age on breast cancer mortality and other cause mortality after 10 years of follow‐up, taking into account competing causes of death.
Keywords: Geriatric oncology, Breast cancer, Aging, Comorbidities, Mortality, Prediction
Abstract
Background.
The aim was to study the impact of comorbidities and age on breast cancer mortality, taking into account competing causes of death.
Subjects, Materials, and Methods.
Cohort analysis of Dutch and Belgian patients with postmenopausal, early hormone receptor‐positive breast cancer included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. This is a randomized controlled trial of patients who had completed local treatment with curative intent and were randomized to receive exemestane for 5 years, or sequential treatment of tamoxifen followed by exemestane for a duration of 5 years. Patients were categorized by number of comorbidities (no comorbidities, 1–2 comorbidities, and >2 comorbidities) and age (<70 years and ≥70 years). Main outcome was breast cancer mortality considering other‐cause mortality as competing event; cumulative incidences were calculated using the Cumulative Incidence Competing Risk Methods, and the Fine and Gray model was used to calculate the effect of age and comorbidities for the cause‐specific incidences of breast cancer death, taking into account the effect of competing causes of death.
Results.
Overall, 3,159 patients were included, of which 2,203 (69.7%) were aged <70 years and 956 (30.3%) were aged ≥70 years at diagnosis. Cumulative incidence of breast cancer mortality was higher among patients ≥70 without comorbidities (22.2%, 95% CI, 17.5–26.9) compared with patients <70 without comorbidities (15.6%, 95% CI, 13.6–17.7, reference group), multivariable subdistribution hazard ratio (sHR) 1.49 (95% CI, 1.12–1.97, p = .005) after a median follow‐up of 10 years. Use of chemotherapy was lower in older patients (1%, irrespective of the number of comorbidities) compared with younger patients (50%, 44%, and 38% for patients with no, 1–2, or >2 comorbidities, p < .001).
Conclusion.
Older patients without comorbidities have a higher risk of dying due to breast cancer than younger counterparts, even when taking into account higher competing mortality, while use of chemotherapy in this group was low. These findings underline the need to take into account comorbidities, age, and competing mortality in the prognosis of breast cancer for accurate decision making.
Implications for Practice.
Older patients without comorbidity are at increased risk of dying from breast cancer, despite a higher other‐cause mortality. This study shows that including age and comorbidity for the assessment of breast cancer mortality and other‐cause mortality is indispensable for treatment decision making in older patients. Future prognostic tools for breast cancer prognosis should incorporate these items as well as risk of toxicity of adjuvant chemotherapy to adequately predict outcomes to optimize personalized treatment for older patients with early breast cancer.
Introduction
Increasing life expectancy and decreased birth rates are important factors contributing to rapid aging of the population [1]. As increasing age is an important predictive factor for the development of breast cancer, it is expected that the number of older patients diagnosed with breast cancer will rapidly increase concomitantly [2]. In older patients, breast cancer occurs against a background of other diseases as multimorbidity (having two or more chronic diseases) is strongly associated with increasing age [3]. In contrast, studies have shown that increasing longevity may be accompanied by an extended period of good health, resulting in a relevant population of older patients with breast cancer and minimal comorbidity [4]. This diversity in health status in older patients is challenging for clinicians in decision making when balancing the benefits and toxicities of breast cancer treatment.
To provide optimal decision making in older patients, it is important to consider breast cancer prognosis as well as the chance of dying from causes other than breast cancer for the forthcoming years. Accurate estimation of breast cancer mortality risk in this group should take into account other‐cause mortality by applying competing risk analysis [5]. Increasing age and comorbidity are independently associated with reduced life expectancy [6], [7], and this influences the risk of other‐cause mortality in patients diagnosed with breast cancer. Although several studies have shown that increasing age at diagnosis is associated with worse breast cancer outcomes [8], [9], this association for comorbidities remains a matter of debate [6].
The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial compared two types of adjuvant endocrine therapy (exemestane monotherapy versus tamoxifen followed by exemestane) in postmenopausal patients with hormone receptor‐positive early breast cancer, and recently our group reported no difference in outcomes between both treatment groups after 10 years of follow‐up [10], [11]. Data on comorbidities at time of diagnosis and long‐term follow‐up were collected in enrolled TEAM patients in two countries (The Netherlands and Belgium). In this analysis, we studied the impact of comorbidities and age at diagnosis on breast cancer mortality and other‐cause mortality after 10 years of follow‐up, taking into account competing causes of death.
Subjects, Materials, and Methods
The TEAM study is a randomized controlled trial of which the details have previously been described [10], [11]. In summary, postmenopausal patients with early hormone receptor‐positive breast cancer who had completed local treatment with curative intent were included between January 2001 and January 2006 and randomized to receive exemestane (25 mg, once daily) for 5 years or sequential treatment of tamoxifen (20 mg, once daily) followed by exemestane for a duration of 5 years. Patients with a previous malignancy 5 years before breast cancer diagnosis, significant cardiac, or other diseases that interfered with study participation or an Eastern Cooperative Oncology Group performance status >2 were considered ineligible. Information on the type of surgery, radiotherapy, and chemotherapy was collected at the case report form (CRF) at time of inclusion. During follow‐up, information was registered on disease recurrence and cause of death. The database was locked on February 19, 2016. Patients were censored at date of last follow‐up or at database lock for event‐free patients. After 10 years of follow‐up, no difference was observed for the primary endpoint (disease‐free survival) between the two treatment arms [10], and thereafter the cohort has been used for observational research to explore determinants and outcomes of breast cancer.
For this analysis, all Dutch and Belgian patients were selected from the central TEAM database, as these countries collected information on comorbidities at inclusion and on long‐term follow‐up. For the present analyses, comorbidities recorded at the time of breast cancer diagnosis were used. Selected patients were categorized into two age categories for age at diagnosis (<70 years and ≥70 years) according to the International Organization for Geriatric Oncology (SIOG) recommendations [12]. Information on comorbidities at diagnosis was extracted from medical charts and registered on the CRF in free text areas. For further analysis, all comorbidities were classified according to the ICD‐10 classification of diseases [13], as we aimed to include all comorbidities without selection that were recorded in the study. The number of all comorbidities was categorized into three categories (no comorbidities, 1–2 comorbidities, >2 comorbidities). Severity of the comorbidities was not recorded, which complicated using a comorbidity index. Cause of death was indicated on the CRF and later verified and categorized into ten prespecified groups defined in the protocol (supplemental online Table 1) by the central TEAM data center.
Table 1. Patient and tumor characteristics by age group and for all patients.
Abbreviation: IQR, interquartile range.
Endpoints in the current study were breast cancer mortality and other‐cause mortality. Breast cancer mortality was defined as time from randomization to death because of breast cancer, considering other‐cause mortality as a competing event. As defined in the protocol, death that occurred after distant recurrence was defined as caused by breast cancer. Other‐cause mortality was defined as all other causes of death than death from breast cancer whereby breast cancer mortality was considered as a competing event.
The study was performed in compliance with the guidelines of the Declaration of Helsinki, International Conference on Harmonization, and Good Clinical Practice. Approvals from the respective ethical committees were obtained. All patients provided written informed consent. The TEAM trial was registered in The Netherlands and Belgium (The Netherlands Trial Registry NTR267; Ethics Commission Trial 27/2001).
Statistical Analysis
Pearson χ2 test was used to compare proportional differences of tumor and treatment characteristics between subgroups. Cumulative incidences of breast cancer‐related mortality and other‐cause mortality were calculated using the Cumulative Incidence Competing Risk Methods [14], [15], which assumes that patients who experienced a competing event remain in the risk set calculation for the event of interest and, as a consequence, estimates actual probabilities of reaching different endpoints [5]. The Fine and Gray model was used to calculate the effect of risk factors for the cause‐specific incidences of death, thereby taking into account the effect of competing causes of death [15]. The effect of risk factors is expressed in terms of subdistribution hazard ratio's (sHR) [14], [15]. The multivariable model included the covariates that were included in the PREDICT+ prognostication tool (tumor size [in millimeters], histological grade, lymph‐node stage according to the Tumor‐Node‐Metastasis classification, estrogen receptor [ER] status, and human epidermal growth receptor [HER2] status; mode of detection, Ki67, and chemotherapy regimen were unfortunately not recorded in the trial) [16]. Missing values were addressed by multiple imputation by chained equation using five imputed data assuming that distribution of missing data is at random (MAR) [17]. Results were based on pooled results of the imputed data using the Rubin's rules. All statistical analyses were performed in R statistics version 3.3.3 using the survival, cmprsk, and mice packages [18]. Results were considered statistically significant when two‐sided p value was less than .05.
Additional Analysis
Sensitivity analysis was performed to test the robustness of the “breast cancer mortality” endpoint definition as described in the TEAM protocol. For this additional analysis, breast cancer mortality was defined as death from breast cancer following the information as registered on the CRF (and not assuming that deaths that occurred after distant recurrence were defined as breast cancer‐related deaths).
Results
Overall, 3,159 Dutch and Belgian patients were included in the TEAM trial, of which 2,203 (69.7%) were aged <70 years and 956 (30.3%) were aged ≥70 years at diagnosis. Median follow‐up was 10.2 years (interquartile range [IQR], 9.9–10.8). Table 1 shows the baseline characteristics overall and by age group. Median age at diagnosis was 60 years (IQR, 56–64) and 75 years (IQR, 72–79) in the younger and older cohort, respectively. Tumor size was significantly higher in patients aged ≥70 years at time of diagnosis. Older patients more likely had a higher number of comorbidities at diagnosis (Table 1). For both younger and older patients, hypertension, arthrosis (osteoarthritis), and diabetes were the most prevalent types of comorbidities, although the proportions of patients having these comorbidities were higher in older patients (Table 2).
Table 2. Ten most prevalent comorbidities by age group.
Abbreviation: COPD, chronic obstructive pulmonary disorder.
Figure 1 and supplemental online Table 2 show treatment characteristics by age group and number of comorbidities. Breast‐conserving surgery was performed less frequently in case of >2 comorbidities among patients diagnosed at <70 years (51%, 52%, and 43% in patients without, with 1–2, and more than 2 comorbidities, respectively). Patients aged ≥70 years at diagnosis were less likely to undergo breast‐conserving surgery compared with younger patients, but this did not vary across the different comorbidity groups (34%, 31%, and 32%, respectively). Virtually all patients received radiotherapy after breast‐conserving surgery. In patients aged <70 years at diagnosis, the administration of chemotherapy decreased with an increasing number of comorbidities (50%, 44%, and 38% in patients without, with 1–2, and more than two comorbidities, respectively), whereas almost none of the older patients received chemotherapy, irrespective of comorbidity status (1%, <1%, and 1%, respectively).
Figure 1.
Types of treatment by age group and number of comorbidities. Type of breast surgery: mastectomy (filled bar) and breast‐conserving surgery (dotted bar); radiotherapy represents the proportion of patients receiving radiotherapy after breast‐conserving surgery.
Figure 2 shows the cumulative incidences of breast cancer mortality and other‐cause mortality stratified by age group and number of comorbidities. Cumulative incidence of breast cancer mortality 10 years after diagnosis in patients aged <70 years without comorbidities was 15.6% (95% CI, 13.6–17.7, reference group; Table 3). Compared with this reference group, the cumulative incidence of breast cancer mortality in patients aged ≥70 years without comorbidities was significantly higher (22.2%; 95% CI, 17.5–26.9; sHR, 1.45; 95% CI, 1.09–1.91; p = .009), which remained significant after adjusting for the confounders size, grade, N‐stage, ER and HER2 (sHR, 1.49; 95% CI, 1.12–1.97; p = .005; Table 3). For patients with 1–2 comorbidities, the cumulative incidence of breast cancer mortality over the 10 year period was not higher than that in the reference group, applying for both age cohorts. Furthermore, compared with the reference group, the cumulative incidence of breast cancer mortality appeared to be higher in patients with >2 comorbidities in both age groups, being 21.3% (95% CI, 14.4–28.3) in patients <70 years and 21.3% (95% CI, 14.3–28.2) in patients aged ≥70 years, respectively, but this was not statistically significant (Table 3).
Figure 2.
Cumulative incidence of breast cancer mortality and other‐cause mortality by age group and number of comorbidities. Stacked cumulative incidence of breast cancer mortality (red) and other‐cause mortality (blue) by age group and number of comorbidities from time since diagnosis in years.
Table 3. Breast cancer mortality and other‐cause mortality by age group and number of comorbidities.
Covariates included in the model: tumor size, histological grade, lymph‐node, estrogen‐receptor status, HER2‐receptor status).
Abbreviations: CI, confidence interval; sHR, subdistribution hazard ratio.
The cumulative incidence of other‐cause mortality 10 years after diagnosis was higher with increasing numbers of comorbidities and with older age at diagnosis (Fig. 2, Table 3).
Additional Analysis
Applying a different definition for breast cancer mortality (see Subjects, Materials, and Methods), 30 patients previously categorized as having died from breast cancer were now assumed to have died from other causes. Univariate and multivariable regression analyses yielded comparable results for breast cancer mortality (supplemental online Table 3).
Discussion
In this subanalysis of Dutch and Belgian TEAM patients, we observed a higher risk of dying from breast cancer ten years after diagnosis in older patients without comorbidities when compared with younger patients without comorbidities, which was independent of the tumor characteristics size, grade, N‐stage, ER, and HER2 status. In the other subgroups, breast cancer mortality was not significantly different. Other‐cause mortality increased significantly with age as well as the number of comorbidities, but this higher other‐cause mortality did not lead to lower breast cancer mortality. Moreover, administration of adjuvant chemotherapy was more driven by age than by comorbidities.
To our knowledge, long‐term follow‐up analysis of mortality outcomes in postmenopausal patients with breast cancer stratified for both age at diagnosis and comorbidities has not been performed before. One recent study reported that patients aged 70 and older with breast cancer with severe comorbidity are at increased risk of dying from breast cancer, even after adjusting for adjuvant chemotherapy and other tumor and treatment differences. However, this study applied a Cox proportional hazards model and therefore did not take into account the effect of competing mortality [19]. Hence, estimation of cancer‐related mortality might be overestimated [5]. Several studies reported an increased risk of breast cancer mortality with increasing age [8], [9], [20], [21], [22], [23]. In observational studies, an increased risk of breast cancer death or breast cancer recurrence was observed in patients with one or more comorbidities (not stratified for age at diagnosis) [7], [20], [24], [25], [26]. In contrast, the ATAC trial described no impact of comorbidities on breast cancer recurrence [27]. In addition, in most comparable studies on the effect of comorbidities on breast cancer and other‐cause mortality, the Cox proportional hazards model was used [7], [20], [24], [26], [27], whereby patients who died because of other causes were censored and were assumed to have the same risk of breast cancer mortality as noncensored patients. Results described in studies using this methodology are therefore likely to be overestimated [5]. In the study performed by Berglund et al. [25] and in our study, competing risk analyses were performed enabling to take into account competing causes of death, which in our opinion is a more optimal method of analysis. In view of the conflicting findings and the importance of the question for clinical practice, it is warranted to reach consensus on appropriate statistical models to assess the impact of comorbidities and age on breast cancer mortality.
Several factors may explain why older patients without comorbidity, in contrast with patients with comorbidity, had a higher risk of breast cancer mortality than younger patients without comorbidity. Older patients without comorbidity had a lower other‐cause mortality than older patients with one or more comorbidities (Fig. 2, Table 3) and therefore were surviving for a longer time period in which they remained at risk for disease recurrence and breast cancer death. Also, although older patients presented with larger tumors, adjuvant chemotherapy was rarely administered (approximately 1%) compared with 50% of younger patients without comorbidity (Table 1, supplemental online Table 2, Fig. 1), which possibly explained an increased risk of disease recurrence. This indicates potential undertreatment of fit older patients and underlines the importance of optimal treatment.
Other factors could also have contributed to higher breast cancer mortality in the healthy older patient group. Previous studies have shown that older patients experience more adverse events during and after adjuvant chemotherapy or radiotherapy [12], [28]. However, as adjuvant chemotherapy was administered in only 1% of older patients overtreatment is not likely to have contributed to the observed higher breast cancer mortality. Lack of compliance of endocrine therapy in the TEAM trial has been reported to be higher among older than among younger patients [29]. However, this was reported to be independent of the number of comorbidities in the mentioned study and does not explain the higher breast cancer mortality in older patients without comorbidities in our study cohort.
Endocrine therapy might lead to an increased risk of other‐cause mortality, especially among older patients. The BIG 1‐98 trial investigating either letrozole or tamoxifen as adjuvant endocrine therapy reported higher rates of lethal adverse events, all being of cardiovascular origin and more cerebrovascular accidents among patients aged >75 years versus younger patients [30]. In the current study cohort, cardiovascular disease was the second cause of death after breast cancer among older patients, but it is difficult to estimate to what extent endocrine therapy might have attributed to this risk.
Virtually none of the older patients in this study cohort received adjuvant chemotherapy, irrespective of the presence and the number of comorbidities and despite larger tumors at diagnosis. This was in line with the Dutch guidelines, but these findings have also been reported in other countries where guidelines for chemotherapy were not age restricted [31]. Because of the very low proportion of older patients receiving chemotherapy in our study, further analysis on the potential effect of chemotherapy on breast cancer mortality was not possible. Also, as the number of older patients included in trials investigating chemotherapy strategies is limited due to either eligibility criteria (excluding older patients) or poor accrual in studies for specifically older patients [32], current guidelines do not contain clear recommendations for chemotherapy in older patients. In the CALGB trial including fit older patients (aged >65 years, good performance score, no major organ dysfunction), standard intravenous chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide/doxorubicin) was compared with oral capecitabine. Better outcomes for disease recurrence and overall survival were observed in the standard chemotherapy group at the cost of moderate to severe toxic effects [33]. In both therapy arms, however, a substantial percentage of patients experienced toxicity, needed dose reduction or stopped therapy prematurely. Weekly paclitaxel in older patients is feasible but the efficacy in hormone receptor‐positive breast cancer is not clear [34], [35]. Potentially the chemotherapy toxicity tool in older patients with cancer, as was developed by Hurria and colleagues [36], might be helpful in decision making and recommending adjuvant chemotherapy.
In line with other studies, comorbidities were strongly related to other‐cause mortality [6], [7], [20], [24], [25], [26], [27], [37], [38], [39], [40]. Our data, however, also indicate that age appears to be a driving factor of other‐cause mortality (Fig. 2, Table 3); patients ≥70 years without comorbidities had higher other‐cause mortality compared with patients <70 years with >2 comorbidities. Therefore, in our opinion it is important to include both age and number of comorbidities in the risk assessment of other‐cause mortality and also in the toxicity prediction tool.
To adequately address the clinical benefit of adjuvant systemic therapy in elderly patients with breast cancer, the following aspects should be considered. First, life expectancy should be evaluated to estimate the risk of other‐cause mortality using age, comorbidities, and other geriatric indicators for prediction [41], [42]. Second, tumor stage and molecular characteristics including genetic profiling should be considered to estimate the breast cancer prognosis. Third, estimation of risk of toxicity or complications of treatment using available tools must be taken into account [36], [43].
Some limitations of this study should be mentioned. First, classification of cause of death could be subject to misclassification. To address this, we performed a sensitivity analysis using a less stringent definition of breast cancer mortality to estimate the effect of comorbidity and age hereon, but this did not change our findings (supplemental online Table 3). Second, we were not able to code the severity of comorbidities as this was not collected on the CRF. Besides, by counting the number of comorbidities, the difference in impact on breast cancer mortality by each individual comorbidity or combinations of specific comorbidities was not assessed; this might be part of future research. Moreover, only comorbidities recorded at the time of diagnosis were used in these analyses, whereas in this aging population it is possible that new comorbidities arose over time. Third, participation in the TEAM trial was restricted by the in‐ and exclusion criteria (see Subjects, Materials, and Methods). Especially older patients participating in this trial were relatively healthy compared with the general population and this could hamper the interpretation of our findings [44]. Strengths of the presents study were the long‐term follow‐up of a well recorded cohort including older patients with registration of comorbidity items at the moment of diagnosis, the analyses of breast cancer mortality with competing risk analyses and the large number of patients which we were able to include in the present data set.
Conclusion
Overall, this study provides further insight into the role of age at diagnosis and comorbidities on the long‐term risk of breast cancer mortality and other‐cause mortality in postmenopausal patients with early breast cancer, which especially for the older patient cohorts is very relevant. Despite the number of comorbidities or older age, both contributing to increasing other‐cause mortality, we did not observe a decrease in breast cancer mortality after a follow‐up time of ten years. Furthermore, we found that older patients without comorbidities were at increased risk of dying from breast cancer, despite a higher other‐cause mortality. In the light of the changing demographics, this group will expand in future years and there is an urgent need to pursue optimal treatment for healthy older patients. Also, this study underlines the clinical challenge with respect to decision making, balancing between undertreatment and overtreatment of older patients, and indicates that assessment of risk for both breast cancer mortality and other‐cause mortality is indispensable for treatment decision making in older patients. Ideally, future prognostic tools for breast cancer prognosis should incorporate these items as well as risk of toxicity of adjuvant chemotherapy to adequately predict outcomes to optimize personalized treatment for older patients with early breast cancer.
Acknowledgments
We thank all the participating hospitals and patients for participation in the trial. Furthermore, we thank the Datacenter Heelkunde for data collection and preparation of the datasets. The study complies with the current laws of the country in which they were performed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The study was funded by an unrestricted grant from Pfizer, Dutch Cancer Foundation [UL 2010‐4674].
Author Contributions
Conception/design: Marloes G.M. Derks, Esther Bastiaannet, Johanneke E.A. Portielje, Gerrit‐Jan Liefers
Collection and/or assembly of data: Cornelis J.H. van de Velde, Caroline Seynaeve, Johan W.R. Nortier, Luc Y. Dirix
Data analysis and interpretation: Marloes G.M. Derks, Daniele Giardiello, Hein Putter
Manuscript writing: Marloes G.M. Derks, Esther Bastiaannet, Johanneke E.A. Portielje, Gerrit‐Jan Liefers
Final approval of manuscript: Marloes G.M. Derks, Cornelis J.H. van de Velde, Daniele Giardiello, Caroline Seynaeve, Hein Putter, Johan W.R. Nortier, Luc Y. Dirix, Esther Bastiaannet, Johanneke E.A. Portielje, Gerrit‐Jan Liefers
Disclosures
The authors indicated no financial relationships.
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