Men Have a Stronger Monocyte-Derived Cytokine Production Response upon Stimulation with the Gram-Negative Stimulus Lipopolysaccharide than Women: A Pooled Analysis Including 15 Study Populations.

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1ß, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.

Prediction of functional decline in community-dwelling older persons in general practice: a cohort study.

BACKGROUND: A first step to offer community-dwelling older persons proactive care is to identify those at risk of functional decline within a year. This study investigates the predictive value of registered information, questionnaire and GP-opinion on functional decline. METHODS: In this cohort study, embedded within the ISCOPE-trial, participants (≥75 years) completed the ISCOPE-screening questionnaire on four health domains. GPs gave their opinion on vulnerability of participants. Functional status was measured at baseline and 12 months (Groningen Activities Restriction Scale [GARS]). The outcome was functional decline (death, nursing home admission, 10% with greatest functional decline). The predictive value of pre-selected variables (age, sex, polypharmacy, multimorbidity, living situation; GPs' opinion on vulnerability, number of domains with problems [ISCOPE-score]) was compared with the area under the curves (AUC) for logistic regression models. RESULTS: 2018 of the 2211 participants (median age 82.1 years [IQR 78.8-86.5], 68.0% female, median GARS 31 [IQR 24-41]) were visited at 12 months (median GARS 34 [IQR 26-44]). 394 participants (17.8%) had functional decline (148 died, 45 nursing home admissions, 201 with greatest functional decline). The AUC for age and sex was 0.602, increasing to 0.620 (p = 0.029) with polypharmacy, multimorbidity and living situation. The GPs' opinion added more (AUC 0.672, p < 0.001) than the ISCOPE-score (AUC 0.649, p = 0.007). AUC with all variables was 0.686 (p = 0.016), and 0.643 for GPs' opinion alone. CONCLUSIONS: The GPs' opinion and ISCOPE-score improve this prediction model for functional decline based on readily available variables. GPs could identify older patients for further assessment with their clinical judgement. TRIAL REGISTRATION: Netherlands trial register, NTR1946 . Registered 10 August 2009.

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers.

OBJECTIVES: To examine the Framingham Stroke Risk Profile (FSRP); the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, and oxi-inflammatory load (cumulative risk score of three blood biomarkers-homocysteine, interleukin-6, C-reactive protein) for associations with cognitive decline using three cohort studies of very old adults and to examine whether incorporating these biomarkers with the risk scores can affect the association with cognitive decline. DESIGN: Three longitudinal, population-based cohort studies. SETTING: Newcastle-upon-Tyne, United Kingdom; Leiden, the Netherlands; and Lakes and Bay of Plenty District Health Board areas, New Zealand. PARTICIPANTS: Newcastle 85+ Study participants (n = 616), Leiden 85-plus Study participants (n = 444), and Life and Living in Advanced Age, a Cohort Study in New Zealand (LiLACS NZ Study) participants (n = 396). MEASUREMENTS: FSRP, CAIDE risk score, oxi-inflammatory load, FSRP incorporating oxi-inflammatory load, and CAIDE risk score incorporating oxi-inflammatory load. Oxi-inflammatory load could be calculated only in the Newcastle 85+ and the Leiden 85-plus studies. Measures of global cognitive function were available for all three data sets. Domain-specific measures were available for the Newcastle 85+ and the Leiden 85-plus studies. RESULTS: Meta-analysis of pooled results showed greater risk of incident global cognitive impairment with higher FSRP (hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.08-1.98), CAIDE (HR = 1.53, 95% CI = 1.09-2.14), and oxi-inflammatory load (HR = 1.73, 95% CI = 1.04-2.88) scores. Adding oxi-inflammatory load to the risk scores increased the risk of cognitive impairment for the FSRP (HR = 1.65, 95% CI = 1.17-2.33) and the CAIDE model (HR = 1.93, 95% CI = 1.39-2.67). CONCLUSION: Adding oxi-inflammatory load to cardiovascular risk scores may be useful for determining risk of cognitive impairment in very old adults.

Physical Functioning in Older Patients With Breast Cancer: A Prospective Cohort Study in the TEAM Trial.

BACKGROUND: Previous retrospective studies have shown that physical functioning in older cancer survivors is affected after treatment, yet prospective data are lacking. The aim of this study was to assess change in physical functioning in different age groups of patients with hormone receptor-positive breast cancer who were enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial. METHODS: Two physical parameters were assessed. Physical functioning was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire 1 year (T1) and 2 years (T2) after diagnosis. Physical activity was measured in metabolic equivalent of task (MET) hours/week at T1 and T2. Physical activity before diagnosis (T0) was assessed retrospectively at the T1 questionnaire. Patients were divided into three age groups: <60, 60-69, and ≥70 years. Decline in physical functioning was assessed using linear regression analysis. Differences in mean values of physical activity levels were calculated using repeated-measures one-way analysis of variance. RESULTS: A total of 431 patients were included for analysis. In all age groups, physical activity levels at T1 and T2 were significantly lower than prediagnostic physical activity levels (T0) (p < .001 for all age groups). Age ≥70 years was independently associated with decline in physical functioning between T1 and T2 (ß = -4.62, 95% confidence interval -8.73 to -0.51, p = .028). CONCLUSION: Patients aged 70 years or older treated with breast surgery and adjuvant hormonal therapy did not improve between years 1 and 2 after diagnosis to the same extent as did younger patients. IMPLICATIONS FOR PRACTICE: Although older patients constitute a large share of the breast cancer population, little is known about the effect and consequences of treatment of breast cancer in this specific age group. This study revealed that, unlike younger patients, older patients do not regain their physical abilities after surgical and adjuvant treatment for breast cancer. In older adults, the effect of treatment on physical functioning and independency could be more relevant than survival outcomes. Clinicians and older patients should be aware of the impact of treatment on physical functioning and prevent older patients from experiencing physical decline, which could lead to institutionalization and loss of independence. There is a need for age-specific guidelines that take into account the heterogeneity of the older population and for evidence-based treatment that focuses not only on cancer-specific outcomes but also on the consequences of treatment for physical and cognitive functioning and quality of life.

The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis.

Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non-metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy.

Performing Survival Analyses in the Presence of Competing Risks: A Clinical Example in Older Breast Cancer Patients.

An important consideration in studies that use cause-specific endpoints such as cancer-specific survival or disease recurrence is that risk of dying from another cause before experiencing the event of interest is generally much higher in older patients. Such competing events are of major importance in the design and analysis of studies with older patients, as a patient who dies from another cause before the event of interest cannot reach the endpoint. In this Commentary, we present several clinical examples of research questions in a population-based cohort of older breast cancer patients with a high frequency of competing events and discuss implications of choosing models that deal with competing risks in different ways. We show that in populations with high frequency of competing events, it is important to consider which method is most appropriate to estimate cause-specific endpoints. We demonstrate that when calculating absolute cause-specific risks the Kaplan-Meier method overestimates risk of the event of interest and that the cumulative incidence competing risks (CICR) method, which takes competing risks into account, should be used instead. Two approaches are commonly used to model the association between prognostic factors and cause-specific survival: the Cox proportional hazards model and the Fine and Gray model. We discuss both models and show that in etiologic research the Cox Proportional Hazards model is recommended, while in predictive research the Fine and Gray model is often more appropriate. In conclusion, in studies with cause-specific endpoints in populations with a high frequency of competing events, researchers should carefully choose the most appropriate statistical method to prevent incorrect interpretation of results.

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Treatment strategies and survival of older breast cancer patients - an international comparison between the Netherlands and Ireland.

OBJECTIVES: Forty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland. MATERIAL AND METHODS: From the Dutch and Irish national cancer registries, women aged ≥65 years with non-metastatic breast cancer were included (2001-2009). Proportions of patients receiving guideline-adherent locoregional treatment, endocrine therapy, and chemotherapy were calculated and compared between the countries by stage. Secondly, 5-year relative survival was calculated by stage and compared between countries. RESULTS: Overall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients. CONCLUSION: Treatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.

Survival and relapse free period of 2926 unselected older breast cancer patients: a FOCUS cohort study.

BACKGROUND: Previous studies have shown that breast cancer survival decreases with increasing age among older patients who participate in trials. However, trial participants differ from patients in the general population. Therefore, the aim of this study was to evaluate the association between age and breast cancer outcome in an unselected group of older breast cancer patients. METHODS: We included all older (65 years and older) consecutive breast cancer patients, diagnosed between 1997 and 2004 from a geographically defined area in the Netherlands. Primary outcome was relative survival and the secondary endpoint was breast cancer recurrence. These outcomes were compared between two age-categories (65-74 years and ≥75 years). RESULTS: Five-year relative survival was 91.9% in patients aged 65-74 years, and 84.3% in patients aged ≥75 years. This corresponded with a higher excess risk of death in patients aged ≥75 years as compared to patients aged 65-74 years (multivariable relative excess risk of death: 1.73 (95% CI 1.20-2.49)). The risks of locoregional recurrence, distant recurrence and contralateral breast cancer were similar in both age-categories. CONCLUSIONS: Breast cancer survival deteriorates with increasing age among unselected older breast cancer patients. Of note, this was not accompanied by an increased risk of recurrence. This study shows that not only in relatively healthy patients who participate in a trial, but in all older breast cancer patients, outcome deteriorates with increasing age. These findings urge the need for age-specific breast cancer studies, in order to obtain evidence-based medicine in this large and heterogeneous group of patients.

Biological correlates of blood pressure variability in elderly at high risk of cardiovascular disease.

BACKGROUND: Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons. METHODS: Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70-82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis. RESULTS: Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability. CONCLUSION: In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure.

Effect of implementation of the mass breast cancer screening programme in older women in the Netherlands: population based study.

OBJECTIVE: To assess the incidence of early stage and advanced stage breast cancer before and after the implementation of mass screening in women aged 70-75 years in the Netherlands in 1998. DESIGN: Prospective nationwide population based study. SETTING: National cancer registry, the Netherlands. PARTICIPANTS: Patients aged 70-75 years with a diagnosis of invasive or ductal carcinoma in situ breast cancer between 1995 and 2011 (n=25,414). Incidence rates were calculated using population data from Statistics Netherlands. MAIN OUTCOME MEASURE: Incidence rates of early stage (I, II, or ductal carcinoma in situ) and advanced stage (III and IV) breast cancer before and after implementation of screening. Hypotheses were formulated before data collection. RESULTS: The incidence of early stage tumours significantly increased after the extension for implementation of screening (248.7 cases per 100,000 women before screening up to 362.9 cases per 100,000 women after implementation of screening, incidence rate ratio 1.46, 95% confidence interval 1.40 to 1.52, P<0.001). However, the incidence of advanced stage breast cancers decreased to a far lesser extent (58.6 cases per 100,000 women before screening to 51.8 cases per 100,000 women after implementation of screening, incidence rate ratio 0.88, 0.81 to 0.97, P<0.001). CONCLUSIONS: The extension of the upper age limit to 75 years has only led to a small decrease in incidence of advanced stage breast cancer, while that of early stage tumours has strongly increased.

Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.

BACKGROUND: Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II). METHODS: Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage. RESULTS: Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage. CONCLUSIONS: We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.

Validity of Adjuvant! Online program in older patients with breast cancer: a population-based study.

BACKGROUND: Adjuvant! Online is a prediction tool that can be used to aid clinical decision making in patients with breast cancer. It was developed in a patient population aged 69 years or younger, and subsequent validation studies included small numbers of older patients. Since older patients with breast cancer differ from younger patients in many aspects, the aim of this study was to investigate the validity of Adjuvant! Online in a large cohort of unselected older patients. METHODS: We included patients from the population-based FOCUS cohort, which included all consecutive patients aged 65 years or older who were diagnosed with invasive or in-situ breast cancer between Jan 1, 1997, and Dec 31, 2004, in the southwestern part of the Netherlands. We included all patients who fulfilled the criteria as stated by Adjuvant! Online: patients with unilateral, unicentric, invasive adenocarcinoma; no evidence of metastatic or residual disease; no evidence of T4 features; and no evidence of inflammatory breast cancer. We entered data from all patients with the "average for age" comorbidity status (model 1) and with an individualised comorbidity status (model 2). FINDINGS: We included 2012 patients. Median age of patients in the cohort was 74·0 years (IQR 69·0-79·0). 904 (45%) of 2012 patients died during follow-up, whereas 326 (16%) patients had recurrence. Median follow-up for overall survival was 9·0 years (IQR 7·4-10·7), and 6·6 years (4·4-6·6) for patients without recurrence. Using model 1, Adjuvant! Online overestimated 10-year overall survival by 9·8% ([95% CI 5·9-13·7], p<0·0001) and 10-year cumulative recurrence survival by 8·7% ([6·7-10·7], p<0·0001). By contrast, when using model 2, Adjuvant! Online underestimated the 10-year overall survival by -17·1% ([95% CI -21·0 to -13·2], p<0·0001). However, when using model 2, Adjuvant! Online predicted cumulative recurrence accurately in all patients (-0·7% [95% CI -2·7-1·3], p=0·48). INTERPRETATION: Adjuvant! Online does not accurately predict overall survival and recurrence in older patients with early breast cancer. FUNDING: Dutch Cancer Foundation.

Physical activity and survival of postmenopausal, hormone receptor-positive breast cancer patients: results of the Tamoxifen Exemestane Adjuvant Multicenter Lifestyle study.

BACKGROUND: Physical activity has been related to improved breast cancer outcomes. Especially in the older breast cancer population, physical activity may be important because old age is associated with comorbidities and decreased physical function. The purpose of this study was to investigate the relation between physical activity and overall survival, breast cancer-specific survival, and recurrence in several age groups of postmenopausal breast cancer patients. METHODS: The Tamoxifen Exemestane Adjuvant Multinational Lifestyle study was a side study of the Tamoxifen Exemestane Adjuvant Multinational trial and prospectively investigated lifestyle habits of postmenopausal, hormone receptor-positive breast cancer patients. The relations between prediagnosis and postdiagnosis physical activity and overall survival, breast cancer-specific survival, and recurrence-free survival were assessed with Cox regression and competing risk regression models. RESULTS: Among 521 patients, high levels of physical activity before and after the diagnosis were associated with better overall survival (the multivariate hazard ratios were 0.50 [95% confidence interval = 0.26-0.98] and 0.57 (95% confidence interval = 0.26-1.40] for patients who were very active before and after the diagnosis, respectively, in comparison with inactive patients). This was most evident in patients who were 65 years old or older. Physical activity was not significantly associated with breast cancer-specific survival or the relapse-free period. CONCLUSIONS: Overall survival was better for patients who were active before and after the diagnosis. In contrast with previous studies, breast cancer survival and the risk of recurrence were not significantly associated with physical activity. These findings confirmed the need for more studies investigating the use of physical activity to supplement breast cancer treatment in older patients.

Comparison of frequencies and prognostic effect of molecular subtypes between young and elderly breast cancer patients.

PURPOSE: To compare the distribution and prognostic effect of the breast cancer molecular subtypes in young and elderly breast cancer patients. PATIENTS AND METHODS: Our study population (n = 822) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. A total of 142/822 fresh frozen tissues were available with good quality RNA and analyzed by gene expression microarray. Gene expression molecular subtypes were determined by correlation to the expression centroids of 534 "intrinsic" genes. Sections of a tissue micro array containing formalin-fixed paraffin-embedded tumor tissue of 714/822 patients were immunohistochemically (IHC) stained for Ki67, EGFR, CK5/6. Tumor expression of ER, PR, HER2 was previously determined. IHC molecular subtypes were defined based on expression of these markers: Luminal A: ER+ and/or PR+, HER2- and Ki67-; Luminal B: ER+ and/or PR+ and ki67+; ERBB2: ER-, PR- and HER2+; Basal-like: ER-, PR-, HER2- and EGFR+ and/or CK5/6+; Unclassified: ER-, PR-, HER2-, EGFR- and CK5/6-. IHC molecular subtypes were validated against gene expression defined molecular subtypes. Assessment of distribution and prognostic effect of molecular subtypes was stratified to age (<65 versus ≥65 years). RESULTS: Validation of molecular subtypes determined by IHC against gene expression revealed a substantial agreement in classification (Cohen's kappa coefficient 0.75). A statistically significant association (p = 0.02) was found between molecular subtypes and age, where Luminal tumors were more often found in elderly patients, while ERBB2, basal-like and unclassified subtypes were more often found in young patients. Molecular subtypes showed a prognostic association with outcome in young patients concerning relapse-free period (RFP) (p = 0.01) and relative survival (RS) (p < 0.001). No statistically significant prognostic effect was found for molecular subtypes in elderly patients (RFP p = 0.5; RS p = 0.1). Additional analyses showed that no molecular subtypes showed a statistically significant difference in outcome for elderly compare to young patients. CONCLUSION: We have shown that molecular subtypes have a different distribution and prognostic effect in elderly compared to young breast cancer patients, emphasizing the fact that biomarkers may have different distributions and prognostic effects and therefore different implications in elderly compared to their younger counterparts. Our results support the premise that breast cancer clinical behavior is significantly affected by patient age. We suggest that competing risks of death in elderly patients, ER-driven differences and micro-environmental changes in biology are underlying these age-dependent variations in patient prognosis.

External validity of a trial comprised of elderly patients with hormone receptor-positive breast cancer.

BACKGROUND: Inclusion in trials is selective, and thus results may not be generalizable to the general population. The aim of this study was to investigate the external validity of randomized clinical trial outcomes for elderly breast cancer patients. METHODS: We compared characteristics and outcomes of breast cancer patients (n = 1325) who participated in a randomized clinical trial (Tamoxifen Exemestane Adjuvant Multinational trial) with unselected breast cancer patients of corresponding age from the general population (n = 1056). Dutch patients aged 65 years or older at diagnosis of hormone receptor-positive breast cancer without distant metastases, with either nodal involvement, a tumor greater than 3cm, or a 1 to 3cm histological grade III tumor, who completed local therapy were included. Analyses were stratified by age (65-74 years; ≥75 years). Primary outcome was overall mortality. Multivariable Cox proportional hazards models were used to assess the association between covariables and overall mortality. All statistical tests were two-sided. RESULTS: Irrespective of age, patients who participated in the trial had fewer comorbid diseases, a higher socioeconomic status, and smaller tumors (all P < .001). In patients aged 65 to 74 years, those who participated in the trial had a similar overall mortality to patients from the general population (multivariable hazard ratio [HR] = 1.08; 95% confidence interval [CI] = 0.73 to 1.60). Alternatively, in patients aged 75 years or older, those who participated in the trial had a lower overall mortality (multivariable HR = 0.72; 95% CI = 0.55 to 0.95; P = .02) than patients in the general population. CONCLUSIONS: Breast cancer trial participants aged 75 years or older do not represent elderly breast cancer patients of corresponding age from the general population, which hampers the external validity of a trial.

Management of primary metastatic breast cancer in elderly patients--an international comparison of oncogeriatric versus standard care.

BACKGROUND: An oncogeriatric approach may affect management of elderly patients with breast cancer. However, little is known about oncogeriatric care in the metastatic setting. Therefore, we performed an international comparison of management of elderly patients with primary metastatic disease who were treated in two different care settings. MATERIALS AND METHODS: Patients who were ≥70years at diagnosis of primary metastatic disease were eligible. The first cohort comprised a population-based cohort of 104 patients (Comprehensive Cancer Center West, The Netherlands), who all received standard care. The second cohort comprised a hospital-based cohort of 42 patients (H. Lee Moffitt Cancer Center, Florida, United States), who all received oncogeriatric care. RESULTS: No large differences in patient and tumor characteristics were observed between both cohorts. Most patients in the standard care cohort received systemic therapy as primary therapy, whereas most patients in the oncogeriatric cohort received a combination of systemic and local therapy. Patients in the standard care cohort received fewer lines of treatment (mean number of treatments 2.1 vs. 3.6, p<0.001), and particularly received less breast surgery, chemotherapy, and trastuzumab. Three-year overall mortality was 71% (95% CI: 61-83%) as compared to 58% (95% CI: 42-75%) among patients in the oncogeriatric care cohort (multivariable HR: 1.59 [95% CI: 0.88-2.87], p=0.125). CONCLUSIONS: In primary metastatic breast cancer, oncogeriatric care intensifies treatment and might improve survival in elderly patients. Future studies on a larger scale should investigate the potential for improved survival, and whether this is accompanied by a better (preservation of) quality of life and functional status.

Impact of comorbidity on outcome of older breast cancer patients: a FOCUS cohort study.

Older breast cancer patients often suffer from comorbid diseases, which may influence life expectancy. The aim of this study was to assess the impact of specific comorbidities on overall survival and distant recurrence free period (DRFP) of older breast cancer patients. Patients were included from the population-based FOCUS cohort which contains 3,672 breast cancer patients aged 65 years or older. The impact of comorbidity on overall survival and DRFP was analyzed using multivariable Cox proportional hazard models and Poisson regression models. Median follow-up time was 6.8 years (range 0-14.0). Irrespective of age; the number of comorbid diseases was significantly associated with worse overall survival [hazard ratio (HR) per increasing number of comorbid diseases: 1.20, 95 % confidence interval (CI) 1.13-1.27 and HR 1.09, 95 % CI 1.05-1.13 for age <75 and age ≥ 75, respectively]. Median follow-up time for DRFP was 5.7 years (range 0-14.0). An increasing number of comorbid diseases was associated with a decreasing risk of metastases among patients aged ≥ 75 (HR 0.94, 95 % CI 0.87-1.02), whereas an increasing risk was shown for patients aged <75 (HR 1.09, 95 % CI 1.01-1.19). This study shows that in older breast cancer, patients overall survival and DRFP are influenced by comorbidity. This reiterates that patient outcome is not only influenced by breast cancer, and non-cancer-related factors should be taken into account.