Early stage breast cancer treatment and outcome of older patients treated in an oncogeriatric care and a standard care setting: an international comparison.

INTRODUCTION: Since older patients with breast cancer are underrepresented in clinical trials, an oncogeriatric approach is advocated to guide treatment decisions. However, the effect on outcomes is unclear. The aim of this study was to compare treatments and outcomes between patients treated in an oncogeriatric and a standard care setting. METHODS: Patients aged ≥ 70 years with early stage breast cancer were included. The oncogeriatric cohort comprised unselected patients from the Moffitt Cancer Center, and the standard cohort patients from a Dutch population-based cohort. Cox models were used to characterize the influence of care setting on recurrence risk and overall mortality. RESULTS: Overall, 268 patients were included in the oncogeriatric and 1932 patients in the standard cohort. Patients in the oncogeriatric cohort were slightly younger, had more comorbidity, and received more adjuvant endocrine therapy and chemotherapy. Oncogeriatric care was associated with a lower risk of recurrence, which remained significant after adjustment for patient and tumour characteristics [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.44-0.99]. Oncogeriatric care was also associated with a lower overall mortality, which also remained significant after adjustment for patient and tumour characteristics (HR 0.69, 95% CI 0.55-0.87). CONCLUSIONS: Patients treated in the oncogeriatric care setting had a lower risk of recurrence, which may be explained by more systemic treatment. Overall mortality was also lower, but other explanations besides care setting could not be ruled out as the cohorts had different patient profiles. Future studies need to clarify the impact of an oncogeriatric approach on outcomes.

Immunotherapy in older patients with non-small cell lung cancer: Young International Society of Geriatric Oncology position paper.

Immunotherapy with checkpoint inhibitors against programmed cell death receptor (PD-1) and programmed cell death ligand (PD-L1) has been implemented in the treatment pathway of patients with non-small cell lung cancer (NSCLC) from locally advanced disease to the metastatic setting. This approach has resulted in improved survival and a more favourable toxicity profile when compared with chemotherapy. Following the successful introduction of single-agent immunotherapy, current clinical trials are focusing on combination treatments with chemotherapy or radiotherapy or even other immunotherapeutic agents. However, most of the data available from these trials are derived from, and therefore might be more applicable to younger and fitter patients rather than older and often frail lung cancer real-world patients. This article provides a detailed review of these immunotherapy agents with a focus on the data available regarding older NSCLC patients and makes recommendations to fill evidence gaps in this patient population.

Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA Breast Cancer Group.

BACKGROUND: Older patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival. METHODS: Population-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated. RESULTS: In total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30-6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium. CONCLUSIONS: There is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

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.

The clinical prognostic value of molecular intrinsic tumor subtypes in older breast cancer patients: A FOCUS study analysis.

INTRODUCTION: It was recently proposed that the molecular breast tumor subtypes are differently distributed in the elderly breast cancer patients, and also lack prognostic value. Given the limited number of elderly patients in previous studies, the aim of this study was to determine the prognostic effect of the molecular intrinsic subtypes in a large older breast cancer population. MATERIAL AND METHOD: Older breast cancer patients with invasive, non-metastatic breast cancer with tumor material available for immunohistochemical determination of Ki67, EGFR, CK5/6 and HER-2 were included. ER and PR expression was retrieved from the pathology report. Molecular subtypes were: Luminal A, Luminal B, ERBB2, Basal-like and Unclassified. Primary endpoint was Relapse Free Period (RFP), taking into account the competing risk of mortality, and adjusted for the most important patient, tumor and treatment characteristics. Secondary endpoint was Relative Survival (RS). RESULTS: Overall, 1362 patients were included. Patients with a Luminal A subtype had the lowest risk of recurrence (11% at 5 yrs). Patients with a Basal (24% at 5yrs) or ERBB2 (34% at 5yrs) molecular breast tumor subtype had the highest risk of recurrence. The ERBB2 subtype had the worst prognosis in terms of RFP (SHR 2.07, 95% CI 1.35-3.20; p = 0.001). The worst RS was again observed for the ERBB2 subtype (48% at 10 yrs). In multivariable analyses, the relative excess risk of death for all molecular subtypes was significantly worse compared to the Luminal A subtype. CONCLUSION: Molecular intrinsic breast tumor subtypes have significant prognostic value in the elderly population, even after taking competing mortality into account.

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.

Variations in compliance to quality indicators by age for 41,871 breast cancer patients across Europe: a European Society of Breast Cancer Specialists database analysis.

OBJECTIVE: The aim of this study is to assess age-specific compliance to quality indicators (QIs) regarding the treatment of breast cancer as defined by European Society of Breast Cancer Specialists (EUSOMA) for patients across Europe. METHODS: All patients entered into this study were affected by in situ or invasive breast cancer, diagnosed and treated between 2003 and 2012 at 27 Breast Units across Europe, who were entered into the EUSOMA database. Patients were categorised according to age; compliance to thirteen QIs was assessed for each age group and per time period (2003-2007 and 2008-2012). Compliance to QIs was tested by multivariable logistic regression models adjusted for breast unit, incidence year and tumour characteristics. RESULTS: Overall, 41,871 patients with a mean age of 59.6years were available for analysis. The highest compliance was reached for patients aged 55-64years and in the time period 2008-2012, whilst the lowest compliance was observed for women aged over 74 or under 40years and in the earlier time period. In multivariable logistic regression models, a significant difference between age categories was shown for 12 out of 13 QIs (P<0.001). Compliance to the QIs for patients aged ⩾75years was significantly lower when compared to patients aged 55-64years for ten QIs, whilst for patients in the youngest age group this was true for seven QIs. CONCLUSION: In conclusion, we found that among the 27 included breast units across Europe, compliance to QIs for breast cancer treatment is often lower in the youngest and oldest breast cancer patients, with a tendency to overtreatment in the youngest patients, and to under-treatment in the elderly.

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.

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.

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.

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.

Breast-conserving surgery with or without radiotherapy in older breast patients with early stage breast cancer: a systematic review and meta-analysis.

BACKGROUND: In early stage breast cancer, radiotherapy is an integral part of locoregional treatment with breast-conserving surgery. However, few older patients are included in the clinical trials upon which these recommendations are based. Therefore, we performed a systematic review and meta-analysis to evaluate outcomes of radiotherapy after breast-conserving surgery in older patients. METHODS: A systematic search of PubMed and Embase was undertaken. Inclusion was restricted to randomized controlled trials in postmenopausal breast cancer patients. Pooled odds ratios were calculated for locoregional recurrence, distant recurrence, and overall survival. RESULTS: We included 5 randomized clinical trials comprising 3,190 patients. Overall, 39 % of the patients were ≥ 70 years old, and most had hormone receptor-positive T1 tumors without nodal involvement. All patients received adjuvant systemic therapy. Patients who received radiotherapy had a lower relative risk of locoregional recurrence (pooled odds ratio [OR] 0.36; 95 % confidence interval [CI] 0.25-0.50). The 5-year absolute risk was 2.2 % (95 % CI 1.6-3.1) among patients who received radiotherapy, versus 6.5 % (95 % CI 5.3-7.9) among patients who did not. The absolute risk difference was 4.3 % (95 % CI 2.9-5.7), corresponding with a number needed to treat of 24. No differences were observed for distant recurrence or overall survival. CONCLUSIONS: Although patients who received radiotherapy had a lower relative risk of locoregional recurrence, the absolute risk was low, and overall survival was not affected. We propose that the debate should not only focus on the relative risk but also on the absolute benefit of radiotherapy and the number needed to treat. Both treatment options may be reasonable in clinical practice.

[Surgical complications in elderly patients with breast cancer]. / Chirurgische complicaties bij ouderen met borstkanker.

Old age is strongly associated with comorbidity and decreased functioning, which in turn affects treatment decisions for elderly breast cancer patients. In recent years, the rate of elderly patients with breast cancer who were not operated on has increased considerably. Older age and an increased number of concomitant diseases are associated with an increased risk of postoperative complications. Mortality is higher in patients who experience complications than in patients who do not. The death of a patient who experiences a complication does not result from the complication itself; rather, it is associated with factors that make such a patient vulnerable e.g. comorbidity and poor functional status. Hormonal therapy could be a good alternative for surgical treatment in vulnerable elderly patients, but sound research into this is lacking. Deciding against the surgical treatment of elderly patients with breast cancer based on the fear of postoperative mortality is not justifiable; however, there is too little evidence on the consequences of breast cancer surgery on outcome measures such as quality of life and functional status yet available to be able to offer strong recommendations on the surgical treatment of elderly patients with breast cancer.