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.

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.

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.

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.

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.

Tumor immune subtypes distinguish tumor subclasses with clinical implications in breast cancer patients.

There is strong evidence that the host's cellular immune response is linked to tumor progression, however its impact on patient outcome in breast cancer is poorly understood. The purpose of this study is to define tumor immune subtypes, focusing on cellular immune responses and investigate their prognostic effect in breast cancer patients. Our training (n = 440) and validation cohort (n = 382) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. Tumor tissue sections were immunohistochemically stained for CD8 (CTL) and PEN5 (NK cells). Tumor expression of classical and non-classical human leukocyte antigen class I, and tumor-infiltrating Tregs were previously determined. Tumor immune subtypes were constructed based on quantification of these markers and biological rationale. High, intermediate, and low immune susceptible tumor immune subtypes were found, respectively, in 16, 63, and 20 % of patients in the training cohort and 16, 71, and 13 % in the validation cohort. The subtypes showed to be statistically significant prognostic in multivariate analyses for relapse free period (RFP) [p < 0.0001, intermediate versus high: hazard ratio (HR) 1.95; low versus high HR 2.98] and relative survival (RS) (p = 0.006, intermediate versus high HR 3.84; low versus high: HR 4.26). Validation of these outcome analyses confirmed the independent prognostic associations: RFP (p = 0.025) and RS (p = 0.040). The tumor immune subtypes that we present represent a prognostic profile with solid underlying biological rationale and with high discriminative power confirmed in an independent validation cohort. Our results emphasize the importance of tumor immune surveillance in the control of tumor development and, therefore, in determining patient prognosis. Tumor immune subtype profiling is promising for prognosis prediction and the achievement of tailored treatment for breast cancer patients.

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.

PURPOSE: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODS: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSION: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Timing of the sentinel lymph node biopsy in breast cancer patients receiving neoadjuvant therapy - recommendations for clinical guidance.

Neoadjuvant chemotherapy (NAC) is an increasingly important component in the treatment of both locally advanced and early-stage breast cancer. With this, a debate on the timing of the sentinel lymph node biopsy (SLNB) has emerged. At the end of the last century, the SLNB was introduced as an axillary staging modality, and this paper aims to further elucidate this issue in the context of NAC. We compiled available data on the SLNB after NAC and provide clinical guidance for timing the SLNB in this context. On the basis of our findings, we recommend that the SLNB can be performed after NAC in all cases. In patients with a clinically node-negative (cN0) status prior to NAC, the SLNB should be performed after NAC, and in case of a histologically confirmed negative SLNB, a completion axillary lymph node dissection (ALND) has no added value and can be omitted. In patients with clinically positive nodal involvement (cN+) prior to NAC, all axillary surgery can also be performed after NAC.

Influence of semi-quantitative oestrogen receptor expression on adjuvant endocrine therapy efficacy in ductal and lobular breast cancer - a TEAM study analysis.

BACKGROUND: Multiple studies suggest better efficacy of chemotherapy in invasive ductal breast carcinomas (IDC) than invasive lobular breast carcinomas (ILC). However, data on efficacy of adjuvant endocrine therapy regimens and histological subtypes are sparse. This study assessed endocrine therapy efficacy in IDC and ILC. The influence of semi-quantitative oestrogen receptor (ER) expression by Allred score was also investigated. METHODS: Dutch and Belgian patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were randomized to exemestane (25mg daily) alone or following tamoxifen (20mg daily) for 5 years. Inclusion was restricted to IDC and ILC patients. Histological subtype was assessed locally; ER expression was centrally reviewed according to Allred score (ER-poor (<7; n=235); ER-rich (7; n=1789)). Primary end-point was relapse-free survival (RFS), which was the time from randomization to disease relapse. FINDINGS: Overall, 2140 (82%) IDC and 463 (18%) ILC patients were included. RFS was similar for both endocrine treatment regimens in IDC (hazard ratio (HR) for exemestane was 0.83 (95%confidence interval (CI) 0.67-1.03)), and ILC (HR 0.69 (95%CI 0.45-1.06)). Irrespective of histological subtype, patients with ER-rich Allred scores allocated to exemestane alone had an improved RFS (multivariable HR 0.71 (95%CI 0.56-0.89)). In contrast, patients with ER-poor Allred scores allocated to exemestane had a worse RFS (multivariable HR 2.33 (95%CI 1.32-4.11)). Significant effect modification by ER-Allred score was confirmed (multivariable p=0.003). INTERPRETATION: Efficacy of endocrine therapy regimens was similar for IDC and ILC. However, ER-rich patients showed superior efficacy to upfront exemestane, while ER-poor patients had better outcomes with sequential therapy, irrespective of histological subtype, emphasising the relevance of quantification of ER expression.

Elderly postmenopausal patients with breast cancer are at increased risk for distant recurrence: a tamoxifen exemestane adjuvant multinational study analysis.

INTRODUCTION: For postmenopausal patients with hormone-sensitive breast cancer, outcome is worse with increasing age at diagnosis. The aim of this study was to assess the incidence of breast cancer recurrence (locoregional and distant), and contralateral breast cancer by age at diagnosis. METHODS: Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. Primary endpoints were locoregional recurrence, distant recurrence, and contralateral breast cancer. Age at diagnosis was categorized as younger than 65 years, 65-74 years, and 75 years or older. RESULTS: Overall, 9,766 patients were included, of which 5,349 were younger than 65 years (reference group), 3,060 were 65-74 years, and 1,357 were 75 years or older. With increasing age, a decreased administration of radiotherapy after breast conserving surgery (94%, 92%, and 88%, respectively) and adjuvant chemotherapy (51%, 23%, and 5%, respectively) was observed. Risk of distant recurrence increased with age at diagnosis; multivariable hazard ratio for patients aged 65-74 years was 1.20 (95% confidence interval [CI]: 1.00-1.44), hazard ratio for patients aged 75 years or older was 1.39 (95% CI: 1.08-1.79). Risks of locoregional recurrence and contralateral breast cancer were not significantly different across age groups. CONCLUSION: Elderly patients with breast cancer were at increased risk for distant recurrence. Other studies have shown that the risk of distant recurrence is mainly affected by adjuvant systemic therapy. All TEAM patients received adjuvant endocrine treatment; however, chemotherapy was administered less often in elderly patients. These findings are suggestive for consideration of chemotherapy in relatively fit elderly breast cancer patients with hormone-sensitive disease.

Older patients with breast cancer: is there bias in the treatment they receive?

Breast cancer is the most frequent malignant tumor in women worldwide and as breast cancer incidence increases with increasing age, over 40% of new cases are diagnosed in women older than 65 years of age. However, older patients are not treated to the same extent as younger patients and increasing age at diagnosis predicts deviation from guidelines for all treatment modalities. Evidence-based medicine in older patients is lacking as they are usually excluded from clinical trials often because of existing comorbidities and limited life expectancy. Accordingly, there is a higher competing risk of death from other causes than breast cancer compared with younger patients and this may have led to the false interpretation that prognosis of breast cancer in older patients is relatively good. However, every treatment modality should be evaluated during treatment decision making. Multimodal therapy should not be routinely withheld as data show that disease-specific mortality increases with age, probably due to undertreatment. Prognostic markers, fitness and comorbidities rather than chronological age should determine optimal, individualized therapy. It is recommended that treatment decisions should be discussed in a multidisciplinary setting, ideally in combination with any form of geriatric assessment, to improve breast cancer outcome in the older population.

[Worse prognosis for older breast cancer patients]. / Slechtere prognose voor oudere borstkankerpatiënt.

The prognosis for older post-menopausal breast cancer patients is worse than for younger post-menopausal patients. This applies to the relatively healthy patients taking part in randomized clinical studies, but is also the case for older breast cancer patients in the general population. The worse prognosis may be explained by inadequate treatment, and possibly also by age-specific tumour and patient characteristics. As older patients are rarely included in randomized trials, it is still insufficiently clear what constitutes adequate treatment for them. It is therefore important to include more elderly patients in clinical studies into the effectiveness of breast cancer therapy. An important aim is to allow correct assessment of which patients will die with, and which patients will die from breast cancer, so that treatment can be adjusted accordingly.

No excess mortality in patients aged 50 years and older who received treatment for ductal carcinoma in situ of the breast.

Background. The incidence of ductal carcinoma in situ (DCIS) has increased at a fast rate.The aim of this study was to assess the incidence and treatment in the Netherlands and estimate the excess mortality risk of DCIS. Methods. From the Netherlands Cancer Registry, adult female patients (diagnosed 1997-2005) with DCIS were selected. Treatment was described according to age. Relative mortality at 10 years of follow-up was calculated by dividing observed mortality over expected mortality. Expected mortality was calculated using the matched Dutch general population. Results. Overall, 8421 patients were included in this study. For patients aged 50-64, and 65-74 an increase in breast-conserving surgery was observed over time (P < 0.001). For patients over 75 years of age, 8.0% did not undergo surgery; this percentage remained stable over time (P = 0.07). Overall, treated patients aged >50 years experienced no excess mortality regardless of treatment (relative mortality 1.0). Conclusion. The present population-based study of almost 8500 patients showed no excess mortality in surgically treated women over 50 years with DCIS.