The impact of geriatric characteristics and comorbidities on distant metastases and other cause mortality in older women with non-metastatic breast cancer treated with primary endocrine therapy.

INTRODUCTION: In recent years, primary surgical treatment of older women with non-metastatic breast cancer has decreased in favor of primary endocrine therapy (PET). PET can be considered in women with a remaining life expectancy of less than five years. The aim of this study was to (1) assess the risk of distant metastases and other cause mortality over ten years in women aged 65 and older with stage I-III breast cancer treated with PET, (2) whether this was associated with geriatric characteristics and comorbidities and to (3) describe the reasons on which the choice for PET was made. METHODS: Women were included from the retrospective FOCUS cohort, which comprises all incident women diagnosed with breast cancer aged 65 or older between January 1997 and December 2004 in the Comprehensive Cancer Center Region West in the Netherlands. We selected women (N = 257) with stage I-III breast cancer and treated with PET from this cohort. Patient characteristics (including comorbidity, polypharmacy, walking, cognitive and sensory impairment), treatment and tumor characteristics were retrospectively extracted from charts. Outcomes were distant metastasis and other cause mortality. Cumulative incidences were calculated using the Cumulative Incidence for Competing Risks method (CICR); and subdistribution hazard ratios (SHR) were tested between groups based on age, geriatric characteristics and comorbidity with the Fine and Gray model. RESULTS: Women treated with PET were on average 84 years old and 41% had one or more geriatric characteristics. Other cause mortality exceeded the cumulative incidence of distant metastasis over ten years (83 versus 5.6%). The risk of dying from another cause further increased in women with geriatric characteristics (SHR 2.06, p < 0.001) or two or more comorbidities (SHR 1.72, p < 0.001). Often the reason for omitting surgery was not recorded (52.9%), but if recorded surgery was omitted mainly at the patient's request (18.7%). DISCUSSION: This study shows that the cumulative incidence of distant metastasis is much lower than other cause mortality in older women with breast cancer treated with PET, especially in the presence of geriatric characteristics or comorbidities. This confirms the importance of assessment of geriatric characteristics to aid counseling of older women.

Gene expression signatures in older patients with breast cancer: A systematic review.

BACKGROUND: Gene expression signatures have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive breast cancer. The objective of this systematic review was to evaluate the prognostic and predictive value of commercially available gene expression signatures as a tool in adjuvant treatment decision-making in older patients with breast cancer. METHODS: PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, and Emcare were reviewed for relevant articles published before December 2021. Eligible studies were randomised trials and cohort studies that externally validated commercially available gene expression signatures in patients aged 65 years and older, including studies that presented subanalyses of this age group. Data extraction and risk of bias assessment was performed independently by two investigators. RESULTS: Fifteen studies were included. Most studies investigated Oncotype DX, while results from other gene expression signatures were limited. Several studies underlined the prognostic performance of Oncotype DX and Prosigna Risk of Recurrence in older patients. Moreover, Oncotype DX was predictive for older patients with an intermediate-risk recurrence score; chemotherapy could be spared in both lymph node-positive and lymph node-negative disease. CONCLUSIONS: Prognostic performance has been demonstrated in older patients for several gene expression signatures. However, additional validation in patients with high-risk tumours is needed before gene expression signatures can be implemented in clinical practice as a prediction tool for adjuvant chemotherapy decision-making in the older age group.

Impact of age on breast cancer mortality and competing causes of death at 10 years follow-up in the adjuvant TEAM trial.

AIM: Due to increasing life expectancy, patients with breast cancer remain at risk of dying due to breast cancer over a long time. This study aims to assess the impact of age on breast cancer mortality and other cause mortality 10 years after diagnosis. METHODS: Postmenopausal patients with hormone-receptor positive breast cancer were included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. Age at diagnosis was categorised as <65 years (n = 3369), 65-74 years (n = 1896) and ≥75 years (n = 854). Breast cancer mortality was assessed considering other cause mortality as competing event using competing risk analysis. RESULTS: After a median follow-up of 9.8 years (interquartile range 8.0-10.3), cumulative incidence of breast cancer mortality increased with increasing age (age <65 years, 11.7% [95% confidence interval {CI}: 10.2-13.2]; 65-74 years, 12.7% (11.2-14.2) and ≥75 years, 15.6% (13.1-18.0)). Univariate subdistribution hazard ratio (sHR) increased with increasing age (age: 65-74 years, sHR: 1.08, 95% CI: 0.92-1.27 and ≥75 years sHR: 1.30, 95% CI: 1.06-1.58, P = 0.013). Multivariable sHR adjusted for tumour and treatment characteristics increased with age but did not reach significance (age 65-74 years, sHR: 1.11, 95% CI: 0.94-1.31; ≥75 years, sHR: 1.18, 95% CI: 0.94-1.48, P = 0.055). CONCLUSION: Ten years after diagnosis, older age at diagnosis is associated with increasing breast cancer mortality in univariate analysis, but it did not reach significance in multivariable analysis. This is not outweighed by a substantially higher other cause mortality with older age. This underlines the need to improve the balance between undertreatment and overtreatment in older patients with breast cancer. The trial was registered in International Trial Databases (ClinicalTrials.govNCT00279448, NCT00032136, and NCT00036270; the Netherlands Trial Registry NTR267).

Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: current and future evidence.

The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented.

Pharmacokinetic/pharmacodynamic modelling of effects of dexamethasone and prednisolone in combination with endogenous cortisol on lymphocyte counts and systemic markers of bone turn over and inflammation in healthy and asthmatic men.

OBJECTIVE: To compare potency and efficacy of dexamethasone (DEXA) and prednisolone (PRED) in assumed equipotent doses in combination with endogenous cortisol, using lymphocyte counts, plasma osteocalcin (OC), and eosinophilic cationic protein (ECP) as effect variables and to evaluate potential differences between healthy subjects and asthmatic patients. METHODS: Eight healthy subjects and six asthmatic patients who had stopped taking their regular inhaled glucocorticosteroid treatment (ICS) for 1 week, were given an IV bolus of DEXA and PRED in assumed equipotent doses of 2.0 mg and 12.5 mg, respectively, on separate occasions, in combination with subcutaneously injected granulocyte-colony-stimulating factor (G-CSF) as a stimulant for ECP production. Plasma levels of DEXA, PRED, cortisol and effect variables were determined over 25 h and pharmacokinetic-pharmacodynamic (PK-PD) modelling was performed. RESULTS: Baseline cortisol concentration was lower in patients than in healthy subjects. Both of the exogenous glucocorticoids (GCs) diminished cortisol production. In the healthy subjects, the cortisol production remained suppressed for the full duration of the study day after DEXA but not after PRED. In the asthmatic patients though, the reappearance of the endogenous production of cortisol was seen after both DEXA and PRED. The E(max) values for lymphocyte counts and OC showed that cortisol acted as partial, and DEXA and PRED as full agonists. The observed responses of DEXA and PRED suppressing cortisol, OC and lymphocyte counts were all of the same relative order of magnitude, in accordance with the estimated PD parameters. However, cortisol was estimated to have very little effect on ECP and modelling further predicted that DEXA and PRED were only partial agonists for this effect, without a difference between healthy and asthmatic subjects. Yet, in healthy subjects, the area under the concentration-time curves (AUCs) indicated unexpectedly that ECP was only suppressed after PRED and not after DEXA, while in patients it was suppressed after both GCs. The rank order of potency on lymphocyte counts, OC and ECP was DEXA>PRED>cortisol, although the different relative potencies of the three GCs involved were not the same for all of the three effect variables and differences were also found between healthy and asthmatic subjects. CONCLUSION: PK-PD modelling studies of GCs demonstrated not only differences in potency of DEXA and PRED on the measured systemic markers, but also different potencies per target tissue and differences between healthy and asthmatic men. The effects caused by the achieved blood concentrations of DEXA and PRED, expressed as AUCs of the effect variables, were in accordance with their respective E(max) values in case of the lymphocytes and OC but not for ECP.

Distinct actions of prednisolone and dexamethasone towards osteocalcin and eosinophilic cationic protein in assumed clinically equivalent doses: a study in healthy men.

OBJECTIVE: To study the effects of prednisolone (PRED) and dexamethasone (DEXA) in assumed clinically equivalent doses towards the lowering of cortisol, osteocalcin (OC) and the stimulated rise of eosinophilic cationic protein (ECP) by granulocyte colony stimulating factor (G-CSF). METHODS: At four separate sessions of 25 h each, saline i.v. alone, G-CSF s.c. alone or in combination with either 12.5 mg PRED i.v. or 2.0 mg DEXA i.v., were randomly administered in eight healthy male subjects. RESULTS: All subjects had equal lowering of cortisol after DEXA and PRED at 10 h, whereas a sustained suppression at 25 h persisted only after administration of DEXA. Between 4 h and 10 h after administration of DEXA and PRED, the change in the area under the concentration-time curve (DeltaAUC4-10) of OC became 24.4% and 2.3% lower, respectively ( p<0.0001). After 25 h, this effect persisted for DEXA. DeltaAUC4-10 of the G-CSF-stimulated ECP response decreased by a mean of 76.8% after PRED compared with DEXA and to controls ( p<0.02), and this difference had disappeared at 25 h. DEXA did not elicit any effect towards the G-CSF-stimulated ECP response. CONCLUSION: PRED and DEXA in formerly assumed clinically equivalent doses induced a similar suppression towards cortisol within the first 10 h, but had different actions towards blood concentrations of OC and ECP following G-CSF stimulation in healthy male subjects.