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Supplementary Data from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Purpose:Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.Experimental Design:Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.Results:This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.Conclusions:From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Purpose: We examined whether pretreatment levels of angiogenesis- or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.Experimental Design: We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.Results: At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P = 0.01) and IL8 (P = 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.Conclusions: Multiple angiogenesis- or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumab-based therapy for prediction of PFS and OS merit further study. Clin Cancer Res; 22(7); 1611–20. ©2016 AACR.

Supplementary Table from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Supplementary Figure from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Supplementary Table 1. Clinical outcome of original trial population and biomarker population Supplementary Table 2. Baseline plasma protein levels vs baseline patient and tumor characteristics Supplementary Table 3. Spearman Rho correlation coefficients among protein levels at baseline Supplementary Table 4. Plasma protein changes vs baseline patient and tumor characteristics Supplementary Table 5. Change in levels of proteins per treatment arm Supplementary Table 6. Spearman Rho correlation coefficients among protein changes on C2D1 from baseline Supplementary Figure 1A. A plot of Martingale residual vs log-transformed CA9 change for death Supplementary Figure 1B. Estimation of an optimal cut-off point for CA9 change Supplementary Figure 1C. Changes in CA9 levels in the subgroups of a high rise and a low/no rise

Background: Previous studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been hypothesised that these differences in survival outcomes could be related to treatment variation. Objectives: We aimed to compare patient and tumour characteristics, treatment selection and survival outcomes between two large prospective cohorts of older patients with operable breast cancer from the United Kingdom (UK) and The Netherlands.Methods: Women diagnosed with operable breast cancer aged >70 years were included. A baseline comprehensive geriatric assessment was performed in both cohorts, with data collected on age, comorbidities, cognition, nutritional and functional status. Baseline tumour characteristics and treatment type were collected. Univariable and multivariable Cox regression models were used to compare overall survival between the cohorts. Results: 3262 patients from the UK Age Gap cohort and 618 patients from the Dutch Climb cohort were included, with median ages of 77.0 (IQR: 72.0-81.0) and 75.0 (IQR: 72.0-81.0) years, respectively. The cohorts were generally comparable, with slight differences in rates of comorbidity and frailty. Median follow-up for overall survival was 4.1 years (IQR 2.9-5.4) in Age Gap and 4.3 years (IQR 2.9-5.5) in Climb. In Age Gap, both the rates of primary endocrine therapy and adjuvant hormonal therapy after surgery were approximately twice those in Climb (16.6% versus 7.3%, p < 0.001 for primary endocrine therapy, and 62.2% versus 38.8%, p < 0.001 for adjuvant hormonal therapy). There was no evidence of a difference in overall survival between the cohorts (adjusted HR 0.94, 95% CI 0.74-1.17, p Z 0.568). Conclusions: In contrast to previous studies, this comparison of two large national prospective longitudinal multi-centre cohort studies demonstrated comparable survival outcomes between older patients with breast cancer treated in the UK and The Netherlands, despite differences in treatment allocation.(C) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction: In older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions of breast cancer mortality versus other-cause mortality after locoregio-nal or distant recurrence in a population-based cohort of older patients analysed by multi-state models. Methods: Surgically treated patients >70 years diagnosed with stage I-III breast cancer in 2003-2009 were selected from the Netherlands Cancer Registry. A novel multi-state model with locoregional and distant recurrence that incorporates relative survival was fitted. Other-cause and breast cancer mortality were indicated as population and excess mortality. Results: Overall, 18,419 patients were included. Ten-year cumulative incidences of locoregio-nal and distant recurrence were 2.8% (95%CI 2.6-3.1%) and 12.5% (95%CI 11.9-13.1%). Other-cause mortality increased from 23.9% (95%CI 23.7-24.2%) in patients 70-74 years to 73.8% (95%CI 72.2-75.4%) in those >80 years. Ten-year probabilities of locoregional or distant recurrence with subsequent breast cancer death were 0.4-1.3% and 10.2-14.6%, respectively. For patients with a distant recurrence in the first two years after diagnosis, breast cancer death probabilities were 95.3% (95%CI 94.2-96.4%), 93.1% (95%CI 91.6-94.6%), and 88.6% (95%CI 86.5-90.8%) in patients 70-74, 75-79, and >80 years. Conclusion: In older patients without recurrence, prognosis is driven by other-cause mortality. Although locoregional recurrence is a predictor for worse outcome, given its low incidence it contributes little to breast cancer mortality after diagnosis. For patients who develop a distant recurrence, breast cancer remains the dominant cause of death, even at old age.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE: To determine the predictive value of lumbar skeletal muscle mass and density for postoperative outcomes in older women with advanced stage ovarian cancer. METHODS: A multicenter, retrospective cohort study was performed in women ≥ 70 years old receiving surgery for primary, advanced stage ovarian cancer. Skeletal muscle mass and density were assessed in axial CT slices on level L3. Low skeletal muscle mass was defined as skeletal muscle index < 38.50 cm2/m2. Low skeletal muscle density was defined as one standard deviation below the mean (muscle attenuation < 22.55 Hounsfield Units). The primary outcome was any postoperative complication ≤ 30 days after surgery. Secondary outcomes included severe complications, infections, delirium, prolonged hospital stay, discharge destination, discontinuation of adjuvant chemotherapy and mortality. RESULTS: In analysis of 213 patients, preoperative low skeletal muscle density was associated with postoperative complications ≤ 30 days after surgery (Odds Ratio (OR) 2.83; 95% Confidence Interval (CI) 1.41-5.67), severe complications (OR 3.01; 95%CI 1.09-8.33), infectious complications (OR 2.79; 95%CI 1.30-5.99) and discharge to a care facility (OR 3.04; 95%CI 1.16-7.93). Preoperative low skeletal muscle mass was only associated with infectious complications (OR 2.32; 95%CI 1.09-4.92). In a multivariable model, low skeletal muscle density was of added predictive value for postoperative complications (OR 2.57; 95%CI 1.21-5.45) to the strongest existing predictor functional impairment (KATZ-ADL ≥ 2). CONCLUSION: Low skeletal muscle density, as a proxy of muscle quality, is associated with poor postoperative outcomes in older patients with advanced stage ovarian cancer. These findings can contribute to postoperative risk assessment and clinical decision making. ispartof: GYNECOLOGIC ONCOLOGY vol:162 issue:2 pages:360-367 ispartof: location:United States status: published

Polypharmacy is common in older adults with cancer and deprescribing potentially inappropriate medications becomes very relevant when life expectancy decreases due to metastatic disease. Especially preventive medications may no longer be beneficial, because they may decrease quality of life and reduction in morbidity and mortality may be futile. Although deprescribing of preventive medication is common in the last period of life, it is still unusual during active cancer treatment for advanced disease, although life expectancy is often limited to less than 1 to 2 years in that stage. We performed a systematic search of the literature in Pubmed and Embase on the discontinuation of commonly utilized groups of preventive medication and evaluated the evidence of potential benefits and harms in patients aged 65 years or older with cancer and a limited life expectancy (LLE). From 21 included studies, it can be concluded that deprescribing lipid lowering drugs, antihypertensive drugs, osteoporosis drugs and antihyperglycemic drugs is feasible in a considerable part of patients with a LLE. Discontinuation may be performed safely, without the occurrence of serious adverse events or decrease of survival. The only study that addressed quality of life after deprescribing showed that discontinuation of statins improves quality of life in patients with a LLE. Recurrence of symptoms requiring reintroduction occurred in 0-13% of patients on antihyperglycemic treatment and 8-60% of patients using antihypertensive drugs. In order to reduce pill burden and futile treatment clinicians should discuss deprescribing of preventive medication with older patients with advanced cancer and a LLE.

PURPOSE For postmenopausal patients with breast cancer, previous subgroup analyses have shown a modest benefit from adjuvant bisphosphonate treatment. However, the efficacy of oral nitrogen-containing bisphosphonates such as ibandronate is unclear in this setting. TEAM-IIB investigates adjuvant ibandronate in postmenopausal women with estrogen receptor–positive (ER+) breast cancer. METHODS TEAM-IIB is a randomized, open-label, multicenter phase III study. Postmenopausal women with stage I-III ER+ breast cancer and an indication for adjuvant endocrine therapy (ET) were randomly assigned 1:1 to 5 years of ET with or without oral ibandronate 50 mg once daily for 3 years. Major ineligibility criteria were bilateral breast cancer, active gastroesophageal problems, and health conditions that might interfere with study treatment. Primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population. RESULTS Between February 1, 2007, and May 27, 2014, 1,116 patients were enrolled, 565 to ET with ibandronate (ibandronate arm) and 551 to ET alone (control arm). Median follow-up was 8.5 years. DFS was not significantly different between the ibandronate and control arms (HR, 0.97; 95% CI, 0.76 to 1.24; log-rank P = .811). Three years after random assignment, DFS was 94% in the ibandronate arm and 91% in the control arm. Five years after random assignment, this was 89% and 86%, respectively. In the ibandronate arm, 97/565 (17%) of patients stopped ibandronate early because of adverse events. Significantly more patients experienced GI issues, mainly dyspepsia, in the ibandronate arm than in the control arm (89 [16%] and 54 [10%], respectively; P < .003). Eleven patients in the ibandronate arm developed osteonecrosis of the jaw. CONCLUSION In postmenopausal women with ER+ breast cancer, adjuvant ibandronate 50 mg once daily does not improve DFS and should not be recommended as part of standard treatment regimens.

OBJECTIVE: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. MATERIALS AND METHODS: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. RESULTS: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication ≤30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57-8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27-10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42-9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41-18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. CONCLUSION: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is associated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions. ispartof: EJSO vol:48 issue:4 pages:896-902 ispartof: location:England status: published

Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types. Experimental Design: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available. Results: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types. Conclusions: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Introduction: Approximately 20% of older patients with breast cancer either present with metastatic disease or develop distant metastases after early breast cancer. The aims of this study were to assess the prevalence of psychosocial problems in older patients with metastatic breast cancer, and to assess longitudinal changes in functional status, psychosocial functioning, and quality of life.Methods: For this prospective cohort study, patients with metastatic breast cancer aged 70 years and older were recruited in four Dutch hospitals. A baseline geriatric assessment was performed evaluating somatic, functional and psychosocial domains. Self-administered questionnaires were performed at baseline, three and six months: the Groningen Activity Restriction Scale, Geriatric Depression Scale. Loneliness scale, Apathy scale, Distress Thermometer and EORTC-QLQ-C30. Longitudinal changes on these scales were assessed by performing crude and adjusted linear mixed models.Results: Of the 100 patients that were included and underwent a geriatric assessment, 85 patients completed the baseline self-administered questionnaires. Almost half of the patients (46%) had depressive symptoms, and up to 64% experienced distress. Apathy was present in 53%, and 36% experienced loneliness. Three- and six-month questionnaires were completed by 77 and 72 patients, respectively. Although a significant increase in loneliness between baseline and six months was seen, this size of this change was not clinically relevant. No other longitudinal changes were found.Conclusion: The prevalence of distress, depressive symptoms, apathy and loneliness in older patients with metastatic breast cancer is high. Timely detection, for which a geriatric assessment is effective, could potentially improve quality of life. (C) 2020 The Authors. Published by Elsevier Ltd.

Background Surgery is increasingly being omitted in older patients with operable breast cancer in the Netherlands. Although omission of surgery can be considered in frail older patients, it may lead to inferior outcomes in non‐frail patients. Therefore, the aim of this study was to evaluate the effect of omission of surgery on relative and overall survival in older patients with operable breast cancer. Methods Patients aged 80 years or older diagnosed with stage I–II hormone receptor‐positive breast cancer between 2003 and 2009 were selected from the Netherlands Cancer Registry. An instrumental variable approach was applied to minimize confounding, using hospital variation in rate of primary surgery. Relative and overall survival was compared between patients treated in hospitals with different rates of surgery. Results Overall, 6464 patients were included. Relative survival was lower for patients treated in hospitals with lower compared with higher surgical rates (90·2 versus 92·4 per cent respectively after 5 years; 71·6 versus 88·2 per cent after 10 years). The relative excess risk for patients treated in hospitals with lower surgical rates was 2·00 (95 per cent c.i. 1·17 to 3·40). Overall survival rates were also lower among patients treated in hospitals with lower compared with higher surgical rates (48·3 versus 51·3 per cent after 5 years; 15·0 versus 19·7 per cent after 10 years respectively; adjusted hazard ratio 1·07, 95 per cent c.i. 1·00 to 1·14). Conclusion Omission of surgery is associated with worse relative and overall survival in patients aged 80 years or more with stage I–II hormone receptor‐positive breast cancer. Future research should focus on the effect on quality of life and physical functioning., Although the selection criteria for omission of surgery in early‐stage breast cancer are ill defined in guidelines, the percentage of patients receiving surgical treatment declines in older age groups. This study evaluated the effect of omission of surgery on survival in patients aged 80 years and older. Omission of surgery was associated with worse relative and overall survival, but no effect was observed in the first 5 years. Surgery superior

Summary Background Current prediction tools for breast cancer outcomes are not tailored to the older patient, in whom competing risk strongly influences treatment effects. We aimed to develop and validate a prediction tool for 5-year recurrence, overall mortality, and other-cause mortality for older patients (aged ≥65 years) with early invasive breast cancer and to estimate individualised expected benefits of adjuvant systemic treatment. Methods We selected surgically treated patients with early invasive breast cancer (stage I–III) aged 65 years or older from the population-based FOCUS cohort in the Netherlands. We developed prediction models for 5-year recurrence, overall mortality, and other-cause mortality using cause-specific Cox proportional hazard models. External validation was performed in a Dutch Cancer registry cohort. Performance was evaluated with discrimination accuracy and calibration plots. Findings We included 2744 female patients in the development cohort and 13631 female patients in the validation cohort. Median age was 74·8 years (range 65–98) in the development cohort and 76·0 years (70–101) in the validation cohort. 5-year follow-up was complete for more than 99% of all patients. We observed 343 and 1462 recurrences, and 831 and 3594 deaths, of which 586 and 2565 were without recurrence, in the development and validation cohort, respectively. The area under the receiver-operating-characteristic curve at 5 years in the external dataset was 0·76 (95% CI 0·75–0·76) for overall mortality, 0·76 (0·76–0·77) for recurrence, and 0·75 (0·74–0·75) for other-cause mortality. Interpretation The PORTRET tool can accurately predict 5-year recurrence, overall mortality, and other-cause mortality in older patients with breast cancer. The tool can support shared decision making, especially since it provides individualised estimated benefits of adjuvant treatment. Funding Dutch Cancer Foundation and ZonMw.

Introduction Previous studies have shown that available tools such as ‘Adjuvant Online!” are not able to accurately predict the prognosis of patients aged 65 years or older with breast cancer. Furthermore, all available tools predict prognosis in terms of recurrence-free survival or overall survival, whilst the risk of other-cause mortality is often high in the older patient with breast cancer. This is highly relevant as it may influence treatment decisions. Patient characteristics such as comorbidity and various geriatric variables have shown to be predictive for these outcomes and could enhance the precision of prognostic tools for this target population. The objective of this study was to develop a prediction tool for recurrence, survival and other-cause mortality for older patients with breast cancer who received locoregional treatment, with incorporation of patient-, tumor- and geriatric variables. The tool additionally predicts expected benefits of systemic treatment. Methods Data from the large population-based FOCUS cohort was used, consisting of consecutive breast cancer patients in the South-Western part of the Netherlands, diagnosed between 1997 and 2004, aged 65 years and older. It contains detailed information on tumor characteristics, treatment, comorbidity and geriatric parameters. We developed a risk prediction model using a Cox proportional hazards regression model for overall survival and cause-specific Cox proportional hazards models for recurrence and other-cause mortality (defined as mortality without recurrence). The included predictors were derived from the PREDICT tool (consisting of age and various tumor variables), since this tool was previously shown to have the best performance in older adults so far. Predictors were complemented with comorbidity and geriatric variables. Discrimination accuracy was evaluated using time-dependent area under the curve (AUC). The potential annual benefit of chemotherapy was calculated assuming a relative risk of chemotherapy on recurrence of 0.7, derived from data from the most recent updates of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Additional benefit of endocrine treatment will be included in further development of the tool. Results A total of 2,744 patients were included for the initial development. For all patients, 5-year follow-up was complete with a high event-rate including 343 recurrences and 831 total deaths of which 586 without recurrence. The strongest predictors for overall survival and non-recurrence mortality were age (HR = 2.14, 95% CI: 1.89 - 2.43 and HR = 2.87, 95% CI: 2.46 - 3.35, respectively) and dementia (HR = 1.52, 95% CI: 1.16 - 1.99 and HR = 1.9, 95% CI: 1.49 - 2.65, respectively), and for recurrence, nodal status (HR = 1.80, 95% CI: 1.45 - 2.24) and tumor grade (HR = 2.96, 95% CI: 1.88 - 4.66). The time-dependent AUC at 5 years for recurrence-specific and other-cause mortality were 0.78 (95% CI: 0.76 - 0.81), and 0.75 (95% CI: 0.72 - 0.78), respectively. The AUC for overall survival was 0.75 (95% CI: 0.72 - 0.78). External validation is currently being performed in a large dataset retrieved from the national cancer registry (N= 13,631). These results will be presented during the symposium. Conclusion We have developed a model for predicting 5-year recurrence, other-cause mortality and overall survival, including expected benefits of adjuvant treatment, for older patients with breast cancer, with a good discrimination performance within a large-population based cohort. To our knowledge, this is the first model specifically designed for the older population, including competing risk as a predicted outcome and with incorporation of geriatric variables. Citation Format: Willeke van der Plas-Krijgsman, Daniele Giardiello, Hein Putter, Ewout W Steyerberg, Esther Bastiaannet, Anne M Stiggelbout, Simon P Mooijaart, Johanneke EA Portielje, Gerrit J Liefers, Nienke A de Glas. The PORTRET-tool: A prediction tool for older patients with breast cancer that predicts recurrence, survival and other-cause mortality [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-08.

Simple SummaryTrials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma. We included 2216 patients aged >= 65 years from the Dutch Melanoma Treatment Registry and described outcomes of immunotherapy. The study showed that responses and severe side effects did not differ from previously reported younger populations and randomized trials, even in the oldest patients and in patients with other diseases. However, patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. We therefore conclude that immunotherapy seems to have similar effects in older patients compared to younger patients, but the impact of less severe toxicity on quality of life should be further studied as older patients are more likely to discontinue treatment.Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged >= 65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade >= 3 toxicity was not associated with age, comorbidities or WHO status. Patients aged >= 75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65-75 and >= 75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently.

The number of older patients with breast cancer has increased due to the aging of the general population. The use of a geriatric assessment in this population has been advocated in many studies and guidelines as it can be used to identify high risk populations for early mortality and toxicity. Additionally, geriatric parameters could predict relevant outcome measures. This systematic review summarizes all available evidence on predictive factors for various outcomes (disease-related and survival, toxicity, and patient-reported outcomes), with a special focus on geriatric parameters and patient-reported outcomes, in older patients with breast cancer. Studies were identified through systematic review of the literature published up to September 1st 2019 in the PubMed database and EMBASe. A total of 173 studies were included. Most studies investigated disease-related and survival outcomes (n = 123, 71%). Toxicity was investigated in 40 studies (23%) and a mere 15% (n = 26) investigated patient-reported outcomes. Various measures that can be derived from a geriatric assessment were predictive for survival endpoints. Furthermore, geriatric parameters were among the most frequently found predictors for toxicity and patient-reported outcomes. In conclusion, this study shows that geriatric parameters can predict survival, toxicity, and patient-reported outcomes in older patients with breast cancer. These findings can be used in daily clinical practice to identify patients at risk of early mortality, high risk of treatment toxicity or poor functional outcome after treatment. A minority of studies used relevant outcome measures for older patients, showing the need for studies that are tailored to the older population.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Objective: To examine implementation and patients' and providers' participation and satisfaction of a newly developed decision support tool (DST) for patients with metastatic colorectal cancer (mCRC) in palliative setting.Methods: Our DST consisted of a consultation sheet and web-based tailored information for mCRC treatment options. We conducted an implementation trajectory in 11 Dutch hospitals and evaluated implementation, participation and satisfaction rates.Results: Implementation rates fluctuated between 3 and 72 handed out (median:23) consultation sheets per hospital with patients' login rates between 36% and 83% (median:57%). The majority of patients (68%) had (intermediate)-high participation scores. The median time spent using the DST was 38 min (IQR:18-56) and was highest for questions concerning patients' perspective (5 min). Seventy-six% of patients were (very) satisfied. The provider DST rating was 7.8 (scale 1-10) and participation ranged between 25 and 100%. Remaining implementation thresholds included providers' treatment preferences, resistance against shared decision-making and (over)confidence in shared decision-making concepts already in use.Conclusion: We implemented a DST with sufficient patient and oncologist satisfaction and high patient participation, but participation differed considerably between hospitals suggesting unequal adoption of our tool.Practice implications: Requirements for structural implementation are to overcome remaining thresholds and increase awareness for additional decision support. (C) 2019 Elsevier B.V. All rights reserved.

Background: As older gastric cancer patients are often excluded from randomized clinical trials, the most appropriate treatment strategy for these patients remains unclear. The current study aimed to gain more insight in treatment strategies and relative survival of older patients with resectable gastric cancer across Europe. Methods: Population-based cohorts from Belgium, Denmark, The Netherlands, Norway, and Sweden were combined. Patients ≥70 years with resectable gastric cancer (cT1-4a, cN0-2, cM0), diagnosed between 2004 and 2014 were included. Resection rates, administration of chemotherapy (irrespective of surgery), and relative survival within a country according to stage were determined. Results: Overall, 6698 patients were included. The percentage of operated patients was highest in Belgium and lowest in Sweden for both stage II (74% versus 56%) and stage III disease (57% versus 25%). For stage III, chemotherapy administration was highest in Belgium (44%) and lowest in Sweden (2%). Three year relative survival for stage I, II, and III disease in Belgium was 67.8% (95% CI:62.8–72.6), 41.2% (95% CI:37.3–45.2), 17.8% (95% CI:12.5–24.0), compared with 56.7% (95% CI:51.5–61.7), 31.3% (95% CI:27.6–35.2), 8.2% (95% CI:4.4–13.4) in Sweden. There were no significant differences in treatment strategies of patients with stage I disease. Conclusion: Substantial treatment differences are observed across North European countries for patients with stages II and III resectable gastric cancer aged 70 years or older. In the present comparison, treatment strategies with a higher proportion of patients undergoing surgery seemed to be associated with higher survival rates for patients with stages II or III disease.

Simple Summary Selecting older patients for adjuvant breast cancer treatments is challenging as its benefits can be diminished by shorter life expectancies. In addition to age, comorbidity increases the risk of dying from other causes than breast cancer. Available prediction tools have either not adjusted for individual comorbidities or have shown inaccurate predictions when a higher number of comorbidities are present. Up to now, an optimal comorbidity score to be used in prediction tools has not been established. Therefore, this study aimed to assess the predictive value of the Charlson comorbidity index for other-cause mortality and to compare these predictions with using a simple comorbidity count. We found that the Charlson index performed similarly as comorbidity count. The use of comorbidity count in the development of new prediction tools for older patients with breast cancer is recommended as its simplicity enhances the tool’s applicability in clinical practice. Abstract Background: Individualized treatment in older patients with breast cancer can be improved by including comorbidity and other-cause mortality in prediction tools, as the other-cause mortality risk strongly increases with age. However, no optimal comorbidity score is established for this purpose. Therefore, this study aimed to compare the predictive value of the Charlson comorbidity index for other-cause mortality with the use of a simple comorbidity count and to assess the impact of frequently occurring comorbidities. Methods: Surgically treated patients with stages I-III breast cancer aged ≥70 years diagnosed between 2003 and 2009 were selected from the Netherlands Cancer Registry. Competing risk analysis was performed to associate 5-year other-cause mortality with the Charlson index, comorbidity count, and specific comorbidities. Discrimination and calibration were assessed. Results: Overall, 7511 patients were included. Twenty-nine percent had no comorbidities, and 59% had a Charlson score of 0. After five years, in 1974, patients had died (26%), of which 1450 patients without a distant recurrence (19%). Besides comorbidities included in the Charlson index, the psychiatric disease was strongly associated with other-cause mortality (sHR 2.44 (95%-CI 1.70–3.50)). The c-statistics of the Charlson index and comorbidity count were similar (0.65 (95%-CI 0.64–0.65) and 0.64 (95%-CI 0.64–0.65)). Conclusions: The predictive value of the Charlson index for 5-year other-cause mortality was similar to using comorbidity count. As it is easier to use in clinical practice, our findings indicate that comorbidity count can aid in improving individualizing treatment in older patients with breast cancer. Future studies should elicit whether geriatric parameters could improve prediction.

ObjectivesWe have developed two questionnaires to assess the shared decision making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.MethodsPhysicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire–physician version. Their patients completed the: iSHAREpatient, 9-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness, and Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.ResultsIn total, 151 treatment decision making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.ConclusionsThe iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.Practice implicationsResults from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice.

A double aging is taking place in Europe and the incidence of pancreatic cancer is highest in the elderly. Although very few elderly patients with pancreatic cancer are receiving chemotherapy, older age and a less favourable performance status are prognostic for poor outcomes in many randomised and non-randomised studies. In elderly patients, physical fitness is being overestimated by performance status alone in comparison with a Comprehensive Geriatric Assessment (CGA). Studies investigating CGA and chemotherapy-treatment specifically in elderly patients with pancreatic cancer are scarce.

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer., Identifying patients that will respond to a particular therapy remains a key challenge in precision oncology. Here, in gastric cancer, the authors show that circulating tumour DNA can predict recurrence, provided that the signal from white blood cells is filtered out.

PURPOSE Most distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

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.

Purpose In the Netherlands, radiotherapy after breast-conserving surgery (BCS) is omitted in up to 30% of patients aged ≥ 75 years. Although omission of radiotherapy is considered an option for older women treated with endocrine treatment, the majority of these patients do not receive systemic treatment following Dutch treatment guidelines. Therefore, the aim of this study was to evaluate the effect of omission of radiotherapy on locoregional recurrence risk in this patient population. Methods Patients aged ≥ 75 years undergone BCS for T1-2N0 breast cancer diagnosed between 2003 and 2009 were selected from the Netherlands Cancer Registry. To minimize confounding by indication, hospital variation was used to assess the impact of radiotherapy-use on locoregional recurrence risk using cox proportional hazards regression. Hazards ratios with 95% confidence interval (CI) were estimated. Results Overall, 2390 patients were included. Of the patients with hormone receptor-positive breast cancer, 39.3% received endocrine treatment. Five-year incidences of locoregional recurrence were 1.9%, 2.8%, and 3.0% in patients treated at hospitals with higher (average radiotherapy-use 96.0%), moderate (88.0%), and lower radiotherapy-use (72.2%) respectively, and nine-year incidences were 2.2%, 3.1%, and 3.2% respectively. Adjusted hazard ratios were 1.46 (95% CI 0.77–2.78) and 1.50 (95% CI 0.79–2.85) for patients treated at hospitals with moderate and lower radiotherapy-use, compared to patient treated at hospitals with higher radiotherapy-use. Conclusions Despite endocrine treatment in only 39.3%, locoregional recurrence risk was low, even in patients treated at hospitals with lower radiotherapy-use. This provides reasonable grounds to consider omission of radiotherapy in patients aged ≥ 75 years with T1-2N0 breast cancer. Electronic supplementary material The online version of this article (10.1007/s10549-019-05412-8) contains supplementary material, which is available to authorized users.

Objective. To provide an overview of treatment strategies for elderly patients with advanced stage epithelial ovarian cancer (EOC) in daily practice, evaluate changes over time and relate this to surgical mortality and survival.Methods. All women diagnosed with advanced stage (FIGO IIB and higher) EOC between 2002 and 2013 were selected from the Netherlands Cancer Registry (n = 10,440) and stratified by age, stage and period of diagnosis. Elderly patients were defined as aged >= 70 years. Time trends in treatment patterns and postoperative mortality were described by age category and tested using multivariable logistic regression. Relative survival was calculated.Results. With advancing age, less patients received ((neo-)adjuvant) treatment. Over time, elderly patients were less often treated (OR 2002-2004 versus 2011-2013: 0.73; 95%CI:0.58-0.92). But if treated, more often standard treatment was provided and 30-day postoperative mortality decreased from 4.5% to 1.9% between 2005 and 2007 and 2011-2013. In all age categories treatment shifted from primary surgery towards primary chemotherapy, in patients aged 70-79 years combination therapy increased (+5%) between 2002 and 2004 and 2011-2013. Five-year relative survival for patients diagnosed in 2008-2010 agedConclusion. Large treatment differences exist between younger and elderly patients. Over time, selection of elderly patients eligible for curative surgical treatment may have improved. More elderly patients were treated with neoadjuvant chemotherapy while less patients underwent surgery and simultaneously postoperative mortality decreased. However, the large and increasing number of elderly patients without treatment and the large survival gap suggests opportunities for further improvements in the care for elderly EOC patients. (C) 2018 Published by Elsevier Inc.

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.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 as65 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.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 (age65 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).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).

Purpose of Review Breast cancer incidence increases with age. In recent years, primary endocrine therapy has been increasingly used as a treatment option for frail elderly women with breast cancer, although surgery is still the guideline-recommended treatment. In this review, we discuss the evidence for primary endocrine therapy versus surgical treatment in older women with early breast cancer. Recent Findings Both randomised controlled trials and recent observational studies showed a favourable progression-free survival but not overall survival for surgery plus adjuvant endocrine therapy versus primary endocrine therapy. Information about quality of life with either treatment strategy is so far lacking. Deciding who is fit for surgery and has sufficiently long life expectation to be at risk of disease progression can be supported by performing an individual geriatric assessment. Summary This review suggests that primary endocrine therapy is a reasonable alternative to primary surgery in frail older women with breast cancer. Future studies should focus on the long-term effects on quality of life and physical functioning.

Despite an aging population and underrepresentation of elderly patients in clinical trials, studies on elderly patients with metastatic pancreatic cancer are scarce. This study investigated the use of chemotherapy and survival in elderly patients with metastatic pancreatic cancer. From the Netherlands Cancer Registry, all 9407 patients diagnosed with primary metastatic pancreatic adenocarcinoma in 2005–2013 were selected to investigate chemotherapy use and overall survival (OS), using Kaplan–Meier and Cox proportional hazard regression analyses. Over time, chemotherapy use increased in all age groups (

Background: Previous studies suggested a relationship between aspirin use and mortality reduction. The mechanism for the effect of aspirin on cancer outcomes remains unclear. The aim of this study was to evaluate aspirin use and survival in patients with gastrointestinal tract cancer. Methods: Patients with gastrointestinal tract cancer diagnosed between 1998 and 2011 were included. The population-based Eindhoven Cancer Registry was linked to drug-dispensing data from the PHARMO Database Network. The association between aspirin use after diagnosis and overall survival was analysed using Cox regression models. Results: In total, 13 715 patients were diagnosed with gastrointestinal cancer. A total of 1008 patients were identified as aspirin users, and 8278 patients were identified as nonusers. The adjusted hazard ratio for aspirin users vs nonusers was 0.52 (95% CI 0.44–0.63). A significant association between aspirin use and survival was observed for patients with oesophageal, hepatobiliary and colorectal cancer. Conclusions: Post-diagnosis use of aspirin in patients with gastrointestinal tract malignancies is associated with increased survival in cancers with different sites of origin and biology. This adds weight to the hypothesis that the anti-cancer effects of aspirin are not tumour-site specific and may be modulated through the tumour micro-environment.

Background The number of older patients with breast cancer is rapidly increasing. A previous study showed that in the Netherlands, between 1990 and 2005, survival of older patients with breast cancer did not improve in contrast to younger patients. In recent years, scientific evidence in the older age group has increased and specific guidelines for older women with breast cancer have been developed. The aim of this study was to assess recent survival outcomes of older patients with breast cancer compared to younger patients. Methods All patients with stage I-IV breast cancer between 2000 and 2017 were included from the Netherlands cancer registry. We assessed changes in treatments over time using logistic regression models. We calculated the changes in relative survival as proxy for breast cancer mortality, stratified by age and stage. Results We included 239,992 patients. Relative survival improved over time for patients in the youngest age-group for all stages. In patients aged 65-75 years, relative survival adjusted for tumour characteristics did not improve in stage I-II but did improve in stage III (RER 0.98, 95% C.I. 0.96-1.00, p = 0.046). Concurrently, was prescribed in an increasing proportion of patients aged 65-75 years (33.6% in 2000 to 52.7, p Conclusions This study shows that over time, the relative survival of patients aged 65-75 years with advanced breast cancer has improved, and concurrently, prescription of systemic treatment increased. These data suggest that older patients with advanced breast cancer do benefit from adjuvant systemic treatment. In order to further improve survival of patients >75 as well, future studies should focus on individualizing treatments based on concomitant comorbidity, geriatric parameters and the risk toxicity of treatments. Legal entity responsible for the study Leiden University Medical Center, Department of Medical Oncology, Geriatric Oncology Research Group. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

The number of older patients with cancer is increasing as a result of the ageing of Western societies. Immune checkpoint inhibitors have improved cancer treatment and are associated with lower rates of treatment-related toxicity compared with chemotherapy in the general population. Nonetheless, immune checkpoint inhibitors have potentially serious immune-related adverse events, which might have a greater impact on older and more vulnerable patients and potentially influence treatment efficacy and quality of life. Previous clinical trials have shown no major increase in immune-related adverse events; however, older patients are underrepresented and relatively healthy in these trials. Observational studies suggest that older and more vulnerable patients may be at a higher risk of immune-related adverse events and early treatment discontinuation. Geriatric assessment could help identify older patients who will benefit from immune checkpoint inhibitors.

Background Studies have demonstrated worse breast cancer-specific mortality with older age, despite an increasing risk of dying from other causes due to comorbidity (competing mortality). However, findings on the association between older age and recurrence risk are inconsistent. The aim of this study was to assess incidences of locoregional and distant recurrence by age, taking competing mortality into account. Materials and methods Patients surgically treated for nonmetastasized breast cancer between 2003 and 2009 were selected from The Netherlands Cancer Registry. Cumulative incidences of recurrence were calculated considering death without distant recurrence as competing event. Fine and Gray analyses were performed to characterize the impact of age (70-74 [reference group], 75-79, and ≥80 years) on recurrence risk. Results A total of 18,419 patients were included. Nine-year cumulative incidences of locoregional recurrence were 2.5%, 3.1%, and 2.9% in patients aged 70-74, 75-79, and ≥80 years, and 9-year cumulative incidences of distant recurrence were 10.9%, 15.9%, and 12.7%, respectively. After adjustment for tumor and treatment characteristics, age was not associated with locoregional recurrence risk. For distant recurrence, patients aged 75-79 years remained at higher risk after adjustment for tumor and treatment characteristics (75-79 years subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.11-1.41; ≥80 years sHR, 1.03; 95% CI, 0.91-1.17). Conclusion Patients aged 75-79 years had a higher risk of distant recurrence than patients aged 70-74 years, despite the higher competing mortality. Individualizing treatment by using prediction tools that include competing mortality could improve outcome for older patients with breast cancer. Implications for practice In this population-based study of 18,419 surgically treated patients aged 70 years or older, patients aged 75-79 years were at higher risk of distant recurrence than were patients aged 70-74 years. This finding suggests that patients in this age category are undertreated. In contrast, it was also demonstrated that the risk of dying without a recurrence strongly increases with age, and patients with a high competing mortality risk are easily overtreated. To identify older patients who may benefit from more treatment, clinicians should therefore take competing mortality risk into account. Prediction tools could facilitate this and thereby improve treatment strategy.

Background The aim was to study the impact of comorbidities and age on breast cancer mortality, taking into account competing causes of death. Subjects, Materials, and Methods Cohort analysis of Dutch and Belgian patients with postmenopausal, early hormone receptor-positive breast cancer included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. This is a randomized controlled trial of patients who had completed local treatment with curative intent and were randomized to receive exemestane for 5 years, or sequential treatment of tamoxifen followed by exemestane for a duration of 5 years. Patients were categorized by number of comorbidities (no comorbidities, 1–2 comorbidities, and >2 comorbidities) and age ( Results Overall, 3,159 patients were included, of which 2,203 (69.7%) were aged 2 comorbidities, p < .001). Conclusion Older patients without comorbidities have a higher risk of dying due to breast cancer than younger counterparts, even when taking into account higher competing mortality, while use of chemotherapy in this group was low. These findings underline the need to take into account comorbidities, age, and competing mortality in the prognosis of breast cancer for accurate decision making.

Background: Decreased cancer specific survival in older colorectal patients is mainly due to mortality in the first year, emphasizing the importance of the first postoperative year. This study aims to gain an overview and time trends of short-term mortality in octogenarians (>= 80 years) with colorectal cancer across four North European countries.Methods: Patients of 80 years or older, operated for colorectal cancer (stage I-Ill) between 2005 and 2014, were included. Population-based cohorts from Belgium, Denmark, the Netherlands, and Sweden were collected. Separately for colon- and rectal cancer, 30-day, 90-day, one-year, and excess one-year mortality were calculated. Also, short-term mortality over three time periods (2005-2008, 2009-2011, 2012-2014) was analyzed.Results: In total, 35,158 colon cancer patients and 10,144 rectal cancer patients were included. For colon cancer, 90-day mortality rate was highest in Denmark (15%) and lowest in Sweden (8%). For rectal cancer, 90-day mortality rate was highest in Belgium (11%) and lowest in Sweden (7%). One-year excess mortality rate of colon cancer patients decreased from 2005 to 2008 to 2012-2014 for all countries (Belgium: 17%-11%, Denmark: 21%-15%, the Netherlands: 18%-10%, and Sweden: 10%-8%). For rectal cancer, from 2005 to 2008 to 2012-2014 one-year excess mortality rate decreased in the Netherlands from 16% to 7% and Sweden: 8%-2%).Conclusions: Short-term mortality rates were high in octogenarians operated for colorectal cancer. Short-term mortality rates differ across four North European countries, but decreased over time for both colon and rectal cancer patients in all countries. (C) 2019 Published by Elsevier Ltd.

Purpose In breast cancer, hormone receptor (HR) status is generally a qualitative measure; positive or negative. Quantitatively measured oestrogen and progesterone receptors (ER and PR) are frequently proposed prognostic and predictive markers, some guidelines even provide different treatment options for patients with strong versus weak expression. Aim To evaluate quantitative HR load assessed by immunohistochemistry as a prognostic and predictive measure in stage 1–3 breast cancer. Methods We reviewed all the available literature on quantitatively measured HRs using immunohistochemistry. Results All included studies (n = 19) comprised a cohort of 30,754 patients. Only 2 out of 17 studies found a clear correlation between higher quantitative ER and better disease outcome. Only one trial examined quantitative ER both as prognostic and predictive marker and found no association between ER% and survival. Ten studies examined quantitative PR load, only two of those found a significant correlation between higher PR load and better disease outcome. Two trials examined quantitative PR both as prognostic and predictive marker, neither found any association between PR% and disease outcome. Conclusions There is no clear evidence for using quantitatively assessed ER and PR as prognostic nor predictive marker in patients with stage 1–3 breast cancer. We recommend only using a qualitative HR status in future guidelines and treatment considerations. Electronic supplementary material The online version of this article (10.1007/s10549-019-05233-9) contains supplementary material, which is available to authorized users.

Background: Effective patient-provider communication is an important condition to deliver optimal care and it supports patients in coping with their disease. The complex and emotionally loaded setting of oncology care challenges both health care providers (HCPs) and patients in reaching effective communication. ListeningTime is developed for elderly patients with cancer and their oncological HCPs to help them (better) prepare the clinical encounter and overcome communication barriers. ListeningTime is a Web-based preparatory communication tool including modeling videos and has an audio-facility to listen back to recorded encounters. Objective: This study aims to evaluate the usability, perceived usefulness, and actual use of ListeningTime, through the eyes of elderly patients with cancer and their oncological HCPs. If highly rated, the ultimate goal is to make ListeningTime publicly available. Methods: First, members of a panel of elderly cancer survivors and patients (age ≥65 years) were approached to evaluate ListeningTime through a Web-based questionnaire. The usability and perceived usefulness were assessed. Second, ListeningTime was evaluated in real-life practice through a pilot study in 3 Dutch hospitals. In these hospitals, elderly patients with cancer and their oncological HCPs were approached to evaluate ListeningTime through a similar Web-based questionnaire, measuring the perceived usefulness. In addition, we examined log files and user statistics to get insight into how the program was used. Results: A total of 30 cancer survivors or patients from the patient panel, and 17 patients and 8 HCPs from the hospitals, evaluated ListeningTime. Overall, both panel members and hospital patients were positive about the ListeningTime website, audio-facility, and video fragments. Some patients suggested improvements with respect to the actors’ performances in the video fragments and believed that ListeningTime is mainly suitable for non experienced patients. HCPs were also positive about ListeningTime; they valued the video fragments for patients and the audio-facility for patients and themselves. However, providers did not relisten their own recorded encounters. Patients did use the audio-facility to relisten their encounters. Conclusions: ListeningTime was highly rated, both by patients and their oncological HCPs. As a result, the video fragments of ListeningTime are now made publicly available for elderly patients with cancer through the Dutch website “kanker.nl.”

ObjectiveMany treatment decisions are preference-sensitive and call for shared decision-making, notably when benefits are limited or uncertain, and harms impact quality of life. We explored if clinical practice guidelines (CPGs) acknowledge preference-sensitive decisions in how they motivate and phrase their recommendations.DesignWe performed a qualitative analysis of the content of CPGs and verified the results in semistructured interviews with CPG panel members.SettingDutch oncology CPGs issued in 2010 or later, concerning primary treatment with curative intent.Participants14 CPG panel members.Main outcomesFor treatment recommendations from six CPG modules, two researchers extracted the following: strength of recommendation in terms of the Grading of Recommendations Assessment, Development and Evaluation and its consistency with the CPG text; completeness of presentation of benefits and harms; incorporation of patient preferences; statements on the panel’s benefits–harm trade-off underlying recommendation; and advice on patient involvement in decision-making.ResultsWe identified 32 recommendations, 18 were acknowledged preference-sensitive decisions. Three of 14 strong recommendations should have been weak based on the module text. The reporting of benefits and harms, and their probabilities, was sufficiently complete and clear to inform the strength of the recommendation in one of the six modules only. Numerical probabilities were seldom presented. None of the modules presented information on patient preferences. CPG panel’s preferences were not made explicit, but appeared to have impacted 15 of 32 recommendations. Advice to involve patients and their preferences in decision-making was given for 20 recommendations (14 weak). Interviewees confirmed these findings. Explanations for lack of information were, for example, that clinicians know the information and that CPGs must be short. Explanations for trade-offs made were cultural-historical preferences, compliance with daily care, presumed role of CPGs and lack of time.ConclusionsThe motivation and phrasing of CPG recommendations do not stimulate choice awareness and a neutral presentation of options, thus hindering shared decision-making.

Background Predicting breast cancer recurrence in patients aged ≥70 years is challenging, as they generally have more indolent tumors and a higher chance of dying of competing causes than younger patients. The 70-gene signature test (MammaPrint) has been shown to accurately predict recurrence in women with early breast cancer and up to 3 positive lymph nodes. Aim To study outcome related to MammaPrint result in patients aged ≥70 years with breast cancer using a population-based cohort. Methods The population-based FOCUS cohort included all 2095 consecutive patients with any stage breast cancer, diagnosed between 1997 and 2004, aged ≥65 years, in the Comprehensive Cancer Center region West, the Netherlands. In the present exploratory sub-study, patients from FOCUS with the following criteria were included: ≥70 years old, T1-2N0-3M0, hormone receptor positive, HER2 negative, no neo-adjuvant treatment and available tumor specimens. MammaPrint is a genomic risk profile based on microarray gene expression analysis, classifying patients as ultralow risk (M-ULR), low (not UL) risk (M-LR) or high risk (M-HR) of developing a recurrence. Patients were considered clinically low risk (C-LR) with T1-2N0 grade 1-2 tumors and clinically high risk (C-HR) with N+ or T2/grade 3 tumors. Primary endpoint was 10-year distant recurrence free interval (DRFi) in relation to genomic risk, estimated from cumulative incidence and Fine and Gray analyses to take competing mortality into account. Results In this study, 422 patients were included. Median age was 78 years, 238 patients (56%) had node negative disease, 235 patients (56%) had T2 tumors and 227 patients (54%) were C-LR. Most patients were treated with endocrine therapy (ET), and 22 patients (5%) were treated with chemotherapy (CT; table 1). Overall, 50 (12%) patients were M-ULR, 226 (53%) were M-LR and 146 (35%) were M-HR. Discrepancies were found between C and M risk groups in 18/50 M-ULR patients with C-HR, and 56/146 M-HR patients with C-LR. Of the 59 patients that experienced a recurrence during 10 years of follow-up, 44 (75%) were distant recurrences. In the M-ULR group, DRFi was 2% (95%CI 0-6) after 10 years of follow-up, this was 8% (95%CI 5-12) in the M-LR group and 17% (95%CI 11-23) in the M-HR group (p Table 1: Baseline characteristics. BCS = breast conserving surgery. RT = radiotherapyM-ULRM-LRM-HRTotal patientsN (%)50 (11.8)226 (53.6)146 (34.6)AgeMedian (IQR)79 (74-85)79 (74-84)77 (74-84)Histological grade [N (%)]I11 (22.0)39 (17.3)5 (3.4)II21 (42.0)92 (40.7)42 (28.8)III1 (2.0)31 (13.7)54 (37.0)Missing17 (34.0)64 (28.3)45 (30.8)T-stage [N (%)]Tis0 (0.0)2 (0.9)0 (0.0)T117 (34.0)111 (49.1)54 (37.0)T233 (66.0)113 (50.0)89 (61.0)Missing0 (0.0)0 (0.0)3 (2.0)N-stage [N (%)]N032 (64.0)140 (61.9)66 (45.2)N117 (34.0)72 (31.9)67 (45.9)N20 (0.0)6 (2.7)6 (4.1)N30 (0.0)2 (0.9)3 (2.1)Missing1 (2.0)6 (2.7)4 (2.7)Clinical risk [N (%)]Low32 (64.0)139 (61.5)56 (38.4)High18 (36.0)87 (38.5)90 (61.6)Local treatment [N (%)]None4 (8.0)5 (2.2)6 (4.1)BCS only3 (6.0)16 (7.1)13 (8.9)BCS + RT9 (18.0)62 (27.4)29 (19.9)Mastectomy34 (68.0)143 (63.3)98 (67.1)Adjuvant ET [N (%)]None24 (48.0)103 (45.6)40 (27.4)Tamoxifen17 (34.0)87 (38.5)80 (54.8)Aromatase inhibitor3 (6.0)11 (4.9)9 (6.2)Unspecified ET6 (12.0)25 (11.1)17 (11.6)Adjuvant CT [N (%)]No46 (92.0)217 (96.0)137 (93.8)Yes4 (8.0)9 (4.0)9 (6.2) Table 2: Primary endpoint stratified by genomic and clinical risk. sHR=subdistribution hazard ratio.M-ULRM-LRM-HRTotalC-LRN=32 (14%). DRFi=3% (95%CI 0-9). sHR=1 (reference).N=139 (61%). DRFi=7% (95%CI 3-12). sHR=2.1 (95%CI 0.3-16.5).N=56 (25%). DRFi=13% (95%CI 4-21). sHR=4.3 (95%CI 0.5-34.7).N=227. DRFi=8% (95%CI 4-12).C-HRN=18 (9%).DRFi=0% (95%CI 0-0). sHR=N/A (n events=0).N=87 (45%). DRFi=10% (95%CI 3-16). sHR=1 (reference).N=90 (46%). DRFi=20% (95%CI 12-28). sHR=3.0 (95%CI 1.3-6.9).N=195. DRFi=14% (95%CI 9-19).TotalN=50 (12%). DRFi=2% (95%CI 0-6). sHR=1 (reference).N=226 (53%). DRFi=8% (95%CI 5-12). sHR=3.8 (95%CI 0.5-28.2).N=146 (35%). DRFi=17% (95%CI 11-23). sHR=9.8 (95%CI 1.3-72.6).N=422. Citation Format: Iris Noordhoek, Esther Bastiaannet, Ersan Lujinovic, Laura Esserman, Jelle Wesseling, Astrid Scholten, Carolien P Schröder, Sjoerd Elias, Nienke A de Glas, Judith R Kroep, Johanneke EA Portielje, Miranda Kleijn, Gerrit-Jan J Liefers. The 70-gene signature (MammaPrint) accurately predicts distant breast cancer recurrence risk in patients aged ≥70 years from the population-based observational FOCUS cohort [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-06.

textabstractBACKGROUND: To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). RESULTS: Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. CONCLUSIONS: Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration.

Objective: Clinical trials investigating breast cancer treatment often exclude or misrepresent older adults. This study compares treatment patterns and survival of older women diagnosed with breast cancer between a Dutch and a British observational cohort.\ud Materials and Methods: Women aged 70 years and older diagnosed with breast cancer after 1990 with a T0-T2 tumor stage and no evidence of metastatic disease were included from a population-based cohort in the Netherlands and a British hospital-based cohort in Nottingham. Main outcomes were proportions of local and systemic treatment, ten-year overall survival and ten-year relative survival for each cohort.\ud Results: 1439 patients from Nottingham and 2180 patients from the Netherlands were included. Median follow-up was 12.4 years (IQR 11.0–14.0) in the FOCUS cohort and 6.4 years (IQR 6.2–6.8) in the Nottingham cohort. British patients were more likely to receive primary endocrine therapy (50.0% vs 7.5%, P