Narrative Review of Multidisciplinary Management of Central Nervous Involvement in Patients with HER2-Positive Metastatic Breast Cancer: Focus on Elderly Patients.

The tumor biology of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) promotes the development of central nervous system (CNS) metastases, with 25% of patients with HER2-positive BC developing CNS metastases. Furthermore, the incidence of HER2-positive BC brain metastases has increased in the last decades, likely because of the improved survival with targeted therapies and better detection methods. Brain metastases are detrimental to quality of life and survival and represent a challenging clinical problem, particularly in elderly women, who comprise a substantial proportion of patients diagnosed with BC and often have comorbidities or an age-related decline in organ function. Treatment options for patients with BC brain metastases include surgical resection, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy, and targeted agents. Ideally, local and systemic treatment decisions should be made by a multidisciplinary team, with input from several specialties, based on an individualized prognostic classification. In elderly patients with BC, additional age-associated conditions, such as geriatric syndromes or comorbidities, and the physiologic changes associated with aging, may impact their ability to tolerate cancer therapy and should be considered in the treatment decision-making process. This review describes the treatment options for elderly patients with HER2-positive BC and brain metastases, focusing on the importance of multidisciplinary management, the different points of view from the distinct disciplines, and the role of oncogeriatric and palliative care in this vulnerable patient group.

Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2- advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial.

BACKGROUND: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) vs. ET alone. METHODS: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2- ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1. RESULTS: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study. CONCLUSIONS: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2- ABC, including populations of interest (NCT02941926). TRIAL REGISTRATION: ClinicalTrials.gov NCT02941926.

The economic burden of metastatic breast cancer in Spain.

Objectives: The study aimed to estimate the burden of metastatic breast cancer (mBC) in Spain over 5 years. Methods: An incidence-based cost-of-illness model was developed in which a cohort of patients with mBC was followed from the diagnosis of metastatic disease over 5 years or death. Resource use data were collected through a physician survey conducted with 10 clinical experts in Spain. The model distinguished patients according to HER2 and hormonal receptor (HR) status, and followed the patient cohort in monthly cycles. Results: The incident cohort was estimated to be 2,923 patients with mBC, consisting of 1,575 HER2-/HR+, 520 HER2+/HR+, 324 HER2+/HR-, and 503 triple negative patients. The estimated mean survival over the 5-year time period was 2.51 years, on average, with longer survival of 3.36 years for HER2+/HR+, 2.41 years for HER2-/HR+, 2.82 years for HER2+/HR- and shortest mean survival of 1.74 years for triple negative patients. The total costs were €469,92,731 for the overall population, €190,079,787 for the HER2-/HR+, €151,045,260 for the HER2+/HR+, €80,827,171 for the HER2+/HR- and €47,540,512 for the triple negative subgroups over 5 years. Per patient total costs were €160,642 on average, €120,664 for HER2-/HR+, €290,346 for HER2+/HR+, €249,152 for HER2+/HR-and €94,572 for triple negative patients over 5 years. Conclusions: The economic burden of mBC in Spain is significant, but differs by HER2 and HR status. HER2-/HR +patients account for the highest burden due to the prevalence of this category, but HER2+/HR +patients have the highest per patient costs.

Probabilistic cost-utility analysis and expected value of perfect information for the Oncotype multigenic test: a discrete event simulation model / Análisis de coste-utilidad probabilístico y valor esperado de la información perfecta para el test multigénico Oncotype: un modelo de simulación de eventos discretos

OBJECTIVE: To carry out a cost-utility analysis of the application of the Oncotype genomic test to inform the decision to use or not to use chemotherapy in the Basque Country (Spain). METHOD: The cost-utility study was carried out using a discrete event simulation model representing the natural history of breast cancer. The decision of treatment with chemotherapy based on Oncotype was compared with the standard of treatment based on clinical-pathological criteria. The model included clinical data from Basque hospitals and the literature and was processed by deterministic and probabilistic analysis to calculate the incremental cost-effectiveness ratio (ICER), the cost-effectiveness plane, the acceptability curve and the expected value of perfect information. The study adopted both a health and societal perspective. RESULTS: From a health perspective, the deterministic analysis estimated an ICER for Oncotype of 17,453 euros/quality-adjusted life year (QALY), discount included, and 9,613 euros/QALY without the discount. Eighty five percent (85%) of the simulations were below the efficiency threshold for Spain. The parametric variability associated with the Oncotype results was the main uncertainty factor in the decision. CONCLUSIONS: Oncotype is a cost-effective intervention from a health system perspective since each QALY gained costs less than 25,000 euros. From a societal perspective, it is dominant since it provides greater health and is accompanied by cost savings

OBJETIVO: Llevar a cabo un análisis de coste-utilidad del uso del test genómico Oncotype en el País Vasco (España) para informar la decisión de uso de quimioterapia. MÉTODO: El estudio de coste-utilidad se realizó mediante un modelo de simulación de eventos discretos que representó la evolución natural del cáncer de mama. La decisión de tratamiento con quimioterapia basada en Oncotype se comparó con el estándar de tratamiento basado en criterios clínico-patológicos. El modelo incluyó datos clínicos de hospitales vascos y la literatura para calcular la ratio de coste-efectividad incremental (RCEI) mediante análisis determinista y probabilístico, el plano coste-efectividad, la curva de aceptabilidad y el valor esperado de la información perfecta. El estudio adoptó una perspectiva tanto sanitaria como social. RESULTADOS: El análisis determinista estimó una RCEI para Oncotype de 17.453 euros/año de vida ajustado por calidad (AVAC) con descuento y 9613 euros euros/AVAC sin descuento, desde la perspectiva sanitaria. El 85% de las simulaciones estuvieron por debajo el umbral de aceptabilidad para España. La variabilidad paramétrica asociada a los resultados de Oncotype fue el mayor factor de incertidumbre de la decisión. CONCLUSIONES: Oncotype constituye una intervención coste-efectiva, ya que cada AVAC ganado tiene asociado un coste inferior a 25.000 euros. El test es dominante desde una perspectiva social al lograr mayor salud acompañada de ahorros

Probabilistic cost-utility analysis and expected value of perfect information for the Oncotype multigenic test: a discrete event simulation model.

OBJECTIVE: To carry out a cost-utility analysis of the application of the Oncotype genomic test to inform the decision to use or not to use chemotherapy in the Basque Country (Spain). METHOD: The cost-utility study was carried out using a discrete event simulation model representing the natural history of breast cancer. The decision of treatment with chemotherapy based on Oncotype was compared with the standard of treatment based on clinical-pathological criteria. The model included clinical data from Basque hospitals and the literature and was processed by deterministic and probabilistic analysis to calculate the incremental cost-effectiveness ratio (ICER), the cost-effectiveness plane, the acceptability curve and the expected value of perfect information. The study adopted both a health and societal perspective. RESULTS: From a health perspective, the deterministic analysis estimated an ICER for Oncotype of 17,453 euros/quality-adjusted life year (QALY), discount included, and 9,613 euros/QALY without the discount. Eighty five percent (85%) of the simulations were below the efficiency threshold for Spain. The parametric variability associated with the Oncotype results was the main uncertainty factor in the decision. CONCLUSIONS: Oncotype is a cost-effective intervention from a health system perspective since each QALY gained costs less than 25,000 euros. From a societal perspective, it is dominant since it provides greater health and is accompanied by cost savings.

Cost-effectiveness analysis of ribociclib versus palbociclib in the first-line treatment of HR+/HER2- advanced or metastatic breast cancer in Spain.

PURPOSE: The aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS). PATIENTS AND METHODS: Disease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations). RESULTS: This cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness. CONCLUSION: From the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.

Clinical and economic impact of the 21-gene recurrence score assay in adjuvant therapy decision making in patients with early-stage breast cancer: pooled analysis in 4 Basque Country university hospitals.

PURPOSE: The 21-gene recurrence score (RS) is a genomic test developed as a prognostic and predictive tool to improve the treatment decision making in cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer. This study examined the clinical and economic impact of its use in 4 Basque Country university hospitals. METHODS: Taking into consideration the RS result, we recorded the recommended initial systemic adjuvant therapy (endocrine therapy with or without chemotherapy) according to standard clinicopathologic factors and the final decision about chemotherapy. Then, if the RS was high, chemotherapy was recommended; it was not recommended if the RS was low; for those with an intermediate RS, clinicopathologic factors were considered, and the initial recommendation based on those factors was maintained. In addition, the probability of switching treatment was calculated. Then, we developed an economic evaluation by measuring the treatment's incremental short-term budget impact from both the societal perspective and that of the Basque Health System. Patients' characteristics and chemotherapy use were analyzed using logistic regressions and receiver operating characteristic curves. RESULTS: Without an RS, chemotherapy would have been prescribed to 56% of 401 patients, but, with RS use, that percentage decreased to 25. The overall rate of decision change was 35.4%. Test inclusion led to a reduction in chemotherapy costs of €922 per patient in the total population. Although this reduction did not entirely offset the cost of the test, the productivity loss per patient was reduced by €1,977. CONCLUSION: The 21-gene RS test significantly changed the indication for chemotherapy. As chemotherapy treatments with no benefit were avoided, patients' quality of life was improved. The short-term economic impact was negative for the Basque Health Service, but savings resulted when sick-leave costs were included.