Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.

BACKGROUND: Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only. CASE: Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly. CONCLUSION: The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.

Cost-effectiveness comparison of dalpiciclib and abemaciclib combined with an aromatase inhibitor as first-line treatment for HR+/HER2- advanced breast cancer.

OBJECTIVES: CDK4/6 inhibitors dalpiciclib and abemaciclib have been approved by the Chinese National Medical Products Administration as first-line treatment for postmenopausal females with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). We aimed to assess the cost-effectiveness of dalpiciclib plus letrozole/anastrozole (non-steroidal aromatase inhibitor [NSAI]) compared with abemaciclib plus NSAI as a first-line treatment for HR+/HER2- ABC in China. METHODS: We constructed a Markov model with three health states to evaluate health and economic outcomes of first-line treatment with dalpiciclib plus NSAI and abemaciclib plus NSAI for HR+/HER2- ABC. Efficacy data was obtained from MONARCH3 and DAWNA-2 trials. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Compared with abemaciclib plus NSAI, dalpiciclib plus NSAI resulted in 4.27 additional QALYs, with an ICER of $14827.4/QALY. At a willingness-to-pay threshold of 3 times gross domestic product per capita in China for 2023 ($37721.5/QALY), the cost-effectiveness probability of dalpiciclib plus NSAI was 77.42%. CONCLUSIONS: From the perspective of Chinese payers, dalpiciclib plus NSAI appears to be a cost-effective strategy compared with abemaciclib plus NSAI for the first-line treatment of patients with HR+/HER2- ABC in China. CLINICAL TRIAL REGISTRATION: MONARCH3, www.clinicaltrials.gov, identifier is NCT02246621 and DAWNA-2, www.clinicaltrials.gov, identifier is NCT03966898.

Estrogen deprivation effects of endocrine therapy in breast cancer patients: Incidence, management and outcome.

Endocrine therapy is one of the standard adjuvant treatments to reduce the risk of recurrence and mortality in patients with hormone receptor positive early breast cancer. Despite its proven efficacy, ET side effects, which persist over time even if low grade, may deteriorate quality of life. During follow-up visits, emphasis is generally placed on the risk of disease recurrence, while the topic of ET side effects is commonly neglected and discussed only briefly. This could lead to poor adherence to therapy and early treatment discontinuation, resulting in worse survival outcomes. The aim of this review is to provide an overview of the available evidence on the incidence and reporting of ET-related side effects (including vasomotor symptoms, musculoskeletal disorders and genitourinary syndrome of menopause, as well as fatigue, psychological and ocular disorders, dysmetabolic effects and loss of bone density) and of the pharmacological and non-pharmacological strategies available to mitigate symptom burden.

Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice.

BACKGROUND: New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) privileges real-world data. As part of the ongoing HTA, this study aimed to evaluate the effectiveness of palbociclib with aromatase inhibitors (AI) and compare it with the efficacy reported in PALOMA-2. METHODS: A population-based retrospective exposure cohort study was conducted including all patients initiating treatment in Portugal with palbociclib under early access use and registered in the National Oncology Registry. The primary outcome was progression free survival (PFS). Secondary outcomes considered included time to palbociclib failure (TPF), overall survival (OS), time to next treatment (TTNT), and proportion of patients discontinuing treatment due to  adverse events (AEs). The Kaplan-Meier method was used and median, 1- and 2-year survival rates were computed, with two-sided 95% confidence intervals (95%CI). STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were used. RESULTS: There were 131 patients included. Median follow-up was 28.3 months (IQR: 22.7-35.2) and median duration of treatment was 17.5 months (IQR: 7.8-29.1). Median PFS was 19.5 months (95%CI 14.2-24.2), corresponding to a 1-year PFS rate of 67.9% (95%CI 59.2-75.2) and a 2-year PFS rate of 42.0% (95%CI 33.5-50.3). Sensitivity analysis showed median PFS would increase slightly when excluding those not initiating treatment with the recommended dose, raising to 19.8 months (95%CI 14.4-28.9). By considering only patients meeting PALOMA-2 criteria, we could observe a major difference in treatment outcomes, with a mean PFS of 28.8 months (95%CI 19.4-36.0). TPF was 19.8 months (95%CI 14.2-24.9). Median OS was not reached. Median TTNT was 22.5 months (95%CI 18.0-29.8). A total of 14 patients discontinued palbociclib because of AEs (10.7%). CONCLUSIONS: Data suggest palbociclib with AI to have an effectiveness of 28.8 months, when used in patients with overlapping characteristics to those used in PALOMA-2. However, when used outside of these eligibility criteria, namely in patients with less favorable prognosis (e.g., presence of visceral disease), the benefits are inferior, even though still favorable.

Systematic review of economic evaluations of aromatase inhibitors in estrogen receptor-positive breast cancer: quality evaluation.

BACKGROUND: Breast cancer (BC) is a leading cause of premature death in women and the most expensive malignancy to treat. Since the introduction of targeted therapies has resulted in changes to BC therapy practices, health economic evaluations have become more important in this area. Taking generic medications, Aromatase Inhibitors (AIs), as a case study, we conducted a systematic review of the recent economic evaluations of AIs for estrogen receptor-positive breast cancer patients and evaluated the quality of these health economic studies. OBJECTIVE: To systematically review and examine the quality of the available economic studies of AIs in estrogen receptor-positive breast cancer. METHODS: A literature search was performed using six relevant databases (MEDLINE, Embase, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, NHS Economic Evaluation Database, and SCOPUS) from January 2010 to July 2021. All economic studies were independently assessed by two reviewers using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist to evaluate the quality of the economic evaluations. This systematic review is registered in the PROSPERO database. To compare the different currencies used in these studies, all costs were converted to international dollars (2021). RESULTS: A total of eight studies were included in the review; six (75%) were performed from the healthcare providers' perspective. They were conducted in seven different countries, and all were model-based analyses using Markov models. Six (75%) considered both Quality Adjusted Life Years (QALYs) and Life Years (LY) outcomes, and all costs were derived from national databases. When compared to tamoxifen, AIs were generally cost-effective in postmenopausal women. Only half of the studies addressed the increased mortality following adverse events, and none mentioned medication adherence. For the quality assessment, six studies fulfilled 85% of the CHEERS checklist requirements and are deemed good quality. CONCLUSION: AIs are generally considered cost-effective compared to tamoxifen in estrogen receptor-positive breast cancer. The overall quality of the included studies was between high and average but characterizing heterogeneity, and distributional effects should be considered in any future economic evaluation studies of AIs. Studies should include adherence and adverse effects profiles to provide evidence to facilitate decision-making among policymakers.

PRECYCLE: multicenter, randomized phase IV intergroup trial to evaluate the impact of eHealth-based patient-reported outcome (PRO) assessment on quality of life in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant.

BACKGROUND: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 -) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients' satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction. METHODS: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 - MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). DISCUSSION: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = "Deterioration of quality of life" (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22.

Adjuvant zoledronic acid therapy for postmenopausal women with early breast cancer in China: a cost-effectiveness analysis.

Combination therapy of zoledronic acid (ZOL) plus aromatase inhibitor (AI) was found to reduce bone metastasis risk and improve overall survival for treatment-naïve postmenopausal women (PMW) with hormone receptor-positive (HR+) early breast cancer (EBC), when compared with AI alone. The objective of this study was to evaluate the cost-effectiveness of adding ZOL to AI in treating PMW with HR+ EBC in China. A 5-state Markov model was constructed to evaluate the cost-effectiveness of adding ZOL to AI for PMW-EBC (HR+) over a lifetime horizon from the perspective of Chinese healthcare provider. Data used were obtained from previous reports and public data. The primary outcomes of this study were direct medical cost, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed to examine the robustness of the presented model. Over a lifetime horizon, adding ZOL to AI was projected to yield a gain of 1.286 LYs and 1.099 QALYs compared with AI monotherapy, which yielded ICER $11 140.75 per QALY with an incremental cost of $12 247.36. The one-way sensitivity analysis indicated that the cost of ZOL was the most influential factor in our study. The probability that adding ZOL to AI was cost-effective at a threshold of $30 425 per QALY in China was 91.1%. ZOL is likely to be cost-effective in reducing bone metastasis risk and improving overall survival for PMW-EBC (HR+) in China.

Adherence to Adjuvant Endocrine Therapy and Survival Among Older Women with Early-Stage Hormone Receptor-Positive Breast Cancer.

BACKGROUND AND OBJECTIVE: Although improving adherence to adjuvant endocrine therapies (AETs) is critical to ensure better patient outcomes, the evidence is still lacking on differences in 5-year AET adherence trajectories. This study aimed to estimate the time trend of adherence by the type of individual AET and the association of adherence to AETs with overall survival among older women with hormone receptor-positive breast cancer. METHODS: This study used the Surveillance, Epidemiology, and End Results-Medicare database 2006-2016. We included women aged ≥ 65 years with newly diagnosed hormone receptor-positive breast cancer and who had initiated AET (anastrozole, letrozole, exemestane, or tamoxifen). Adherence to AETs was defined as the proportion of days covered that was calculated for the follow-up period (5 years). The overall survival time was defined as the time from the date of AET initiation to death. The linear mixed models with repeated measures were used to estimate the changes in adherence to AETs. The Cox proportional hazard model was used to assess the relationships (hazard ratio [HR] and 95% confidence interval [CI]) between adherence to AETs and death. RESULTS: A total of 11,617 patients were included. Anastrozole was the most commonly used (n = 6,908), followed by letrozole (n = 2,586), tamoxifen (n = 1,750), and exemestane (n = 373). The mean (standard deviation) of proportion of days covered for 5 years was 57.4 (34.6), indicating the highest proportion of days covered in the anastrozole group [61.1 (34.1)] and the lowest proportion of days covered in the exemestane group [44.0 (35.1)]. Overall, adherence to AET decreased over the 5-year follow-up period in all AET groups, but the decrease in the tamoxifen group was steeper (42.3% decreased) compared with other AETs. Anastrozole, letrozole, and exemestane groups were associated with a lower risk of death compared with the tamoxifen group (HR = 0.80, 95% CI 0.71-0.89 for anastrozole; HR = 0.82, 95% CI 0.72-0.93 for letrozole; HR = 0.82, 95% CI 0.63-1.07 for exemestane). CONCLUSIONS: Patients who initiated with tamoxifen had a steeper decrease in adherence over the 5 years compared with anastrozole, letrozole, and exemestane groups. Furthermore, higher adherence was associated with a decreased risk of mortality. Physicians should be cognizant of decreasing adherence over time and choose effective treatment options with minimal side-effect profiles to better support adherence by patients with breast cancer.

Cost-effectiveness of ribociclib versus palbociclib in combination with an aromatase inhibitor as first-line treatment of postmenopausal women with HR+/HER2- advanced breast cancer: analysis based on final OS results of MONALEESA-2 and PALOMA-2.

BACKGROUND AND AIMS: Combination of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and an aromatase inhibitor is the standard of care first-line (1L) treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Updated clinical data have become available from the MONALEESA-2 and PALOMA-2 trials for ribociclib and palbociclib, respectively. This analysis with updated data assessed the cost-effectiveness of ribociclib versus palbociclib, both in combination with letrozole, in the setting of 1L therapy of postmenopausal women with HR+/HER2- ABC, from a United Kingdom (UK) National Health Service perspective. METHODS: A three state (progression-free, progressed disease, and death) partitioned survival model with a 1-month cycle was developed. Clinical data were derived from MONALEESA-2 (NCT01958021) and PALOMA-2 (NCT01740427). The treatment effect was modeled using hazard ratios (HRs) for progression-free survival and overall survival derived through a matched-adjusted indirect comparison. Trial data and published literature were used to derive utility values. Cost inputs included drug acquisition, disease monitoring, subsequent therapies, and adverse events. Costs and outcomes were discounted by 3.5%, over a 40-year lifetime horizon. One-way and probabilistic sensitivity analyses were performed. RESULTS: Ribociclib dominated palbociclib, and was both overall cost saving (-£3,273) and more effective (+1.251 quality-adjusted life years [QALYs]). Ribociclib total drug costs were £17,156 lower than palbociclib. At a £30,000 per QALY willingness-to-pay threshold, the probability of ribociclib being cost-effective was almost 100%. Ribociclib remained cost-effective when varying HRs, utilities, drug cost, and health state costs. CONCLUSIONS: Ribociclib is both cost-saving and cost-effective compared with palbociclib for the 1L treatment of postmenopausal women with HR+/HER2- ABC in the UK.

Cost-Effectiveness Analysis of Ultra-Hypofractionated Whole Breast Radiation Therapy Alone Versus Hormone Therapy Alone or Combined Treatment for Low-Risk ER-Positive Early Stage Breast Cancer in Women Aged 65 Years and Older.

PURPOSE: The optimal management of early-stage, low-risk, hormone-positive breast cancer in older women remains controversial. Recent trials have shown that 5-fraction ultrahypofractionated whole-breast irradiation (U-WBI) has similar outcomes to longer courses, reducing the cost and inconvenience of treatment. We performed a cost-utility analysis to compare U-WBI to hormone therapy alone or their combination. METHODS AND MATERIALS: We simulated 3 different treatment approaches for women age 65 years or older with pT1-2N0 ER-positive invasive ductal carcinoma treated with lumpectomy with negative margins using a Markov microsimulation model. The strategies were U-WBI performed with a 3-dimensional conformal technique over 5 fractions without a boost ("radiation therapy [RT] alone"), adjuvant hormone therapy (anastrozole for 5 years) without RT ("aromatase-inhibitor [AI] alone"), or the combination of the 2. The combination strategy was calibrated to match trial results, and the relative effectiveness of the RT alone and AI alone strategies were inferred from previous randomized trials. The primary endpoint was the cost-effectiveness of the 3 strategies over a lifetime horizon as measured by the incremental cost-effectiveness ratio (ICER), with a value of $100,000/quality-adjusted life-year deemed "cost-effective." RESULTS: The model results compared with the prespecified target outcomes. On average, RT alone was the least expensive strategy ($14,775), with AI alone slightly more ($14,998), and combination therapy the costliest ($19,802). RT alone dominated AI alone (the incremental cost-effectiveness ratio [ICER] -$5089). Combination therapy, compared with RT alone, was slightly more expensive than our definition of cost-effective (ICER $113,468) but was cost-effective compared with AI alone (ICER $54,451). Probabilistic sensitivity analysis demonstrated RT alone to be cost-effective in 50% of trials, with combination therapy in 36% and AI alone in 14%. CONCLUSIONS: U-WBI alone appears the more cost-effective de-escalation strategy for these low-risk patients, compared with AI alone. Combining U-WBI and AI appears more costly but may be preferred by some patients.

Real-world assessment of quality-of-life in patients with breast cancer treated with adjuvant endocrine therapy.

Objective: The aim of this study was to investigate quality-of-life (QoL) in breast cancer (BC) patients treated with adjuvant endocrine therapy (AET). Methods: We designed a cross-sectional study of 233 BC patients treated with AET and used the Functional Assessment of Cancer Therapy - Breast questionnaire. Results: No significant difference was observed between endocrine agents. Duration of AET did not affect QoL. In the entire cohort, multivariate analysis determined age (p = 0.034) and switching treatment from tamoxifen to aromatase inhibitors (p = 0.049) as significant positive coefficients of QoL, while comorbidity (p = 0.072) tended to be associated with lower scores. Education level (p = 0.001) and chemotherapy (p = 0.04) were significant predictors of QoL in the tamoxifen group, while comorbidity (p = 0.04), surgery type (p = 0.02), radiotherapy (p = 0.006) and stage (p = 0.009) had a significant impact on QoL in aromatase inhibitors group. Conclusion: Evaluating the well-being of BC patients by QoL questionnaires is of great importance to identify particular subgroups that may require supportive care.

Breast cancer (BC) remains the most common cancer among women worldwide. Hormone receptor-positive (estrogen receptor- and/or progesterone receptor-positive) BC represents 70% of all cases. Advances in the treatment of disease lead to improved patient survival. As a result, quality-of-life (QoL) becomes a major concern in clinical practice. This study aimed to assess the impact of socio-demographic, clinical and treatment-related factors on QoL among patients with BC treated with adjuvant endocrine therapy. We used the Functional Assessment of Cancer Therapy ­ Breast questionnaire to evaluate QoL. In the entire cohort, multivariate analysis determined age and switching treatment from tamoxifen to aromatase inhibitors to be significant positive coefficients of QoL, while comorbidity tended to be associated with lower scores. Education level and chemotherapy were significant determinants of QoL in the tamoxifen group, while comorbidity, surgery type, radiotherapy and disease stage had a significant impact on QoL in the aromatase inhibitor group. These findings can be utilized to identify certain subgroups that may need greater supportive care.

The impact of bone mineral density screening on incident fractures and healthcare resource utilization among postmenopausal breast cancer survivors treated with aromatase inhibitors.

Bone mineral density screening prior to initiating aromatase inhibitor therapy was associated with lower incident bone fractures and healthcare resource utilization among postmenopausal breast cancer survivors. INTRODUCTION: Postmenopausal women with hormone receptor-positive breast cancer (BC) often receive aromatase inhibitor (AI) therapy. However, AIs induce bone loss and BC survivors are at an increased risk of bone fractures. This study determined whether receipt of baseline dual-energy x-ray absorptiometry (DXA) screening is associated with decreased incident fractures and lower healthcare resource utilization. METHODS: We retrospectively analyzed 22,713 stage 0-III primary BC survivors who received AI therapy ≤ 1 year prior to BC diagnosis from the Medicare-Linked Surveillance, Epidemiology, and End-Results database. We categorized DXA screening for those who had a procedural claim within 12 months prior through 6 months after first AI claim. We used propensity score methods to assess the association of DXA screening with bone fractures and health resource utilization. RESULTS: Of the study cohort, 62% received a DXA screening. Women with comorbid dementia, renal disease, and congestive heart failure were less likely to receive a DXA. After adjusting for confounders, BC survivors who received a DXA had a 32% decreased risk of any bone fracture compared to those who did not (hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.60-0.76, p < 0.001). Similarly, those who received a DXA were less likely to be hospitalized (HR 0.73 (0.62-0.86)) or use outpatient services (HR 0.85 (0.74-0.97)). CONCLUSIONS: Bone density screening is associated with decreased incident bone fractures and a lower likelihood of utilizing healthcare resource for fracture-related events. Postmenopausal BC survivors treated with AIs should undergo appropriate bone density screening to reduce morbidity, mortality, and health care expenses.

Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation.

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.

Hormonal Therapy Drug Switching, Out-of-Pocket Costs, and Adherence Among Older Women With Breast Cancer.

BACKGROUND: Adherence to aromatase inhibitors (AIs) and tamoxifen has considerable survival benefits for postmenopausal women diagnosed with hormone receptor-positive breast cancer. Reduced out-of-pocket costs and treatment-related side effects could increase therapy adherence. Given that individuals' side effect profiles could differ across AIs, generic AI entry could facilitate switching between AIs to manage side effects and improve adherence. METHODS: From Surveillance, Epidemiology, and End Results-Medicare, we selected women first diagnosed with hormone receptor-positive breast cancer at age 65+ years and initiated an AI within 1 year of diagnosis between January 1, 2007, and May 31, 2008, or June 1, 2011, and December 31, 2012, and followed them for up to 2 years (N = 20 677). We estimated changes in probabilities of adherence with and without switching for Part D enrollees with and without the low-income subsidy (LIS vs non-LIS) before and after generic entry using linear probability models. Tests of statistical significance are 2-sided. RESULTS: After generic entry reduced out-of-pocket costs of AIs (larger reduction for non-LIS), the percentage of women who ever switched from one AI to another AI increased from 8.8% to 14.6% for non-LIS and from 7.3% to 12.5% for LIS. Adherence without switching increased by 8.0 percentage points (pp) for non-LIS (P < .001) but decreased by 4.9 pp (P < .001) for LIS. Adherence with switching increased for both non-LIS (6.4 pp, P < .001) and LIS (4.4 pp, P < .001). CONCLUSIONS: Increased switching after generic entry contributed to increased adherence, suggesting switching allowed better management of treatment-related side effects. Subsidized women also experienced increased adherence with switching after generic entry, suggesting that patients and physicians might not understand Part D benefit design when making decisions.

Eficacia y seguridad de fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano / Efficacy and safety of fulvestrant in postmenopausal women with metastatic breast cancer, hr positive, her2 negative, without visceral crisis, with intolerance or progression during endocrine therapy with anastrozole and exemestane

ANTECEDENTES: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de fulvestrant (monoterapia), en comparación con la quimioterapia, en el tratamiento de pacientes posmenopáusicas con cáncer de mama metastásico (CMM), receptor hormonal (RH) positivo, receptor 2 del factor de crecimiento epidérmico humano (HER2, por sus siglas en inglés) negativo, sin crisis visceral, con intolerancia o progresión a anastrozol y exemestano. SPECTOS GENERALES Los aspectos generales del cáncer de mama se han descrito previamente en los Dictámenes Preliminares N.° 022-DETS-IETSI-2021 (IETSI-EsSalud 2021a), N° 008- DETS-IETSI-2021 (IETSI-EsSalud 2021b) y N° 050-SDEPFyOTS-DETS-IETSI-2016 (IETSI-EsSalud 2016). Brevemente, el cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo (Institute for Health Metrics and Evaluation 2021). En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres, y cerca de 1,840 muertes debido a esta condición clínica (Institute for Health Metrics and Evaluation 2021). El cáncer de mama con RH positivo es el tipo más común de cáncer de mama, y representa el 75 % de todos los cánceres de mama (Pritchard 2021). El tratamiento de elección del cáncer de mama con RH positivo es la terapia endocrina (Pritchard 2021; National Cancer Institute 2021). Específicamente, en las mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, la terapia endocrina de primera línea más utilizada son los IA, como el agente no esteroideo anastrozol y el agente esteroideo exemestano (National Cancer Institute 2021). Muchos de estos pacientes eventualmente presentan intolerancia o enfermedad progresiva durante la terapia endocrina con IA. En este contexto, las opciones de tratamiento son limitadas, e incluyen el uso de la quimioterapia (National Cancer Institute 2021; Ma and Sparano 2021). TECNOLOGÍA SANITARIA DE INTERÉS: FULVESTRANT: La información detallada sobre esta tecnología sanitaria se encuentra disponible en los Dictámenes Preliminares N.° 022-DETS-IETSI-2021 (IETSI-EsSalud 2021a) y N.° 050- SDEPFyOTS-DETS-IETSI-2016 (IETSI-EsSalud 2016). El fulvestrant es un antagonista competitivo del receptor del estrógeno que bloquea las acciones tróficas de los estrógenos sin poseer actividad agonista parcial (de tipo estrógeno). El mecanismo de acción está asociado con la regulación a la baja de los niveles de la proteína del receptor de estrógeno (U.S. Food and Drug Administration 2021; European Medicines Agency 2021). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con la quimioterapia en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualitát und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorpornáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros; además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.qov/)e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: Guías de práctica clínica Publicaciones incluidas en la evaluación de la evidencia: Cardoso et al., 2020. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (Cardoso et al. 2020). National Comprehensive Cancer Network (NCCN). NCCN Guidelines: Breast Cancer. Version 8.2021 - September 13, 2021 (NCCN 2021). Moy et al., 2021. Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2­Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor­Negative: ASCO Guideline Update (Moy et al. 2021). El siguiente documento se excluyó por tratarse de un consenso de expertos. Pritchard et al., 2013. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: A Canadian consensus statement (Pritchard et al. 2013). CONCLUSIONES: El objetivo del presente dictamen preliminar fue evaluar la mejor evidencia científica sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con la quimioterapia en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano. La búsqueda de literatura permitió identificar tres GPC realizadas por la ESMO, la NCCN y la ASCO. En cuanto a las GPC identificadas, hubo discordancia entre las recomendaciones elaboradas para el tratamiento de mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con progresión durante la terapia endocrina. La NCCN recomienda el uso de la terapia endocrina, incluido fulvestrant, en el subgrupo de pacientes sin resistencia a la terapia endocrina, y la quimioterapia en el subgrupo con resistencia a la terapia endocrina. La ESMO recomienda el uso de la terapia endocrina, incluido fulvestrant, en la población objetivo, y no elabora recomendaciones sobre la quimioterapia. La ASCO recomienda el uso de la terapia endocrina con o sin terapia dirigida y la quimioterapia de un solo agente, sin preferencias entre una u otra. Sobre la evidencia utilizada para realizar las recomendaciones, la ESMO no citó evidencia alguna, mientras que la NCCN y la ASCO citaron evidencia que no respondía a la pregunta PICO establecida en el presente dictamen. En el momento actual no hay evidencia que compare la terapia endocrina con fulvestrant (monoterapia) versus la quimioterapia en mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, con intolerancia o progresión durante la terapia endocrina. En ese sentido, existe incertidumbre sobre el beneficio adicional del uso de fulvestrant sobre la quimioterapia en la población objetivo. La quimioterapia de agente único es una opción de tratamiento recomendada por la guía de la ASCO para la población objetivo de la presente evaluación. En EsSalud, hay varias opciones de quimioterapia disponibles en la Petitorio Farmacológico y existe una amplia experiencia en el uso de la quimioterapia en el tratamiento del CMM. Por lo expuesto, el IETSI no aprueba el uso de fulvestrant en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano.

Assessment of Breast Cancer Management in Sub-Saharan Africa.

PURPOSE: To document progress and bottlenecks in breast cancer management in sub-Saharan Africa, subsequent to a 2013 pilot survey conducted through the African Organization for Research and Treatment in Cancer (AORTIC) network. METHODS: An anonymous survey of breast cancer management was conducted in 2018 among AORTIC members. Results concerning respondent specialty, access to tumor boards, treatment accessibility, diagnostic services, and factors influencing treatment outcomes were compared with the 2013 findings. RESULTS: Thirty-seven respondents from 30 facilities in 21 sub-Saharan Africa countries responded. The majority (92%) were clinical oncologists. Radiotherapy facilities were available in 70% of facilities. Seventy-eight percent of these had linear accelerators, and 42% had cobalt60 machines. Eighty percent of facilities had multidisciplinary tumor boards. Immunohistochemistry was routinely performed in 74% of facilities, computed tomography scan in 90%, bone scan in 16%, and positron emission tomography scans in 5%. Anthracyclines, taxanes, tamoxifen, letrozole, anastrozole, and zoledronic acid were available in the majority; trastuzumab, fertility, and genetic counseling were available in 66%, 58%, and 16%, respectively. There were a 50% increase in oncologist respondents over 2013 and a > 50% increase in radiotherapy facilities, particularly linear accelerators. Availability of trastuzumab, aromatase inhibitors, and taxanes increased. Immunohistochemistry capacity remained the same, whereas facilities harvesting at least 10 axillary lymph nodes increased. Bone scan facilities decreased. Responses suggested improved diagnostic services, systemic therapies, and radiotherapy. Sociocultural and economic barriers, system delays, and advanced stage at presentation remain. CONCLUSION: Clinicians in sub-Saharan Africa have basic tools to improve breast cancer outcomes, recording positive strides in domains such as radiotherapy and systemic therapy. Socioeconomic and cultural barriers and system delays persist. Workforce expansion must be prioritized to improve quality of care to improve outcomes.

Eficacia y seguridad de ribociclib en combinación con un inhibidor de la aromatasa y un agonista de lhrh en pacientes premenopáusicas con cáncer de mama metastásico, rh positivo, her2 negativo, sin crisis visceral, y sin tratamiento sistémico previo para la enfermedad metastásica / Efficacy and safety of ribociclib in combination with an aromatase inhibitor and an lhrh agonist in premenopausal patients with rh-positive, her2-negative, metastatic breast cancer without visceral crisis, and without prior systemic treatment for metastatic disease

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de ribociclib en combinación con un IA y un agonista de LHRH en pacientes premenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, y sin tratamiento sistémico previo para la enfermedad metastásica. El cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo. En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres; y se registraron 1,840 muertes debido a esta neoplasia. Específicamente, el cáncer de mama metastásico (CMM) es una condición incurable. Se estima que la mediana de sobrevida global (SG) en pacientes con CMM es de aproximadamente tres años y que la tasa de SG hasta los 5 años es de aproximadamente 27 %. En ausencia de una enfermedad rápidamente progresiva o una crisis visceral, la terapia endocrina (TE) con supresión ovárica se considera el tratamiento de primera línea para las mujeres premenopáusicas, con CMM, receptor hormonal (RH) positivo, receptor 2 del factor de crecimiento epidérmico humano (HER2) negativo. Las opciones de TE comúnmente utilizadas incluyen moduladores selectivos del receptor de estrógeno (p. ej., tamoxifeno) e inhibidores de aromatasa (IA) no esteroideos (p. ej. anastrozol) o esteroideos (p. ej. exemestano). En EsSalud, este grupo de pacientes es tratado con TE (tamoxifeno, anastrazol, exemestano) más supresión ovárica. Sin embargo, el IETSI recibió una solicitud de evaluación de ribociclib en combinación con TE con IA más supresión ovárica, argumentándose la necesidad de evaluar terapias alternativas que proporcionen mejoras en la SG y calidad de vida de estos pacientes, y que a su vez tengan perfiles de seguridad favorables. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de ribociclib en combinación con un IA y un agonista de LHRH en pacientes premenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, y sin tratamiento sistémico previo para la enfermedad metastásica. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), como el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros; además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S3, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: El objetivo del presente dictamen preliminar fue evaluar la mejor evidencia científica sobre la eficacia y seguridad de ribociclib en combinación con un IA y un agonista de LHRH en pacientes premenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, y sin tratamiento sistémico previo para la enfermedad metastásica (primera línea de tratamiento para la enfermedad metastásica). El comparador de interés fue la TE con tamoxifeno o un IA (anastrazol, exemestano) más la supresión ovárica. Se incluyeron tres GPC elaboradas por la ESMO, la NCCN y la ASCO; tres ETS realizadas por la CADTH de Canadá, el IQWiG de Alemania y la CONETEC de Argentina; y tres publicaciones del estudio MONALEESA-7 (Tripathy et al. 2018; Im et al. 2019; Harbeck et al. 2020). Las tres GPC identificadas recomendaron el uso de un inhibidor de CDK 4/6, como ribociclib, combinado con un IA más supresión ovárica con un agonista de LHRH, en la población de interés. La NCCN y la ESMO también recomendaron el uso de TE (IA o tamoxifeno) más supresión ovárica en esta población. La evidencia utilizada para respaldar la recomendación fue el estudio MONALEESA-7. En cuanto a las recomendaciones de las ETS internacionales, el IQWiG y la CONETEC realizaron recomendaciones desfavorables para ribociclib, mientras que la CADTH elaboró una recomendación a favor del uso de ribociclib. Las recomendaciones se basaron en los resultados del estudio MONALEESA-7. En líneas generales, los resultados de MONALEESA-7 (ECA de fase 3, doble ciego) sugieren una mayor SG y SLP con ribociclib respecto al placebo en la población objetivo del presente dictamen. Además, el ribociclib se asoció con una mayor tasa de EA serios y severos, y una calidad de vida similar en relación con el placebo. Sobre la calidad de la evidencia, MONALESSA-7 presenta limitaciones metodológicas que amenazan la validez de los resultados reportados. En primer lugar, los resultados de eficacia se basaron en análisis de desenlaces basados en imágenes radiográficas, como la SLP (que no es una medida directa de beneficio clínico), y análisis interinos con datos prematuros de SG. Además, los análisis de calidad de vida presentaron una importante pérdida de información. Así se evidencia un alto grado de incertidumbre en relación al beneficio clínico de ribociclib. A ello se le suma la tasa significativa de EA severos y serios reportados con ribociclib en el corto plazo, y la incertidumbre sobre la certeza de los resultados de calidad de vida. Ribociclib es un medicamento que, de aprobarse, tendría un impacto presupuestario importante en el contexto de EsSalud, por lo que su alto costo tendría que traducirse en un claro beneficio clínico, el cual pueda justificar que se deje de invertir en tecnologías efectivas y menos costosas para los asegurados para que, en su lugar, se financie ribociclib. La población objetivo del presente dictamen tiene una alternativa de tratamiento disponible en EsSalud, que es la TE (tamoxifeno o un IA) con supresión ovárica, opción de tratamiento que sigue siendo recomendada en las GPC internacionales, y tiene una amplia experiencia de uso en la institución. Por todo lo expuesto, el IETSI no aprueba el uso de ribociclib en combinación con un IA y un agonista de LHRH en pacientes premenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, y sin tratamiento sistémico previo para la enfermedad metastásica.

Eficacia y seguridad de fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico, rh positivo, HER2 negativo y progresión de la enfermedad después del uso de un inhibidor de aromatasa / Efficacy and safety of fulvestrant in postmenopausal women with metastatic, rh-positive, HER2-negative breast cancer and disease progression after use of an aromatase inhibitor

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de fulvestrant (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. El cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo. En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres; causando cerca de 1,840 muertes en el mismo año. El cáncer de mama metastásico (CMM) es una condición incurable. Se estima que la mediana de sobrevida global (SG) en pacientes con CMM es de aproximadamente tres años y que la tasa de SG hasta los 5 años es de aproximadamente 27 %.  En EsSalud, las pacientes posmenopáusicas con CMM, receptor hormonal (RH) positivo, receptor 2 del factor de crecimiento epidérmico humano (HER2) negativo y cuya enfermedad progresa después del uso de terapia endocrina con un inhibidor de aromatasa (IA) son generalmente tratadas con otro IA. Sin embargo, algunos especialistas han señalado que el uso de fulvestrant ofrece un mejor perfil de eficacia y seguridad. Por este motivo, el IETSI recibió una solicitud de evaluación de fulvestrant como una alternativa de tratamiento al uso de un IA. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan ETS y GPC, incluyendo el Healthcare Improvement Scotland, el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: Se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S3 , siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: El objetivo del presente dictamen preliminar fue evaluar la mejor evidencia científica sobre la eficacia y seguridad de fulvestrant 500 mg (monoterapia) en comparación con anastrazol o exemestano en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA. En el contexto de primera línea para la enfermedad avanzada, la GPC de ESMO recomendó indistintamente el uso de monoterapia con fulvestrant o los IA; mientras que NCCN realizó una recomendación más fuerte para el tratamiento con monoterapia con fulvestrant respecto a los IA. En el contexto de segunda línea para la enfermedad avanzada, las GPC de ESMO y NCCN recomendaron el uso de fulvestrant o IA, sin preferencias entre uno u otro. No hubo recomendaciones específicas para la población con progresión a un IA. La evidencia disponible respecto a la pregunta PICO del presente dictamen no permite determinar un beneficio adicional con fulvestrant 500 mg en comparación con los IA. Los resultados de dos meta-análisis en red que compararon fulvestrant 500 mg versus los IA en mujeres posmenopáusicas, con CMM, RH positivo y tratamiento endocrino previo mostraron ausencia de diferencias estadísticamente significativas en la SLP, la SG, los EA de grado 3 o 4 y la discontinuación debido a EA; sin embargo, la heterogeneidad de las poblaciones de los estudios incluidos afecta la validez de estos resultados. Aunque un estudio observacional reportó una mejor SLP con fulvestrant 500 mg (respecto a exemestano) en pacientes posmenopáusicas, con CMM, RH positivo, HER2 negativo, que progresaron durante la terapia adyuvante con IA no esteroideos, la calidad de la evidencia fue baja y los efectos reportados en la SLP no fueron clínicamente relevantes en términos de capacidad predictiva sobre la SG. Dado que la evidencia disponible no ha mostrado que la relación riesgo-beneficio sea favorable a fulvestrant 500 mg, en comparación con anastrozol o exemestano, la aprobación de uso de fulvestrant en EsSalud no sería una decisión costo-oportuna; considerando la disponibilidad de tratamientos eficaces, con perfiles de seguridad aceptables y menos costosos en la institución (i.e. anastrozol y exemestano). Estos medicamentos se recomiendan en las GPC internacionales más recientes para la población de interés del presente dictamen. Por lo expuesto, el IETSI no aprueba el uso de fulvestrant en mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, y progresión de la enfermedad después del uso de un IA.

Cost Effectiveness of Ribociclib Plus a Nonsteroidal Aromatase Inhibitor in Pre-/Perimenopausal, HR+ and HER2- Advanced Breast Cancer: A Canadian Healthcare Perspective.

BACKGROUND AND OBJECTIVES: The MONALEESA-7 trial demonstrated the efficacy and safety of ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) [with goserelin] for pre-/perimenopausal women with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer. This analysis evaluated the cost effectiveness of ribociclib plus NSAI vs NSAI monotherapy and tamoxifen monotherapy from the perspective of the Canadian healthcare system. METHODS: The incremental cost-effectiveness ratio expressed as incremental costs per quality-adjusted life-year (QALY) gained for ribociclib plus an NSAI vs an NSAI and vs tamoxifen was estimated using a semi-Markov cohort model developed in Microsoft Excel with a 15-year time horizon and states for progression-free survival, post-progression survival, and dead. Survival distributions for progression-free survival, post-progression survival, and time to discontinuation as well as health-state utilities were estimated using data from MONALEESA-7. Direct costs of advanced breast cancer treatment were based on Canadian-specific values from published sources. Costs ($CAN 2019) and QALYs were discounted at 1.5% annually. RESULTS: Ribociclib plus an NSAI was estimated to yield gains of 1.42 life-years and 1.17 QALYs vs an NSAI, and 2.61 life-years and 2.12 QALYs vs tamoxifen, at incremental costs of $209,701 and $220,836, respectively. In probabilistic analyses, the incremental cost-effectiveness ratio for ribociclib plus an NSAI was estimated to be $178,872 per QALY gained vs an NSAI and $104,400 per QALY gained vs tamoxifen. Results of deterministic analyses were similar (incremental cost-effectiveness ratios of $177,245 and $103,316 vs NSAI and tamoxifen, respectively). Results were sensitive to parametric distributions used for projecting progression-free survival and the time horizon. CONCLUSIONS: At its current list price, ribociclib used in combination with NSAI is likely to be co-effective relative to an NSAI alone or tamoxifen alone if the willingness-to-pay threshold is less than approximately $178,000 per QALY. These results have informed deliberations regarding reimbursement and access to this treatment in Canada and may be useful for decision makers in other settings.