Cost Effectiveness of CDK4/6 Inhibitors in the First-Line Treatment of HR+/HER2- Metastatic Breast Cancer in Postmenopausal Women in the USA.

BACKGROUND AND OBJECTIVE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors improve progression-free survival when combined with endocrine therapies in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, the comparative cost effectiveness of utilizing three US Food and Drug Administration-approved CDK4/6 inhibitors is unknown. Therefore, we aimed to evaluate the cost effectiveness of individual CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) with letrozole versus letrozole monotherapy in the first-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the USA. METHODS: We constructed a Markov-based decision-analytic model to evaluate the cost effectiveness of CDK4/6 inhibitors plus endocrine therapies over a 40-year lifetime from a third-party payer perspective. The model incorporated health states (progression-free disease, progressive disease, and death), major adverse events (neutropenia), and cancer-specific and all-cause mortality. Using clinical efficacy and quality-of-life scores (utility) data from clinical trials, we estimated quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios using Medicare charges reported in US dollars per 2022 valuation and a discount rate of 3% applied to costs and outcomes. We performed deterministic and probabilistic sensitivity analyses to evaluate parametric and decision uncertainty. RESULTS: Compared to letrozole, the model estimated an increase of 5.72, 5.87, and 6.39 in QALYs and costs of $799,178, $788,168, and $741,102 in combining palbociclib, ribociclib, and abemaciclib plus letrozole, respectively. Palbociclib or ribociclib plus letrozole were dominated by abemaciclib plus letrozole. Compared with letrozole, abemaciclib plus letrozole resulted in an incremental cost-effectiveness ratio of $457,538 per QALY with an incremental cost of $553,621 and an incremental QALY gain of 1.21. The results were sensitive to the cost of abemaciclib, disease progression utility, and patients' age. CONCLUSIONS: At a willingness to pay of $100,000/QALY gained, our model predicts that combining CDK4/6 inhibitors plus letrozole is not cost effective with a marginal increase in QALYs at a high cost. Lowering the cost of these drugs or identifying patients who can receive maximal benefit from CDK4/6 inhibitors would improve the value of this regimen in patients.

Health-related quality of life among elderly breast cancer patients treated with adjuvant endocrine therapy: a U.S Medicare population-based study.

OBJECTIVES: The evidence regarding the impact of individual adjuvant endocrine therapies (AET) on health-related quality of life (HRQoL) is limited. We aimed to assess the association between the type of AET and HRQoL and to examine the relationship between HRQoL and one-year mortality among women with breast cancer in the USA. METHODS: This retrospective cross-sectional study used the 2006-2017 Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey database to identify older women with early-stage hormone receptor-positive breast cancer. Multivariate linear regressions were used to assess the association between types of AET (anastrozole, letrozole, exemestane, and tamoxifen) and HRQoL scores (physical component summary (PCS) and mental component summary (MCS)). Multivariate logistic regressions were used to predict the impact of PCS and MCS on one-year mortality. RESULTS: Out of 3537 older women with breast cancer, anastrozole was the most commonly prescribed (n = 1945, 55.0%). Regarding PCS, there was no significant difference between the four AET agents. Higher MCS scores, which indicate better HRQoL, were reported in patients treated with anastrozole (vs. letrozole [ß = 1.26, p = 0.007] and exemestane [ß = 2.62, p = 0.005) and tamoxifen (vs. letrozole [ß = 1.49, p = 0.010] and exemestane [ß = 2.85, p = 0.004]). Lower PCS and MCS scores were associated with higher one-year mortality, regardless of type of AET initiated, except for tamoxifen in MCS. CONCLUSION: Although there was no significant difference in physical HRQoL scores between AET agents, anastrozole and tamoxifen were associated with better mental HRQoL scores.

Letrozole-associated controlled ovarian hyperstimulation in breast cancer patients versus conventional controlled ovarian hyperstimulation in infertile patients: assessment of oocyte quality related biomarkers.

BACKGROUND: Fertility preservation (FP) protocols in case of breast cancer (BC) include mature oocyte cryopreservation following letrozole associated controlled ovarian hyperstimulation (Let-COH). To date, the impact of Let-COH on the follicular microenvironment has been poorly investigated, although a high androgen/estrogen ratio was previously associated with low oocyte quality. METHODS: In this prospective study, follicular fluid (FF) steroid levels (estradiol, testosterone, progesterone) and cumulus cell (CC) gene expression related to oocyte quality (HAS2, PTGS2, GREM1) were compared between 23 BC patients undergoing Let-COH for FP and 24 infertile patients undergoing conventional COH without letrozole. All patients underwent an antagonist COH cycle, and ovulation was triggered with hCG or GnRHa in both groups. RESULTS: FF estradiol levels were significantly lower while testosterone levels were significantly higher in the study group compared to controls irrespective of the trigger method. However, estradiol levels increased significantly with GnRHa triggering compared to hCG in the study group (median = 194.5 (95.4-438) vs 64.4 (43.8-152.4) ng/ml, respectively, p < 0.001), but not in the control group (median = 335.5 (177.5-466.7) vs 354 (179-511) ng/ml, respectively). After hCG trigger, Cumulus cell (CC) gene expression was lower in the study group compared to the control group, and difference was significant for PTGS2. Conversely, CC gene expression of PTGS2 and GREM1 was significantly higher in the study group compared to controls when ovulation was triggered with GnRHa. CONCLUSIONS: Let-COH triggered with hCG may negatively impact oocyte quality. However, ovulation triggering with GnRHa may improve the oocyte microenvironment and cumulus cell genes expression in Let-COH, suggesting a positive impact on oocyte quality in breast cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov - NCT02661932 , registered 25 January 2016, retrospectively registered.

Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

INTRODUCTION: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non-fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: •Diagnosis:▪when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;▪requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and▪adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.•Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.•Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate.

Economic Evaluation of Letrozole for Early Breast Cancer in a Health Resource-Limited Setting.

OBJECTIVE: Long-term aromatase inhibitor (AI) therapy is expected to improve the health outcomes with high health resource consumption in early breast cancer. The aim of the study was to assess the cost-effectiveness of letrozole for postmenopausal women with estrogen receptor positive early breast cancer in a health resource-limited setting. METHODS: A Markov model was developed to project the lifetime outcomes based on the clinical course of early breast cancer. The clinical and utility data were derived from reported results. Costs were estimated from the perspective of Chinese health care. The quality-adjusted life-year (QALY) and incremental cost-effective ratio (ICER) were measured. Probabilistic sensitivity and one-way analyses were conducted. RESULTS: Compared to 5 years of tamoxifen therapy, 5 years of AI treatment with letrozole improved the QALYs (10.44 versus 10.84) and increased the lifetime costs (CNY ¥13,613 versus CNY ¥28,797), resulting in an ICER of CNY ¥38,092 /QALY. The ICER of 5 years of letrozole versus 2-3 years of tamoxifen and then letrozole was CNY ¥68,233 /QALY. Sensitivity analyses showed that the age of initiating adjuvant endocrine therapy was the most influential parameter. CONCLUSIONS: In health resource-limited settings, adjuvant endocrine therapy with letrozole is a cost-effective strategy compared to tamoxifen in women with early breast cancer.

Eficacia y seguridad de palbociclib más letrozol en el tratamiento del cáncer de mama metastásico con receptores hormonales positivos, her2 negativo y sin tratamiento endocrino previo / Efficacy and safety of palbociclib plus letrozole in the treatment of metastatic breast cancer with positive hormonal receptors, her2 negative and without previous endocrine treatment

INTRODUCCIÓN: El presente informe expone la evaluación del uso de palbociclib más letrozol para el tratamiento de pacientes post menopáusicas, con cáncer de mama metastásico, con receptores hormonales positivos, factores de crecimiento epidérmico humano 2 negativo (RH+/HER2-) y sin tratamiento endocrino previo. El cáncer de mama puede clasificarse según la expresión de receptores de las células tumorales: 1) receptores hormonales (RH); 2) receptor 2 del factor de crecimiento epidérmico humano (HER2+, con o sin expresión de RH), y 3) ninguno de estos receptores (triple-negativo). Esta clasificación descrita es relevante porque determina el tratamiento sistémico. En el caso de las pacientes postmenopáusicas con cáncer de mama metastásico, HR+/HER2- y sin crisis visceral, el tratamiento de preferencia de primera línea es la terapia endocrina (TE). Esta recomendación se basó en evidencia que mostró eficacia similar entre TE y quimioterapia, en términos de sobrevida global, aunque con menor toxicidad en el caso de la TE. TECNOLOGÍAS SANITARIA DE INTERÉS: Palbociclib (Ibrance, Pfizer) es una pequeña molécula que inhibe selectivamente a las quinasas 4 y 6, dependientes de ciclina, previniendo así la síntesis de ADN por medio de la interrupción de la progresión de la fase G1 a la fase S del ciclo celular (Fry 2004 y Toogood 2005), y por lo tanto la división celular y la formación de nuevas células cancerosas. METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de palbociclib más letrozol para el tratamiento de pacientes post menopáusicas, con cáncer de mama metastásico, con receptores hormonales positivos, HER-2 negativo (RH+/HER2-) y sin tratamiento endocrino previo. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), The Canadian Agency for Drugs and Technologies in Health (CADTH) y The Scottish Medicines Consortium (SMC). Esta búsqueda se completó ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica para el sustento del uso de palbociclib + letrozol para el tratamiento de pacientes post menopáusicas, con cáncer de mama metastásico, con receptores hormonales positivos, factores de crecimiento epidérmico humano 2 negativo (RH+/HER2-) y sin tratamiento endocrino previo. CONCLUSIONES: La búsqueda de la evidencia científica identifico dos estudios que evaluaron los efectos de agregar palbociclib a la monoterapia con letrozol (PALOMA 1 y PALOMA 2). Además, se incluyeron tres GPC de manejo de pacientes con cáncer de mama avanzado y dos ETS. Todas las GPC consultadas concurren en recomendar como tratamiento preferido la endocrinoterapia como tratamiento de primera línea en pacientes postmenopáusicas con cáncer de mama metastásico, RH+, HER2-. Esta recomendación se basó en evidencia que mostró eficacia similar entre endocrinoterapia y quimioterapia, en términos de sobrevida global, aunque con menor toxicidad. El estudio PALOMA-2 evaluó los efectos de la agregar palbociclib a un inhibidor de aromatasa, como letrozol, en mujeres posmenopáusicas con cáncer de mama localmente avanzado o metastásico, RH+/HER2- y sin tratamiento previo para su enfermedad. Se observó una ganancia absoluta de aproximadamente 10 meses en la SLP a favor de la combinación sobre el tratamiento solo. Para la SG, solo están disponibles los resultados del análisis intermedio. Este análisis se realizó después de la observación de 131 muertes (es decir, el 33 % de la cantidad de eventos esperados para el análisis final). En esta fecha, no se encontraron diferencias entre los dos grupos de tratamiento con este criterio: 95 muertes (21 %) habían ocurrido en el grupo de palbociclib y 38 muertes (17 %) habían ocurrido en el grupo de placebo. De acuerdo con el protocolo, el análisis final de la supervivencia global se realizará después de la observación de 390 eventos. Las GPC de ESMO y ASCO hace mención de la combinación de palbociclib + letrozol como una opción más de tratamiento, lo hacen señalado que aún están pendientes los datos de SG del estudio pivotal (PALOMA 2) y asumiendo un beneficio potencial la SLP en desenlaces clínicamente relevantes, aunque esta misma carece de evidencia que lo sustente. Existe mayor toxicidad con el tratamiento combinado con palbociclib respecto a la monoterapia con letrozol, incluyendo efectos adversos como neutropenia, fatiga, anemia, náuseas, alopecia. La neutropenia ocurría en mayor proporción en el brazo que contenía palbociclib respecto a la monoterapia con letrozol y que una pequeña proporción de pacientes que recibieron palbociclib + letrozol sufrieron fiebre neutropénica. El Instituto de Evaluación de Tecnologías en Salud e Investigación IETSI no aprueba el uso de palbociclib en combinación con letrozol en pacientes con cáncer de mama con receptores hormonales positivos, Her2 negativo y con progresión de enfermedad luego de hormonoterapia y quimioterapia de segunda línea.