Bone modifying agents in postmenopausal breast cancer patients treated with aromatase inhibitors: beyond bone protection?

Estrogen-receptor positive tumours represent the majority of breast cancers in postmenopausal women. Adjuvant endocrine therapy with aromatase inhibitors (AIs), continued for up to 10 years in high-risk patients, reduces by 40% the risk of recurrence. However, this therapy, among other side effects, is burdened with a higher incidence of osteoporotic bone fractures. To date, both bisphosphonates and denosumab are recognized as first-line drugs in the primary prevention of osteoporotic fractures in patients treated with AIs. They have demonstrated their effectiveness in increasing bone mineral density and in reducing the incidence of fractures, but they have also been shown to improve disease free survival (DFS).

Review of bone health in women with estrogen receptor-positive breast cancer receiving endocrine therapy.

In estrogen-receptor-positive tumors, adjuvant endocrine therapy has been shown to be highly beneficial for both overall and disease-free survival. Estradiol is key in regulating bone and mineral physiology, and several studies found a strong correlation between these therapies and the risk of fractures. Since these therapies are often given for 5 through 10 years, the timing for bisphosphonates or denosumab initiation seems essential to managing bone metabolism. However, gray zones and discrepancies between guidelines remain as to the best threshold when to start antiresorptive treatment, or whether antiresorptive treatment should be administered to every woman undergoing adjuvant endocrine therapy, independent of their risk factors for fractures. Treatment options and strategies should be discussed at the start of hormone adjuvant therapy to come to a shared decision with the patient, with the final aim of reducing the risk of future fractures as much as possible. This review will cover present guidelines and literature on antiresorptive treatment in this setting, to provide clinicians with useful clues for managing these patients.

[A real-world study of the effects of endocrine therapy on liver function in breast cancer].

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

A real-world study of the effects of endocrine therapy on liver function in breast cancer / 中华外科杂志

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

Changes in Vertebral Marrow Fat Fraction Using 3D Fat Analysis & Calculation Technique Imaging Sequence in Aromatase Inhibitor-Treated Breast Cancer Women.

Aromatase inhibitor (AI) is a cornerstone drug for postmenopausal women with estrogen receptor-positive early-stage breast cancer. Fat-bone interactions within the bone marrow milieu are growing areas of scientific interest. Although AI treatment could lead to deterioration of the skeleton, the association between AI medication and subsequent marrow adiposity remains elusive. A total of 40 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients who underwent treatment with adjuvant AIs and 40 matched controls were included. Marrow proton density fat fraction (PDFF) at the L1-L4 vertebral bodies using 3D Fat Analysis & Calculation Technique imaging (FACT) sequence at 3.0T, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and serum bone turnover biomarkers were determined at baseline and at 6 and 12 months. We found that, in comparison to baseline, an increase of type I collagen cross-linked telopeptide was detected at 12 months (P <0.05). From baseline to 12 months, the PDFF measured using FACT was greatly increased. At 12 months, the median percent change of PDFF (4.9% vs. 0.9%, P <0.05) was significantly different between the AI treatments and controls. The same trend was observed for the marrow PDFF at 6 months relative to the respective values at baseline. Although BMD values were significantly reduced after 12 months in AI-treated women, changes in BMD vs. baseline condition were not significantly different between the AI-treated and control groups [Δ BMD -1.6% to -1.8% vs. -0.3% to -0.6%, respectively, P > 0.05]. In the AI-treated group, Δ PDFF was associated with Δ BMD at the lumbar spine (r = -0.585, P < 0.001), but not in the controls. Taken together, over a 12-month period, spinal marrow fat content assessed with FACT sequence significantly increased in postmenopausal women with hormone-receptor-positive breast cancer receiving AI treatment.

Implications and Efficacy of Aromatase Inhibitors in Combination and Monotherapy for the Treatment of Lung Cancer.

BACKGROUND: Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation. METHODS: The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies. RESULT: Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC50 values after 48 hours of treatment with exemestane were 176, 180, and 120 µM in A549, H661, and H1299, respectively. Curcumin IC50 values after 48 hours were 80, 43, and 68 µM in A549, H661, and H1299, respectively. The combined treatment of exemestane or curcumin with cisplatin, raloxifene, and celecoxib resulted in a synergistic effect in the A549 lung cell line with a combination index of less than 1, suggesting synergism. Exemestane resulted in approximately 96% inhibition of wound closure at 100 µM, while curcumin resulted in approximately 63% inhibition of wound closure at 50 µM. Exemestane and curcumin inhibited the formation of cell colonies by reducing the number and size of formed colonies of A549, H661, and H1299 cell lines in a concentration dependent manner. Exemestane and curcumin had significantly induced apoptosis in A549 cells compared to control of untreated cells. CONCLUSION: Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.

Endocrine therapy initiation among women with stage I-III invasive, hormone receptor-positive breast cancer from 2001-2016.

PURPOSE: This retrospective cohort study examined patterns of endocrine therapy initiation over time and by demographic, tumor, and treatment characteristics. METHODS: We included 7777 women from three U.S. integrated healthcare systems diagnosed with incident stage I-III hormone receptor-positive breast cancer between 2001 and 2016. We extracted endocrine therapy from pharmacy dispensings, defining initiation as dispensings within 12 months of diagnosis. Demographic, tumor, and treatment characteristics were collected from electronic health records. Using generalized linear models with a log link and Poisson distribution, we estimated initiation of any endocrine therapy, tamoxifen, and aromatase inhibitors (AI) over time with relative risks (RR) and 95% confidence intervals (CI) adjusted for age, tumor characteristics, diagnosis year, other treatment, and study site. RESULTS: Among women aged 20+ (mean 62 years), 6329 (81.4%) initiated any endocrine therapy, and 1448 (18.6%) did not initiate endocrine therapy. Tamoxifen initiation declined from 67 to 15% between 2001 and 2016. AI initiation increased from 6 to 69% between 2001 and 2016 in women aged ≥ 55 years. The proportion of women who did not initiate endocrine therapy decreased from 19 to 12% between 2002 and 2014 then increased to 17% by 2016. After adjustment, women least likely to initiate endocrine therapy were older (RR = 0.81, 95% CI 0.77-0.85 for age 75+ vs. 55-64), Black (RR = 0.93, 95% CI 0.87-1.00 vs. white), and had stage I disease (RR = 0.88, 95% CI 0.85-0.91 vs. stage III). CONCLUSIONS: Despite an increase in AI use over time, at least one in six eligible women did not initiate endocrine therapy, highlighting opportunities for improving endocrine therapy uptake in breast cancer survivors.

Simulation modeling of breast cancer endocrine therapy duration by patient and tumor characteristics.

BACKGROUND: Extending endocrine therapy from 5 to 10 years is recommended for women with invasive estrogen receptor (ER)-positive breast cancers. We evaluated the benefits and harms of the five additional years of therapy. METHODS: An established Cancer Intervention and Surveillance Network (CISNET) model used a lifetime horizon with national and clinical trial data on treatment efficacy and adverse events and other-cause mortality among multiple birth cohorts of U.S. women ages 25-79 newly diagnosed with ER+, non-metastatic breast cancer. We assumed 100% use of therapy. Outcomes included life years (LYs), quality-adjusted life years (QALYs), and breast cancer mortality. Results were discounted at 3%. Sensitivity analyses tested a 15-year time horizon and alternative assumptions. RESULTS: Extending tamoxifen therapy duration among women ages 25-49 reduced the lifetime probability of breast cancer death from 11.9% to 9.3% (absolute difference 2.6%). This translates to a gain of 0.77 LYs (281 days)/woman (undiscounted). Adverse events reduce this gain to 0.44 QALYs and after discounting, gains are 0.20 QALYs (73 days)/woman. Extended aromatase inhibitor therapy in women 50-79 had small absolute benefits and gains were offset by adverse events (loss of 0.06 discounted QALYs). There were greater gains with extended endocrine therapy for women with node-positive versus negative cancers, but only women ages 25-49 and 50-59 had a net QALY gain. All gains were reduced with less than 100% treatment completion. CONCLUSION: The extension of endocrine therapy from 5 to 10 years modestly improved lifetime breast cancer outcomes, but in some women, treatment-related adverse events may outweigh benefits.

Dietary Supplement Use and Interactions with Tamoxifen and Aromatase Inhibitors in Breast Cancer Survivors Enrolled in Lifestyle Interventions.

The use of dietary supplements is common in the general population and even more prevalent among cancer survivors. The World Cancer Research Fund/American Institute for Cancer Research specifies that dietary supplements should not be used for cancer prevention. Several dietary supplements have potential pharmacokinetic and pharmacodynamic interactions that may change their clinical efficacy or potentiate adverse effects of the adjuvant endocrine therapy prescribed for breast cancer treatment. This analysis examined the prevalence of self-reported dietary supplement use and the potential interactions with tamoxifen and aromatase inhibitors (AIs) among breast cancer survivors enrolled in three randomized controlled trials of lifestyle interventions conducted between 2010 and 2017. The potential interactions with tamoxifen and AIs were identified using the Natural Medicine Database. Among 475 breast cancer survivors (2.9 (mean) or 2.5 (standard deviation) years from diagnosis), 393 (83%) reported using dietary supplements. A total of 108 different types of dietary supplements were reported and 36 potential adverse interactions with tamoxifen or AIs were identified. Among the 353 women taking tamoxifen or AIs, 38% were taking dietary supplements with a potential risk of interactions. We observed a high prevalence of dietary supplement use among breast cancer survivors and the potential for adverse interactions between the prescribed endocrine therapy and dietary supplements was common.

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.

Does the Time of Day at Which Endocrine Therapy Is Taken Affect Breast Cancer Patient Outcomes?

BACKGROUND: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. LITERATURE REVIEW: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. CONCLUSIONS: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41-72% and 31-73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.

Bone recurrence in early breast cancer patients: The paradox of aromatase inhibitors induced bone resorption.

BACKGROUND: Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20-45% of them will experience a disease recurrence, particularly bone metastases in 60-80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases. PATIENTS AND METHODS: In this single-institution cohort study, we performed a retrospective analysis of "luminal-like" EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR). RESULTS: 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45-65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25-54), while among patients who did not was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p = 0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p = 0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR. CONCLUSIONS: In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.

Correlation between bone mineral density and endometrial thickness over time in women with breast cancer history.

As the efficacy of chemotherapy and adjuvant endocrine therapy for breast cancer increase, the quality-of-life to cancer survivors could be more important issue in strategies of breast cancer treatment. Bone health has become more compelling in care of breast cancer survivor than ever before. This retrospective study was aimed to evaluate factors relating to the change in BMD and to ascertain the correlation between changes in BMD and EMT of women with breast cancer in follow-up. Records of 164 women who underwent surgery for breast cancer were reviewed in this study. The basal characteristics included parity, menopausal state, medication with vitamin D, bisphosphonate, selective estrogen modulator (SERM), aromatase inhibitor (AI), gonadotrophin releasing hormone agonist (GnRHa), chemotherapy, radiotherapy, cancer type including positivity of estrogen receptor, progesterone receptor and HER2, combined the other gynecologic disease or the other origin cancer. At initial and follow-up visit, all subjective were checked with BMD, endometrial thickness (EMT). The mean age was 52.1 ± 8.5 years old and overall interval between initial and follow-up visits were 17.6 ± 7.5 month in this study. The BMDs of L1-4 (1.040 ± 0.166 g/cm2 vs 1.070 ± 0.181 g/cm2, p < 0.001), femur neck (0.850 ± 0.121 g/cm2 vs 0.870 ± 0.136 g/cm2, p < 0.001), and femur total (0.902 ± 0.132 g/cm2 vs 0.915 ± 0.138 g/cm2, p < 0.001) at follow-up visit were significantly lower than those at initial visit. The change in BMDs of L1-4 (ΔBMDL1-4, r = 0.353, p < 0.001, and r = 0.228, p = 0.003), femur neck (ΔBMDNeck, r = 0.198, p = 0.011, and r = 0.282, p < 0.001), femur total (ΔBMDTotal, r = 0.294, p < 0.001, and r = 0.327, p < 0.001) had positive correlation with age and the change in EMT (ΔEMT). After age correction, ΔEMT had positive correlation with ΔBMDNeck (r = 0.245, p = 0.002) and ΔBMDTotal (r = 0.273, p < 0.001). ΔBMDL1-4 and ΔBMDNeck differed according to menopausal state (p < 0.001 and p = 0.035), bisphosphonate (p < 0.001 and p < 0.001), and GnRHa (p < 0.001 and p < 0.001). In follow-up of women with history of breast cancer, ΔEMT could be an alternative screening marker for BMD decrease.

Eficacia y seguridad de ribociclib más fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico RH-Positivo YyHER2-Negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica / Efficacy and safety of ribociclib plus fulvestrant in postmenopausal women with HR-positive and HER2-negative metastatic breast cancer, treatment-naïve or on a prior line of endocrine therapy for metastatic disease

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con cáncer de mama metastásico, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para 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; 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 en pacientes con CMM es de aproximadamente tres años y que la tasa de sobrevida global hasta los 5 años es de aproximadamente 27%. Los tipos de medicamentos que se usan para el CMM dependen del estado menopáusico de la paciente, del estado del receptor hormonal (RH) y del receptor 2 del factor de crecimiento epidérmico humano (HER2) del cáncer. En el contexto de EsSalud, las mujeres posmenopáusicas con CMM, RH-positivo, HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica, a menudo se tratan con un inhibidor de la aromatasa (anastrozol o exemestano). El IETSI-EsSalud recibió una solicitud de evaluación de ribociclib más fulvestrant como una alternativa terapéutica al uso de inhibidores de la aromatasa, argumentándose una potencial prolongación de la sobrevida global de los pacientes, junto con un perfil de seguridad aceptable. Al respecto, el IETSI-EsSalud consideró que existe la necesidad de terapias nuevas y efectivas para los pacientes con CMM que proporcionen mejoras en la sobrevida global del paciente, tengan perfiles de toxicidad más favorables y mejoren la calidad de vida. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS, priorizándose la evidencia proveniente de ensayos clínicos controlados aleatorizados. 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 realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de ribociclib más fulvestrant, en comparación con exemestano o anastrozol, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la mejor evidencia sobre la eficacia y seguridad sobre la eficacia y seguridad de ribociclib más fulvestrant, en comparación con anastrozol y exemestano, en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica. La evidencia clave para evaluar el uso de ribociclib en combinación con fulvestrant en la población de interés proviene de MONALEESA-3, un ECA de fase III, doble ciego, controlado con placebo, de grupos paralelos. El estudio MONALEESA-3 tuvo la limitación de no responder directamente a la pregunta PICO de interés, ya que evaluó el uso de ribociclib más fulvestrant en comparación con fulvestrant solo, y no versus el comparador de interés del presente dictamen (anastrozol o exemestano). Cabe señalar que el uso de fulvestrant como monoterapia no está aprobado en EsSalud porque no se ha demostrado que sea diferente del exemestano, en términos de calidad de vida y eventos adversos en pacientes posmenopáusicas con CMM, RH-positivo y tratamiento endocrino previo, y no hay evidencia que permita generar conclusiones definitivas respecto a la sobrevida global (Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 050-SDEPFyOTS-DETS-IETSI-2016). Los resultados de MONALESSA-3 no permiten determinar un beneficio neto con ribociclib más fulvestrant en comparación con fulvestrant más placebo por las siguientes razones: i) los resultados disponibles de SG son aún preliminares (corresponden a análisis interinos) y requieren de un mayor seguimiento (resultados del análisis final de SG) para determinar si realmente existe un beneficio en la prolongación de la vida de los pacientes, más aun en vista de una modesta reducción en el riesgo de mortalidad y una gran incertidumbre en las estimaciones reportadas (amplio intervalo de confianza, con valores cercanos al valor de la no diferencia), ii) los resultados muestran que ribociclib más fulvestrant no mejora la calidad de vida de los pacientes y, iii) los resultados muestran que ribociclib más fulvestrant aumenta significativamente el riesgo de EA serios y discontinuación debido a EA asociados a la medicación. Debido a la incertidumbre en la relación de riesgo-beneficio con ribociclib más fulvestrant, en comparación con anastrozol y/o exemestano, dada principalmente por la ausencia de evidencia que responda directamente a la pregunta PICO establecida en el presente dictamen, la aprobación de uso de ribociclib más fulvestrant no sería una decisión costo-oportuna; dada la disponibilidad de tratamientos efectivos, con perfiles de seguridad aceptables y menos costosos en la institución (anastrozol y exemestano), los cuales son recomendados en las GPC internacionales más recientes para la población de interés del presente dictamen. Por lo expuesto, el IETSI no aprueba el uso de ribociclib más fulvestrant en mujeres posmenopáusicas con CMM, RH-positivo y HER2-negativo, sin tratamiento previo o con una línea previa de terapia endocrina para enfermedad metastásica.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

Effect of GnRH-antagonist, mifepristone and letrozole on preventing ovarian hyperstimulation syndrome in rat model.

RESEARCH QUESTION: Can luteolysis-targeted drugs, gonadotrophin-releasing hormone antagonist (GnRH-ant), mifepristone and letrozole, administered separately or in combination, prevent the progression of ovarian hyperstimulation syndrome (OHSS) in a rat model? DESIGN: Thirty-six female Wistar rats were randomly divided into six groups, including control group (OHSS group, ovarian hyperstimulation-induced OHSS); GnRH-ant group (OHSS with GnRH-ant treatment); mifepristone group (OHSS with mifepristone treatment); letrozole group (OHSS with letrozole treatment); combination group (OHSS with GnRH-ant, mifepristone and letrozole treatment in combination). The main outcomes were the alterations in OHSS-related indices, including ovarian weight, vascular permeability, serum oestradiol and progesterone levels, corpus luteum proportion and diameter, ovarian vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), caspase-3 and cleaved caspase-3 levels. RESULTS: No significant difference was found in body weight gain among the six groups. Compared with the control group, the OHSS group showed significant increases in all OHSS-related indices. GnRH-ant treatment showed decreases in vascular permeability, serum oestradiol level, corpus luteum diameter, ovarian VEGF /IL-6 mRNA levels, and increases in ovarian caspase-3 and cleaved caspase-3 levels. Mifepristone treatment demonstrated reduction in serum progesterone level and corpus luteum diameter, and elevation in ovarian caspase-3 and cleaved caspase-3 levels. Letrozole treatment displayed a decline in serum oestradiol level and corpus luteum diameter, and up-regulation in ovarian caspase-3 and cleaved caspase-3 levels. The combination treatment by GnRH-ant, mifepristone and letrozole showed enhanced synergistic effect on reducing OHSS-related indices. CONCLUSIONS: GnRH-ant, mifepristone and letrozole are beneficial in preventing the progression of OHSS through different luteolytic mechanisms. Cocktail style treatment shows enhanced synergistic effect on preventing the progression of OHSS.

Effect of Traditional Chinese Medicine on Musculoskeletal Symptoms in Breast Cancer: A Systematic Review and Meta-Analysis.

CONTEXT: Traditional Chinese Medicine (TCM) has been widely used as a complementary medical treatment for arthralgia and other types of pain. The available literature on the effectiveness of TCM on breast cancer patients with musculoskeletal symptoms reports controversial results. OBJECTIVES: The objective of this review is to assess the effectiveness of TCM as a treatment option for musculoskeletal symptoms in patients with breast cancer who were treated with aromatase inhibitors (AIs). METHODS: A comprehensive literature search was conducted using PubMed, the Cochrane Library, SAGE journals, Scopus, EMBASE, Web of Science, Medline, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), Wanfang, and Chinese Medical Journal Database (CMJ) from May 2020 to November 2020. The literature review included randomized controlled trials (RCTs) of TCM for AI-related musculoskeletal symptoms. RESULTS: Four RCTs incorporating TCM were assessed by meta-analysis and reported favorable effects in reducing worst pain score (n = 284, mean difference [MD]: 2.31; 95% CI, 1.74 to 2.88; P < 0.00001). Three trials showed favorable effects of TCM in reducing pain interference (n = 211, MD: 2.62; 95% CI, 1.29 to 3.94; P = 0.0001), while two trials reported no significant effects of TCM on stiffness (n = 147, MD: 1.21; 95% CI, -0.39 to 2.82; P = 0.14). The meta-analysis of three trials also found no significant effect of TCM on bone mineral density (n = 214, MD, -0.01; 95% CI, -0.07 to 0.05; P = 0.71). The physical aspect of quality of life was significantly increased in breast cancer patients after TCM treatment (n = 220, MD, 5.13; 95% CI, 2.04 to 8.22; P = 0.001). In addition, three RCTs reported minimal TCM-related adverse events. CONCLUSION: The results suggest that TCM could be an effective treatment in relieving pain especially worst pain and pain interference as well as improving quality of life caused by AI-related musculoskeletal symptoms. However, further investigation of the molecular pathway involved and in-depth safety profile are needed.

Aromatase Inhibitor Symptom Management Practices: A Retrospective Study.

PURPOSE: Aromatase inhibitor (AI)-associated symptoms contribute to early therapy discontinuation. Although guidelines exist for management of these symptoms, little is known about the degree to which physicians address symptoms and adhere to the guidelines for treatment. PATIENTS AND METHODS: In this retrospective chart review, women with hormone receptor-positive breast cancer who were prescribed an AI between October 15, 2012, and September 14, 2017, were randomly selected from the institution's cancer registry. Patient medical records were reviewed to identify the prevalence of symptom documentation and management. Documented symptoms were categorized into musculoskeletal, vasomotor, and urogenital. Symptom treatment guidelines were compiled from the National Comprehensive Cancer Network (NCCN) and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO). Treatments were categorized as either meeting or not meeting the guidelines. Among patients with symptoms recorded, chi-square tests and time-to-event models were used to examine factors associated with treatment and factors associated with guideline-based treatment. RESULTS: Among 179 women prescribed an AI, 82% had at least one symptom and 46% had multiple symptoms. Of the 147 women with any documented symptom, 97 (66%) received some form of symptom-palliating treatment. Seventy-seven patients (52%) received guideline-based treatments or guideline-based treatments in combination with non-guideline-based treatments. There were no differences in receipt of treatment overall (ie, guideline based or non-guideline based) for either vasomotor or musculoskeletal symptoms by age, race, or stage. CONCLUSION: Although 82% of patients had symptoms documented in their medical records, just over half of those patients received guideline-based treatment.

The Potential Role of Nutraceuticals as an Adjuvant in Breast Cancer Patients to Prevent Hair Loss Induced by Endocrine Therapy.

Nutraceuticals, natural dietary and botanical supplements offering health benefits, provide a basis for complementary and alternative medicine (CAM). Use of CAM by healthy individuals and patients with medical conditions is rapidly increasing. For the majority of breast cancer patients, treatment plans involve 5-10 yrs of endocrine therapy, but hair loss/thinning is a common side effect. Many women consider this significant, severely impacting on quality of life, even leading to non-compliance of therapy. Therefore, nutraceuticals that stimulate/maintain hair growth can be proposed. Although nutraceuticals are often available without prescription and taken at the discretion of patients, physicians can be reluctant to recommend them, even as adjuvants, since potential interactions with endocrine therapy have not been fully elucidated. It is, therefore, important to understand the modus operandi of ingredients to be confident that their use will not interfere/interact with therapy. The aim is to improve clinical/healthcare outcomes by combining specific nutraceuticals with conventional care whilst avoiding detrimental interactions. This review presents the current understanding of nutraceuticals beneficial to hair wellness and outcomes concerning efficacy/safety in breast cancer patients. We will focus on describing endocrine therapy and the role of estrogens in cancer and hair growth before evaluating the effects of natural ingredients on breast cancer and hair growth.

Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: A randomised controlled trial to evaluate the effect of short message service (SMS) reminder.

BACKGROUND: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors. METHODS: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat. RESULTS: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups. CONCLUSION: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability.