Aromatase Inhibitors In Postmenopausal Women Research Articles

Palbociclib or Ribociclib with Aromatase Inhibitor in Post-menopausal Women with ER+/HER2– Advanced Breast Cancer? Real-world Overall Survival Evidence

Purpose: The CDK4/6 inhibitors, palbocilib [1] and ribociclib [2,3], have shown significant improvements in progression-free survival (PFS) in ER+/HER2– advanced breast cancers. In the MONALEESA-2 trial, ribociclib showed a significant median overall survival (OS) of 63.9 months [4]. However, in the PALOMA-2 study [5], palbociclib showed a median OS of 53.9 months that was non-significant. The observed differences in OS have generated uncertainty around which CDK4/6 inhibitor to choose in routine clinical practice. In this context, real-world data analysis can be a useful guide to therapy.

Abstract PD10-08: PD10-08 Immune cell infiltration associated with poor anti-proliferative response to aromatase inhibitors in postmenopausal women with primary ER-positive HER2-negative breast cancer

Abstract Background: Aromatase inhibitors (AIs) are one of the main treatment strategies for the clinical management of estrogen receptor-positive (ER+) breast cancer (BC). Despite prolonged time to recurrence and initial clinical responses, >20% of patients eventually relapse, and previous studies have shown an association of poor anti-proliferative response to AIs and worse outcome. High immune activity in ER+ tumors may be associated with worse outcome, in contrast to ER-negative BC where immune infiltration is a feature associated with better outcome. Our work focused on understanding the correlations between immune cell infiltration and response to AI. Methods: All patients with ER+ HER2- tumors within the bottom 15% of Ki67 anti-proliferative responders to AIs (poor responders [PRs]; n=177) were selected from the PeriOperative Endocrine Therapy for Individualizing Care (POETIC) trial and matched on baseline Ki67 levels to good responders (GRs) within the 50% showing the best response (n=190). Response to AI was measured by the Ki67 percentage change after 2 weeks of treatment. PRs were further divided into groups expressing high ESR1 (PRs ESR1HIGH; n=119) and low ESR1 (PRs ESR1LOW; n=58) levels to represent PR subgroups that showed partial or no response to AIs. The percentage of stromal tumor-infiltrating lymphocytes (TILs) was assessed. Multiple immunofluorescence was performed for ER, CD3, CD20, CD68, FOXP3, and CD3/FOXP3 in 15 baseline samples from each of the GR, PR ESR1HIGH, and PR ESR1LOW populations and immune cell density in stromal or tumor compartments was estimated. Spearman correlations of TILs with Consensus tumor microenvironment (TME) deconvolution and Molecular Signatures Database hallmark gene sets were conducted. The relationship between the immune markers’ density and genes, hallmark gene sets and Consensus TME was assessed. Results: The percentage of TILs was significantly higher in the PR ESR1HIGH and PR ESR1LOW compared to the GRs (adjusted p< 0.05). As expected, TILs were highly correlated with T cells (particularly T-regulatory cells) and immune hallmark gene sets. There was a tendency for higher density of each of the immune markers in PRs compared to GRs, with significant differences being observed in stromal B-cell marker CD20 density (p< 0.05). Analysis showed a significant correlation between TILs and stromal FOXP3 marker density (FDR< 0.05), and stromal biomarker density was highly correlated to the gene expression of the encoding genes of the same tumors (CD3/CD3D, FOXP3/FOXP3, and CD20/MS4A1) (FDRs< 0.05). There was also a strong and significant correlation between the stromal expression of CD20, CD3, FOXP3, and CD3/FOXP3 with the immune hallmark gene sets (FDRs< 0.05). Finally, the immune phenotyping showed the expected correlations with TME deconvolution, with particularly strong correlations of CD20 and CD3 with B- and T-cell gene signatures, respectively (FDRs< 0.05). Conclusions: Different immune features indicated a broad involvement of several immune cell types in PRs to AIs, suggesting that the immune system might be associated with resistance of ER+ breast tumors to AI treatment. Spatial gene expression profiling is ongoing to characterize these tumors further and investigate potential mechanisms of AI resistance. Citation Format: Anastasia Alataki, Gene Schuster, Lila Zabaglo, Perry Maxwell, Elena López-Knowles, Elizabeth Folkerd, David Evans, Kally Sidhu, Holly Tovey, Nicholas Turner, Stephen Johnston, Maggie Chon U Cheang, John Robertson, Manuel Salto-Tellez, Ian Smith, Judith Bliss, Mitch Dowsett. PD10-08 Immune cell infiltration associated with poor anti-proliferative response to aromatase inhibitors in postmenopausal women with primary ER-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD10-08.

Abstract P1-02-06: Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients

Abstract Background: Poor survival outcome in young women with hormone-sensitive breast cancer was reported. And previous studies have demonstrated that the addition of ovarian function suppression (OFS) significantly improved disease-free survival (DFS) in patients with premenopausal hormone receptor–positive breast cancer. In this study, we examined whether ovarian function suppression treatment in premenopausal women is effective in survival comparable to postmenopausal status. Methods: We evaluated 1,298 breast cancer patients included in the post-trial follow-up of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial who received either tamoxifen (TAM) only (n=647) or TAM + OFS (n=635), randomly assigned in a 1:1 ratio and postmenopausal patients in AMC (Asan Medical Center; Seoul, Korea) treated with aromatase inhibitor (AI) (n=603). All patients analyzed in this study underwent surgery between March 2009 and November 2011. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS). We use propensity-score matching by lymph node status, tumor size, tumor grade, histologic type of cancer, human epidermal growth factor receptor-2 (HER2) status, chemotherapy regimen, surgical modality, and radiotherapy in the overall cohort and in separate subgroups according to anti-hormonal therapy regimens. Results: In the overall matched cohort, there was a significant difference between the postmenopausal AI group and premenopausal Tam only group in DFS (hazard ratio for the postmenopausal AI group, 0.654; 95% CI, 0.432 to 0.991) and OS was not significantly different between the premenopausal Tam only group and postmenopausal AI group (p=0.061). On the other hand, there was no significant difference between the postmenopausal AI group and premenopausal Tam+OFS group in disease free survival (hazard ratio for the postmenopausal AI group, 1.156; 95% confidence interval [CI], 0.735 to 1.820) or the overall survival (hazard ratio for the postmenopausal AI group, 1.04; 95% CI, 0.553 to 1.956). Conclusion: This study’s findings suggest that the poor prognosis of young women with hormone-sensitive breast cancer is improved by adding OFS to Tam and the effect is not inferior to that of using AI in post-menopausal women. Outcomes in a Cohort of Patients Matched for Propensity Scores postmeno AI, postmenopausal patients who treated with aromatase inhibior in Asan Medical Center; premeno Tam+OFS, premenopausal ASTRRA participants who treated with tamoxifen and ovarian function suppression; premeno Tam, premenopausal ASTRRA participants who treated with tamoxifen only Citation Format: Young-jin Lee, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Seonok Kim, Hee Jeong Kim. Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-06.

The 5-Year Disease-Free Survival of Third Generation Aromatase Inhibitor for Postmenopausal Women with HR-Positive HER2-Negative Non-Metastatic Breast Cancer.

Background: Several studies showed the superiority of aromatase inhibitor (AI) as first-line therapy for patients with hormone-receptor (HR)-positive breast cancer (BC). For the clinician, studies in the real world are warranted to determine treatment based on the efficacy of each drug. We compared a 5-y disease-free survival (DFS) of each AI in terms of survival benefit. Materials and Methods: We evaluated 450 medical records of postmenopausal women who were diagnosed with HR-positive HER2-negative BC (stage I - III) at Dr. Sardjito General Hospital from January to December 2019. All patients had undergone surgery and chemotherapy or radiation therapy. Moreover, study participants received anastrozole, letrozole, or exemestane for at least one year. Kaplan Meier estimation survival curve was used to analyze the survival rate. Result: Of 79 patients meeting inclusion criteria, there were 21.52% distant metastases documented. Time to disease progression of anastrozole, letrozole, and exemestane was 49 months, 58 months, and 53 months, respectively. Letrozole was found better than anastrozole (hazard ratio (HR)=4.342, 95% CI 0.95-19.95; p=0.038). Letrozole versus exemestane (HR=2.757, 95% CI 0.53-14.33; p=0,206) and anastrozole versus exemestane (HR=1.652, 95% CI 0.56-4.84; p=0.351) were found not significantly different. 5-y DFS rate of letrozole was better found (87.5%) than exemestane (73.7%) and anastrozole (61.4%). Conclusion: 5-year letrozole administration could be proposed as first-line therapy for postmenopausal women with HR-positive HER2-negative BC. A considerable subject and long-term follow-up are needed for validation.

Aromatase Inhibitors and Risk of Metabolic and Cardiovascular Adverse Effects in Breast Cancer Patients-A Systematic Review and Meta-Analysis.

Aromatase inhibitors (AIs) have been considered first-line therapy for patients with hormone-dependent breast cancer due to their high efficacy and good tolerability. However, AIs are not free of adverse events, and studies show that therapy with AIs is associated with an increased risk of cardiovascular events and the development of insulin resistance and diabetes. We searched the Cochrane Central Register of Controlled Trials, PubMed and EMBASE up to 27 October 2020 for the prevalence of cardiovascular and/or metabolic adverse effects during treatment with AIs in postmenopausal women with breast cancer. A meta-analysis was performed using a random effects model. Odds ratios and 95% confidence intervals were calculated and illustrated using forest plot charts. We performed separate analyses depending on trial design. Twenty two studies met the inclusion criteria. AIs were associated with a higher risk of cardiovascular events, especially when we compared study arms in which AIs were used (alone or in sequence with TAM) with the arms in which TAM was used alone (OR = 1.16; 95%CI 1.04–1.30) or when comparing patients taking AIs alone to patients taking TAM alone or in sequence with AIs (OR = 1.24; 95%CI 1.11–1.38). A pooled analysis of five trials comparing adjuvant AIs to TAM showed the odds for arterial hypertension being 1.31 times higher for patients taking AIs; however, this did not reach statistical significance (OR = 1.31; 95%CI 0.47–3.65). We have not shown an increased risk of dyslipidemia or weight gain with the use of AIs. Our results suggest that postmenopausal women with breast cancer treated with AIs have an increased risk of cardiovascular events in comparison with TAM, potentially due more to a cardioprotective effect of the latter than the cardiotoxicity of AIs. We were unable to prove a similar association for hypertension, dyslipidemia, hyperglycemia or weight gain. Further high-quality RCTs and post-marketing safety observational studies are needed to definitively evaluate the impact of AIs on metabolic disorders in breast cancer patients.

Bone Safety Profile of Steroidal Aromatase Inhibitor in Comparison to Nonsteroidal Aromatase Inhibitors in Postmenopausal Women with Breast Cancer: A Network Meta-Analysis

Background and Objectives: Aromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for postmenopausal patients with breast cancer (BC). Large trials resulted better outcomes with AIs. Adjuvant therapy with AIs reduced the risk of relapse compared with tamoxifen. Systemic therapies for BC can interfere with bone turnover, either by affecting gonadal steroid hormone production or by inhibiting peripheral aromatization into estrogen. We aimed to evaluate the safety profile of bone-related events by comparing 3 AIs with tamoxifen and a placebo. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for network meta-analyses (NMAs). Searches were performed using PubMed, Embase/Medline, Cochrane, and Ovid databases. Randomized controlled trials comparing tamoxifen and placebo or other AIs to steroidal or nonsteroidal AIs in patients with BC reporting bone-related safety events were included in NMA. NMA in a Bayesian approach was performed using R software (ver 3.2), Gemtc package. Results: Seventeen studies reporting 4 different bone-related endpoints were included. Although there was no statistical significance, treatment with exemestane lowered the incidence of bone pain (odds ratio [OR] vs. anastrozole and letrozole: 0.63, 0.54), fracture episodes (OR vs. anastrozole and letrozole: 0.84, 0.80), and osteoporosis (OR vs. anastrozole and letrozole: 0.85, 0.73) compared with letrozole and anastrozole. Reduction in bone mineral density was lesser in exemestane than in anastrozole (mean reduction in hip: 1.05; lumbar spine: 1.25). Treatment ranking with the surface under the cumulative ranking curve showed that exemestane was found to reduce the incidence of bone-related adverse events. Conclusion: A lower incidence of bone-related safety events was observed in patients treated with exemestane.

Bone safety profile of steroidal aromatase inhibitor in comparison to non-steroidal aromatase inhibitors in postmenopausal women with breast cancer: A network meta-analysis.

527 Background: Steroidal and non-steroidal aromatase inhibitors (AIs) provide better therapeutic response in comparison to other endocrine therapies in the adjuvant treatment of breast cancer (BC). They interfere with bone turnover which may lead to increased incidence of bone related safety events. There are no head-on studies comparing the incidence of bone safety events and hence we performed this network meta-analysis (NMA) to compare the incidence of bone safety events among patients treated with steroidal and non-steroidal AIs. Methods: Literature searches were performed in PubMed and Embase with key words to identify randomized controlled trials in BC patients treated with AIs in adjuvant settings compared against tamoxifen or other AIs, reporting any bone-related safety events. The study was designed as per PRISMA guidelines; publication bias was evaluated by comparison-adjusted funnel plots. Bayesian NMA was done by R software (ver 3.2), GemtC package. Odds ratio (OR) and the surface under the cumulative ranking curve (SUCRA) values were used to interpret the results. Results: 15 studies reporting 6 different bone-related endpoints were included. Treatment with steroidal AI, exemestane led to lower incidence of bone pain (OR Vs anastrozole and letrozole: 0.59, p=0.63; 0.54, p=0.75), fracture episodes (OR Vs anastrozole and letrozole: 0.84, p=0.41; 0.85, p=0.73), joint stiffness (OR Vs anastrozole: 0.55, p=0.73) and osteoporosis (OR Vs anastrozole and letrozole: 0.86, p=0.41; 0.74, p=0.29) (Table) in comparison to letrozole and anastrozole. Reduction in bone mineral density was also lesser in exemestane than anastrozole (mean reduction in hip: 1.08; lumbar spine: 1.34). SUCRA values suggested exemestane to be the drug with maximum likelihood for reducing the incidence of bone-related adverse events. Conclusions: This NMA suggested that bone-related safety events might be lower in early BC patients treated with exemestane in comparison to non-steroidal AIs, anastrozole and letrozole. Although there was no statistical significance, further head-on studies are required to substantiate our results.[Table: see text]

Neoadjuvant endocrine therapy use in early stage breast cancer during the covid-19 pandemic.

PurposePhysician treatment preferences for early stage, estrogen positive breast cancer (ER + BC) patients were evaluated during the initial surge of the COVID-19 pandemic in the US when neoadjuvant endocrine therapy (NET) was recommended to allow safe deferral of surgery.MethodsA validated electronic survey was administered May–June, 2020 to US medical oncologists (MO), radiation oncologists (RO), and surgeons (SO) involved in clinical trials organizations. Questions on NET use included practice patterns for locoregional management following NET.Results114 Physicians from 29 states completed the survey—42 (37%) MO, 14 (12%) RO, and 58 (51%) SO. Before COVID-19, most used NET ‘rarely’ (49/107, 46%) or ‘sometimes’ (36, 33%) for ER + BC. 46% would delay surgery 2 months without NET. The preferred NET regimen was tamoxifen for premenopausal and aromatase inhibitor for postmenopausal women. 53% planned short term NET until surgery could proceed. Most recommended omitting axillary lymph node dissection (ALND) for one micrometastatic node after 1, 2, or 3 months of NET (1 month, N = 56/93, 60%; 2 months, N = 54/92, 59%; 3 months, N = 48/90, 53%). With longer duration of NET, omission of ALND decreased, regardless of years in practice, percent of practice in BC, practice type, participation in multidisciplinary tumor board, or number of regional COVID-19 cases.ConclusionMore physicians preferred NET for ER + BC during the pandemic, compared with pre-pandemic times. As the duration of NET extended, more providers favored ALND in low volume metastatic axillary disease. The Covid-19 pandemic affected practice of ER + BC; it remains to be seen how this may impact outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10549-021-06153-3.

Aromatase Inhibitors in Postmenopausal Women with Hormone Receptor-Positive Breast Cancer: Profiles of Psychological Symptoms and Quality of Life in Different Patient Clusters

Background: Aromatase inhibitors (AIs) as adjuvant therapy after breast cancer (BC) surgery have demonstrated to reduce the risk of disease recurrence, to lower the risk of contralateral BC, and to improve survival when compared to tamoxifen in patients with limited-stage hormone receptor-positive (HR+) BC. However, AIs are associated with adverse events that can have a significant impact on patient quality of life (QoL). Aim: This study aimed to identify profiles of psychological symptoms and QoL in HR+ BC patients undergoing AI therapy. Method: Data were collected with questionnaires administered at three time points: AI initiation (t0); 3 months after AI initiation (t1); and 6 months after AI initiation (t2). The FACT-G, FACT-B, and FACT-ES questionnaires were used to assess QoL; psychological symptoms were assessed using the SCL-90-R. Results: 43 women were enrolled in the study (t0), and 37 completed the t1 evaluation and 29 the t2 evaluation. We found (1) a progressive decrease over time in FACT-G and FACT-ES scores, in particular in the Physical, Emotional, and Endocrine subscales, and an increase in the SOM (somatization) subscale of the SCL-90-R; (2) the presence of 4 clusters related to different psychological symptoms and QoL evolution over time; (3) that patients belonging to the cluster characterized by worsening symptoms and QoL during time differed from the others in the Emotional subscale of the FACT-B and in the GSI (Global Score), OCD (obsessive-compulsive), DEP (depression), ANX (anxiety), and SLP (sleep disorders) dimensions of the SCL-90-R and had significantly higher BMI levels; and (4) that 3 items from the SCL-90-R and 2 items from FACT Emotional Well-Being subscale were predictive of the “worst” cluster. Conclusions: Although larger studies are needed to confirm these results, our data open up new ways of investigation into the effects of AIs on QoL in HR+ BC patients.

Steroidal aromatase inhibitors have a more favorable effect on lipid profiles than nonsteroidal aromatase inhibitors in postmenopausal women with early breast cancer: a prospective cohort study.

Background:Aromatase inhibitors (AIs) influence blood lipid profiles. However, relatively few studies have directly compared the treatment effects of steroidal and nonsteroidal AIs.Methods:A prospective single-center cohort study was conducted to investigate the effects of steroidal and nonsteroidal AIs on lipid profiles during the first 24 months of endocrine therapy in hormone receptor-positive postmenopausal patients with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, while the secondary endpoints were changes in lipid profiles and lipid event-free survival.Results:Comparison of the lipid profiles of the two groups showed that triglycerides (TGs) and total cholesterol (TC) levels were significantly higher in the nonsteroidal AI group over 24 months (p < 0.05), whereas low-density lipoprotein cholesterol (LDL-C) was significantly higher only at 3 months (p = 0.017) and 6 months (p = 0.026). High-density lipoprotein cholesterol (HDL-C) was significantly lower in the steroidal group at all time points (p < 0.05), except at 18 months (p = 0.085). The cumulative incidence of lipid events in the steroidal and nonsteroidal groups at 24 months was 25.3% and 37.0%, respectively. Multivariate analysis results indicated that TG, LDL-C, and steroidal AIs were independently associated with blood lipid events.Conclusion:This trial showed that a significantly higher cumulative incidence of lipid events occurred in the nonsteroidal AI group than in the steroidal AI group, which indicated that steroidal AIs exerted a protective effect against blood lipid events in postmenopausal women receiving an AI as adjuvant therapy for breast cancer.ClinicalTrials.gov identifier:NCT02765373

The effects of adjuvant endocrine therapy on bone health in women with breast cancer.

In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.

Abstract P4-14-09: A nationwide data on the cardiovascular protective effect of tamoxifen and aromatase inhibitor in postmenopausal women with breast cancer

Abstract A large proportion of breast cancer patients receive hormonal therapy as their adjuvant treatment options. For postmenopausal women, the initial choice for the hormonal therapy is aromatase inhibitor (AI), and tamoxifen (TM) is reserved for women experiencing severe side effects against AI or having low bone density. An important but unresolved clinical question regarding the use of AI in postmenopausal women is the safety of AI regarding the risk cardiovascular events. Studies have shown inconsistent results over the cardiovascular safety of AI and TM. In this study, we investigated the risk of developing cardiovascular and cerebrovascular events in women with breast cancer who receive hormonal therapy using AI, TM, or both. To this end, we used the National Health Insurance Sharing Service in Korea which is provided by National Health Insurance Service. The database provides anonymized insurance data for research purposes after the approval of the review committee. In the database, we identified 47,569 women with the age older than 55 who were diagnosed with breast cancer. Patients were classified as no hormonal treatment group (n=18,807), AI group (n=19,584), TM group (n=7,081), or Switch group (n=2,097). The Switch group was defined as the women with history of both AI and TM prescriptions. During the studied period, a total of 2,032 cardiovascular or cerebrovascular events (CVE) were recorded. Overall, the women prescribed with TM had significantly less hazard ratio for developing CVE when compared to the women who did not receive any hormonal treatment (HR 0.809 95% C.I. 0.706-0.928). However, this protective effect of tamoxifen was not observed in either AI or Switch group (HR 0.917 95% C.I. 0.833-1.010, and HR 0.856 95% C.I. 0.695-1.053, respectively). The protective effect of TM was also similar in women older than 60 (HR 0.808 95% C.I. 0.696-0.938). The cardiovascular and cerebrovascular protective effects of tamoxifen was also substantial in high risk women defined by their family history of cardiovascular diseases and the diagnosis of hypertension or diabetes. Our results suggest that the use of TM is associated with a substantial protective effect against developing cardiovascular or cerebrovascular events in women with breast cancer. However, the protective effect was not observed for women receiving AI. Our data suggest the potential tailored approach in hormonal treatment in breast cancer patients who are at high risk of cardiovascular of cerebrovascular events. Citation Format: Moon H-G, Choi SH, Park Y, Jung JG, Ju YW, Kim KE, Kim Y, Lee E, Lee H-B, Han W, Noh D-Y, Yoon H-J. A nationwide data on the cardiovascular protective effect of tamoxifen and aromatase inhibitor in postmenopausal women with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-09.

Extended duration of adjuvant aromatase inhibitor in breast cancer: a meta-analysis of randomized controlled trials.

The risk of hormone positive breast cancer extends beyond 5 years. Extended duration of tamoxifen to 10 years has been shown to improve overall survival (OS) and disease-free survival (DFS). In post-menopausal women aromatase inhibitor (AI) is the gold standard for adjuvant endocrine therapy. Several randomized controlled trials (RCTs) showed benefit with extending the duration of AIs in post-menopausal women. However, the duration and the overall benefit is still controversial. Eligible 8 RCTs comprising of 17,190 participants were included in this meta-analysis. Extending the duration of AI did not show any statistically significant advantage in OS with OR of 1.033 (95% CI: 0.925-1.154, P=0.56), DFS OR of 1.049 (95% CI: 0.930-1.185, P=0.435), recurrence-free survival (RFS) OR of 1.063 (95% CI: 0.952-1.187, P=0.276), and contralateral breast cancer (CBC) OR of 1.094 (95% CI: 0.920-1.301, P=0.311). Higher rates of side-effects of arthralgia, myalgia, hot flushes and bone toxicity was seen among the extended AI group. Based on this meta-analysis and current literature review, extended use of AI after 5 years of endocrine therapy should be used in selected women with high risk tumour factors. Molecular markers and genomic profiling may assist in identifying the high-risk patients. It is important to consider quality of life and patient satisfaction when considering extending the duration of AI.

Efficacy and safety of fulvestrant in postmenopausal patients with hormone receptor-positive advanced breast cancer: a systematic literature review and meta-analysis.

This meta-analysis was conducted to compare the efficacy and safety of fulvestrant with aromatase inhibitors in postmenopausal women with hormone receptor-positive (estrogen and/or progesterone receptor positive) advanced breast cancer. Electronic databases were searched for randomized controlled trials comparing the efficacy and safety of fulvestrant with three aromatase inhibitors (anastrozole/letrozole/exemestane) published through August 31, 2017. Time to progression/progression-free survival was the primary outcome, while overall survival and safety were the secondary outcomes. Time to progression/progression-free survival was evaluated in subgroups determined on age, hormone receptor status, visceral metastasis, and measurable disease. Hazard ratios with 95% confidence intervals were analyzed by STATA 12.0. Total of seven randomized controlled trials, with 3168 patients were included for analysis. In the overall population, fulvestrant and aromatase inhibitors had similar time to progression/progression-free survival (Hazard ratio 0.93; 95% confidence interval 0.86-1.01, P = 0.102); however, time to progression/progression-free survival for fulvestrant 500mg was significantly longer compared with aromatase inhibitors (hazard ratio 0.75; 95% confidence interval 0.62-0.91, P = 0.003). Subgroup analysis revealed significant prolongation of time to progression/progression-free survival with fulvestrant compared with aromatase inhibitors in the patients of estrogen and progesterone receptor-positive (hazard ratio 0.86; 95% confidence interval, 0.75-0.98, P = 0.022) and patients aged ≥ 65years (hazard ratio 0.81; 95% confidence interval 0.68-0.96, P = 0.014). Overall survival was similar in both groups (hazard ratio 0.89; 95% confidence interval 0.70, 1.13, P = 0.334). In postmenopausal women with estrogen and/or progesterone receptor-positive advanced breast cancer, fulvestrant 500mg showed better efficacy than aromatase inhibitor, which was not seen with fulvestrant 250mg. Compared to aromatase inhibitors, fulvestrant prolonged time to progression/progression-free survival in the subgroups including estrogen and progesterone receptor-positive patients and those aged ≥ 65years.

In vitro and in vivo metabolic investigation of the Palbociclib by UHPLC-Q-TOF/MS/MS and in silico toxicity studies of its metabolites

Palbociclib (PAB) is a CDK4/6 inhibitor and U. S Food and Drug Administration (FDA) granted regular approval for the treatment of hormone receptor (HR) positive, metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women. Metabolite identification is a crucial aspect during drug discovery and development as the drug metabolites may be pharmacologically active or possess toxicological activity. As there are no reports on the metabolism studies of the PAB, the present study focused on investigation of the in vitro and in vivo metabolic fate of the drug. The in vitro metabolism studies were carried out by using microsomes (HLM and RLM) and S9 fractions (Human and rat). The in vivo metabolism of the drug was studied by administration of the PAB orally to the Sprague–Dawley rats followed by analysis of urine, faeces and plasma samples. The sample preparation includes simple protein precipitation (PP) followed by solid phase extraction (SPE). The extracted samples were analyzed by ultrahigh-performance liquid chromatography–quadruple time-of-flight tandem mass spectrometry (UHPLC/Q-TOF/MS/MS). A total of 14 metabolites were detected in in vivo matrices. The PAB was metabolized via hydroxylation, oxidation, sulphation, N-dealkylation, acetylation and carbonylation pathways. A few of the metabolites were also detected in in vitro samples. Metabolite identification and characterization were performed by using UHPLC/Q-TOF/MS/MS in combination with HRMS data. To identify the toxicity potential of these metabolites, in silico toxicity assessment was carried out using TOPKAT and DEREK softwares.

Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment.

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Abstract P3-11-02: A randomized phase II trial of toremifene (120 mg) versus fulvestrant (500 mg) after prior non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer (Hi-FAIR fx study)

Abstract Background: After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with advanced/metastatic breast cancer (BC), it is unclear which of the various kinds of endocrine monotherapy is the most appropriate. In a previous report it was found that toremifene 120 mg (TOR 120), a selective estrogen receptor modulator (SREM), was superior to steroidal AI in terms of progression-free survival after ns-AI in the Hi-FAIR ex trial. A phase II randomized trial of TOR 120 versus fulvestrant 500 mg (FUL 500), a selective estrogen receptor down regulator (SERD), was also conducted to select the most promising endocrine monotherapy after ns-AI in advanced/metastatic BC(Study registry number: UMIN000010087). Patients and Methods: Postmenopausal women (n=106) with advanced/metastatic hormone-receptor positive BC from October 2011 to September 2014 were enrolled in this study. Fifty-three of the patients were randomly assigned to the TOR 120 (120 mg daily p.) group and 53 of the patients were randomly assigned to the FUL 500 group. In the FUL 500 group they were administered 500 mg of fulvestrant intramuscularly (im) on day 0, then 500 mg im on days 14 and 28 and every 28 days thereafter). If treatment failure occurred in either of the randomly assigned groups the patients were then removed and treated accordingly. A full analysis set was targeted for all cases that received the protocol treatment even once (TOR 120 (n=53) and FUL 500 (n=52)). The primary end point was the clinical benefit rate (CBR). The secondary end points were the objective response rate (ORR), progression-free survival (PFS), time to chemotherapy (TTCT), overall survival (OS), toxicity, and CBR, ORR and PFS after crossover of non-assigned treatment. Results: A median follow up period of 30 months revealed that the CBR of FUL 500 (57.7%) tended to be superior to the CBR of TOR 120 (45.3%), the odds ratio (OR) was 1.70 (95% CI 0.74–3.62), and the median PFS was 7.8 months in the FUL 500 group and 5.8 months in the TOR 120 group. Moreover the hazard ratio (HR) was 0.79 (95% CI 0.52–1.21). However, there was no difference between the two groups in terms of ORR (17.7% and 15.1%, respectively), TTCT (13.3 months vs. 17.7 months, HR = 0.94 (95%CI 0.57 – 1.53)), and OS (33.4 months vs. not reached HR 1.29; 95% CI 0.80–2.09). At the cross-over phase, 33 and 24 patients after failure of assigned treatment were treated with FUL 500 and TOR 120, respectively. The CBR and PFS of FUL 500 after TOR 120 was better than that of TOR 120 after FUL 500 (CBR; 42.4% vs. 20.8%, OR = 0.33, 95%CI 0.09 – 1.11, median PFS; 6.2 months vs. 3.4 months; HR = 1.95, 95%CI 1.08–3.51). No difference between the two groups was observed in PFS from randomization to the end of the crossover phase. Moreover, there were few severe adverse events in either of the two groups. Conclusions: FUL 500 used as a subsequent endocrine therapy for advanced/metastatic BC patients who failed ns-AI could potentially be more effective than TOR 120. However, the efficacy of SERM after failure of FUL 500 may be limited. Citation Format: Nishimura R, Yamamoto Y, Narui K, Kijima Y, Hozumi Y, Ikeda M, Takao S, Ohtani S, Iwase H. A randomized phase II trial of toremifene (120 mg) versus fulvestrant (500 mg) after prior non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer (Hi-FAIR fx study) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-02.

Targeting HER2 by Combination Therapies.

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor–Positive Metastatic Breast Cancer: ALTERNATIVE. December 15, 2017 ARTICLE CITATION DOI: 10.1200/JCO.2017.77.1899 Journal of Clinical Oncology - published online before print January 30, 2018 PMID: 29381433 Targeting HER2 by Combination Therapies Ana Ruiz-SaenzxAna Ruiz-SaenzSearch for articles by this author and Mark M. MoasserxMark M. MoasserSearch for articles by this author Show More Ana Ruiz-Saenz, University of California at San Francisco, San Francisco, CA; and Mark M. Moasser, University of California at San Francisco, San Francisco, CA https://doi.org/10.1200/JCO.2017.77.1899 First Page Full Text PDF Figures and Tables © 2018 by American Society of Clinical Oncology Companion Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor–Positive Metastatic Breast Cancer: ALTERNATIVE

Pharmacogenetics of Aromatase Inhibitors in Endocrine Responsive Breast Cancer: Lessons Learnt from Tamoxifen and CYP2D6 Genotyping

Genetics play a significant role in drug metabolism of endocrine therapy of breast cancer. These aspects have been studied extensively in patients on tamoxifen, but the pharmacogenetics of aromatase inhibitors are less established. In contrast to the protective effect of tamoxifen, aromatase inhibitors are linked with an increased risk for bone loss and fractures. This review outlines key issues in the implementation of pharmacogenetics of cytochrome P450 and tamoxifen as a model for optimal use of aromatase inhibitors in postmenopausal women with estrogen receptor positive breast cancer. Lessons learnt from the association between tamoxifen and CYP2D6 genotyping were applied to identify polymorphisms with the potential to change clinical decision-making in patients on aromatase inhibitors. The ability of next generation sequencing to supersede single-gene analysis was furthermore evaluated in a subset of breast cancer patients on aromatase inhibitors selected from a central genomics database. Methodological flaws in major randomised controlled trials and continued referral to incorrect results in expert consensus statements are important factors delaying the implementation of CYP2D6 pharmacogenetics in tamoxifen treatment. This highlighted the importance of a clinical pipeline including comprehensive genotyping, to define the target population most likely to benefit from aromatase inhibitor pharmacogenetics. The clinical utility of CYP2D6 genotyping is well-established in patients at increased risk of tamoxifen resistance due to cumulative risk. The pharmacogenetics of CYP19A1 requires further clarification in terms of bone risk assessment for appropriate use in the treatment algorithm of high-risk patients at the onset of aromatase inhibitors.

Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score–matched cohort study

BackgroundManagement of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters. MethodsAmong 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography. ResultsAmong 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m2), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol–lowering effect of TMX. ConclusionsTMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C.