Hormone Therapy Group Research Articles

Effect of cyclin-dependent kinase 4 and 6 inhibitors (CDKIs) on body composition (BC) in patients (pts) with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC).

e13033 Background: CDKIs with endocrine therapy (ET) is first-line treatment in HR+/HER2- MBC. Mouse models have shown that CDKIs prevent pRB phosphorylation in the mediobasal hypothalamus, a pathway hyper-activated in diet-induced obesity; and CDKIs lead to fat mass decrease without significant effect on lean mass. We aimed to assess the impact of CDKIs on weight (wt) and BC in pts with HR+/HER2- MBC. Methods: We identified pts with HR+/HER2- MBC who received CDKIs and ET from 2015-2018. To isolate the effect of CDKIs on BC, we identified another cohort of pts who only received ET. Body mass index (BMI), wt, and computed tomography (CT) records were reviewed. BC was analyzed at L3 on CT scans using Tomovision’s SliceOmatic v5.0 and included skeletal muscle area (SMA), skeletal muscle density (SMD), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and muscle adiposity (MA). Total adipose tissue (TAT) was defined as SAT+VAT+MA. BC changes at 3 and 6 months of therapy were evaluated using paired t-tests. Results: There were 107 pts who received CDKI plus ET - 43% were Black, and 41% were Hispanic. CDKIs used were palbociclib (85%), abemaciclib (9%), and ribociclib (6%). ETs used were letrozole (47%), fulvestrant (39%), anastrozole (12%), and exemestane (2%). Median number of prior chemo and ET lines was 0 (range 0-5). 63 pts received ET alone. There was no difference in age (63 vs. 65 years, p = 0.26), BMI (28.80 vs. 28.12kg/m2, p = 0.48), and visceral disease (69% vs. 65%, p = 0.64) between CDKI plus ET and ET alone group. At month 3 of CDKI plus ET, there was a significant decrease in wt (-0.30kg, Interquartile range [IQR] -2.55-0.95, p = 0.02), BMI (-0.12kg/m2, IQR -1.06-0.46, p = 0.02), SAT (-8.05cm2, IQR -32.58-14.74, p = 0.01), and TAT (-8.51cm2, IQR -50.42-17.84, p < 0.01), with similar results at month 6. These findings were not seen in pts on ET only at 3 months (wt: 0.00kg, IQR -2.65-2.38, p = 0.98; BMI: 0.00kg/m2, IQR -1.07-0.91, p = 0.93; SAT: -2.97cm2, IQR -26.10-25.15, p = 0.60; TAT: -0.58cm2, IQR -44.39-27.43, p = 0.18), or at 6 months. There were no significant changes in VAT, SMA, SMD, or MA in both groups at 3 or 6 months. In the CDKI plus ET group, baseline wt (74.64 vs. 72.72kg, p = 0.60), BMI (29.21 vs. 27.88kg/m2, p = 0.31), and SAT (280.29 vs. 252.75cm2, p = 0.31) were not significantly different for those who did or did not develop grade 3/4 toxicities. We obtained similar results when stratifying toxicities into hematological- and GI-related events. Conclusions: CDKIs are associated with decrease in BMI and SAT with no significant effect on VAT, SMA, or SMD. Given the known effect of obesity on breast cancer prognosis, CDKIs may have an additional effect on breast cancer prognosis by modulating body fat. Further studies are required to determine if decrease in SAT is associated with breast cancer outcomes or toxicities in pts on CDKIs.

146P Impact of breast cancer treatment on sexual health in pre-menopausal women

With increasing awareness and provision of better treatment modalities, younger women with breast cancer have increased survival. However, due to long term treatment related side effects, they experience an overall decline in sexual health. The study aimed to analyze the incidence of sexual dysfunction in breast cancer survivors and the impact of various treatment modalities on female sexuality. All non-metastatic pre-menopausal women diagnosed with breast cancer or undergoing therapy for breast cancer were enrolled in the study between January to December 2020; and were assessed by Female Sexual Function Index questionnaire (FSFI) before starting therapy, immediately (4 weeks) after completion of therapy and at 3 months follow up. Comparison of FSFI scores between patients who underwent mastectomy versus breast conservation surgery (BCS) and patients on hormonal therapy versus non-hormonal therapy on follow up was done. A total of 150 patients were included in the study. Seventy percent patients underwent mastectomy (n=104) and the rest underwent BCS (n=46). Based on the cut off of 26.55, 82.6% (124) patients had persisting sexual dysfunction at 3 months post treatment. The median scores of BCS group was significantly better than mastectomy group at 3 months (22.85 +/- 2.19 versus 21.75 +/- 2.09, p= 0.002). When individual domains were compared between the two groups at 3 months, arousal, lubrication, orgasm and pain showed more reduction in patients undergoing MRM as compared to BCS, however the differences were not statistically significant. Median FSFI scores were comparable in patients receiving hormonal therapy, versus non- hormonal therapy group (22.3 +/- 2.15 versus 21.9 +/- 2.23, p=0.718). When individual domain were compared desire, arousal and pain showed more reduction in hormonal group as compared to non-hormonal group, however the differences were not statistically significant. Overall, high incidence of sexual dysfunction was seen in breast cancer survivors, which was significantly more in patients who underwent mastectomy. Further studies are needed to address sexual dysfunction in breast cancer survivors and measures to alleviate the same.

Impact of adjuvant endocrine therapy on prognosis in small hormone receptor-positive, HER2-negative early breast cancer.

The efficacy of adjuvant endocrine therapy for hormone receptor-positive breast cancer has been previously established. However, significant adverse events related to endocrine therapy cannot be ignored. T1 breast cancer is expected to have a good prognosis. Therefore, adjuvant endocrine therapy for T1a breast cancer patients is controversial. Thus, in this study, we examined the effect of endocrine therapy on the prognosis of T1N0 hormone receptor-positive, HER2-negative breast cancer patients in each tumor size group, and re-considered the application of endocrine therapy. We retrospectively obtained clinical and pathological data from medical records of 7635 patients who underwent surgery for breast cancer at Aichi Cancer Hospital between January 2000 and December 2017. The primary end point of our analysis was disease-free survival (DFS). The secondary end points were distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS). The log-rank test, cumulative survival generated curves with Kaplan-Meier methods and the hazard ratio (HR) calculated with a Cox regression model were used to assess the effects of endocrine therapy on prognosis. The 5-year DFS was worse in the non-endocrine therapy (non-ET) group (78%) than the endocrine therapy (ET) group (95%) in the T1c population (p < 0.001, HR 0.25). However, there was no statistically significant difference in DFS between the ET and the non-ET groups in T1a (ET 96% vs non-ET 93%, p = 0.9314, HR 0.94) and T1b (ET 96% vs non-ET 93%, p = 0.1481HR 0.53) breast cancer. The OS, DDFS, and BCSS of the patients also showed that endocrine therapy was associated with improvement of the prognosis in the T1c group, but not in the T1a and T1b groups. Adjuvant endocrine therapy may be essential for T1c breast cancer patients. In contrast, this therapy should be discussed for T1a and T1b luminal breast cancer patients under some circumstances, such as suffering from adverse events.

Impact of adjuvant endocrine therapy in older patients with comorbidities and estrogen receptor‐positive, node‐negative breast cancer—A National Cancer Database analysis

Data are lacking about the benefit of adjuvant endocrine therapy (ET) in older patients with multiple comorbidities. The authors sought to determine the effect of ET on the survival of older patients who had multiple comorbidities and estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, pathologic node-negative (pN0) breast cancer. Women aged ≥70 years in the National Cancer Database (2010-2014) with Charlson/Deyo comorbidity scores of 2 or 3 who had pathologic tumor (pT1)-pT3/pN0, ER-positive/HER2-negative breast cancer were divided into 2 cohorts: adjuvant ET and no ET. Propensity scores were used to match patients based on age, comorbidity score, facility type, pT classification, chemotherapy, surgery, and radiation therapy. A Cox proportional hazards model was used to estimate the effect of ET on overall survival (OS). In the nonmatched cohort (n = 3716), 72.8% of patients received ET (n = 2705), and 27.2% did not (n = 1011). The patients who received ET were younger (mean age, 76 vs 79 years; P < .001) and had higher rates of breast conservation compared with those who did not receive ET (lumpectomy plus radiation: 43.4% vs 23.8%, respectively; P < .001). In the matched cohort (n = 1972), the median OS was higher in the ET group (79.2 vs 67.7 months; P < .0001). In the adjusted analysis, ET was associated with improved survival (hazard ratio, 0.70; 95% CI, 0.59-0.83). In older patients who have pN0, ER-positive/HER2-negative breast cancer with comorbidities, adjuvant ET was associated with improved OS, which may have been overestimated given the confounders inherent in observational studies. To optimize outcomes in these patients, current standard recommendations should be considered stage-for-stage based on life expectancy and the level of tolerance to treatment.

Abstract PS13-01: Primary analysis of OVERSTEP: A multicenter, randomized clinical trial of capecitabine or endocrine therapy as a maintenance therapy after the 1st-line chemotherapy in hormone receptor positive and HER2-negative advanced/metastatic breast cancer

Abstract Background: Endocrine therapy(ET) and Chemotherapy(CT) are used as standard maintenance therapy for HR+ and HER2- metastatic breast cancer(MBC) in clinical practice. There was no prospective study data on which is better. In OVERSTEP, we provide some strong evidence for clinical practice. Methods: OVERSTEP(NCT02597868) is a multicenter, randomized, open-label, prospective clinical trial that enrolled 181 patients in China. patients aged 18-70 years without chemotherapy for ABC/MBC previously, histologically confirmed metastatic HR+ and HER2- breast cancer, and ECOG performance status of 0-1. These patients were received capecitabine plus another chemotherapy drug as 1st-line salvage chemotherapy at least 4 cycles. The patients response are CR, PR and SD carried maintenance treatment next, randomly assigned (1:1) to receive either capecitabine single or endocrine therapy. Randomization was done centrally with stratification by endocrine resistance and visceral metastasis. The primary endpoint was progression-free survival(PFS) and analyses were base on all patients who received at least one dose maintenance therapy. We take superiority test in the 2 groups. Results: 136(75.14%) patients were randomized after combined chemotherapy to capecitabine single or endocrine therapy groups for maintenance treatment. 45(24.86%) patients are progress disease (PD) after combined chemotherapy. After a median follow-up of 24.3 months (IQR 20.46-37.25 ) in the endocrine maintenance therapy group and 24.1 months(IQR 20.67-36.77) in the Capecitabine maintenance therapy group ,the hazard ratio for PFS was 0.625(95%CI 0.429-0.909 P=0.013),Median PFS was 17.5 months(95%CI 11.544-23.856) in endocrine maintenance therapy group and 12,2 months(95%CI 11.170-13.230) in capecitabine maintenance therapy group. In endocrine sensitive group, the hazard ratio for PFS was 0.515(95%CI0.269-0.988 P=0.042), Median PFS was 29.3 months(95%CI 14.605-43.995) in endocrine maintenance therapy group and 14.8 months(95%CI 7.445-22.155) in capecitabine maintenance therapy group. In endocrine resistance group, the hazard ratio for PFS was 0.791(95%CI 0.499-1.253 P=0.314), Median PFS was 13.6 months(95%CI 9.111-18.089) in endocrine maintenance therapy group and 12.0 months(95%CI10.357-13.643) in capecitabine maintenance therapy group. In visceral metastasis group, the hazard ratio for PFS was 0.668(95%CI0.410-1.089 P=0.101), Median PFS was 14.3 months(95%CI 11.113-17.487) in endocrine maintenance therapy group and 11.0 months(95%CI 8.140-13.860) in capecitabine maintenance therapy group. In non-visceral metastasis group, the hazard ratio for PFS was 0.54(95%CI0.300-0.972 P=0.037), Median PFS was 25.3 months(95%CI 15.278-35.322) in endocrine maintenance therapy group and 17.0months(95%CI 10.783-23.217) in capecitabine maintenance therapy group. Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, ET maintenance has a better survival benefits than CT,especially for ET-sensitive and non-visceral involved cases. So ET maintenance is the first choice for ABC/MBC after 1st-line combined chemotherapy. Citation Format: Jian Huang, Xiying Shao, Li Cai, Yanxia Shi, Zhanhong Chen, Ping Huang, Yongmei Yin, Lili Zhang, Peng Shen, Wenming Cao, Weiwu Ye, Yuan Huang, Caijin Lou, Lei Lei, Yabin Zheng, Weibin Zou, Junqing Chen, Xiaojia Wang. Primary analysis of OVERSTEP: A multicenter, randomized clinical trial of capecitabine or endocrine therapy as a maintenance therapy after the 1st-line chemotherapy in hormone receptor positive and HER2-negative advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-01.

Abstract PS5-19: Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study

Abstract Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS. Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p&amp;lt;0.05) in compared to no survival difference in Arm B (p=0.284). PFS difference between LumA and LumB was not statistically significant in Arm A (p=0.196). PIK3CA mutation (41%), TP53 mutation (33%), GATA3 mutation (25%), CCDN1 CNV (29%), BRCA2 mutation (14%) were the most frequently detected in this population. High TMB, TP53 mutation, ClinVar pathogenic somatic BRCA2 mutation (3.5%) showed worse prognosis in Arm A (p&amp;lt;0.05). Non-luminal patients with TP53 or BRCA2 mutations were poor prognosis in Arm A. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless PAM50 subtypes, and luminal patients showed longer PFS compared to non-luminal patients among patients without BRCA2 pathogenic mutations in Arm A. RB1 loss, known as a resistant biomarker of CDK4/6 inhibitor was found in 4% of Arm A, and was associated with shorter PFS (log2 HR=2.26, 95% CI 0.51 to 4.01, p=0.011). AURKA mutation/amplification and RAD51C amplification were significantly associated to the patients with PFS less than 6 month. ESR1 mutations were found in 3.5% of patients, which was less than PEARL (29.4%) and PALOMA-3 (25.1%) trials. ESR1 mutations and ESR1/2 expression were not associated with shorter PFS. Notch 2/3/4 pathway expression was lower in patients with longer PFS (PFS more than 20month). ETIMATE ImmuneScore was higher in non-luminal compared to luminal patients, and didn’t show survival difference in Arm A, but luminal patients with low ImmuneScore showed better prognosis. The relative proportion of 22 immune cell types was deconvoluted by CIBERSORT, and T cell CD4 memory resting, Macrophage M0 and M2 were abundant. NK cell activated was higher proportion in patients with longer PFS. Low TIL patients with low interferon and high T cell regulation expression showed worse prognosis. Germline BRCA mutation and integrated analyses of genomic and transcriptomic profiles will be reported. Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746. Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-19.

Body Composition Analysis of 10 Years versus 5 Years of Adjuvant Endocrine Therapy in Patients with Nonmetastatic Breast Cancer.

Objective Our study aims to investigate the association of extended adjuvant endocrine therapy with disease-free survival (DFS), muscle mass, muscle strength, and visceral adipose tissue in patients with nonmetastatic breast cancer and the effect of extended endocrine therapy on body composition. Patients and Methods. Patients (N = 90) with nonmetastatic breast cancer aged between 60 and 65 years old were prospectively recruited in this study, compromising a cohort of subjects rece iving 5 years or 10 years of adjuvant endocrine therapy. Patients' DFS was compared between these two groups. Patients' body composition including muscle and fat using CT scans, muscle strength, and gait speed was evaluated in these two groups. Results Dietary behavior was recorded with the food frequency questionnaire (FFQ). Patients' age, body weight, and body mass index (BMI) did not differ between the two groups. An extended adjuvant endocrine therapy into 10 years could translate into DFS benefit (123.8 vs. 102.2 months, P=0.038). Patients receiving 10 years of adjuvant endocrine therapy had less skeletal muscle and more visceral fat compared with patients receiving 5 years of adjuvant endocrine therapy. The skeletal muscle index was 50.3 ± 1.6 cm2/m2 versus 46.5 ± 1.3 cm2/m2 in the 10 years or 5 years of adjuvant endocrine therapy group (P=0.042). The visceral fat was 28.9 ± 2.9 cm2/m2 versus 55.0 ± 3.2 cm2/m2 in the 10 years or 5 years of adjuvant endocrine therapy group (P=0.011). The muscle strength, gait speed, and FFQ results in the two groups not reaching statistical difference. Conclusion In conclusion, breast cancer patients with 10 years of adjuvant endocrine therapy had DFS benefit, but with more muscle loss and adipose tissue deposits compared to patients receiving 5 years of adjuvant endocrine therapy.

Efficacy and Safety of Acupuncture Vs. Hormone Therapy for Menopausal Syndrome: A Systematic Review and Meta-Analysis.

Menopausal syndrome (MPS) is a common gynecological disorder around the time of menopause, and hormone therapy (HT) is the first-line treatment for it. However, HT is prone to cause adverse reactions in MPS patients treated with HT. Acupuncture is a popular non-pharmaceutical therapy for MPS, but the differences in the efficacy and safety between acupuncture and HT remain unclear. The purpose of this evidence-based study is to address this issue. Five databases were searched for potentially eligible RCTs. All RCTs comparing acupuncture with HT in the treatment of MPS were included in this study. The clinical effective rate was the primary outcome. Kupperman index, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E[Formula: see text], and side effects were the secondary outcomes. A total of 15 RCTs recruiting 1376 MPS patients were included. Results of meta-analysis showed that compared with HT, acupuncture significantly improved clinical effective rate (RR = 1.09, 95% CI 1.03 to 1.16, [Formula: see text] = 0.005), decreased the Kupperman index (WMD = -2.55, 95% CI = -2.93 to -2.17, [Formula: see text] < 0.00001) and the incidence of side effects (RR = 0.14, 95% CI = 0.06-0.32, [Formula: see text] < 0.00001). There were no statistically significant differences in serum FSH (WMD = -1.36, 95% CI = -3.25-0.53, [Formula: see text] = 0.16), E2(WMD = -1.11, 95% CI = -2.59-0.37, [Formula: see text] = 0.14), or LH (WMD = -1.87, 95% CI = -4.58-0.83, [Formula: see text] = 0.17) between the acupuncture and HT groups. Based on the current evidence, manual acupuncture is safer and more effective than HT and is recommended for the treatment of MPS, but the evidence for the efficacy of other types of acupuncture is inconclusive.

A multicenter analysis of treatment patterns and clinical outcomes of subsequent therapies after progression on palbociclib in HR+/HER2- metastatic breast cancer.

Introduction:Endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) are standard treatment options for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer (MBC). However, the efficacy of standard subsequent therapies after CDK4/6i-based treatment is unclear. This study aimed to examine physician practice patterns and treatment outcomes of subsequent therapies administered after progression on palbociclib therapy in clinical practice.Methods:The study included 200 patients with HR+/HER2– MBC who underwent subsequent treatments after progressing on palbociclib-based regimens in five Chinese institutions between August 2017 and April 2020. The treatment pattern, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were reported.Results:A total of 200 patients were included, of whom 147 (73.5%) and 53 (26.5%) received subsequent chemotherapy and endocrine therapy, respectively. The frequently used monochemotherapy regimens were taxane (n = 29), capecitabine (n = 21), and vinorelbine (n = 17), while the endocrine therapy regimens were chidamide plus exemestane (n = 16) and everolimus plus exemestane (n = 9). The overall median PFS (mPFS) was 5.5 months, with no significant difference in mPFS between the chemotherapy and endocrine therapy groups (p = 0.669). However, among patients not sensitive to prior palbociclib treatment, those administered chemotherapy had significantly longer PFS than those administered endocrine therapy (p = 0.006). The mPFS with endocrine therapy after first-, second-, and subsequent-line palbociclib was 13.4, 3.1, and 4.1 months, respectively (p = 0.233); in contrast, the mPFS with chemotherapy was 7.2, 6.5, and 4.9 months after first-, second-, and subsequent-line palbociclib, respectively (p = 0.364). The median OS was not achieved. The ORR was 10.6% among the 198 patients included in the analysis.Conclusions:Physicians prefer chemotherapy over endocrine therapy for the treatment of patients with HR+/HER2– MBC who develop progression on palbociclib. Sensitivity to previous palbociclib treatment might be one of the indicators for predicting response to subsequent treatment.ClinicalTrials.gov identifier: NCT04517318

Implications of Tamoxifen Resistance in Palbociclib Efficacy for Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Subgroup Analyses of KCSG-BR15-10 (YoungPEARL).

PurposeYoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study.Materials and MethodsPatients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC.ResultsIn total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients.ConclusionThis post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2− MBC patients irrespective of tamoxifen sensitivity.

Preservation of white matter integrity on DTI 3 years after early menopausal hormone therapies

AbstractBackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.MethodParticipants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fractional anisotropy (FA) and mean diffusivity (MD) differences between treatment groups (uncorrected p&lt;0.001).ResultVoxel based analysis showed higher FA, a measure of white matter integrity, in the superior corona radiata, anterior limb of the internal capsule and splenium of the corpus callosum of participants treated with oCEE compared to placebo (p &lt;0.001, Figure 1A). Furthermore, higher FA was observed in the superior corona radiata, anterior limb of internal capsule and thalamus in participants treated with tE2 compared to placebo (p &lt;0.001, Figure 1B). There were no differences in FA findings between oCEE and tE2 groups, and no MD differences between treatments groups.ConclusionA relatively higher FA in a variety of white matter regions in the oCEE and tE2 groups compared to placebo suggest that mHT may have long‐term protective effects on white matter integrity. Previously, we had shown that women in the tE2 group preserved their dorsolateral prefrontal cortex volumes better than the placebo group over 7 years. Our findings suggest that the tracts that connect the dorsolateral prefrontal cortex and the thalamus such as the superior corona radiata and the anterior limb of internal capsule may particularly benefit from mHT.

Effect of adjunctive hormonal therapy on testicular descent and spermatogenic function among children with cryptorchidism: a systematic review and meta-analysis

To systematically evaluate the effect of adjunctive hormonal therapy on testicular descent and spermatogenic function among children with cryptorchidism. A comprehensive literature search of electronic databases up to February 21, 2019 was performed. Continuous data of fertility indices were evaluated using weighted mean difference (WMD) with 95% confidence interval (CI), while nominal data of fertility indices and the complete descent rates were analyzed by risk ratio (RR) with 95% CI. A fixed effect or random effect model was used. A total of 27 previous studies were included for the current analysis. Hormonal therapy increased complete testicular descent rate, reaching statistical significance (RR = 3.74; 95% CI, 2.78-5.04; P < 0.001). The success rate was 22.43%. A similar result was found in subgroup analysis of hormonal category and effect on unilateral or bilateral cryptorchidism. Studies reporting primary outcome as continuous data showed that cryptorchid males have significantly increased germ cell numbers per tubule (WMD = 0.10; 95% CI, 0.01-0.20, P = 0.032) after hormonal therapy. The nominal data of pooled studies showed no significant difference (RR = 1.62; 95% CI, 0.65-4.00, P = 0.298). In addition, a significant result was noted in the luteinizing hormone-releasing hormone (LHRH) therapy group but not in those undergoing human chorionic gonadotropin (hCG) treatment. Our findings have demonstrated that hormonal therapy can effectively increase the success rate of complete testicular descent, while some boys may benefit as regards improvement of the fertility index.

Analysis of subsequent therapy in Japanese patients with hormone receptor\u2012positive/human epidermal growth factor receptor 2\u2012negative advanced breast cancer who received palbociclib plus endocrine therapy in PALOMA-2 and -3

BackgroundIn the double-blind, phase 3 PALOMA-2 and PALOMA-3 studies, palbociclib plus endocrine therapy (ET) demonstrated significant improvement in progression-free survival versus placebo plus ET in patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer. This analysis assessed subsequent treatment patterns after palbociclib therapy in Japanese patients enrolled in the PALOMA-2 and PALOMA-3 studies.MethodsPALOMA-2 included postmenopausal women who had not received prior systemic therapy for advanced disease. PALOMA-3 included pre- or postmenopausal women who had progressed on previous ET. Types of subsequent therapy were assessed, and treatment durations of subsequent therapy were estimated using the Kaplan–Meier method.ResultsJapanese patients were enrolled in PALOMA-2 (n = 46) and PALOMA-3 (n = 35). In both studies, the most common first subsequent therapy was ET (PALOMA-2, 77% in the palbociclib group and 75% in the placebo group; PALOMA-3, 55% and 43%, respectively), followed by chemotherapy (PALOMA-2, 18% and 8%; PALOMA-3, 32% and 57%). The median (95% CI) duration of first subsequent therapy was 6.4 (2.3‒13.9) months with palbociclib plus letrozole and 6.7 (2.8‒13.0) months with placebo plus letrozole in PALOMA-2 and 3.8 (2.4‒5.7) months with palbociclib plus fulvestrant and 9.7 (1.0‒not estimable) months with placebo plus fulvestrant in PALOMA-3.ConclusionsThe types of first subsequent therapy received by Japanese patients in the palbociclib plus ET and placebo plus ET groups were similar. Further evaluation of subsequent therapy data in the real-world setting is warranted considering the small sample size of this analysis.

Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives.

The aim of the study was to evaluate whether combined oral contraceptives (COCs) can be used as hormone therapy (HT) to preserve bone mineral density (BMD) in women with premature ovarian insufficiency (POI). An observational study of women with POI comparing the use of COC (ethinylestradiol 30 μg + levonorgestrel, continuously) with: low-dose HT (continuous conjugated estrogen 0.625 mg plus medroxyprogesterone or continuous estradiol [E2] 1 mg + norethisterone), high-dose HT (continuous conjugated estrogen 1.25 mg + medroxyprogesterone or continuous E2 2 mg + norethisterone), tibolone 2.5 mg, or no treatment. Bone density scans were performed every 2 ± 1 years. The difference between final and initial (delta) BMD values was calculated for the lumbar spine, total femur, and femoral neck. Generalized estimating equations were used to analyze the effect of treatment over time. Variables without normal distribution were transformed into ranks. Overall, 420 scans (210 deltas) of 119 women were analyzed. The women were 30.3 ± 9.2 years old (mean ± SD). BMD deltas at the lumbar spine and total femur were grater in the COC and high-dose HT groups. At the lumbar spine, the differences between two scans were greater in the COC group when compared to low-dose HT group: -0.043 (95% CI -0.062 to -0.024), untreated: -0.056 (-0.080 to -0.032), and tibolone: -0.050 (-0.094 to -0.006) groups. Total femur BMD decreases and the delta were lower in the low-dose HT group -0.038 (-0.052 to -0.024) when compared to COC. Continuous COC was associated with increased BMD in women with POI compared to low-dose HT, with similar improvement in the COC and high-dose HT groups. : Video Summary:http://links.lww.com/MENO/A620.

Health-Related Quality of Life and Survival in Prostate Cancer Patients in a Real-World Setting

Objective: To analyze the health-related quality of life (HRQoL) and survival of real-world prostate cancer (PC) patients and to calculate quality-adjusted life-years (QALYs) experienced under different treatment strategies. Materials and Methods: PC patients undergoing active surveillance (n = 226), radiation treatment (n = 280), surgery (n = 299), or hormonal treatment (n = 62) responded to the generic 15-dimensional (15D) HRQoL questionnaire at the time of the diagnosis and were followed up 3, 6, 12, and 24 months later. QALYs experienced during the follow-up were calculated for each treatment group, and variables associated with survival were analyzed using Cox proportional hazards models. Results: HRQoL was stable during the first 2 years after diagnosis in all other treatment groups, except in patients treated with hormonal therapy. The overall survival within 6.5-year follow-up time was 84.4%. The number of QALYs experienced during the 2-year follow-up was similar in patients in active surveillance (1.790), surgery (1.784), and radiation groups (1.767), but significantly lower in the hormonal therapy group (1.665). Conclusions: Patients receiving hormonal treatment had significantly impaired HRQoL and survival compared with other treatments. Although the number of QALYs experienced was similar in the 3 other treatment lines, there were marked differences between treatment lines on some 15D dimensions.

Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy.

There are limited data regarding the impact of body mass index (BMI) on outcomes in advanced breast cancer, especially in patients treated with endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors. A pooled analysis of individual patient-level data from MONARCH 2 and 3 trials was performed. Patients were classified according to baseline BMI into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2) and divided into 2 treatment groups: abemaciclib + ET vs placebo + ET. The primary endpoint was progression-free survival (PFS) according to BMI in each treatment group. Secondary endpoints were response rate, adverse events according to BMI, and loss of weight (≥5% from baseline) during treatment. This analysis included 1138 patients (757 received abemaciclib + ET and 381 placebo + ET). There was no difference in PFS between BMI categories in either group, although normal-weight patients presented a numerically higher benefit with abemaciclib + ET (Pinteraction= .07). Normal and/or underweight patients presented higher overall response rate in the abemaciclib + ET group compared with overweightand/or obese patients (49.4% vs 41.6%, odds ratio = 0.73, 95% confidence interval = 0.54 to 0.99) as well as higher neutropenia frequency (51.0% vs 40.4%, P = .004). Weight loss was more frequent in the abemaciclib + ET group (odds ratio = 3.23, 95% confidence interval = 2.09 to 5.01). Adding abemaciclib to ET prolongs PFS regardless of BMI, showing that overweight or obese patients also benefit from this regimen. Our results elicit the possibility of a better effect of abemaciclib in normal and/or underweight patients compared with overweight and/or obese patients. More studies analyzing body composition parameters in patients under treatment with cyclin-dependent kinase 4/6 inhibitors may further clarify this hypothesis.

Preference for Masculine or Feminine Gender Roles and Its Relationship to Well-Being in Transgender Persons: Comparing Pre-Treatment, Hormonal Therapy, and Post-Surgery Groups.

This article aims at identifying different preferences for gender roles in transgender persons and the associations of those preferences with well-being at the different stages of medical transition. A total of 148 Russian transgender subjects (64 in pre-treatment, 41 in hormonal therapy, and 43 in hormonal therapy after some surgery) and 120 Russian cisgender persons filled out the Minnesota Multiphasic Personality Inventory-2. The transgender participants were less satisfied with their lives than the cisgender individuals, and less frequently preferred masculine gender roles, which were related to higher well-being in both groups. However, both preference for masculine gender roles and well-being were higher in the hormonal therapy group, and especially after surgery, regardless of whether they were females transitioning into males or vice versa. In the transwomen, having only hormonal therapy was associated with the poorest satisfaction, while those undergoing hormonal therapy after surgery were much more satisfied with their lives. Those differences are reasonable, considering the visible changes in the body and mood after hormonal therapy in transmen, and because results after surgery are more promising for transwomen than for transmen.

The effect of hormone therapy on the ocular surface and intraocular pressure for postmenopausal women: a systematic review and meta-analysis of randomized controlled trials.

The aim of the study was to investigate the impact of hormone therapy (HT) on the ocular surface and intraocular pressure in postmenopausal women. This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement. PubMed, EMBASE, Cochrane Library of Systematic Reviews, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure were searched from inception to November 2019 without language restrictions. Only randomized controlled trials that evaluated the impact of HT on the ocular surface and intraocular pressure in postmenopausal women were eligible. The trials had to report at least one of the following outcomes: break-up time, Schirmer test, corneal staining, ocular surface symptom score, and intraocular pressure. Two investigators independently extracted the information, assessed the risk of bias, and evaluated the publication bias. All data were analyzed by Review Manager V.5.3. Sensitivity analysis and subgroup analysis were performed to find the source of heterogeneity and evaluate the different effects among subgroups. Nine randomized controlled trials (N = 612) were included. The HT group showed significant improvements compared with the control group in break-up time (mean difference [MD] = 2.09, 95% confidence interval [CI] 1.00-3.19, P = 0.0002), Schirmer test without anesthesia (MD = 4.17, 95% CI 1.55-6.80, P = 0.002), Schirmer test with anesthesia (MD = 1.44, 95% CI 0.71-2.18, P = 0.0001), and corneal staining scores (standardized mean difference [SMD] = -0.85, 95% CI -1.39 to -0.30, P = 0.002). Moreover, significant beneficial effects were observed on all four symptoms, including dryness (SMD = -1.21, 95% CI -1.99 to -0.44, P = 0.002), foreign body sensation (SMD = -1.02, 95% CI -1.29 to -0.76, P < 0.00001), ocular fatigue (SMD = -1.74, 95% CI -2.12 to -1.36, P < 0.00001), and burning (SMD = -0.53, 95% CI -0.78 to -0.29, P < 0.0001) after HT. Subgroup analysis revealed that, in terms of break-up time, postmenopausal women younger than 55 years achieved more improvements (MD = 0.88, 95% CI 0.16-1.59, P = 0.02) than women older than 55 years old (MD = 2.60, 95% CI -1.34 to 6.55, P = 0.20), and the estrogen subgroup received more benefits (MD = 3.11, 95% CI 0.93-5.30, P = 0.005) than the estrogen plus progestogen subgroup (MD = 0.42, 95% CI -0.02 to 0.85, P = 0.06). Sensitivity analysis and subgroup analysis suggested that the heterogeneity might derive from the methodological quality, the age of participants, and the intervention of the control group. Intraocular pressure (MD = -1.54, 95% CI -3.39 to 0.32, P = 0.10) was not evidently decreased after HT. No more specific adverse events (relative risk = 1.66, 95% CI 0.41-6.77, P = 0.48) were found in the HT group. Our study revealed that HT could improve ocular surface function in postmenopausal women effectively and safely, especially for those who were younger than 55 years, and estrogen only showed more improvements than estrogen plus progestogen. The effectiveness of HT in treating dry eye in postmenopausal women is, however, still a controversial topic. In addition, we did not find HT led to a significant reduction of intraocular pressure.

Immediate breast reconstruction surgery with expander/direct implant and use of acellular dermal matrix: Does hormone therapy increases the risk of infection?

The use of hormone therapy (tamoxifen and aromatase inhibitors) has been shown to increase venous thromboembolism. However, while estrogens play a crucial role in wound healing, no study has assessed the impact of tamoxifen or aromatase inhibitors on other postoperative breast reconstruction complications, including infections, necrosis, capsular contracture and seroma. As breast cancer patients undergoing Implants-ADMs breast reconstruction are often receiving hormone therapy, it is unclear whether this increased infection risk is associated with increased infections cases. A prospective study was performed on patients undergoing breast reconstruction at an academic institution from 2013 to 2016. Patients were divided by use of hormone therapy at the time of surgery. Complication rates, including infections, necrosis, seroma and hematomas, were compared and analyzed using univariate and logistic regression models. Among a total of 112 patients (183breasts), 58 patients (91 breasts) were receiving hormone therapy and 54 patients (92 breasts) were not. The hormone therapy group had a higher incidence of postoperative mastectomy skin infection (20.7% versus 7.4%; P=0.0447), we didn't find any significant differences in necrosis. Hormone therapy was associated with a higher incidence of Infections after breast reconstruction with ADMs and implants. The authors propose an individualized approach to the preoperative cessation of tamoxifen or aromatase inhibitors. Immediate breast reconstruction surgery with expander/direct implant and use of acellular dermal matrix: does hormone therapy increases the risk of infection?

Growth hormone therapy for people with thalassaemia.

Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. This review on the role of growth hormone was originally published in September 2017 and updated in April 2020. To assess the benefits and safety of growth hormone therapy in people with thalassaemia. We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 14 November 2019. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Date of latest search: 06 January 2020. Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity. Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The certainty of the evidence was assessed using GRADE criteria. We included one parallel trial conducted in Turkey. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The certainty of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate-certainty evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate-certainty evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period. A small single trial contributed evidence of moderate certainty that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.