Aromatase Inhibitors In Women Research Articles

Effect of whole-body cryotherapy versus placebo cryotherapy on joint pain induced by aromatase inhibitors in women with early stage breast cancer: a randomised clinical trial

IntroductionHormone therapy (HT) is a major adjuvant treatment for breast cancer. Despite their effectiveness, aromatase inhibitors can cause several side effects, including arthralgia in 35%–50% of patients. These side effects...

The Value of Anti-Müllerian Hormone in Predicting Ovulation Induced by Aromatase Inhibitors in Women With Polycystic Ovary Syndrome

ObjectivesThis study aimed to evaluate the value of anti-Müllerian hormone (AMH) in predicting ovulation induced by aromatase inhibitors (AI) and pregnancy outcomes in women with polycystic ovary syndrome (PCOS). MethodsFrom January 2018 to December 2020, this prospective cohort study enrolled women with PCOS aged between 18 and 45 years who underwent ovulation induction using AI protocol and intrauterine insemination (IUI) for infertility at a Center for Reproductive Endocrinology and Infertility, University Hospital. Receiver operating characteristic curves were used to estimate the chance of ovulation responses and pregnancy outcomes. ResultsIn total, 64% of 65 women with PCOS were recruited following AI treatment, and the clinical pregnancy rate was 19.4% following IUI. Patients who experienced ovulation had a lower mean serum AMH concentration than non-responders (7.11 ng/mL vs. 8.95 ng/mL, respectively), but the difference was not statistically significant. Between the pregnancy and non-pregnancy groups, statistically significant differences in AMH concentrations were observed (8.71 ng/mL vs. 6.73 ng/mL, respectively, P = 0.040). The area under the curve of the receiver operating characteristic for non-ovulation prediction was 0.445, 95% CI (0.284–0.606) with P = 0.467, and for clinical pregnancy was 0.735, 95% CI (0.561–0.910) with P = 0.104. ConclusionsIn women with PCOS, the AMH level does not predict ovarian responsiveness to AI treatment, but it does predict the success of IUI cycles.

Abstract GS4-08: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer

Abstract We have previously shown in a phase 3 trial that tamoxifen 5 mg/day for 3 years decreased by 52% the incidence of recurrence of invasive breast cancer or DCIS after a median follow-up of 5.1 years in women with excised non invasive breast disease, including atypical ductal hyperplasia, DCIS or LCIS (DeCensi et al. JCO 2019; 37:1629). Toxicity was negligible with only an extra hot flash per day in the tamoxifen arm compared with the placebo arm. These findings were incorporated into the ASCO clinical practice guidelines for breast cancer risk reduction as an alternative option to standard doses and duration of tamoxifen or aromatase inhibitors in women with non-invasive disease (Visvanathan et al. JCO 2019; 37:3152). In the present study we update the findings on breast cancer recurrence after a median of 9.14 years (interquartile range, IQR, 7.16-10.73) and a total of 10.57 person years of follow up to see if the treatment effect is retained with more events and after a median of approximately 6 years from treatment cessation. We conducted a national multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. Between November 1, 2008, and March 31, 2015, 1,160 women were screened and 500 aged 75 years of age or younger were included in the study. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses. The mean age was 54 years (standard deviation, 9 years), and 55% of participants were postmenopausal. The mean (SD) body mass index, kg/m2, was 25.7 (4.8) on tamoxifen and 25.3 (4.2) on placebo. Twenty percent had ADH, 11% had LCIS, and the remaining 69% had DCIS. After a median follow-up of 9.14 years, there were 22 neoplastic events (invasive breast cancer or DCIS) with tamoxifen and 37 with placebo (annual rate 11.09, 95% CI, 7-30-16.84 on T vs 19.71, 95% CI, 14.28-27.21 on P per 1,000 person-years; hazard ratio, 0.56; 95% CI, 0.33 to 0.95; P = .03), which resulted in a 5-year number needed to treat of 18. Overall, 71% of the recurrences were invasive breast cancer. The follow-up was updated with the most recent visit within 12 months in two thirds of the participants, so an update of all participants will be performed by Sept 30th with full analysis of neoplastic events, annual risk rate ratio, serious adverse events and deaths. Moreover, an updated analysis of potential effect modifiers will be conducted, including menopausal status, baseline estradiol levels, menopausal symptoms, BMI, smoking status and Ki-67 of the primary lesion. In conclusion, our findings indicate that low dose tamoxifen given for 3 years still significantly prevents recurrences from non-invasive breast cancer after a median of 6 years from treatment cessation, providing a valid prevention/interception option in this disease group. Supported by Ente Ospedaliero Ospedali Galliera, Genova, Italy, the Italian Ministry of Health (RFPS-2006-1-339898), the Italian Association for Cancer Research (IG 2008 Grant No. 5611), and the Italian League against Cancer (LILT 7-08). Citation Format: Andrea De Censi, Matteo Lazzeroni, Matteo Puntoni, Luca Boni, Aliana Guerrieri Gonzaga, Tania Buttiron Webber, Marianna Fava, Irene Maria Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive 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 GS4-08.

Effect of Denosumab on Glucose Homeostasis in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors: A Pilot Study.

Background Aromatase inhibitors in women with breast cancer have been associated with cancer treatment-induced bone loss (CTIBL), increased fracture risk, and impairment of glucose metabolism. Denosumab (Dmab), a monoclonal antibody against RANKL, which is a key regulator of the osteoclast activity, is effective as an antiresorptive agent in the treatment of CTIBL. Since RANKL/RANK pathway may contribute to the pathogenesis of glucometabolic disorders, it has been suggested that Dmab may improve glucose homeostasis. Our pilot study evaluated the effect of a single administration of 60 mg Dmab on glucose metabolism in a cohort of women with breast cancer treated with aromatase inhibitors. Methods Fifteen postmenopausal nondiabetic women were prospectively enrolled. Oral glucose tolerance test (OGTT) and metabolic parameters, including FGF21, were assessed at baseline and one month after Dmab injection. Midterm glucose control was evaluated by measuring glycated haemoglobin (HbA1c) levels 5 months after Dmab. Results Parameters of glucose metabolism were not different one month after Dmab but circulating FGF21 levels significantly decreased (128.5 ± 46.8 versus 100.2 ± 48.8 pg/mL; p=0.016). Considering patients with insulin resistance at baseline (HOMA-IR > 2.5 and Matsuda Index < 2.5; n = 5), reduced mean fasting insulin levels (16.3 ± 4.9 versus 13.5 ± 3.5 mcU/mL; p=0.029) and increased insulin sensitivity index QUICKI (0.317 ± 0.013 versus 0.327 ± 0.009; p=0.025) were found. Nonetheless, HbA1c increased 5 months after Dmab (36.0 ± 2.3 versus 39.6 ± 3.1 mmol/mol; p=0.01). Conclusions Although RANKL blockade induced a short-term positive effect on insulin sensitivity, particularly in insulin-resistant patients, a benefit on long-term glucose metabolism was not evident. In conclusion, Dmab is safe for glucose metabolism in aromatase inhibitor-treated women with breast cancer.

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

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

Abstract P5-14-17: Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance)

Abstract Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p&amp;lt;0.001 at 6 mo); vasomotor (p&amp;lt;0.001 at 1, 3, 6 mo), psychosocial (p=0.006 at 6 mo) and sexual (p=0.01 at 6 mo)]. Joint pain and stiffness increased [BPI-SF pain subscale (p=0.048 at 3, p=0.01 at 6 mo); AIMS2 joint pain subscale (p=0.03 at 1, p&amp;lt;0.001 at 3 and 6 mo); AIMS2 stiffness subscale (p=0.004 at 3, p=0.01 at 6 mo)]. Intentional and nonintentional adherence did not significantly change over time (p&amp;gt;0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org. Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-17.

NewsCAP: The USPSTF recommends tamoxifen, raloxifene, or aromatase inhibitors for women at high breast cancer risk.

NewsCAP: The USPSTF recommends tamoxifen, raloxifene, or aromatase inhibitors for women at high breast cancer risk.

Abstract P4-14-06: A study of adverse vascular effects of adjuvant therapy with aromatase inhibitors in women with breast cancer

Abstract Background: There is a debate concerning risk of cardiovascular disease (CVD) from adjuvant therapy with aromatase inhibitors (AI). Randomized trials have indicated higher CV risk and one observational study higher risk of myocardial infarction, whereas other studies have pointed out no elevated risk. The first morphological sign of developing atherosclerosis is a thickening of the arterial intima layer, whereas in the longer perspective the media layer gets thinner - a process not captured when using conventional Carotid intima-media-thickness (CIMT). We therefore used high resolution ultrasound (HRU), to separately estimated the intima and media layers and calculate the I/M thickness ratio. A thicker intima and higher I/M thickness ratio are signs of adverse vascular effects. This principle of estimating vascular aging can strongly distinguish 70-yr old subjects with and w/o prevalent CVD, yielding C-values up to 0.90 in ROC-analysis. Patients and Methods: We included 150 postmenopausal breast cancer women of whom 50 were treated with AI during at least 3 years, 50 with at least 3 years of tamoxifen and 50 were without endocrine therapy. Patients were investigated with non-invasive HRU (22MHz) of the common carotid artery (CCA). Non-parametric statistical methods were used, including Bootstrap quantile regression to obtain 95% confidence intervals (CI) and adjustment for potential confounders: age, smoking, use of statins, HbA1c and previous HRT. Results: Of 150 included women, 132 remained having a technically acceptable ultra sound scans and no AI therapy before tamoxifen therapy; AI (#48); tamoxifen (#40) and no anti-hormone therapy (#44). Corresponding median ages were 66, 65 and 65 yrs and median treatment durations were 54 (AI) and 58 (tamoxifen) months. AI therapy, compared to tamoxifen, showed a significantly thicker CCA-intima layer, p = 0.031. However, mean values of both CCA-intima thickness and I/M thickness ratio were very similar in the tamoxifen and the no anti-estrogen group; Thus, AI compared to the other two groups combined, had a significantly thicker intima layer (p = 0.009) and higher I/M ratio (p = 0.047), both indicating adverse vascular effects from AI therapy. After adjustment for potential confounders, AI therapy still showed a thicker CCA intima layer of 0.015 mm (95% CI .003, .027); p = 0.016. In contrast, corresponding analysis using conventional Carotid intima-media thickness (CIMT), revealed no significant group differences or association to AI treatment duration. Conclusion: More than three years of adjuvant therapy with aromatase inhibitors, compared to women having no anti-estrogen therapy or tamoxifen, was associated with signs of adverse vascular effects; thicker intima layer and higher intima/media ratio of the common carotid artery. After adjustment, the thicker intima layer remained significant. These findings are in accordance with reports of increased risk of cardiovascular events following adjuvant therapy with aromatase inhibitors. Citation Format: Lindman H, Dahlberg L, Larsson M, Naessén T. A study of adverse vascular effects of adjuvant therapy with aromatase inhibitors in 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 P4-14-06.

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

BackgroundMedication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk-benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy.Methods/DesignIn this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the χ2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (< 18.4 pmol/L versus ≥18.4 pmol/L) will be compared using the χ2 test, and the logistic regression. Further, the assessment of knowledge, attitude, behaviour, and barriers and facilitating factors of medication adherence will be made via logistic regression.DiscussionThis will be the first study to evaluate short-term clinical outcomes from SMS reminder for breast cancer patients on aromatase inhibitor therapy. Random allocation to SMS reminder or control arm ensures that patients in both arms will be comparable with respect to demographic and clinical characteristics, and any difference in outcomes can be attributed to the intervention. Participants are not blinded to the assignment of intervention, thus there may be potential for bias in outcome assessments.Trial registrationNCT02524548. Retrospectively registered on 17 August 2015.

Abstract GS4-04: Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200)

Abstract Background: Musculoskeletal symptoms are the most common side effect of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Pilot data from two prior single institution studies showed that acupuncture decreased AI-induced joint symptoms in breast cancer (BC) patients. Methods: We conducted a SWOG multicenter randomized controlled trial among postmenopausal women with early stage BC. Patients taking an AI for ≥30 days and having a worst pain score of ≥3 out of 10 using the Brief Pain Inventory (BPI-WP) were eligible. Subjects were randomized at a 2:1:1 ratio to true acupuncture (TA) vs. sham acupuncture (SA) vs. waitlist control (WC). The TA protocol used a standardized protocol of body and auricular acupoints tailored to joint symptoms. The similarly standardized SA protocol utilized superficial needling of non-acupoints. Both the TA and SA protocols consisted of a 12 week intervention, with 12 sessions administered over 6 weeks, followed by 1 session per week for 6 additional weeks. The primary endpoint was change in the BPI-WP (worst pain) score at 6 weeks. Secondary outcomes included other BPI scores, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for the hips and knees, the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH), and functional testing with grip strength and "Timed Get Up and Go" (TGUG). The design specified alpha=.025 two-sided tests to account for two independent comparisons (TA vs. SA and TA vs. WC). Results: Among 226 patients registered, 110 were randomized to TA, 59 to SA and 57 to WC. Baseline characteristics were similar between the groups. In a linear regression adjusting for the baseline score and stratification factors, 6-week mean BPI-WP scores were 0.92 points lower (correlating with less pain) in the TA compared to SA arm (95% CI: 0.20-1.65, p=.01), and were 0.96 points lower in the TA compared to WC arm (95% CI: 0.24-1.67, p=.01). The proportion of patients experiencing a clinically meaningful (&amp;gt;2) reduction (i.e. improvement) in BPI-WP was 58% for TA compared to 33% on SA and 31% on WC. Patients randomized to TA had improved symptoms compared to SA at week 6 according to all other BPI pain measures (average pain, p=.04; pain interference, p=.02; pain severity, p=.05; worst stiffness, p=.02). Results were similar compared to WC. Patients randomized to TA compared to SA or WC had statistically significant or marginally statistically significant improvements in BPI pain measures at week 12. Patients randomized to TA had generally improved symptoms compared to SA or WC at week 6 and at week 12 according to the M-SACRAH and WOMAC measures (p&amp;lt;0.05). With regard to adverse events, more patients on the TA arm experienced Grade 1 bruising compared to SA (47% vs. 25%, p=.01). No other differences by arm for selected adverse events were observed. Conclusions: This study was the first large multicenter trial to investigate the effect of acupuncture in treating AI-induced joint symptoms in BC patients. According to multiple measures, TA generated better outcomes than either SA or WC with minimal toxicity. Citation Format: Hershman DL, Unger JM, Greenlee H, Capodice J, Lew DL, Kengla AT, Melnik MK, Jorgensen CW, Kreisle WH, Minasian LM, Fisch MJ, Henry L, Crew KD. Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200) [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 GS4-04.

Treatment with Ruta graveolens 5CH and Rhus toxicodendron 9CH may reduce joint pain and stiffness linked to aromatase inhibitors in women with early breast cancer: results of a pilot observational study.

To determine the possible effect of two homeopathic medicines, Ruta graveolens 5CH and Rhus toxicodendron 9CH, in the prevention of aromatase inhibitor (AI) associated joint pain and/or stiffness in women with early, hormone-receptor positive, breast cancer. This prospective, unrandomized observational study was carried out between April and October 2014. Women were recruited in two groups, according to which of the two study centres they attended: one receiving homeopathy in addition to standard treatment (group H) and a control group, receiving standard treatment (group C). All women were treated with an AI. In addition, women in group H also took Ruta graveolens 5CH and Rhus toxicodendron 9CH (5 granules, twice a day) up to 7 days before starting AI treatment. The homeopathic medicines were continued for 3 months. Demographic and clinical data were recorded using a self-assessment questionnaire at inclusion (T0) and 3 months (T3). Primary evaluation criteria were the evolution of scores for joint pain and stiffness, the impact of pain on sleep and analgesic consumption in the two groups after 3 months of treatment. Forty patients (mean age 64.9±8.1 years) were recruited, 20 in each group. Two-thirds of the patients had joint pain before starting AI treatment. There was a significant difference in the evolution of mean composite pain score between T0 and T3 in the two groups (-1.3 in group H vs. +3.4 in group C; p=0.0001). The individual components of the pain score (frequency, intensity and number of sites of pain) also decreased significantly in group H. Nine patients in group C (45%) vs. 1 (5%) in group H increased their analgesic consumption between T0 and T3 (p=0.0076). After 3 months of treatment, joint pain had a worse impact on sleep in patients in group C (35% vs. 0% of patients; p=0.0083). The differences observed in the evolution of morning and daytime stiffness between the two groups were smaller (p=0.053 and p=0.33, respectively), with the exception of time necessary for the disappearance of morning stiffness which was greater in group C (37.7±23.0 vs. 17.9±20.1min; p=0.0173). These preliminary results suggest that treatment with Ruta graveolens 5CH and Rhus toxicodendron 9CH may decrease joint pain/stiffness in breast cancer patients treated with AIs. A larger-scale randomized study is required to confirm these results.

10P - A Phase 1 Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Enzalutamide Alone or Combined with an Aromatase Inhibitor in Women with Advanced Breast Cancer

10P - A Phase 1 Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Enzalutamide Alone or Combined with an Aromatase Inhibitor in Women with Advanced Breast Cancer

Abstract PD3-6: A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide (previously MDV3100) alone or in combination with an aromatase inhibitor in women with advanced breast cancer

Abstract Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of androgen receptor (AR) signaling. AR expression is observed in ∼70% of breast cancers (BC) and across the 3 major histologic subtypes (ER+, HER2+ and triple negative) [Collins LC et al. Mod Pathol 2011; 24:924-31]. Based on findings in preclinical models of AR+ BC, the potential therapeutic effect of ENZA in AR+ BC is being evaluated. This is the first trial of ENZA in women with advanced BC (aBC). Methods: This Phase 1 study in patients (pts) with aBC comprised a dose-escalation stage evaluating ENZA 80 mg/d or 160 mg/d (3+3 design) to determine the Phase 2 dose, and a dose-expansion stage evaluating the Phase 2 dose alone (C1) or in combination with the aromatase inhibitors (AI), anastrozole (C2) or exemestane (EXE; C3). Pts on single-agent ENZA must have received ≥2 treatment regimens for aBC. Tumor tissue was collected at screening for central analysis of AR expression. In the dose-escalation stage, single-dose ENZA was given on Day 1 with pharmacokinetic (PK) sampling through Day 8, followed by ENZA daily until discontinuation criteria were met, dose-limiting toxicities (DLTs) were recorded through Day 35. In C2 and C3, pts received ≥14 days of AI before starting ENZA, and AI PK sampling occurred on Days -1 and 29 of ENZA dosing to assess PK interactions. Blood for central assessment of estrogens was collected at Days 1, 29 and with tumor assessments performed at 2 months then ∼every 3 months thereafter. Results: The dose-escalation stage (n = 15) defined the Phase 2 dose as 160 mg/d. A single DLT (adrenal insufficiency) occurred in a pt at the 80 mg/d dose. This pt had pre-existing history of adrenal insufficiency and a PK interaction with her daily steroids could not be excluded. As of 1 May 2013, the dose-expansion stage has enrolled 3 pts in C1, 10 in C2, and 16 in C3. For pts receiving single-agent ENZA (n = 18) median age/ECOG was 58/1 and median prior therapies for aBC was 5; these values were 55/0 and 3 for combination cohorts (n = 26). Common (&amp;gt;15%) treatment-related adverse events (AEs) in the single-agent ENZA cohorts included nausea and nasal congestion and in C2 and C3 included nausea, fatigue, back pain, decreased appetite, and hot flush. To date, no serious treatment-related AEs have been reported for single-agent ENZA (other than the DLT) or in C2; in C3 back pain, hypercalcemia and nausea were observed. For single-agent ENZA, a preliminary PK analysis indicates that the apparent clearance and volume of distribution are approximately 0.4 L/h and 120 L, respectively, and steady-state trough concentration is approximately 13 μg/mL. ENZA + EXE resulted in ∼50% reduction in exposure to EXE (AUC pre vs post ENZA: 134±65 vs 70±39 ng.h/mL). PK, tolerability, estrogen levels and anti tumor activity in all cohorts will be presented. Conclusions: The PK and tolerability of single-agent ENZA appear similar in women with aBC vs. data reported in men. As ENZA reduced exposure to EXE, effects on estrogens (i.e., EXE pharmacodynamics) are being assessed and will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-6.

To evaluate the effectiveness of Emotional Freedom Techniques (EFT) to reduce the side effects caused by Tamoxifen and Aromatase Inhibitors in women with breast cancer: A preliminary service evaluation

To evaluate the effectiveness of Emotional Freedom Techniques (EFT) to reduce the side effects caused by Tamoxifen and Aromatase Inhibitors in women with breast cancer: A preliminary service evaluation

PARAGON: Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynecologic neoplasms: ANZGOG 0903.

TPS5614 Background: Many gynaecological cancers of different pathological type express estrogen and/or progesterone hormone receptors (ER/PR). Reports of tumour response and clinical benefit with hormonal therapies show variable rates of activity. There is a need to prospectively study the role of aromatase inhibitors in women with potentially hormone responsive recurrent gynaecological cancers to establish response rates, clinical benefit, quality of life (QoL) and identify predictors of response. Methods: PARAGON is phase II Gynecologic Cancer InterGroup trial lead by the Australia New Zealand Gynaecological Oncology Group, Cancer Research UK and the Belgian Gynaecological Oncology Group. The study is designed to facilitate research in rare tumours. The protocol allows postmenopausal women with recurrent gynaecological cancers to enrol into one of 7 subgroups; epithelial ovarian cancer (EOC) with only rising CA125 after first line chemotherapy, platinum resistant/refractory EOC, low grade EOC, endometrial carcinomas, endometrial stromal sarcomas, miscellaneous sarcomas and granulosa cell tumours and other sex cord stromal tumours. ER/PR positivity must be confirmed by immunohistochemistry. Each subgroup will enrol 25-50 patients with defined stopping rules based on response and reviewed by independent data monitoring committee (IDMC). Eligible patients receive 1 mg anastrozole daily until disease progression or unacceptable toxicity. Primary objective: clinical benefit (partial or complete response or stable disease). Secondary objectives: progression free survival, response duration, QoL, toxicity. Blood and tumour samples are being collected for translational studies and confirmation of ER/PR positivity. Recruitment commenced in 2011 in Australia, New Zealand and the United Kingdom. One hundred and fourteen of 350 planned patients have been enrolled to January 2013. In November 2012 IDMC recommended continuing recruitment to the EOC with rising Ca125 only and resistant/refractory subgroups based on review of activity outcomes for the first 25 patients. The trial will open in Belgium in April 2013. ACTRN12610000796088 Clinical trial information: 12610000796088.

Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial.

9000 Background: Musculoskeletal (MS) pain and fatigue are common in women on adjuvant Aromatase Inhibitors (AIs) and lead to reduced compliance. Pilot studies suggest a positive impact of vit D on MS pain and disability from AIs. We conducted a bi-institutional, double blind, placebo controlled randomized trial to study the impact of 30,000 I.U of vit D3 in preventing worsening of MS pain and fatigue in women starting letrozole. Methods: Women with stage I-III breast cancer starting adjuvant AI and a 25(OH)D level of 40 ng/ml or less were eligible. Women with prior renal stones or hypercalcemia were excluded. All subjects received letrozole, plus standard dose vitD3 (600 IU) and calcium (1200 mg) daily, all provided by the study. Women were randomly assigned to 30,000 IU of oral vitD3 wkly (vitD arm) or matched placebos (PL arm) for 24 weeks. The following were assessed at baseline, 12 wks, and 24 wks (end of study): 1) 25OHD levels, 2) symptoms tools (BFI – Brief Fatigue Inventory, HAQII - Health Assessment Questionnaire II, Qualitative Joint Pain (none, mild, moderate, severe), BPI – Brief Pain Inventory) and 3) hand grip strength with a dynamometer. Results: 160 women (80/arm) were enrolled from 4/09 to 7/10. There were no differences between the two arms in demographics/tumor characteristics. Median age was 61, median BMI was 29.8 kg/m2. 43% had adjuvant chemotherapy. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 wks and 31 at 24 wks in the PL arm and 22, 53 and 57 in vitD arm. One patient in the PL arm developed mild hypercalcemia. There were no SAEs. 147 subjects were evaluable for efficacy. 3 subjects, all in the PL arm discontinued early due to a MS adverse event. At wk 24, a higher proportion of women in PL (51%) vs vitD arm (37%) had a protocol defined MS event (worsening of joint pain, disability from joint pain or discontinuation of Letrozole due to MS symptoms) (p=0.069). A significantly higher proportion of women in PL (72%) vs vitD arm (42%) had an adverse QOL event (worsening of pain, disability or fatigue) (p=&lt;0.001). Conclusions: 30,000 IU/week of vitamin D3 is safe and results in decreased adverse QOL events from adjuvant aromatase inhibitors in women with breast cancer.

Sekundäre Osteoporose – praxisrelevante Besonderheiten bei der Diagnostik und Therapie

Osteoporosis is a systemic skeletal disease causing increased fracture risk. According to pathogenesis, primary (70 - 80 %) and secondary osteoporosis (20 - 30 %) are distinguished. Secondary osteoporosis comprises all entities in which osteoporosis is predominantly and causally associated with certain diseases or conditions. The aim of this review article is to put attention to special features in diagnosis, prophylaxis and treatment of secondary osteoporosis in general and to demonstrate some forms of secondary osteoporosis which seem particularly important during clinical practice. The manuscript refers to the guidelines of the DVO 2009 for prevention, diagnosis and therapy of osteoporosis and selective original papers considering the special types of secondary osteoporosis. History, clinical examination and basic laboratory tests are indicative for the diagnosis of secondary osteoporosis. Its clinical presentation is frequently characterized by rapid development and multiple fractures. Therefore, early diagnosis, prophylaxis and causal treatment is decisive. If causal treatment is impossible, risk adaption of bone mineral density (BMD) for osteoporosis specific treatment is essential. Common causes are medications, endocrine, gastrointestinal and hematologic diseases. Glucocorticoid induced osteoporosis, antihormonal therapy (aromatase inhibitor in women with breast cancer, androgen deprivation therapy in men with prostate cancer) and vitamin D deficiency causing secondary hyperparathyroidism are presented in detail. History and basic laboratory testing are decisive to identify possible causes for secondary osteoporosis and to initiate early diagnostic procedures. The risk of severe osteoporosis can be reduced by early and causal treatment or by risk stratified early bone specific medication if causal therapy is impossible.

Effects of Exemestane, Anastrozole and Tamoxifen on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Early Breast Cancer Patients: Results of N-SAS BC 04, the TEAM Japan Substudy

Background: Use of aromatase inhibitors in women with postmenopausal breast cancer accompanies risks of bone loss. We evaluated changes in bone mineral density (BMD) and bone turnover markers in patients treated with exemestane, anastrozole or tamoxifen for hormone-sensitive postmenopausal early breast cancer. Patients and Methods: Sixty-eight patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational Japan bone substudy were randomly assigned to receive tamoxifen, exemestane or anastrozole. During a 2-year study period, lumbar spine BMD was measured using dual-energy X-ray absorptiometry, and urinary type I collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP) were also measured. Results: BMD at 2 years of treatment was higher in tamoxifen patients compared with exemestane and anastrozole patients; however, the intergroup difference was not significant (p = 0.2521 and p = 0.0753, respectively). BMD was higher in exemestane patients compared with anastrozole patients; however, the intergroup difference was not significant (p = 0.7059 and p = 0.8134, respectively). NTX and BAP were significantly lower in tamoxifen patients compared with exemestane and anastrozole patients at 1 and 2 years of treatment (p < 0.05). Conclusion: Tamoxifen may provide better bone protection compared with exemestane or anastrozole. The effect of exemestane and anastrozole on bone loss may be comparable in Japanese postmenopausal women.

Inhibiteurs de l’aromatase, analogues de la LH-RH et ostéoporose

The use of aromatase inhibitors is frequent in adjuvant therapy of postmenopausal women with hormone-responsive breast cancer. Estrogen deprivation caused by administration of aromatase inhibitors may lead to a decrease in bone mineral density and, according to some studies, to an increased risk of fractures. LH-RH agonists can be used in premenopausal women with breast cancer, or for other indications such as endometriosis. They are more frequently prescribed for men with prostate cancer so as to carry out a chemical castration; in this setting LH-RH agonists are responsible for a rapid bone loss which is greater at the beginning of treatment, and for an increased risk of fractures. Patients being treated for cancer should receive adequate bone health monitoring. Prevention of bone adverse events observed with aromatase inhibitors in women and with LHRH agonists in men depends on detection of other fracture risk factors, bone mineral density measurement, lifestyle modifications with correction of calcium and vitamin D deficiency, and treatment, notably using bisphosphonates, when patients have past history of fracture or low bone mineral density.

Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double-blind, placebo-controlled trial

In 36 women with polycystic ovary syndrome and clomiphene citrate resistance, letrozole, an aromatase inhibitor, statistically significantly increased the ovulation rate by 33.3% in the treatment group, indicating that letrozole can be used as an effective and simple alternate ovulation-inducing agent in these women.