May Ziller

Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer

BACKGROUND The level of adherence of various pharmacological therapies in chronic diseases varies, but is predominantly low. With tamoxifen (TAM), 23% and 50% nonadherence after 1 and 4 years have been reported. Day-to-day clinical observation suggests that adherence may even be lower with aromatase inhibitors, but limited data exist on the situation in daily clinical routine. The aim of this study was to evaluate the rate of adherent patients in a randomly selected sample of postmenopausal women with primary breast cancer, who had been assigned to an adjuvant endocrine treatment with TAM or anastrozole (ANA). MATERIALS AND METHODS We investigated a random sample of 100 postmenopausal women with breast cancer (50 TAM and 50 ANA) who had received surgery for their primary breast cancer at our hospital in 2004/2005 and thereafter had been assigned to an adjuvant endocrine treatment. We evaluated the adherence rate with a detailed questionnaire and additionally carried out a retrospective prescription check of the hospital chart as well as calling the local physicians of our patients. A patient was counted as adherent with a self-reported tablet intake of 80% or more and if a medication possession ratio of 80% or more was achieved. RESULTS Regarding the baseline characteristics, a significant difference in mean age was noticed in women on ANA versus TAM [65 (+/-3) and 72 (+/-3); P<0.001]. All women on TAM and ANA reported to be adherent (100%). After controlling for prescriptions, only 40 (80%) and 27 (69%) of the women on TAM and ANA were still classified as adherent (P<0.01 and P<0.01 versus self-report). We found no significant correlation of adherence to any baseline characteristics or side-effects in a logistic regression model. CONCLUSIONS An important goal of any therapeutic intervention is to achieve comparable efficacy in routine clinical practice to that demonstrated in randomised clinical trials. However, a similar magnitude of adherence will be necessary in routine clinical practice to assure comparable clinical effects. Our results further support the data on suboptimal adherence of women with breast cancer on adjuvant TAM treatment. Here, we evaluated for the first time the patient reported and real-world adherence on adjuvant ANA and were able to show a similarly low adherence compared with TAM. More prospective studies are needed to increase our understanding of the underlying reasons for nonadherence in women with breast cancer.

The effect of exemestane or tamoxifen on markers of bone turnover: Results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial

Adjuvant treatment of breast cancer with aromatase inhibitors has been associated with increased bone loss. In this study, postmenopausal patients with oestrogen receptor positive breast cancer were randomised to exemestane for 5 years or tamoxifen for 2-2.5 years, followed by exemestane for 2-2.5 years. Levels of bone formation markers (bone specific alkaline phosphatase, amino terminal propeptide of type I procollagen, osteocalcin), and the bone resorption marker (carboxyterminal crosslinked telopeptide of type I collagen), were assessed at baseline and after 3, 6 and 12 months of treatment. Exemestane (n=78) resulted in increases from baseline in all bone turnover marker levels at all timepoints. In contrast, levels of all bone marker turnovers decreased with tamoxifen (n=83). Differences between tamoxifen and exemestane were statistically significant for all bone turnover markers at all timepoints. In conclusion, exemestane results in increases in markers of bone formation and resorption, while decreases are observed with tamoxifen.

The influence of chemotherapy on bone mineral density, quantitative ultrasonometry and bone turnover in pre-menopausal women with breast cancer

INTRODUCTION The effects of doxorubicin/cyclophosphamide (A/C; 6 cycles) chemotherapy on bone mineral density (BMD), quantitative ultrasonography (QUS) and bone turnover markers in pre-menopausal women with oestrogen receptor-negative breast cancer (BC) were compared with age-matched controls. METHODS Among 106 women (BC=53, controls=53), BMD (spine and hip), QUS (calcaneus and phalanges) and bone marker levels were measured at baseline, 6 and 12 months. Correlations between parameters were determined by Spearmans rho. RESULTS All BC patients became amenorrhoeic after chemotherapy and remained so for the duration of treatment. BC patients had significant bone loss at all sites (P.005) and significant increases in bone turnover (P.05). There were significant correlations between BMD, QUS and bone markers (P.05). CONCLUSIONS Results confirm A/Cs deleterious influence on bone health in pre-menopausal women with BC and established QUSs utility for monitoring bone effects. Large-scale longitudinal studies are needed to further understand and prevent bone changes following chemotherapy.

Adherence and persistence in patients with severe osteoporosis treated with teriparatide.

Abstract Introduction: Medical intervention plays a key role in the treatment of postmenopausal osteoporosis and patients’ adherence to therapy is essential for optimal clinical outcomes. While adherence in RCTs is usually around 70–90%, a previous study showed that in clinical practice only 27.8% and 46.5% of the women on oral daily vs. weekly alendronate were still on treatment after 12 months. Data on adherence to teriparatide (TPTD) treatment of severe postmenopausal osteoporosis are available from only few countries. This study assessed adherence and persistence with TPTD in Germany. Material and methods: A sample of 50 women with severe postmenopausal osteoporosis treated with TPTD in accordance to the German osteoporosis guidelines was included. Treatment was initiated 12–24 months before recruitment. Patient self report was assessed using a validated questionnaire. In addition medication possession ratio (MPR) was calculated by counting prescription refills, and therefore all physicians who were treating the patients for any disease were contacted. Patients were classified adherent at 12 months of therapy if self-reported adherence and an MPR of ≥80% were achieved. Persistence was calculated in months and analysed with a Kaplan–Meier estimate. Results: Apart from a significantly lower age at menopause in the adherent group (46.1 vs. 50.0; p < 0.006) there were no significant differences in baseline demographics between adherent and non-adherent patients. After 12 months, 80% of the patients treated with TPTD were adherent, while 20% were non-adherent. A significant correlation with treatment adherence was found for self-reported medication tolerability (p < 0.001). Furthermore 79% of patients were persistent after 12 months. Conclusion: These results indicate that more patients seem to be adherent and persistent with TPTD than with oral treatments of postmenopausal osteoporosis. As these patients suffered from severe osteoporosis and sustained several fragility fractures, the generalisability of our retrospective study analysing a small sample is limited. The major factor that reduced adherence and persistence was tolerability. These findings are of practical relevance as numerous studies on antiresorptive therapies have shown that high adherence and persistence were needed to ensure an optimal therapeutic outcome.

Use of antidiabetic agents in the treatment of gestational diabetes mellitus in Germany, 2008–2012

Adequate blood glucose control during pregnancy is important because gestational diabetes mellitus (GDM) is known to have adverse effects on the mother and child. Due to an increasing prevalence of GDM in recent years, more information on the use of different antidiabetic agents is required, which was the aim of the present study.

The ZOTECT study: Effect of zoledronic acid on bone metabolism in patients with bone metastases from prostate or breast cancer

Purpose The ZOTECT study assesses the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients. Methods This prospective, single-arm, open-label study in bisphosphonate-naive (≥6 months) patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) enrolled at 98 German sites (May 2006 to July 2008) investigated the effect of ZOL (4 mg intravenously every 4 weeks×4 months, with a final follow-up at 12 months) on bone-marker levels. Secondary assessments: skeletal-related event (SRE) rate, pain, quality of life (QoL), and prostate-specific antigen levels. Endpoints were assessed using summary statistics by visit/tumor type and Kaplan–Meier analyses. Results ZOL treatment significantly decreased bone-marker levels (amino-terminal propeptide of type I collagen [P1NP], C-terminal cross-linking telopeptide of type I collagen [CTX]; P<0.0001), and this decrease was maintained through the final 1-year follow-up visit. Baseline P1NP and CTX levels correlated with extent of bone disease (P<0.0001, each) and on-treatment decreases in marker levels. Skeletal disease burden and bone-marker levels were similar between PC and BC patients, and ZOL did not significantly influence osteoprotegerin/receptor activator of nuclear factor-κB ligand levels. Only 13 SREs occurred in 11 patients, supporting the known ZOL-mediated reduction in SREs. On-treatment bone-marker level changes did not correlate with SRE rate, pain scores, or QoL. Generally, ZOL was well tolerated and adverse events were consistent with its known safety profile. Conclusions This study confirms that ZOL therapy significantly reduces bone turnover (measured as P1NP and CTX levels) in patients with bone metastases from PC or BC.

Evaluation of efficacy, safety and effects on symptoms of androgenization of a generic oral contraceptive containing chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg☆

BACKGROUND This prospective noninterventional study assessed the contraceptive efficacy, safety and the effects on signs of androgenization of the generic oral contraceptive containing 2 mg chlormadinone acetate/0.03 mg ethinylestradiol (CMA/EE) in a real-world setting. STUDY DESIGN A total of 1440 women were investigated during a six-cycle period by 229 gynecological practices throughout Germany. RESULTS The adjusted Pearl index was 0.136 (unadjusted: 0.271). Of 463 patients with cycle irregularities at baseline, 83.4% had regular cycles after six cycles. Likewise, 74.1% of 162 patients with spotting or breakthrough bleeding at baseline were free from these symptoms at the end of study. The percentage of patients with dysmenorrhea decreased significantly from baseline (36.5%) to visit 3 after six cycles (12.3%; p=.0001), with a significant reduction in the use of pain medication (p<.0001). Additionally, the number of patients with skin and hair problems was significantly reduced (skin: 56.3% at baseline, 19.6% after six cycles; hair: 45.7% at baseline, 13.4% after six cycles; p=.001). CMA/EE was well tolerated by the patients, and 89.44% of the gynecologists were satisfied with the treatment. CONCLUSION Generic CMA/EE exhibits very good contraceptive efficacy, cycle control and dysmenorrhea reduction. Furthermore, treatment with generic CMA/EE led to a favorable reduction of skin and hair problems in our study.

P2-19-03: Influence of Zoledronic Acid on BMD in Premenopausal Women with Breast Cancer and Neoadjuvant or Adjuvant Chemotherapy and/or Endocrine Treatment – The ProBone Studies.

Background: Based on baseline bone mineral density (BMD), adjuvant chemotherapy or endocrine therapy for early breast cancer patients can lead to substantially increased fracture risk. A significant decrease of BMD >10% after 2 years of chemotherapy (CT) and/or endocrine therapy (ET) has been reported. In recent studies, zoledronic acid (ZOL) produced an increase in BMD in premenopausal and postmenopausal patients with breast cancer (ABCSG-12, Z-FAST, ZO-FAST, etc). In addition, a significant increase in disease-free survival (DFS) with ZOL vs no ZOL was observed in most of these studies. Methods: The aim of 2 single-center, placebo-controlled, randomized studies—Probone I and Probone II—was to investigate the effect of adjuvant treatment with ZOL on BMD in premenopausal women with early breast cancer treated with CT and/or ET. Patients with hormone-receptor-negative (HR − ) breast cancer (Probone I) were treated with (neo)adjuvant CT; patients with hormone-receptor-positive (HR+) breast cancer (Probone II) were treated with ET alone or in combination with (neo)adjuvant CT. Randomized patients received ZOL 4 mg or placebo IV every 3 months for 24 months. The primary objective was the change in BMD at the lumbar spine between baseline and month 24 (measured by dual-energy X-ray absorptiometry [DXA]). Secondary objectives included DFS; BMD at total hip, femur, and os calcis; quantitative ultrasonometry (QUS) at os calcis and phalanges; markers of bone turnover (C-telopeptide of type I collagen [CTX] and N-terminal propeptide of type I procollagen [P1NP]); endocrine hormones (follicle-stimulating hormone [FSH], estradiol, testosterone, sex hormone-binding globulin [SHBG], parathyroid hormone [PTH], vitamin D, anti-Mullerian hormone [AMH], inhibin A/B, etc); pathologic fractures; and safety and tolerability. Results: 70 HR+ and 11 HR − breast cancer patients have been enrolled into the studies. The last patient will have been treated for 24 months by the end of June 2011. Conclusions: The effects of ZOL on lumbar spine BMD at 24 months and secondary endpoints will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-03.

Abstract P5-11-08: Effects of Exemestane or Tamoxifen on Bone Health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial: A Meta-Analysis

Background: TEAM is the largest AI phase III trial comparing exemestane with tamoxifen followed by exemestane as adjuvant breast cancer therapy in postmenopausal women. We performed a meta-analysis of three randomized sub-studies of the TEAM trial conducted in Germany, the Netherlands/Belgium and the United States to determine the effects on bone health. Methods: Patients were randomised to exemestane or tamoxifen as adjuvant therapy for hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12 and 24 months’ treatment. Bone turnover markers were also measured. Results: 412 patients were evaluable. Patients in the tamoxifen group showed a mean increase in lumbar spine BMD of 1.2% from baseline to month 12 and 0.2% to month 24. Patients in the exemestane group showed a mean decrease from baseline of 2.6% after 12 months and 3.5% after 24 months. There were significant differences in the changes in BMD at the lumbar spine between treatment groups (P Conclusions: After 24 months, exemestane treatment resulted in decreases in BMD and increases in bone turnover markers. In contrast, BMD was increased and bone turnover markers were decreased with tamoxifen. BMD and bone turnover changes appeared to stabilise after initial treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-08.

Bone effects of exemestane vs. tamoxifen within the TEAM trial: results of a prospective randomized bone sub study.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1143 Background: A prospective open label randomized multicenter trial was performed in the German TEAM Trial Group to compare the effects of the steroidal aromatase inhibitor Exemestane (EXE) and the ER agonist/antagonist Tamoxifen (TAM) on bone mineral density (BMD) and markers of bone turnover during adjuvant treatment of postmenopausal women with estrogen receptor positive breast cancer. Methods: 200 postmenopausal estrogen receptor positive breast cancer women were included in the bone substudy. Women with a history of osteoporosis or a disease or treatment known to effect bone metabolism were excluded. BMD and markers of bone turnover were assessed at baseline, after 6 and 12 months of treatment. BMD was performed using dual x-ray absorptiometry (DXA) at the lumber spine and femoral neck (FN). Marker of bone formation, PINP, bone specific alkaline phosphatase (BAP) and osteocalcin (OC) as well as bone resorption marker (ICPM) were analysed using standardised methods. Intent-to-treat analysis was performed based on 200 patients. The primary endpoint was to compare Exemestane and Tamoxifen with regard to changes from baseline to month 12 in BMD (g/cm²) in lumbar spine (integral of L1-L4). Results: 156 patients with a mean age of 61 yr. (+/- 7.3 yr.) were available for final analysis. Both groups were comparable regarding age, height, tumor grade and stage. Compared to women on Tamoxifen, who comprised an BMD increase of +0.9% and +0.9% after 6 and 12 months at the spine, women on EXE showed a decrease of -2.8% and -3.6%. Conversely, BMD at the FN showed a decrease of -2.1% and -2.2% in women on TAM while women on EXE showed a decrease of -3.4% after 6 and an increase of +1.1% after 12 months, respectivly. Bone formation and absorption was modulated in both groups. Details will be presented at the meeting.Conclusion: The results of the 12 months analysis in the TEAM Bone substudy confirm the bone protective effect of TAM at the spine while conversely the results at the FN showed a decrease. Women on EXE showed a decrease at the spine while there was a neutral effect at the FN. Futher evaluation of the 24 months data as well as the fracture rate of the total TEAM trial are nessecary to evaluate the effect of EXE on bone health. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1143.