Therapy In Postmenopausal Women Research Articles

Androgens in Women before and after the Menopause and Post Bilateral Oophorectomy: Clinical Effects and Indications for Testosterone Therapy

In postmenopausal women, the ovaries produce significant amounts of androgens for many years after the menopause. Bilateral oophorectomy markedly reduces circulating testosterone (T) in both pre- and postmenopausal women. Oral estrogen therapy in postmenopausal women increases sex hormone-binding globulin and decreases T bioavailablity. Circulating androgens decrease with increasing age. The occurrence of an androgen deficiency syndrome associated with loss of libido and sense of well-being is disputed, but in several randomized controlled trials, transdermal T patches produced a significant improvement in hypoactive sexual desire disorder in postmenopausal women who had bilateral oophorectomy and in some women who had a natural menopause. T therapy is legitimate and is clinically indicated in such women. T therapy may have other benefits in postmenopausal women including an increase in lean body mass and bone mineral density. T therapy should become an integral part of hormone therapy in selected postmenopausal women in the future.

A decade of postmenopausal hormone therapy prescribing in the United States

Nearly a decade ago, landmark clinical trials revealed an increase in the risks associated with hormone therapy in postmenopausal women, leading to early changes in prescribing patterns. Long-term prescribing patterns in the United States after these trials are unknown. The objective of this study was to describe changes in hormone therapy prescribing including dose, formulation, patient age, and prescriber specialty from 2000 to 2009. A national pharmacy claims database was used to describe the annual prevalence and incidence rates of hormone therapy prescribing from 2000 to 2009 in women 50 years and older. Throughout the decade, a number of prescribing trends were observed: a continuous decline in hormone therapy overall, an initial drop in new therapy that stabilized after 2003, a decline in oral formulations and increase in vaginal formulations, a decline in standard- and high-dose and an increase in low-dose oral formulations, and an increase in the proportion of women who received hormone therapy from gynecologists. Overall prescribing of hormone therapy continued to decline during the past decade, suggesting a long-term impact of the Women's Health Initiative findings. During this same time, treatment regimens shifted to favor vaginal and lower-dose oral formulations.

PCN69 Cost-Effectiveness Analysis of Aromatase Inhibitors and Tamoxifen As an Adjuvant Therapy in Postmenopausal Women with Early-Stage Hormone Receptor Positive Breast Cancer

PCN69 Cost-Effectiveness Analysis of Aromatase Inhibitors and Tamoxifen As an Adjuvant Therapy in Postmenopausal Women with Early-Stage Hormone Receptor Positive Breast Cancer

Neoadjuvant chemotherapy versus neoadjuvant hormonal therapy in postmenopausal women with ER-positive, HER2/neu negative locally advanced breast cancer.

595 Background: Postmenopausal women with large ER+/HER-2 negative tumors frequently receive neoadjuvant chemotherapy (NC), but pathological complete response (pCR) rates are low. Neoadjuvant hormonal therapy (NH) may offer benefit in this setting. Methods: Retrospective review of medical records from University of Miami/Jackson Memorial Hospital from 1998-2011. Primary outcomes: pCR (absence of invasive tumor in breast and lymph nodes at surgery), recurrence free survival (RFS) and tumor size reduction evaluated through comparison of palpable breast mass size at presentation with pathological tumor size in surgical specimen, and categorized as good response (GR) ≥ 30% reduction or no response (NR) < 30%. The Kaplan-Meier method and the log-rank test were used in the analysis of RFS. Results: Data from 151 post-menopausal women with ER+/HER-2 negative BC who received NC (57%) or NH (43%) was analyzed. Median follow-up among alive patients with no evidence of disease was 5.4 years in NC and 2.9 years in NH. Mean age was higher in the NH group (63.3 vs 56.1, p<0.0001). There were no racial or ethnic differences between the groups. Clinical stage was comparable in NC and NH (IIA 5.8% vs 9.2%, IIB 25.6% vs 20%, IIIA 37.2% vs 29.2%, IIIB/IIIC 31.4% vs 41.5%, p=0.775). Tumor histology was predominantly ductal in both groups (NC 85.7% and NH 78.5%, p=0.247). pCR was similar in NC and NH (4.7% vs 0%, p=0.078) along with RFS (median 8.5 yrs vs 6.0 yrs, p=0.946). In the NC group, GR was significantly more frequent (77.9% vs 60%, p=0.017). Among patients in the NH group, having GR was predictive of longer RFS (5-year rate 83.7% vs 50.5%, p=0.014). Breast only pCR occurred at equivalent rates between NC and NH (9.3% vs 3.1%, p=0.189) as did the absence of lymph node metastasis (29.1% vs 26.2%, p=0.606). In the NH cohort 38.5% received no adjuvant chemotherapy. Conclusions: NH provides an effective alternative to NC and, if there is a GR, may preclude the need for chemotherapy in over one third of postmenopausal women with large ER positive/HER-2 negative breast cancer.

Real-world aromatase inhibitor use and failure in women with metastatic ER+/HER2- breast cancer.

593 Background: Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line therapy for postmenopausal women with metastatic, ER+ breast cancer (BC). However, little information is available on the real-world use of AIs. The objectives of this retrospective claims study were to compare demographic, clinical and treatment characteristics of postmenopausal women with metastatic ER+/HER2- BC treated with AIs and experiencing 0, 1, 2 or ≥ 3 AI failures (AIF). Methods: Women ≥ 55 years old, newly diagnosed with metastatic BC (index) were identified in the 2006-2010 Thomson Reuters MarketScan databases and followed until chemotherapy or 03/31/2011. ER+/HER2- disease was defined as any endocrine therapy (ET: tamoxifen, fulvestrant) or AI (anastrozole, letrozole, or exemestane) use and no trastuzumab or lapatinib use in the 6-month pre-or variable post-index periods. Those with any post-index AI use were retained for study. AIF post-index was defined as a switch to an alternative AI, ET or chemotherapy, or AI discontinuation with no further BC treatment. Patients were stratified by number of post-index AIF: 0, 1, 2 or ≥ 3. Results: Among 4,274 patients identified, 61% had ≥ 1 AIF (1: 80%, 2: 15%, ≥3: 5%). There was no difference in pre-index AI use across AIF cohorts: 0, 1, 2, and ≥3 (54%, 52%, 48%, 56%; p=0.073). AIFs increased with Medicare-eligibility (51%, 56%, 60%, 61%) and bone metastases at index (48%, 53%, 62%, 63%). Among those with ≥1 AIF, median follow-up (FU) increased with each failure but there was no notable pattern to reason for FU end. Median FU of the 0 AIF cohort (408 days) fell between those of the 1 and 2 AIF cohorts, 335 and 517 days. Anastrozole was the most common first line treatment for all cohorts except ≥ 3 AIFs where letrozole was most common. Pre-index and first line fulvestrant use both increased with the number of post-index AIFs: 0.3%, 1.9%, 2.0%, 5.0% and 0.7%, 2.5%, 4.0%, 14.9% respectively. There was no association between number of AIFs and chemotherapy use (36%, 29%, 38%). Conclusions: Over 60% of women with ER+/HER2- metastatic BC treated with AIs failed at least 1 and 20% of those failed ≥ 2. Surprisingly, increased rates of prior fulvestrant treatment appear associated with increasing numbers of AIF.

Abstract 4248: A high-fat diet induces an inflammatory tumor microenvironment in MNU-induced estrogen receptor positive mammary tumors

Abstract The link between obesity and breast cancer has received much attention because it is associated with an increased risk of breast cancer, an increased incidence of recurrence, higher death rates, and reduced sensitivity to anti-hormonal therapy in post-menopausal women. In addition, obesity is associated with a chronic, low grade inflammatory status. Surprisingly, obesity can have different effects in pre-menopausal women where patient outcome is actually better in obese than lean women. This study was conducted to create an animal model to examine the effects of high-fat (HF) diet on estrogen-dependent mammary tumors in cycling rats. Sprague-Dawley rats were injected with N-Methyl-N-Nitrosourea (MNU) at 6 weeks of age to induce mammary tumors. The next day they received HF diet (45% kcal from fat) or normal fat (NF) diet (10% fat) (n=6-7) and animals were kept on these diets for an average of 15 weeks. Ninety-six percent of rats developed mammary tumors and all the tumors were ER positive. The tumor volume, tumor weight and tumor growth rate were not different between the HF or NF diet groups. Also, the HF diet did not influence the body weight, liver weight and adipose mass weight. However, the expression of pro-inflammatory cytokines, such as TNFa and IL-1b, was significantly up-regulated in tumors of the HF diet group compared to control. Macrophage infiltration was also increased in the tumors of the HF diet group. There was also a tendency of increased NFkB DNA binding activity in the HF diet group. Moreover, macrophage infiltration was significantly correlated with the amount of proinflammatory cytokine gene expression in the HF but not the NF diet group. In agreement with clinical data, cycling rats on the HF diet responded better to tamoxifen than did rats on the NF diet, with a greater reduction in tumor size over 20 days of treatment. Taken together, these results indicate that a HF diet induces a pro-inflammatory tumor microenvironment without causing obesity in cycling rats and that these tumors may be more responsive to endocrine therapy. Our findings also provide a model for future studies into the mechanism by which high fat diet may affect tumor growth and response to therapy in premenopausal women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4248. doi:1538-7445.AM2012-4248

391 Higher Risk of Locoregional Recurrences for Women Treated with Mastectomy Compared to Breast-Conserving Therapy in Postmenopausal Women with Early Breast Cancer Treated on the TEAM Trial

391 Higher Risk of Locoregional Recurrences for Women Treated with Mastectomy Compared to Breast-Conserving Therapy in Postmenopausal Women with Early Breast Cancer Treated on the TEAM Trial

Strontium ranelate treatment improves oxidative damage in osteoporotic rat model

BackgroundOsteoporosis is the most common skeletal disorder and is considered a risk of fracture. Most medication used for the treatment of osteoporosis is antiresorptive; however, strontium ranelate (Sr) therapy in postmenopausal women has shown a double effect on resorption and bone formation. In this study, the effect of Sr on status of the oxidative stress and antioxidant defence system was investigated. MethodsTwenty-one adult albino female Wistar rats were used. The animals were randomly assigned into three groups, control (sham operated rats, received saline), OVX (ovariectomized rats), OVX + Sr (4 months later ovariectomy, strontium ranelate treatment was begun and continued for 120 days) each containing 7 animals. Strontium ranelate (500mg/kg/day) and placebo (saline) were administered via oral gavage. At the end of the treatment, liver and kidney of rats were removed and malondialdehyde (MDA) level, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined by biochemical analysis methods. ResultsIn liver, MDA levels were significantly higher in the OVX and OVX + Sr groups than the control group. GSH-Px activity decreased in OVX group and increased in OVX + Sr group compared with values of control group. CAT activity was increased in the OVX + Sr group when compared to control group. In kidney, MDA level was increased in OVX group. SOD activity was decreased in the OVX + Sr group. GSH-Px activity decreased in OVX group and increased in OVX + Sr group compared with control group.CAT activity increased in the OVX + Sr group when compared to control. ConclusionAccording to our results, Sr has preventive effect on oxidative damage in ovariectomized rats.

BMD screening in older women: Initial measurement and testing interval

Screening is the early diagnosis of presymptomatic disease among well individuals in the general population.(1) The purpose of osteoporosis screening using bone mineral density (BMD) testing by dual energy X-ray absorptiometry (DXA) is to identify a presymptomatic condition (osteoporosis as defined by World Health Organization diagnostic criteria) that can be treated to prevent an adverse clinical outcome (fragility fractures). An osteoporosis screening program primarily targets the prevention of hip and clinical vertebral fractures because these fractures are associated with the majority of morbidity and health care utilization attributable to osteoporotic fractures. The U.S. Preventive Services Task Force(2) (USPSTF) assigned osteoporosis screening an evidence grade B based on findings from prospective cohort studies of DXA testing and results of randomized controlled trials (RCTs) demonstrating that pharmacologic therapy in postmenopausal women with osteoporosis(3–6) reduced the incidence of fractures. Until recently, prospective data regarding an osteoporosis screening interval were lacking,(7) and several organizations(8–13) recommended BMD screening intervals of about 2 to 5 years based on expert opinion.

The Tissue-Selective Estrogen Complex (TSEC): A Promising New Therapy for Menopausal Symptoms and Postmenopausal Osteoporosis

The menopausal transition may be associated with bothersome symptoms and increased risk of osteoporosis that can decrease quality of life for women. The primary treatment option is hormone therapy, which has been associated with some safety and tolerability concerns. The tissue-selective estrogen complex (TSEC) is a novel therapy that pairs a selective estrogen receptor modulator with one or more estrogens. The first TSEC in clinical development partners bazedoxifene (BZA) with conjugated estrogens (CE) and has been evaluated in the phase 3 Selective estrogens, Menopause, And Response to Therapy (SMART) trials. BZA 20 mg/CE 0.45 and 0.625 mg have been shown to be effective in reducing the frequency and severity of hot flushes and improving measures of vulvar/vaginal atrophy. These BZA/CE doses have also been shown to increase bone mineral density and reduce bone turnover without stimulating the endometrium and breast. BZA/CE represents a promising new therapy for postmenopausal women.

Hormonal effects on blood vessels

The incidence of cardiovascular disease (CVD) is lower in younger women than in men of the same age, but it increases after menopause, implicating the atheroprotective action of endogenous estrogen. Although observational studies have suggested the efficacy of estrogen therapy in postmenopausal women, placebo-controlled, randomized trials, such as the Women's Health Initiative, have not confirmed effects of estrogen therapy on CVD. Conversely, basic, experimental research has progressed and provided mechanistic insight into estrogen's action on blood vessels. By contrast, the vascular effects of androgens remain poorly understood and have been controversial for a long time. In recent years, an increasing body of evidence has suggested that androgens may exert protective effects against the development of atherosclerosis, at least in elderly men. Epidemiological studies have shown that the incidence of and mortality due to CVD were increased in elderly men with low testosterone levels, although the efficacy of androgen therapy remains unknown. Furthermore, recent experimental studies have demonstrated the direct action of androgens on the vasculature. In this review, we illustrate the effects of sex steroids on the cardiovascular system, focusing on the action of testosterone on the blood vessels.

Knowledge and attitude of primary care doctors towards management of postmenopausal symptoms

BackgroundAccording to the current recommendations, women with post-menopausal symptoms should be managed. Knowledge and perception of primary care physicians towards management of postmenopausal symptoms are deficient. AimThe aim of the present study was to explore knowledge and attitude of primary care doctors towards management of postmenopausal symptoms. MethodsThis study is a cross-sectional survey that was conducted from October to December 2010 in the five health regions in Kuwait. Two centers were selected randomly from each health region. All physicians who were currently working in the selected centers were asked to participate in the study. Out of 209 physicians, 142 agreed to participate and completed a self-administered questionnaire. ResultsThe study revealed that 82.4% of physicians had moderate knowledge about treatment options for postmenopausal symptoms, 88.0% discussed postmenopausal symptoms with their patients, and 45.1% of them either described or referred their patients for hormonal replacement therapy (HRT). The correct answers regarding 10 statements related to the Women Health Initiative finding were ranging from 2.8% to 78.9% which indicated low level of knowledge. Regarding the effectiveness of hormonal replacement therapy in postmenopausal women, the majority of the physicians agreed correctly that HRT is effective in prevention of osteoporosis (87.3%), treatment of vasomotor symptoms (83.7%), and treatment of vulvo-vaginal symptoms (82.4%). There was a variation among physicians opinion about the effectiveness of certain treatment options for managing hot flushes in postmenopausal women. ConclusionThe results suggest that there is a lack of primary care physicians knowledge and confidence in recognizing signs and symptoms of menopause and in identifying and prescribing appropriate management.

Mortality Associated with Hormone Replacement Therapy in Postmenopausal Women

There was controversy about decrease in mortality as the eventual result of hormone replacement therapy (HRT). The reduction of mortality was known in large observational-cohort studies in women with HRT compared with non-HRT after correction of confounding factors. The second analysis of Women’s Health Initiative (WHI) results revealed that the 30% decrease in mortality was observed in HRT users. These findings resemble with the results of past observational studies. The meta-analysis including the second analysis of WHI results showed that HRT use in young menopausal women decrease the mortality. Although there was a chaos about the risk and benefit of HRT since the first announcement of WHI study in 2002, HRT in young menopausal women could decrease the morbidity and mortality related to coronary heart disease and stroke. (J Korean Soc Menopause 2012;18: 133-138)

Risiko for brystkreft ved hormonbehandling i klimakteriet

The Norwegian "Women and cancer" study has shown that when combination hormone replacement products were used for more than five years the relative risk of breast cancer was almost tripled. The population attributable risk was 27 %. In a nested case-control study we have updated the risk estimates for hormone replacement therapy in post-menopausal women since 2002. We selected an age-matched control for each of the 589 women (aged 46-63) who were found in the period 2004-8 to have invasive breast cancer or cancer in situ. These women responded in 2003-6 to a questionnaire on menstruation and the use of hormone replacement therapy. The data from this and earlier questionnaires were compared and analysed using logistical regression. 226 (26 %) of the women were using hormone replacement at the time of the survey. The average time of use was ten years. Current users had a higher risk of breast cancer than never-users: adjusted OR 2.1 (95 % CI 1.5-3.0). The use of combination therapy for more than five years resulted in the highest risk: OR 3.0 (95 % CI 1.9-4.7). Earlier use of oestrogen products did not result in a higher risk. Neither oestradiol nor tibolon caused a statistically significant increase in risk. 232 cases of breast cancer (17 %) in women aged 45-64 could be attributed to the use of hormones. Long-term use of combination products increases the risk of breast cancer. Relative risk estimates have undergone little change since the previous study, but population attributable risk has fallen along with the decline in new users.

Adjuvant Hormonal Therapy in Postmenopausal Women with Breast Cancer: Physician’s Choices

The choice of adjuvant hormonal therapy in postmenopausal women with hormone receptor positive breast cancer has remained a matter of controversy and debate. The variety of agents is available, with each claiming to be superior. This clinical survey was undertaken to get an impression of the physician's first choice of therapy in an attempt to find out what questions still need to be answered in the making of “standard of care.” A web-based clinical survey was sent to the cancer physicians around the world, and 182 physicians responded to the survey. Most were medical oncologists in a tertiary care hospital. 36.3% preferred Anastrozole, 35.2% Tamoxifen, and 22.2% Letrozole as their first choice. Data support (67.8%) and safety concerns (30%) were given as the main reasons for the choice, 63.7% switched their therapy, and 24% had to switch because of side effects. 73.6% used 5 years of adjuvant hormonal therapy, 6.6% for 7 years, and 4.4% for 10 years. 61.5% follow their patients 3 times monthly, and 73.2% used laboratory and radiological assessment at each followup. Conclusion. Physicians show disagreement over the choice and duration of hormonal therapy in this patient population. Clinical trials leading to firm recommendations to set standards from which patients benefit the most are needed.

Change in Undercarboxylated Osteocalcin Is Associated with Changes in Body Weight, Fat Mass, and Adiponectin: Parathyroid Hormone (1-84) or Alendronate Therapy in Postmenopausal Women with Osteoporosis (the PaTH Study)

Change in Undercarboxylated Osteocalcin Is Associated with Changes in Body Weight, Fat Mass, and Adiponectin: Parathyroid Hormone (1-84) or Alendronate Therapy in Postmenopausal Women with Osteoporosis (the PaTH Study)

Response: Higher Glycated Hemoglobin Level Is Associated with Increased Risk for Ischemic Stroke in Non-Diabetic Korean Male Adults (Diabetes Metab J 2011;35:551-7)

We appreciate the interest and comments on our study, “Higher glycated hemoglobin level is associated with increased risk for ischemic stroke in non-diabetic Korean male adults,” which was published in Diabetes & Metabolism Journal 2011;35:5517. We have responded to the questions below. In our study, we excluded patients with iron-deficiency ane mia, end-stage renal disease, a history of alcohol abuse, persons older than 80 years, pregnant women, children, cancer patients, subjects without fasting blood glucose and HbA1c level data, patients with a history of diabetes or fasting blood glucose level ≥126 mg/dL and patients with cardioembolic ischemic stroke, or recurrent stroke. We analyzed the risk of ischemic stroke only in adult males because our aim was to determine if there were any gender differences considering the fact that HbA1c failed to predict cardiovascular disease in nondiabetic women in a previous report [1]. We also failed to show the usefulness of HbA1c as a predictor of ischemic stroke in non-diabetic Korean women. This re sult might be due to a lack of consideration for hormonal changes or hormonal replacement therapy in postmenopausal women. Recent studies reported that sex hormone and sex hormone-binding globulin, in addition to HbA1c, are associated with a risk of type 2 diabetes [2,3]. Because the women in our study were in their sixties, on average, most female subjects were postmenopausal and likely undergoing drastic hormonal changes, making it difficult to identify HbA1c as a pre dictor of ischemic stroke. Although the smoking rate was significantly different between the control and the stroke patients, our results are reliable because we assessed the risk of ischemic stroke according to the HbA1c levels after adjusting for age, smoking, body mass index, high density lipoprotein cholesterol, low density lipoprotein cholesterol, systolic and diastolic blood pressure, and HbA1c quartile. This was a cross-sectional study such that a definite relationship between HbA1c and ischemic stroke cannot be assumed. Further research in a more ethnically diverse group must be conducted to clarify this relationship. In spite of these limitations, the results of this study are meaningful in that this study was the first to report the association of increasing HbA1c with risk of ischemic stroke in non-diabetic Korean male adults. Our findings warrant future large-scale, long-term prospective cohort studies to evaluate the association between HbA1c and stroke morbidity.

PD06-07: COMPliance and Arthralgias in Clinical Therapy (COMPACT): Assessment of the Incidence and Severity of Arthralgia, Treatment Costs and Compliance within the First Year of Adjuvant Anastrozole Therapy.

Abstract Introduction: Aromatase inhibitors (AI) are well established as adjuvant endocrine treatment for postmenopausal (PMP) women with HR+ early breast cancer (EBC). However, according to retrospective data, compliance to adjuvant endocrine therapy for EBC may drop to below 70% after one year and to as low as 50% by year 4. In clinical trials, AI are significantly more frequently associated with arthralgia than tamoxifen. Yet, prospective real world data on the effects of AI-associated arthralgia on patient compliance, patient outcomes as well as treatment costs of arthralgia are lacking. Methods: COMPACT is an open, prospective, non-interventional study assessing the incidence and severity of arthralgia, treatment costs, and compliance within the first year of adjuvant anastrozole therapy in PMP women with HR+ EBC. The study is sponsored by AstraZeneca Germany and supported by three major German health insurance funds [GWQ ServicePlus AG, DAK, TK]. Patients on adjuvant treatment for 3–6 months were enrolled at 620 breast centres and practices throughout Germany and stratified by, a) initial adjuvant anastrozole therapy or, b) switch from tamoxifen to anastrozole. All patients receive regular standardized information about EBC from baseline to week 20 to support treatment compliance. Data on patient demographics, occurrence of and treatment of arthralgia, and quality of life will be collected at baseline, 3, 6 and 9 months. Primary endpoints are scaled data on arthralgia, assessed with a visual analogous scale (VAS) via patient questionnaire, and compliance to anastrozole in both strata, assessed by patient and investigator questionnaire. Secondary endpoints include the incidence of arthralgia, treatment costs, reasons for non-compliance, and the influence of arthralgia on clinical outcome. For a subgroup of patients data on arthralgia treatment and compliance will be validated with corresponding data of the participating health insurance funds. Results: Between April 2009 and February 2011, 2313 patients were recruited, 2007 receiving upfront anastrozole and 306 patients on switch therapy. Preliminary baseline data for 2313 patients show the following patient characteristics: mean age 64.5 years, mean BMI 27.7. Only 16.8% of patients had received hormone replacement therapy prior to their cancer. 41.5% of patients had concomitant symptoms relating to skeleton or musculature, and 11.9% stated arthralgias existing prior to anastrozole treatment. 13.1% reported a worsening of pre-existing arthralgias or new arthralgia after starting on anastrozole treatment. Conclusion: COMPACT aims to provide valid real world data on the incidence and severity of AI-associated arthralgia, treatment modalities and treatment costs. Our results will help to understand and better counsel patients about AI-associated arthralgia to improve adherence to AI-treatment, breast cancer outcomes, and therapy costs. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD06-07.

P4-12-13: A Multi-Center Randomized Controlled Double Blind Trial Assessing the Effect of Acupuncture in Reducing Musculoskeletal Symptoms in Breast Cancer Patients Taking Aromatase Inhibitors: First Interim Analysis.

Abstract Background: Aromatase inhibitors (AIs) are recommended as first-line adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive breast cancer, as monotherapy or sequential therapy after tamoxifen. AI-associated musculoskeletal symptoms (AIMSS) occur in approximately 50% of women receiving AIs and in some may result in discontinuation of treatment. Symptom management is essential to ensure that breast cancer patients receive the full recommended duration of AI therapy. We conducted a randomized, placebo-controlled trial to evaluate the effect of acupuncture on AIMSS and report the first interim analysis. Method: Postmenopausal women with early stage breast cancer, experiencing AIMSS, who had not had acupuncture in the year prior to the study, were eligible. Patients were randomized to 8 weekly acupuncture or sham acupuncture. Health assessment questionnaire disability index (HAQ-DI ranging 0–3.0) and pain visual analog scale (VAS ranging 0–100) were used to assess clinical musculoskeletal disorder severity at weeks 0, 4, 8, and 12 or 24. Change in HAQ-DI (ΔHAQ-DI) and VAS scores (ΔVAS) from baseline were compared between patients receiving acupuncture versus sham acupuncture using exact Wilcoxon rank sum test. Serum samples were collected for measurements of estrogens and beta endorphin concentrations and cytokine profile before and after the intervention to evaluate the etiology of AIMSS and the mechanism of acupuncture in treating AIMSS. Results: Between May 2008 and June 2011, 48 patients were enrolled, 2 patients were not evaluable due to noncompliance to treatment and lost to follow up, 10 were still receiving treatment and therefore not evaluable. Thirty-six were evaluable, and were equally distributed between the real and sham acupuncture groups. Baseline characteristics were balanced between the two groups with regard to age, race, and body mass index (BMI) with the exception that baseline mean HAQ-DI was higher in the acupuncture group (0.9 vs 0.55, p=0.04). White/Black/Asian: 26/7/3, Median (range): age: 61 (45-82); BMI (kg/m2): 31.1 (22.9−59.6). At week 8, both groups showed a wide range of ΔHAQ-DI (ΔHAQ-DI =HAQ-DIweek8-HAQ-DIbaseline): from −1.38 to 0.5 in the acupuncture group versus from −1 to 0.12 in sham acupuncture group. There was no statistically significant difference in mean ΔHAQ-DI between the real and sham acupuncture groups (−0.33 vs −0.33, p=0.87). Eleven patients in each group (61%) reported decreased HAQ-DI scores, which correlated with improved function. There was no difference in mean ΔVAS between the real and sham acupuncture groups (−9.27 vs −13.82, p=0.67). No significant side effects were reported. Changes in other time points and in serum biomarkers will be presented at the meeting. Conclusions: The majority of breast cancer patients experiencing AIMSS who participated in our study reported a reduced HAQ-DI score both from acupuncture and sham acupuncture. We did not observe significant differences between responses to real versus sham acupuncture after 8 weekly treatments. The study remains open to accrual to reach 50 evaluable patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-13.

P3-16-15: Phase I Study with Biomarker Evaluation of Neoadjuvant Sunitinib in Combination with Exemestane in Post-Menopausal Women with Hormone-Sensitive, Her-2 Negative Primary Breast Cancer.

Abstract Background In preclinical models, oestrogen causes a rapid induction of VEGF in mammary tumours leading to tumour angiogenesis, tumor growth and cell migration whereas aromatase inhibitors (AI) have the opposite effect. Exemestane (E) is an AI, effective in metastatic hormone-dependent breast cancer, as well as in the adjuvant and neoadjuvant settings. Sunitinib (S) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic activities via inhibition of VEGFR, PDGFR, KIT, RET, CSF-1R and FLT-3, and direct antitumor activity shown in heavily pretreated subjects with advanced breast cancer. The use of antiangiogenic agents at initial stages of the disease, when fewer proangiogenic factors are present, may result in significantly greater efficacy than using these agents at a later stage. Safety profiles of both agents indicate only modest toxicity and do not overlap. We hypothesize that since antiangiogenic and hormonal agents use different mechanisms of action, combination will have additive activity. Regarding (S), continuous dosing (CD) at low doses might result in improved efficacy while maintaining good tolerability. Methods: This is a phase I study to evaluate the safety of (S) in combination with (E) administered for 24 weeks (1cycle=4weeks) as neoadjuvant therapy for post-menopausal women with newly diagnosed hormone-sensitive, Her-2 negative primary breast cancer. We report the results of the first dose escalation part of the study intended to determine a safe dose level of (S) that can be combined with (E) at conventional fixed dose of 25mg/d. Preliminary efficacy data in terms of objective clinical response by WHO criteria will also be reported. Results: 18 postmenopausal women with ER-positive invasive breast cancer, adequate organ function and ECOG 0–1 were enrolled in the study (median age 74, range 57–84) to be treated at two dose levels: 25 mg of (E) with either 25mg or 37.5mg of (S) CD. Two DLTs were identified: grade 3 mucositis at level 25mg of (S) and grade 3 asthenia at level 37.5mg of (S). Main toxicities were asthenia, leucopenia, mucositis, diarrhea and HBP. 78% of patients had grade 2 toxicities; 22% had grade 3. There were no serious adverse events reported. Median time on treatment with the combination was 23 weeks (range 2–24). 16% of patients needed one dose reduction of (S), 16% needed two or more and 28% suspended (S) administration due to toxicity. 50% of patients completed 24 weeks of treatment. None of the patients at 37.5mg (S) level could tolerate full doses for the entire treatment period, therefore in our study the recommended dosage of (S) that can be safely combined with (E) is 25mg. Concerning efficacy, 11 out of 18 patients had partial response (61%), 6 out of 18 had SD (33%) and only one patient had PD (5%) as best response. Conclusion: Safety profile of the combination seems to be manageable in most patients. Toxicities were observed mainly within the two first cycles. Response rates were similar than those previously observed with (E) as monotherapy in the neoadjuvant setting. Biomarkers information will be provided. This study was supported by an Independent Investigator Research grant from Pfizer, Inc. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-15.