Adjuvant Treatment Of Postmenopausal Women Research Articles

Switching from nonsteroidal aromatase inhibitors to exemestane and its impact on menopausal symptoms.

e13098 Background: Aromatase inhibitors (AIs) are the most used adjuvant treatment in post-menopausal women with favorable oncotype, hormone receptor-positive (HR+) early breast cancer. Nonsteroidal AIs, such as anastrozole and letrozole, are associated with menopausal side effects including arthralgias, vaginal dryness, and hot flashes. Steroidal AIs, such as exemestane, however, have mild androgenic activity, thus minimizing the risk for these side effects. While studies show exemestane exhibits less bone toxicity compared to anastrozole, there has not yet been a proven significant difference in all menopausal symptoms. Nevertheless, switching from nonsteroidal to steroidal AI is still commonly seen in clinical practice. In this study, we aimed to examine the impact of switching from nonsteroidal to steroidal AI on menopausal side effects. Methods: We performed a retrospective review of patients diagnosed with HR+ breast cancer managed at an urban academic center from 2010-2023. Patients initially treated with anastrozole or letrozole and switched to exemestane were identified. Pathology records, treatment plans, and documented side effects were abstracted from medical records, as were baseline demographics. Symptoms were graded based on severity before and after each hormone therapy: mild grade described intermittent symptoms that did not require intervention; moderate grade described persistent daily symptoms or those that improved with additional intervention; severe grade described persistent disabling symptoms that required change in hormone therapy. Wilcoxon signed-rank tests were used to compare severity of menopausal symptoms before and after switching to exemestane. Results: There were 128 patients included in the study. Median age at diagnosis was 62.5 years; 13% pre-menopausal, 80% post-menopausal, 4% perimenopausal, and 3% unknown. Most patients were diagnosed with invasive ductal carcinoma (80%) and 45% were found to have stage IA breast cancer. The median amount of time on first and second lines of endocrine therapy were 11 and 25 months, respectively. Ninety-six patients (75%) reported menopausal symptoms on nonsteroidal AI, and 66% subsequently switched to exemestane due to severity of these symptoms. The most reported symptoms were arthralgias (79%), hot flashes (27%), body aches (25%), fatigue (10%), and vaginal dryness (9%). Of those with menopausal symptoms, 51% noted a decrease in symptom severity after switching to exemestane: 4 improved from moderate to mild, 21 from severe to moderate, and 24 from severe to mild. This decrease in severity was statistically significant across all menopausal symptoms (p<0.001). Conclusions: HR+ breast cancer patients exhibited a significant decrease in all menopausal symptoms when switching from nonsteroidal to steroidal AI. Further research is needed to examine the impact of this switch on a wider range of symptoms.

Abstract PD3-06: Robotic Stereotactic APBI for Early-Stage Breast Cancer: 2-year Outcomes of a Prospective Multi-Institutional Trial

Abstract Purpose: Outcomes following adjuvant accelerated partial breast irradiation (APBI) in select women with early-stage breast cancer are comparable to whole breast irradiation. Robotic stereotactic accelerated partial breast irradiation (RSAPBI) with fiducial tracking is an attractive treatment option, but limited outcomes data are available for this approach. We report 2-year outcomes for a prospective multi-institutional trial treating select women with RSAPBI. Materials and Methods: Post-menopausal women with DCIS and Stage IA breast cancer were treated over a five-year period extending from November 2015 to November 2020 and were followed for a minimum of 18 months. Treatments were delivered with a robotic radiosurgery system. Four gold fiducials were implanted around the lumpectomy cavity prior to the start of treatment for tumor bed delineation and target tracking. The CTV was defined as the lumpectomy cavity with a uniform 5-15 mm expansion confined to the breast tissue and the PTV was defined as the CTV with a 0-5 mm uniform expansion. The PTV was prescribed 30 Gy in 5 fractions. Disease status assessments were completed at 4 weeks, 3 months, 6 months, 12 months, 18 months, 24 months and yearly intervals thereafter for five years. Results: Eighty-one patients (median age 68 years) with hormone receptor-positive tumors were treated over a median 9 days (range, 5-15). Sixty-eight women had invasive ductal carcinoma (84%) and thirteen had DCIS (16%). The median treated PTV was 108 cm3 (IQR 66-156) and the median prescription isodose line was 81% (IQR 79-83). The median CTV expansion was 10 mm (range 5-10) and the median PTV expansion was 3 mm (range 0-5). At a median follow up of 2 years there was one new ipsilateral breast tumor diagnosed. There were no local, regional, or distant treatment failures. Conclusions: Two-year results suggest that RSAPBI with fiducial tracking is an effective technique for the adjuvant treatment of post-menopausal women with hormone receptor-positive early-stage breast cancer. Additional follow-up is planned to confirm this preliminary finding. Citation Format: Jonathan M. Cantalino, David D’Ambrosio, Arica Hirsch, Brian Collins, Malika Danner, Dawn Matsanka, Sonali Rudra, Simeng Suy, Sean Collins, Monica Pernia Marin, Michael Good, Jing Feng, John Lamond, Deborah Markiewicz, Rachelle Lanciano, Olusola Obayomi-Davies. Robotic Stereotactic APBI for Early-Stage Breast Cancer: 2-year Outcomes of a Prospective Multi-Institutional Trial [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 PD3-06.

Abstract 650: Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen (TAM), a SERM and AIs are the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreventive activities of tamoxifen and AIs, many initially responsive breast tumors develop resistance and ultimately recur. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. While the tumor microenvironment is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, our previous work shows that the critical molecular and cellular players secreted from a crosstalk between breast cancer cells and stromal cells can regulate the tumor growth and process of metastasis in breast cancer. In this report, using established endocrine resistant breast cancer (ERBC) cells and ESR1 mutant cells (Y537S and D538G), we screened the secreted factors in crosstalk between cancer cells and fibroblasts using cytokine antibody arrays and found that CXCL1 is highly upregulated in fibroblasts. To investigate a potential impact given the current clinical landscape of endocrine resistant breast cancer, we performed a high throughput cell-based screen to identify effective combinations of drugs that will be tested in vivo using reparixin, CXCR1/2 inhibitor, tamoxifen (SERM), fulvestrant (SERD), and CDK4/6 inhibitors (Palbociclib and Ribociclib) in co-culture with ERBC cells and fibroblast. Significantly, reparixin decreased ERBC cell viability compared to vehicle while reparixin in combination with tamoxifen and fulvestrant, enhanced the inhibitor effects in ERBC cell growth. We found that the combination treatment of reparixin and Palbociclib and ribociclib significantly inhibited ERBC cell growth and migration compared the single treatment. The inhibitory effect of reparixin was higher in combination with CDK4/6 inhibitors that the combination with tamoxifen and fulvestrant. Furthermore, reparixin in combination with CDK4/6 inhibitors decreased ERBC cell migration and promotes apoptosis.These findings implicate CXCL1 signaling as a critical event in ERBC tumor growth and metastasis via crosstalk between cancer cells and stromal components. Further, these studies suggest that CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the CXCL1 and CDK4/6 signaling pathway has the potential to circumvent ERBC growth and metastasis. Citation Format: Sneha Pandithar, Olivia Reff, Kideok Jin. Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 650.

Aromatase inhibitors for breast cancer therapy: Analysis of real-world FAERS data.

1051 Background: Aromatase inhibitors (AIs) are extremely effective adjuvant treatment in postmenopausal women with hormone receptor-positive breast cancer (HRPBC). We utilized the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate the musculoskeletal (MSK), fractures, and ischemic heart disease (IHD) adverse events (AEs) caused by AIs. Methods: We conducted a retrospective FAERS public database review to assess the MSK, fracture, and IHD AEs for the three AIs (anastrozole, letrozole, and exemestane) from 2001 through 2021. Chi-square was used to compare categorical variables. Results: A total of 31,683 AEs reports were identified, out of which, 15,140 (47.8%) were MSK, 13,311 (42.0%) were fracture, and 3,232 (10.2%) were IHD. The differences in AEs distributions among the three drug classes were statistically significant for MSK and fracture AEs (P < 0.001) but not reached statistical significance for IHD AEs (P = 0.140). MSK AEs were mostly reported with anastrozole, followed by exemestane, and letrozole in 35.23%, 33.97%, and 32.06%, respectively (P < 0.001). Compared to older individuals, younger adults (≤65 years) had higher rates of MSK AEs—mostly with anastrozole (38.43%, P < 0.001), followed by exemestane (36.37%, P = 0.006) and letrozole (34.28%, P < 0.001). Fracture AEs were mostly reported, in descending order, with letrozole, exemestane, and anastrozole in 12.07%, 11.41%, and 9.34% respectively (P < 0.001). Older adults (> 65 years) had higher rates of fracture AEs with letrozole (16.77%, P < 0.001) and anastrozole (10.37%, P < 0.001), while unable to demonstrate statistical significance with exemestane (13.48%, P = 0.108). Among older adults (> 65 years), IHD AEs were significantly reported with anastrozole (21.56%, P < 0.001) and exemestane (14.18%, P = 0.016) but no statistical significance reached for letrozole (14.12%, P = 0.528). Conclusions: The findings in this study highlight trends for selected AEs with various AI regimens, provide further insights, and help guide therapeutic decisions for patients with HRPBC.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Role of Exemestane in the Treatment of Estrogen-Receptor-Positive Breast Cancer: A Narrative Review of Recent Evidence.

Breast cancer (BC) is the most common type of cancer diagnosed among women worldwide with an estimated 2.3 million new cases every year. Almost two-thirds of all patients with BC have estrogen receptor-positive (ER+) tumors. In this review, the clinical evidence of exemestane in different treatment settings in ER+ BC is presented and summarized. A search strategy with the keywords "breast cancer [MeSH Terms]" AND "exemestane [Title/Abstract]" was devised and a search was performed in PubMed. The efficacy of exemestane in different treatment settings has been established by numerous clinical studies. Exemestane is recommended as an adjuvant treatment in postmenopausal women previously treated with tamoxifen in trials comparing 5years of tamoxifen with 2-3years of tamoxifen combined with 2-3years of exemestane, which proved that treatment with exemestane provided better survival outcomes. Similarly, exemestane could be considered as a safe treatment option for neoadjuvant treatment, prevention of chemotherapy, and treatment of advanced BC either alone or in combination with other targeted therapy drugs in both pre- and postmenopausal women. Exemestane could be considered as a reasonable therapeutic option in the treatment of ER+ BC at any stage in pre- and postmenopausal women.

Denosumab vs. zoledronic acid treatment in post-menopausal breast cancer: a 2-year prospective observational study

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(–0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (–0.001g/cm2) and a small significant decrease at the femoral neck (–0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference. Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA. Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis. We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years. We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.

We assessed the utility of raloxifene (60mg/day) as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 24-week, double-blind, randomized, placebo-controlled study. Patients were recruited from the inpatient and outpatient services of Parc Sanitari Sant Joan de Déu, Hospital Universitari Institut Pere Mata, and Corporació Sanitària Parc Taulí. Seventy eight postmenopausal women with schizophrenia were randomized to either adjunctive raloxifene or placebo. Sixty-eight beganthe clinical trial (37 women on raloxifene adjunct) and 31 on placebo adjunct. The outcome measures were: memory, attention and executive function. Assessment was conducted at baseline and at week 24. Between groups homogeneity was tested with the Student's t test for continuous variables and/or the Mann-Whitney U test for ordinal variables and the χ2 test or Fisher's exact test for categorical variables. The differences between the two groups in neuropsychological test scores were compared using the Student's t test. The sample was homogenous with respect to age, formal education, illness duration and previous pharmacological treatment. The addition of raloxifene to antipsychotic treatment as usual showed no differences in cognitive function. The daily use of 60mg raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia has no appreciable effect.ClinicalTrials.gov Identifier: NCT01573637.

Abstract LB-101: Crosstalk between stromal components and endocrine resistant breast cancer via secreted factors enhances tumor growth and metastasis

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen (TAM), a SERM and AIs are the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreventive activities of tamoxifen and AIs, many initially responsive breast tumors develop resistance and ultimately recur. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. While the tumor microenvironment is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, our previous work shows that the critical molecular and cellular players secreted from a crosstalk between breast cancer cells, and stromal cells can regulate the tumor growth and process of metastasis in breast cancer. In this report, we established a tamoxifen-resistant breast cancer (TAMR) cells. We screened secretomes from normal fibroblasts in co-culture of TAMR cells using cytokine antibody arrays to target 105 human cytokines simultaneously. We identified upregulation of IL-6, CXCL5, IL-8, EMMPRIN, CXCL1, GM-CSF, GDF-15, CCL5, BDNF, BAFF, LIF, and CXCL10 in the secretomes from fibroblasts in crosstalk of ERBC cells. We ranked the expression level of each factor by real-time qRT-PCR and determined that CXCL1 and IL-6 were the top candidates. We confirmed by U-PLEX (MSD) that CXCL1 and IL-6 secreted from fibroblasts treated with TAMR tumor-conditioned medium (TCM) was upregulated compared to treatment with serum free media (SFM). Our data showed that the proliferation of TAMR cells co-cultured with fibroblasts was enhanced compared to monoculture. Furthermore, TAMR cell migration, a key step in tumor metastasis, was promoted by conditioned medium (CM) from TCM-induced fibroblasts. Significantly, inhibition of the CXCL1 and IL-6 signaling pathway by Reparixin, an inhibitor of the CXCL1 receptor CXCR1/2, and Tocilizumab, an inhibitor of the IL-6 receptor abrogated TAMR cell growth and migration. These findings implicate IL-6 and CXCL1 signaling as a critical event in ERBC tumor growth and metastasis via crosstalk between cancer cells and stromal components. Further, these studies suggest that IL-6 and CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the IL-6 and CXCL1 signaling pathway has the potential to circumvent ERBC growth and metastasis. Citation Format: Kideok Jin. Crosstalk between stromal components and endocrine resistant breast cancer via secreted factors enhances tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-101.

Abstract P6-11-01: Final results of the randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia

Abstract Aromatase inhibitors (AIs) have been used in the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer as a consequence of the significant benefit in DFS and OS when compared with tamoxifen. However the patients who receive AIs have an increased risk of arthralgia, at most 50% of patients did not take AIs and the 20% of the discontinued patients were within the first year of use. The HOPE study demonstrated that exercise was effective in improving AI-induced arthralgia. We conducted the AIAI (Arthralgia Improvement for the patients with Aromatase Inhibitors) study using wider eligibility criteria that the HOPE study to assess the impact on AI induced arthralgia in breast cancer patients. Patients were randomly assigned, in a 3:1 ratio, to exercise intervention or usual care. Following randomization participants could choose from 3 types of exercise including group 1 (120-150 minutes per week of walking or running), group 2 (daily NIPPON HOSO KYOKAI: NHK broadcast exercise in Japan) and group 3 (going up the stairs- frequency, etc). The primary endpoint was the arthralgia change at 6 and 12 months, which was assessed using the BPI (Brief Pain Inventory). Secondary endpoints included the BPI according to the completion rate of exercise (70% and more or less than 70%), the BPI change of the patients with arthralgia (the patients who had arthralgia at the time they enrolled this study; BPI worst pain 3≤), the BPI of the each exercise group, the BPI according to the duration of AIs therapy (24 months and more or less than 24 months), the correlation between the BMI change and the BPI change, adherence of AIs and safety. 102 were randomly assigned to exercise intervention group (22 patients dropped out of this study) and 37 to usual care group (9 patients dropped out of this study).Trends for differentiations of pain interference at 12 months was detected between exercise intervention group and usual care group, but the differences did not reach statistical significance (p = .067). There was statistically better pain interference of the 70% and more exercise completion group than the usual care group at 12 months (-0.29±1.22 for exercise intervention group and 0.33±0.88 for usual care group, p= .002). The change of pain interference was statistically better for the exercise intervention group than the usual care group at 12 months (p= .017, -0.61±0.69 for exercise intervention group and 1.14±1.56 for usual care group). There was statistically significant difference of pain interference between group 1 exercise intervention group and the usual care group at 12 months (-0.14±0.68 for group 1 exercise intervention group and 0.33±0.88 for the usual care group, p= .009). Tendencies were detected in the AIs therapy less than 24 months group. Trends for the correlation between BPI and BMI were detected in worst pain at 6 month, pain severity at 6 month and pain interference at 12 month. There was a statistically significant difference of AIs adherence between the exercise intervention group (99%) and the usual care group (92%) (P=0.03). Exercise may be effective in improving and preventing AI-induced arthralgia. Citation Format: Tamaki K, Takaesu M, Nagamine S, Terukina S, Kamada Y, Uehara K, Takigami N, Arakaki M, Yamashiro K, Miyashita M, Ishida T, McNamara KM, Tamaki N, Sasano H. Final results of the randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia [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 P6-11-01.

The effect of anastrozole on bone mineral density during the first 5years of adjuvant treatment in postmenopausal women with early breast cancer.

PurposeThe administration of aromatase inhibitors is associated with bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole as initial adjuvant therapy.MethodsPostmenopausal women with hormone receptor-positive breast cancer receiving anastrozole as adjuvant therapy at our center since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral bisphosphonate (Bis) treatment was initiated when patients were diagnosed with osteoporosis having a T-score of −2.5 or lower.ResultsFifty-five patients were enrolled in the study between 2004 and 2011, and the mean follow-up period was 53.6 months. Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). After 6 months of hormone therapy, BMD decreased by 0.5% from baseline at the lumbar spine (LS) and BMD decreased by 1.5% at the femoral neck (FN). However, BMD increased by 1.9% at the LS and BMD decreased by 1.5% at the FN for 60 months of treatment. In patients treated with upfront Bis (n = 19), 5.4% BMD increase from baseline was noted at the LS whereas in those without Bis (n = 21) BMD decreased by 4.3% from baseline within 24 months (P < 0.0001). Fractures were observed in 4 patients (7.3%), and 1 patient (1.8%) had a fragility fracture.ConclusionsUpfront treatment of Bis with anastrozole significantly increased BMD at the LS and an optimal use of Bis would not increase bone fractures.Trial registrationUMIN0000017571

Breast cancer chemoprevention: little progress in practice?

Breast cancer chemoprevention: little progress in practice?

Effects of raloxifene on cognition in postmenopausal women with schizophrenia: A double-blind, randomized, placebo-controlled trial

Studies of estrogen therapy in postmenopausal women provide evidence of an effect of sex hormones on cognitive function. Estrogen has demonstrated some utility in the prevention of normal, age-related decline in cognitive functions, especially in memory. The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator (SERM), appears to act similarly to conjugated estrogens on dopamine and serotonin brain systems, and may be a better option since it lacks the possible negative effects of estrogen on breast and uterine tissue. We assessed the utility of raloxifene as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 12-week, double-blind, randomized, placebo-controlled study. Patients were recruited from both the inpatient and outpatient departments. Thirty-three postmenopausal women with schizophrenia (DSM-IV) were randomized to receive either adjuvant raloxifene (16 women) or adjuvant placebo (17 women) for three months. The main outcome measures were: Memory, attention and executive functions. Assessment was conducted at baseline and week 12. The total sample is homogenous with respect to: age, years of schooling, illness duration, baseline symptomatology and pharmacological treatment. The addition of raloxifene (60mg) to regular antipsychotic treatment showed: we found significant differences in some aspects of memory and executive function in patients treated with raloxifene. This improvement does not correlate with clinical improvement. The use of raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia seems to be useful in improving cognitive symptoms.

The effect of anastrozole on bone mineral density during the first 5 years of adjuvant treatment in postmenopausal women with early breast cancer.

e11604 Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole (ANA) as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine responsive breast cancer receiving ANA as adjuvant therapy at our hospital since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed as having osteoporosis with a T-score of -2.5 or lower. Results: Fifty-seven patients were enrolled in the study between 2004 and 2011. Patients’ median age was 65 years (range 50~85) and the median follow-up period was 46.3 months (9.6~83.8). Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). Within 6 months of hormone therapy, BMD decreased by 0.3% from baseline at the lumbar spine and BMD decreased by 1.2% at the femoral neck. However, BMD increased by 2.8% at the lumbar spine and BMD decreased 0.5% at the femoral neck for 60 months of treatment. In patients treated with upfront Bis (n=24), 4.9% BMD increase from baseline was noted at the lumbar spine whereas in those without Bis (n=20) BMD decreased by 4.6% from baseline within 24 months (p=0.0002). Fractures were observed in 4 patients (7.0%), and 1 patient (1.8%) had fragility fracture. Conclusions: Oral Bis prevented ANA-induced bone loss, and upfront treatment of Bis significantly increased BMD at the lumber spine.

Abstract P2-10-15: Evaluation of Prognostic and Predictive Performance of Breast Cancer Index and Its Components in Hormonal Receptor-Positive Breast Cancer Patients: A TransATAC Study

Abstract Background: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared the efficacy and safety of 5 years of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with localized HR+ breast cancer. At a median follow-up of 10 years, a statistically significant improvement with anastrozole vs. tamoxifen for disease-free survival, time to recurrence and time to distant recurrence was observed. The HOXB13:IL17BR gene expression ratio (H/I) quantifies recurrence risk in ER positive (ER+) breast cancer patients and is predictive of benefit from endocrine therapy. Molecular Grade Index (MGI) is a five-gene index that provides quantitative and objective molecular assessment of tumor grade and proliferative status. Breast Cancer Index (BCI) combines H/I and MGI into a continuous risk model that provides a likelihood of distant recurrence in patients treated with endocrine therapy, and efficacy from neoadjuvant chemotherapy. In the current analysis, evaluation of the prognostic and predictive performance of BCI, H/I and MGI in the ATAC study cohort was conducted. Methods: Under the TransATAC protocol, formalin-fixed, paraffin-embedded (FFPE) blocks of primary tumor were collected from HR+ patients from each monotherapy arm. The current study examined samples collected from the United Kingdom, which constituted 79% of the collection. RNA extracted from 1102 samples from the TransATAC study was amplified, converted to cDNA and subjected to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A, CENPA, NEK2, RACGAP1 and RRM2. H/I, MGI and BCI were calculated and risk groups were determined using pre-specified cutpoints. Results: Of 1102 tumor specimens assayed, 29 failed QC criteria, leaving 1073 samples for analysis. Detailed results on the prognostic and predictive performance of BCI, H/I and MGI will be presented. Data on whether BCI and its components provided independent prognostic information in the presence of classical variables, their prognostic value for risk of late recurrence, interaction by treatment arms, and comparative performance vs other models will also be discussed. Discussion: The ATAC trial has established the long-term efficacy and safety of anastrozole over tamoxifen as initial adjuvant treatment for post-menopausal early stage breast cancer patients. Continued efforts are needed to improve on quantification of residual risk in patients who were treated with endocrine therapy to guide decision-making in selecting additional adjuvant chemotherapy and/or administering extended endocrine treatment. This study will help to establish the strategy to more effectively select patients for adjuvant therapies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-15.

Aromatase Inhibition in Obese Women: How Much Is Enough?

Aromatase Inhibition in Obese Women: How Much Is Enough?

Adjuvant zoledronic acid (ZOL) in postmenopausal women with breast cancer and those rendered postmenopausal: Results of a meta-analysis.

513 Background: A number of groups have now reported results of randomised trials of adjuvant zoledronic acid (ZOL) for women with early stage breast cancer. Following an interaction effect observed in the AZURE trial, where postmenopausal women appeared to benefit from ZOL, we performed a meta-analysis, from both publications and presented data, of the most recent results from these trials. We also looked at recently reported large studies of clodronate and ibandronate in older or postmenopausal women to further examine this hypothesis. Methods: DFS data from 8735 women in 7 trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN) that included a randomization to ZOL vs. control or clodronate/ibandronate vs. control were examined. Median follow-up was 5 years. 14% of women experienced a DFS event. The ABCSG-12 study was included since, although it included only premenopausal women, they were all treated with goserelin, effectively rendering them postmenopausal, prior to and during treatment with ZOL. We analysed the subgroup of women aged ≥50 in the NSABP-B34 study in the absence of information on menopausal status, and included only postmenopausal women from the AZURE and GAIN trials. Sensitivity analyses confirmed that exclusion of some older, small, clodronate studies that lacked DFS data, or failed to report by age or menopausal status would be unlikely to alter these findings. Results: For the 5 ZOL studies alone, there was a very substantial and highly significant DFS benefit for ZOL, 2P=.0006, with a hazard ratio of 0.76, and therefore a DFS risk reduction of 24% (95% CI 11%-35%). The results were, in the main, extremely consistent, with the exception of the very small E-ZO-FAST study, which had only 30 events. The risk reduction lessened to 18% (95% CI 8%-26%) when adding in the clodronate and ibandronate studies, but the result remained highly significant (2P=.00075). Conclusions: These meta-analysis results, including more than 8000 women in a range of studies, now provide strong evidence that ZOL is an effective adjuvant treatment for postmenopausal women with early stage breast cancer, and that the treatment benefits are substantial.

Raloxifene as an Adjunctive Treatment for Postmenopausal Women With Schizophrenia

The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator, appears to act similarly to conjugated estrogens on dopamine and serotonin brain systems and may be a better option since it lacks the possible negative effects of estrogen on breast and uterine tissue. In this study, we assess the utility of raloxifene as an adjunctive treatment for negative symptoms and other psychotic symptoms in postmenopausal women with schizophrenia. This was a 12-week, double-blind, randomized, placebo-controlled study. Patients were recruited from both the inpatient and outpatient departments of Parc Sanitari Sant Joan de Déu, Barcelona, Spain, and Corporació Sanitària Parc Taulí, Sabadell, Spain. Thirty-three postmenopausal women with schizophrenia (DSM-IV criteria) who exhibited prominent negative symptoms were randomized to either adjunctive raloxifene (16 women; mean age = 60.14 years, SD = 6.41 years) or adjunctive placebo (17 women; mean age = 62.66 years, SD = 4.54 years) for 12 weeks. The period of recruitment lasted from January 2005 through June 2009. Psychopathological symptoms were assessed at baseline and weeks 4, 8, and 12 by means of the Positive and Negative Syndrome Scale. The addition of raloxifene (60 mg/d) to regular antipsychotic treatment significantly reduced negative (P = .044), positive (P = .031), and general psychopathological (P = .045) symptoms during the 12-week trial as compared with women receiving placebo. Raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia who exhibit prominent negative symptoms appears to be useful in improving negative, positive, and general psychopathological symptoms. If more extensive and longer-term studies confirm and expand upon these positive results, the use of raloxifene could be recommended in postmenopausal patients with schizophrenia. clinicaltrials.gov Identifier: NCT01041092.

Exercise Intervention in Breast Cancer Patients with Treatment-Induced Arthralgia

Aromatase inhibitors (AIs) are widely used as an adjuvant treatment in postmenopausal women with estrogen receptor-positive breast cancer. AIs arrest the final step in the synthesis of estrogen by blocking the activity of the enzyme aromatase. One of the most common side effects of AI treatment is joint pain, particularly in the hand and fingers. PURPOSE: To examine the effectiveness of an 8-week home-based exercise program in reducing joint pain and improving quality of life (QOL) and functional performance in breast cancer patients treated with AIs. METHODS: Participants underwent baseline measures of height, body mass, waist and hip circumference, and body composition. Functional performance was evaluated using grip strength, arm curl to exhaustion, and sit-to-stand. A 3-minute step test determined subject's cardiovascular endurance. Subjective measures of joint pain and QOL were conducted using self-administered surveys. Participants were instructed how to execute lower and upper body resistance exercises using Thera-BandR exercise bands and different hand exercises using an elastic band. A video was provided to each participant illustrating these exercises, as well as warm up, flexibility, and cool down. Participants were instructed how to monitor heart rate in order to pace aerobic activity. This was an 8 week, individualized, home-based program in which participants recorded daily activity on exercise logs and received interactive weekly phone calls to provide support. RESULTS: No significant pre-post changes were observed in the anthropometric measures (BMI, WHR, body composition). Grip strength, bicep curls to exhaustion and sit-to-stand improved significantly (8%, 45%, and 19%, respectively). HR recovery after the step test trended toward significance (5% reduction). Subjectively, participants reported an improvement in QOL, but no change in joint pain. CONCLUSIONS: An 8-week, home-based exercise program significantly improved functional performance and QOL in breast cancer patients suffering joint pain secondary to treatment with aromatase inhibitors. Supported by Susan G Komen for the Cure, WNY Affiliate.

A critical evaluation of the role of aromatase inhibitors as adjuvant therapy for postmenopausal women with breast cancer

The introduction of aromatase inhibitors (AI) has provided more options for adjuvant treatment of postmenopausal women; they are associated with improved disease-free survival, but less commonly with improvements in overall survival. Current evidence suggests that women at high risk of recurrence, especially those with node-positive disease, should receive an AI for 2 years as part of their treatment, but routine prescription of AIs to postmenopausal patients with low-risk disease is not appropriate. Not only the expected benefits but also the specific toxicity of the prescribed hormone therapy, and its cost, should be considered when selecting treatment.