Postmenopausal Breast Cancer Patients Research Articles

Fulvestrant in hormonal treatment of breast cancer

Fulvestrant is a selective oestrogen receptor (ER) down-regulator (SERD), which lacks partial agonistic properties characteristic for selective oestrogen receptor modulators (SERM). The drug is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antioestrogen therapy. The initial recommendation of a 250-mg dose was based on the results of clinical trials, which revealed that fulvestrant was non-inferior to anastrozole in this indication. However, the higher the dose of fulvestrant, the more effective it is. The CONFIRM trial compared a 500-mg dose with the approved dose of fulvestrant of 250 mg per month for treatment of postmenopausal women with oestrogen receptor-positive advanced breast cancer, who progressed after prior endocrine therapy. It showed that the higher dose was associated with a statistically significant increase in progression-free survival without increased toxicity, and it became the basis of approval of a fulvestrant dose of 500 mg in 2010. The drug should be administered intramuscularly on days 0, 14 and 28 and once monthly thereafter. The phase III FALCON trial, to which postmenopausal breast cancer patients who had not received previous endocrine therapy were eligible, revealed that a 500-mg fulvestrant dose reduced the risk of progression by 20% compared with anastrozole in first-line treatment. Fulvestrant is also beneficial in third and further lines of hormonal treatment of breast cancer and remains efficacious in young patients treated with LHRH analogue. There have also been numerous trials investigating the efficacy of fulvestrant combined with molecular targeted therapy in patients with hormone-resistant metastatic breast cancers. This review summarises the mechanism of action of fulvestrant and the results of the most important clinical trials dedicated to this drug.

Challenges of measuring accurate estradiol levels in aromatase inhibitor-treated postmenopausal breast cancer patients on vaginal estrogen therapy.

Breast cancer patients who are taking adjuvant Aromatase Inhibitor (AI) therapy typically have extremely low estradiol levels, which are undetectable by routine clinical laboratories. Thus, it becomes difficult to assess the safety of interventions such as low‐dose vaginal estrogen, which may increase estradiol levels. In this study, we aimed to assess the utility of enzyme‐linked immunosorbent assay (ELISA) to measure low estradiol concentrations in breast cancer survivors on AI therapy treated with either vaginal estrogen or lubricant for atrophic vaginitis as a part of clinical trial. The samples were tested using two independent ELISA kits. Some of the samples were also evaluated using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) for comparison. We found that while the results by ELISA were reproducible, they were not accurate when compared to LC‐MS/MS. It is possible that medications or supplements may cross‐react with the ELISA reagents and confound the assessment; however, those were often not the reason for the discrepancy. Our results highlight the need for developing novel, reliable, and clinically accessible assays to measure ultra‐low estradiol levels to improve care of breast cancer survivors. At this stage, based on our findings, we recommend using MS‐based assays for estradiol quantitation for breast cancer survivors, whenever necessary.

Abstract 5612: Cancer-immune interactions in luminal breast cancers: PI3KCA mutations, PI3K/AKT/mTOR activation and tumor-infiltrating lymphocytes

Abstract Introduction: Therapy resistance to adjuvant tamoxifen in estrogen receptor positive (ER+) breast cancer (BC) is related to activation of downstream proteins in the PI3K/AKT/mTOR pathway. However, clinical efficacy of mTOR inhibitors has so far been modest. Growing evidence shows that genomic make-up of cancer cells plays a crucial role in an anti-cancer immune response and this is reflected in the presence of tumor infiltrating immune cells. This begs the need for understanding the relationship between tumor-related immune activity, PIK3CA hot-spot mutations (PIK3CAm) and PI3K/AKT/mTOR pathway activation in ER+BC. Material and methods: The IKA trial recruited stage I to III postmenopausal BC patients (1982 till 1994), who were randomized to tamoxifen or no adjuvant therapy. Sequenom mass spectrometry-based genotyping was used for PIK3CAm assessment. Immune markers and phosphorylation status of proteins in the PI3K/AKT/mTOR pathway [p-AKT (Thr308 and 473), p-mTOR, p-ERK1/2, p-p-70S6K and p-4EBP1] were assessed by immunohistochemistry and scored by two pathologists. Expression of CD4, CD8 and FOXP3 was evaluated using automatic scoring by image-analysis software (SlidePath® or AxioVision®) and compared with manual scoring by two pathologists. Associations were assessed using multivariable logistic regression models, including as co-variables: age, tumor grade, lymph node status, tumor size, and progesterone receptor and HER2 status. Results: We included 563 ER+BC cases. PIK3CAm were found in 159 (32%) of the 486 tumors genotyped. On average, PI3K/AKT/mTOR downstream proteins and immune markers were scored in 409 tumors (range: 366 to 438). Stromal CD8 expression, but not CD4 or FOXP3, was significantly higher in PIK3CA mutated tumors (OR=1.11; 95%CI: 1.02-1.22). Stromal FOXP3 expression, but not CD4 or CD8, was significantly increased in tumors with activated proteins from the PI3K/AKT/mTOR pathway (except p-mTOR). The largest association was with p-4EBP1 (OR=1.34; 95%CI: 1.21-1.48) and smallest with p-70S6K (OR=1.15; 95%CI: 1.08-1.22). Conclusion: In our dataset of ER+BC, PIK3CAm are associated with higher level of CD8+ T cells. Tumors with activation of the PI3K/Akt/mTOR pathway tend to have more FOXP3+ T cells. Together, our results suggest that PIK3CA mutation/activation harbor an immune-related tumor microenvironment. Citation Format: Marcelo Sobral-Leite, Izhar Salomon, Mark Opdam, Karin Beelen, Ronald L. van Vlierberghe, Erik J. Blok, Hugo M. Horlings, Joyce Sanders, Koen Van de Vijver, Peter J. Kuppen, Sabine Linn, Marjanka K. Schmidt, Marleen Kok. Cancer-immune interactions in luminal breast cancers: PI3KCA mutations, PI3K/AKT/mTOR activation and tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2017-5612

Impact of Time Since Last Childbirth on Survival of Women with Premenopausal and Postmenopausal Breast Cancers.

Reproductive factors are associated with risk of breast cancer, but the association with breast cancer survival is less well known. Previous studies have reported conflicting results on the association between time since last childbirth and breast cancer survival. We determined the association between time since last childbirth (LCB) and survival of women with premenopausal and postmenopausal breast cancers in Malaysia. A historical cohort of 986 premenopausal, and 1123 postmenopausal, parous breast cancer patients diagnosed from 2001 to 2012 in University Malaya Medical Centre were included in the analyses. Time since LCB was categorized into quintiles. Multivariable Cox regression was used to determine whether time since LCB was associated with survival following breast cancer, adjusting for demographic, tumor, and treatment characteristics. Premenopausal breast cancer patients with the most recent childbirth (LCB quintile 1) were younger, more likely to present with unfavorable prognostic profiles and had the lowest 5-year overall survival (OS) (66.9; 95% CI 60.2-73.6%), compared to women with longer duration since LCB (quintile 2 thru 5). In univariable analysis, time since LCB was inversely associated with risk of mortality and the hazard ratio for LCB quintile 2, 3, 4, and 5 versus quintile 1 were 0.53 (95% CI 0.36-0.77), 0.49 (95% CI 0.33-0.75), 0.61 (95% CI 0.43-0.85), and 0.64 (95% CI 0.44-0.93), respectively; P trend=0.016. However, this association was attenuated substantially following adjustment for age at diagnosis and other prognostic factors. Similarly, postmenopausal breast cancer patients with the most recent childbirth were also more likely to present with unfavorable disease profiles. Compared to postmenopausal breast cancer patients in LCB quintile 1, patients in quintile 5 had a higher risk of mortality. This association was not significant following multivariable adjustment. Time since LCB is not independently associated with survival in premenopausal or postmenopausal breast cancers. The apparent increase in risks of mortality in premenopausal breast cancer patients with a recent childbirth, and postmenopausal patients with longer duration since LCB, appear to be largely explained by their age at diagnosis.

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3months of AI treatment and drug concentrations were measured after 1 or 3months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n=200, LET n=200). Thirty (7.6%) patients (EXE n=13, LET n=17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p>0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States

BackgroundWith several new therapies becoming available, treatment of metastatic breast cancer (mBC) is evolving. The objective of this study is to describe patient characteristics, treatment patterns and real-world clinical outcomes in post-menopausal women with ER+, HER2- mBC and to obtain insight into patient outcomes and potential unmet needs with current therapies.MethodsThe current study is a physician survey followed by a retrospective chart review of patient medical records by physicians in the US between March and April 2015. One hundred three physicians were asked to complete an online survey aiming to understand their satisfaction and expectations with current available treatments and potential areas of unmet need for mBC patients. Medical records from 178 females were extracted for the chart review. Using these data from medical records, patient characteristics and treatment patterns were analyzed descriptively. Time to progression (TTP) on first line, and progression-free survival (PFS) on second and third line of therapy were analyzed using the Kaplan-Meier method.ResultsSixty-seven percent (n = 119) of patients had metastatic disease at initial diagnosis of breast cancer. Mean age at chart data extraction was 65.8 (SD: 9.4) years. Aromatase inhibitors (AIs) were prescribed for 58% and around 13% of patients in first line and second line, respectively. Chemotherapy was prescribed to 14% in first line and 31% in second line. Median TTP on first line therapy was 12 months for patients receiving AIs as compared to 7.9 months for patients receiving chemotherapy. Across all treatment lines, bone pain and fatigue were reported as the main symptoms associated with disease progression which had an impact on patient quality of life. Physicians expressed that prolonging life was deemed the most important treatment goal, followed by preservation or improvement of quality of life.ConclusionIn this study the majority of patients received endocrine therapy as first line treatment and current therapies still resulted in a short time to progression in first line. Results from the chart review and the physician survey highlight a quantitative unmet need for more effective treatments which delay disease progression and improve survival outcomes while maintaining quality of life.

Role of the UGT2B17 deletion in exemestane pharmacogenetics

Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of breast cancer. The major metabolic pathway for EXE is reduction to form the active 17β-dihydro-EXE (17β-DHE) and subsequent glucuronidation to 17β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc) by UGT2B17. The aim of the present study was to determine the effects of UGT2B17 copy number variation on the levels of urinary and plasma 17β-DHE-Gluc and 17β-DHE in patients taking EXE. Ninety-six post-menopausal Caucasian breast cancer patients with ER+ breast tumors taking 25 mg EXE daily were recruited into this study. UGT2B17 copy number was determined by a real-time PCR copy number variant assay and the levels of EXE, 17β-DHE and 17β-DHE-Gluc were quantified by UPLC/MS in patients’ urine and plasma. A 39-fold decrease (P<0.0001) in the levels of creatinine-adjusted urinary 17β-DHE-Gluc was observed among UGT2B17 (*2/*2) subjects vs subjects with the UGT2B17 (*1/*1) genotype. The plasma levels of 17β-DHE-Gluc was decreased 29-fold (P<0.0001) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with UGT2B17 (*1/*1) genotype. The levels of plasma EXE-adjusted 17β-DHE was 28% higher (P=0.04) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with the UGT2B17 (*1/*1) genotype. These data indicate that UGT2B17 is the major enzyme responsible for 17β-DHE-Gluc formation in vivo and that the UGT2B17 copy number variant may play a role in inter-individual variability in 17β-DHE levels in vivo.

Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis.

549 Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P &lt; 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P &lt; 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.

Utilization, trend and impact of neoadjuvant endocrine therapy compared to neoadjuvant chemotherapy in postmenopausal breast cancer patients: Analysis of the National Cancer Data Base.

578 Background: Three small prospective trials that compared the efficacy of neoadjuvant endocrine therapy (NET) to neoadjuvant chemotherapy (NCT) showed no statistically significant difference. We report the differences in utilization of NET and NCT using National Cancer Data Base (NCDB) and their trend, response rates (RR) and breast conservation rates (BCR). Methods: A retrospective review of hormone receptor positive breast cancer patients ≥ 50 yrs without metastasis using NCDB was performed (2004-2014). Patients underwent NET or NCT prior to definitive surgery. Utilization pattern, practice trend, RR and BCR between NET and NCT was assessed using univariate and multivariate logistic analysis. Results: Out of 2,246,279 breast cancer patients reported in NCDB, 38,632 met our inclusion criteria. 9178 received NET and 29,454 received NCT. On multivariate analysis NET use was higher in academic vs community centers [Odds ratio (OR) 1.355, 95% CI 1.270-1.445], age &gt;70 vs &lt; 70 (OR 6.603, 95% CI 6.110-7.137) and high vs low Charlson Deyo comorbidity index (OR 1.817, 95% CI 1.548-2.133). NET use was lower in black vs white (OR 0.790, 95% CI 0.712- 0.875), tumors with higher vs lower grade (OR 0.153, 95% CI 0.138-0.169), higher vs lower T stage (OR 0.372, 95% CI 0.340-0.407), higher vs lower N stage (OR 0.274, 95% CI 0.243-0.310) and private vs no insurance (OR 0.600, 95% CI 0.509- 0.707), (all p&lt;0.0001). A significant upward trend in utilization of NET was observed from year 2011 (25.9%) compared to before (22.2%), p&lt;0.0001. RR was significantly higher for patients receiving NCT (90.5%) compared to NET (77.2%), with an [adjusted OR (aOR) 2.413; 95% CI 2.116-2.752], however the BCR was superior in the NET group (50.0%) compared to NCT group (31.1%) with (aOR 1.676; 95% CI 1.567-1.794). Conclusions: Our study is the first to compare NET and NCT utilization and their efficacy using NCDB database. Our results have shown striking differences in outcome among these two strategies as compared to other prospective trials. Despite high RR, more patients underwent mastectomy in the NCT group. We also see a steady upward trend in usage of NET from year 2011.

A phase III, open label, prospective, randomized, multicenter, neoadjuvant study of chemotherapy versus endocrine therapy in premenopausal patient with hormone responsive, HER2 negative, breast cancer (KBCSG 012).

517 Background: Neoadjuvant endocrine therapy has shown efficacy in hormone-responsive postmenopausal breast cancer patients. We aimed to assess the efficacy and safety of cytotoxic chemotherapy versus endocrine therapy for hormone-responsive lymph node-positive premenopausal breast cancer patients in a neoadjuvant setting. (NCT01622361). Methods: In this phase 3, randomized, double blind, parallel group, multicenter study, we enrolled premenopausal women with estrogen receptor (ER)-positive, HER2-negative, and lymph node-positive premenopausal breast cancer patients. Patients were randomized to either 24 weeks of neoadjuvant chemotherapy with adriamycin plus cyclophosphamide (AC) followed by taxane (T) or neoadjuvant endocrine therapy with zoladex and tamoxifen. Results: 187 patients were randomly assigned to chemotherapy (n=95) or endocrine therapy (n=92), and 174 patients completed the 24 week neoadjuvant treatment period (n=87, both). More patients in the chemotherapy group had a complete or partial response than did those in endocrine therapy arm on both caliper (chemotherapy 83.9% vs endocrine therapy 71.3%, OR 0.476 95% CI 0.228 to 0.994) and MRI (chemotherapy 83.7% vs endocrine therapy 52.9%, OR 0.219, 95% CI 0.107 to 0.447). Three patient on chemotherapy group (3.4%) and 1 patients (1.15%) on endocrine treatment group showed complete pathologic response. In the patients who had breast cancer with low Ki 67 expression (&lt;20%) on initial biopsy, clinical response on caliper were shown similar on both treatment group (HR 0.958, 95%CI 0.296 to 3.101). Five patients who had no tumor on the breast or lymph node after 24 week neoadjuvant endocrine therapy had higher ER score (all allred score &gt;6), all low grade (1or 2) low Ki 67(≤20%) expression (4/5 patients) on initial biopsy specimen. Conclusions: In premenopausal breast cancer patients, 24 weeks neoadjuvant chemotherapy showed better clinical response than endocrine therapy. Low Ki 67 expression could be a parameter of the endocrine treatment. Clinical trial information: NCT01622361.

Effect of denosumab on bone mineral density (T-score classification of −1.0 to −2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.

552 Background: Adjuvant aromatase inhibitor (AI) therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against receptor of nuclear-κB ligand, was previously proven to protect against AI-induced bone loss. In Japan, however, the efficacy of denosumab in the treatment of AI-associated bone loss has not been proven in a prospective study. Methods: This non-randomized prospective study was conducted at four institutions in Japan. we prospectively evaluated the bone mineral density (BMD) of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n=103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary endpoint was percentage change in lumbar spine BMD from baseline to month 12. The secondary endpoint was percentage change in bilateral femoral neck BMD from baseline to month 12. This is the first trial where the right and left femoral neck BMD are measured separately. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 12 months, lumber spine BMD increased by 4.7 %. The patients who were administered prior AI therapy (n=60) had a 4.8 % increase, and the patients without prior AI therapy (n=40) had a 4.6 % increase. At 12 months, the right and left femoral neck BMD increased by 2.9 % and 2.0 %, respectively. Hypocalcemia ≥ grade2, osteonecrosis of the jaw (ONJ) and non-traumatic clinical fracture were absent in this study. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000013863.

Independent validation of stromal uPA in archived tumor samples from the prospectively randomized ABCSG8 trial to provide level 1b evidence for a prognostic value of uPA immunohistochemistry in endocrine-treated postmenopausal breast cancer patients.

536 Background: We have recently demonstrated that urokinase Plasminogen Activator (uPA), together with its inhibitor PAI-1, have prognostic value in hormone-receptor positive early breast cancer, and can be measured in FFPE archived tumor samples. We have now aimed to validate the prognostic role of uPA protein expression in FFPE archived tumor samples in an independent cohort of endocrine-treated breast cancer patients. Methods: 303 postmenopausal women with hormone receptor–positive, early breast cancer who had received 5 years of endocrine therapy in the prospectively designed ABCSG-08 trial, and in whom FFPE tumor tissue was available, were included in this analysis. Stromal uPA and PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). Results: Stromal uPA was detected in 132 of 297 tumors (44.4%), and 74 out of 269 samples (27.5%) exhibited stromal PAI-1, while co-expression of both proteins was found in 48 of 294 (16.3%) samples. Neither uPA nor PAI-1 expression were associated with tumor size, age, nodal status, grading, or receptor status. Patients whose tumor stroma expressed uPA protein were more likely to have a shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31-5.93; p=0.008 Cox regression analysis) and OS (adjusted HR for death: 1.29; 95% CI 0.86-12.50; p=0.161) than women without uPA expression. No such association was observed for PAI-1 and for the uPA/PAI1 ratio. After a median follow-up of 5.6 years women with uPA-positive tumors experienced a significantly shorter DRFS (93.3% vs 84.8%; p&lt;0.013 log rank test) and tended to have a worse OS (83.0.4% vs 77.3%; p=0.106) compared to women with uPA negative tumors. Conclusions: By confirming the clinical utility of stromal uPA IHC in archived breast cancer samples from an independent prospective randomized trial, we now provide level 1b evidence for a prognostic role of stromal uPA in women with endocrine-responsive early breast cancer.

Preparation of a novel antiserum to aromatase with high affinity and specificity: Its clinicopathological significance on breast cancer tissue.

Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated with pT (p = 0.019), pN (p = 0.001), stage (p < 0.001), histologic grade (p = 0.003), lymphatic infiltration (p < 0.001), venous infiltration (p < 0.001), and Ki-67 index (p < 0.001). However, cancer aromatase expression was independent of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 statuses. This antiserum will be applicable to clinicopathological examination of aromatase in addition to ER and PgR for an appropriate use of aromatase inhibitor on the treatment of breast cancer. Further studies on the relationship between Aromatase inhibitors have been widely used for the endocrine treatment of estrogen-dependent breast cancer in postmenopausal patients. However, clinicopathological studies of aromatase have been limited due to unsatisfactory specificity and/or restricted availability of anti-aromatase antibodies. Here, we have generated a polyclonal antiserum with high affinity and specificity for human aromatase using a monoclonal antibody tagged immunoaffinity chromatography on an industrial production scale. Our preliminary immunohistochemical analysis of 221 invasive breast cancer cases indicated that 87.3% (193/221) had at least 5% aromatase positive cells. The histoscore for aromatase was inversely correlated with pT (p = 0.019), pN (p = 0.001), stage (p < 0.001), histologic grade (p = 0.003), lymphatic infiltration (p < 0.001), venous infiltration (p < 0.001), and Ki-67 index (p < 0.001). However, cancer aromatase expression was independent of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 statuses. This antiserum will be applicable to clinicopathological examination of aromatase in addition to ER and PgR for an appropriate use of aromatase inhibitor on the treatment of breast cancer. Further studies on the relationship between aromatase expression and aromatase inhibitors are warranted.

Analysis of the effect of menopausal status and molecular subtype on survivals among breast cancer patients

Objective: To analyze the associations between molecular subtypes and overall breast cancer survival among premenopausal and postmenopausal breast cancer in Beijing, and to provide basic information for breast cancer clinical researches and control. Methods: All the resident patients diagnosed with breast cancer in four well-established hospitals were retrieved from Beijing cancer registry, related information, such as TNM stages, receptor status, histological grade, height, weight, were collected by case extraction. Cancer registration information and population-based follow-up information were used to acquire survival outcome. All the patients were followed up until 31 December 2015, 4 531 cases with invasive, primary breast were included in the final analysis. All the cases were classified into Luminal and non-Luminal according to receptor status. Five-year survival rates of the two subtypes were estimated by the life-table method. Multivariable Cox proportional hazards models were employed to evaluate the associations between molecular subtypes and breast cancer survival. Results: Of all the 4 531 patients, premenopausal patients accounted for 44.5% (2 017 cases) and postmenopausal patients accounted for 55.5% (2 514 cases). 643 cases died during the study period. Overall five-year survival was 89.5% (95%CI: 88.6%-90.4%), for premenopausal and postmenopausal patients, they were 92.1% (95%CI: 90.9%-93.3%), and 87.5% (95%CI: 86.2%-88.8%), respectively. Among all the patients, 3 730 patients had molecular subtype, 76.7% (2 861 cases) were Luminal breast cancer, and 23.3% (869 cases) were non-Luminal breast cancer. Five-year survival rates for Luminal and non-Luminal were 91.8% (95%CI: 90.8%-92.8%), and 83.2% (95%CI: 80.7%-85.7%), respectively. No matter in premenopausal or postmenopausal patients, non-Luminal breast cancer had significantly higher risk of death compared to Luminal breast cancer (premenopausal: HR=1.85, 95%CI: 1.26-2.73; premenopausal: HR=1.42, 95%CI: 1.07-1.88). Conclusion: For both premenopausal and postmenopausal breast cancer patients, non-Luminal breast cancer had lower five-year survival rates than Luminal breast cancer, which was a risk factor on breast cancer survival.

Incidence of menopausal symptoms in postmenopausal breast cancer patients treated with aromatase inhibitors.

Aromatase inhibitors (AIs) are the standard of care for postmenopausal women with estrogen receptor-positive breast cancer. Here, we performed a meta-analysis to evaluate the occurrence of menopausal symptoms in breast cancer patients receiving the AI therapy. Patients treated with AIs had an increased risk of all-grade arthralgia (1.63 [95% CI: 1.34–1.98]) and insomnia (1.24 [95% CI: 1.14–1.34]). The overall incidence of hot flashes, fatigue, arthralgia, sweating, and insomnia in patients receiving AIs was 30.47% (95% CI: 25.51%–35.93%), 17.16% (95% CI: 14%–20.85%), 17.91% (95% CI: 11.29%–27.22%), 14.64% (95% CI: 11.46%–18.52%), and 16.52% (95% CI: 12.45%–21.6 %), respectively. Both arthralgia (RR = 0.34, 95% CI: 0.16–0.75) and sweating (RR = 11.02, 95% CI: 4.11–29.57) differed between patients with early- and advanced-stage breast cancer. Our findings indicates that AIs are associated with a significant risk of developing arthralgia and insomnia in breast cancer patients. Effective early detection and management of menopausal symptoms would likely lead to safer use of AIs in breast cancer patients.

Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

To characterize determinants of treatment outcome in a real world population of 161 post-menopausal hormone receptor-positive metastatic breast cancer patients treated with fulvestrant. Descriptive statistics for demographics, anthropometrics, clinical and molecular characteristic were compared across subgroups of sensitivity/resistance to prior endocrine therapy and tested in uni/multivariate models. Clinical benefit was more common in sensitive patients with higher estrogen receptor expression and when fulvestrant was given in first line (p=0.02 and 0.046). In resistant patients, PFS was longer with lower BMI (p=0.01). Among endocrine sensitive women, longer PFS was associated with fulvestrant in first-line, single metastasis and no visceral involvement (p=0.01, 0.003 and 0.01). OS was shorter in resistant patients with HER2-positive disease and if fulvestrant was given in second and subsequent line (p=0.03). In sensitive patients, we observed worse OS with multiple metastases (p=0.008). Multivariate analyses confirmed longer PFS in resistant patients with lower BMI and older age (p=0.002 and 0.007). OS in resistant patients was negatively influenced by HER2 positivity and fulvestrant in second and subsequent line (p=0.04). In sensitive women, multiple metastases were associated with poorer survival (p=0.002). This evidence encourages considering patient and disease characteristics in decision making and outcome interpretation for patients candidate to fulvestrant.

Survivorship care for postmenopausal breast cancer patients in Ireland: What do women want?

The aim of this study was to identify the concerns of postmenopausal breast cancer patients in Ireland and inform the development of a survivorship care plan. A qualitative participatory approach was used. Focus group interviews (n=6) with 51 women were undertaken. Following analysis of the focus group discussions, two nominal group technique (NGT) (consensus workshops) involving representatives (n=17) from each of the six focus groups were held. Ten key issues were highlighted by women in the focus groups and these were prioritised at the consensus workshops. The most important issues in survivorship care planning prioritised by the women were as follows: meet the same healthcare professional at each review visit; contact number of a named person that you can contact if you have any concerns between review visits; at each review visit, have a physical examination and blood tests and explanation from health care professional outlining if follow up scans needed and if not, why not; information on signs and symptoms of recurrence; advice on diet, exercise, healthy lifestyle and advice on coping and pacing yourself; information and management of side effects of therapy-long and short term. Survivorship care planning for breast cancer is underdeveloped in Ireland. There is a lack of consensus regarding its provision and a lack of structured approach to its implementation. This study demonstrates the role of postmenopausal breast cancer patients' involvement in identifying their needs and reports that continuity of care was their top priority and the need for an adoption of a survivorship care plan was emphasised by participants.

Abstract P124: Network Meta-analysis of the Effects of Breast Cancer Hormone Therapy on Changes in Lipid Profiles

Introduction: Adjuvant hormone therapy prolongs survival of patients with early-stage hormone receptor-positive breast cancer (BC). For postmenopausal patients, aromatase inhibitors (AIs) have been shown to improve disease free survival compared to tamoxifen, but the impact on overall survival has been inconsistent. A meta-analysis showed higher risk of cardiovascular diseases (CVDs) for patients taking AIs. Deteriorating lipids induced by AIs may contribute to this result. This analysis aims to compare the effects of hormone therapeutic options on changes in lipids from published randomized clinical trials (RCTs). Methods: RCTs evaluating effects of adjuvant hormone therapy on lipids (total cholesterol, high-density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), and/or triglycerides) in postmenopausal early-stage BC patients published in PubMed and Embase, prior to Jan. 31, 2016 were reviewed. Bayesian network meta-analysis was used to compare effects of placebo, selective estrogen receptor modulators (SERMs- tamoxifen and toremifene) and AIs (letrozole, anastrozole, and exemstane) on lipids across longitudinal time points. Heterogeneity was examined by meta-regressions adjusting for mean age, baseline lipid value, and prior tamoxifen use. An arm-based random effect model tested the consistency of the direct and indirect evidence of the drug effects. Results: We identified 17 articles from 13 RCTs for a total of 1,913 subjects. The Table summarizes the results, with statistically significant results bolded. Toremifene significantly improved all lipids and was the best choice regardless of covariate adjustment, while tamoxifen had weaker but significant LDLc lowering but opposite HDLc/triglyceride effects to toremifene. AIs generally had little effect on lipids. Conclusions: In general, AIs tend to have worse effects on lipids than SERMs, while only toremifene had beneficial effects on all lipid values. Patients on AIs with high risk of CVD should monitor their lipids.

P016 - Our experience of adjuvant denosumab (Prolia®) in postmenopausal breast cancer patient with osteoporosis, pursuant to D-CARE trial

P016 - Our experience of adjuvant denosumab (Prolia®) in postmenopausal breast cancer patient with osteoporosis, pursuant to D-CARE trial

Abstract PD1-04: CSMD1 SNPs selectively affect anastrozole response in postmenopausal breast cancer patients

Abstract BACKGROUND: Based on prospective clinical trials, there is no evidence for differences in efficacy between the 3 aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole. The purpose of this study was to identify germline genetic variants associated with response to AIs and to help identify novel mechanisms associated with drug disease efficacy. METHODS: A genome-wide association study (GWAS) was performed for 624 patients (Steroids 2015;99:32-38) to identify SNPs associated with estrogen level change in women with estrogen receptor (ER) positive breast cancer treated with anastrozole. Replication of associated SNPs was performed in a GWAS from the MA.27 trial that compared adjuvant anastrozole and exemestane treatment of post-menopausal women with ER+ breast cancer. Functional studies were subsequently performed to determine SNP effects and underlying mechanisms. RESULTS: Our initial GWAS identified SNPs within CSMD1 that were associated with changes in estrogen levels during anastrozole therapy. An additional SNP in CSMD1 was also associated with breast cancer events in CCTG MA.27. Functionally, we showed that CSMD1 regulates CYP19 expression in a SNP-, and in an anastrozole- dependent fashion. These phenomena were not observed for either letrozole or exemestane. In MA.27, an anastrozole- specific effect was also seen with the minor allele having a protective effect on time to distant metastasis (HR=0.49, p=0.00259), but this was not the case for exemestane (HR=0.71, p=0.111). Our in vitro functional studies indicated that overexpression of CSMD1 sensitized anastrozole or letrozole resistant cells to anastrozole but not to the other two AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane in lymphoblastoid cell lines (LCLs) homozygous for either WT or variant CSMD1 SNP genotypes. Based on these observations, we explored whether anastrozole has additional mechanisms beyond its function as a CYP19 inhibitor. Utilizing an estrogen response element (ERE) luciferase reporter assay in a CYP19 CRISPR knockout breast cancer T47D cell line and a surface plasmon resonance (SPR) assay, we found that anastrozole can also function as an ERα agonist, and can bind to, and result in, proteasome dependent ERα degradation, especially in the presence of E2. Treatment of these CYP19 CRISPR knockout cells with anastrozole in the presence of increasing concentrations of E2 results in greater sensitivity compared with anastrozole alone, while the addition of E2, as expected, does not improve letrozole or exemestane sensitivity. These same observations were also seen in letrozole and anastrazole resistant cells. CONCLUSIONS: Our findings suggest that anastrozole might be more effective than letrozole or exemestane in patients with the CSMD1 SNP. Furthermore, anastrozole can function as an ERα agonist, binding to ERα and resulting in its degradation, especially in the presence of E2. These findings should help to make it possible to develop precision endocrine therapies for women who are candidates for AIs. Citation Format: Cairns J, Ingle J, Dudenkov T, Kalari K, Buzdar A, Kubo M, Robson M, Ellis M, Goss P, Shepherd L, Goetz M, Weinshilboum R, Wang L. CSMD1 SNPs selectively affect anastrozole response in postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD1-04.