Premenopausal ER Research Articles

300P Gene expression landscape of the long-term tamoxifen resistance in premenopausal ER+ breast cancer patients in the STO-5 controlled randomized clinical trial with >20-year follow-up

300P Gene expression landscape of the long-term tamoxifen resistance in premenopausal ER+ breast cancer patients in the STO-5 controlled randomized clinical trial with >20-year follow-up

Abstract CT205: Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial

Abstract Background: Ovarian function suppression (OFS) combined with tamoxifen (TAM) or an aromatase inhibitor (AI) is standard for premenopausal (PM) ER+, HER2- breast cancer (BC). However, > 40% PM patients (pts) are intolerant of OFS. For these pts, TAM is the only FDA approved option. In the neoadjuvant endocrine setting, pts with endocrine sensitive disease (ESD) (Ki-67 ≤ 10% at 4 weeks) have 5yr dDFS > 97%; however, only 45% of TAM pts vs >75% with AI+OFS achieve 4 wk ESD (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent anti-estrogen superior to TAM and AI in xenograft models and with antitumor activity in endocrine-resistant postmenopausal pts. ENDX additionally targets protein kinase C beta 1 (PKCβ1) at concentrations >500 ng/mL, resulting in AKT inhibition and apoptosis (Jayaraman npj Breast Cancer 2023). We hypothesize that ENDX dual targeting of ERα and PKCβ1 will obviate the need for OFS and be non-inferior to AI plus OFS for PM pts with ER+/HER2- BC. Methods: EVANGELINE (NCT05607004) is an ongoing phase 2 multicenter neoadjuvant study with pharmacokinetic (PK) run-in assessing ENDX in PM women with ER+/HER2- BC. The primary objective for the PK run-in is to identify a dose (40 or 80 mg/day) resulting in ENDX steady state concentrations (Css) of 500-1000 ng/mL (to target both ERα and PKCβ1) without significant toxicity. Following PK run-in, the randomized phase II goal is to assess whether the ESD rate with ENDX is non-inferior to exemestane plus goserelin. Women with ESD at wk4 continue treatment for 24 weeks followed by surgery. Here we report the results from the 40 mg/day PK run-in. Results: Seven PM women (6 White, 1 Asian) aged 28-51 (median 46) received ENDX 40 mg/day. Pt characteristics on study were: ER > 90% (all pts), median Ki-67 = 13 (range 4-33%), cTstage (cT2: 6 pts, cT3: 1 pt), and tumor grade (G1: 1 pt, G2: 6 pts). The median ENDX 28 day Css (ng/mL) was 263.6 (range 180.3-376.6). One pt discontinued due to wk4 Ki-67 remaining > 10%. The remaining 6 had ESD, with either wk4 Ki-67 remaining ≤ 10% (3 pts) or decreasing to ≤ 10% (3 pts) and after 24 wks underwent surgery with surgical Ki-67 ≤ 3% (range 0-3%). MRI central review (wk12 and wk24) demonstrated target lesion decreases in all pts with 1 CR, 1 PR and 4 SD (RECIST). Treatment related toxicities included grade 3 headache (n=1), grade 2 amenorrhea (n=1), and grade 2 hot flashes (n=1). The median (range) baseline estrone (n=5) was 54 pg/mL (19-114) with median (range) fold increase from baseline of 9.0 (1.3-23.2) at wk4 and 4.7 (0.4 - 25.9) at wk24. The median baseline estradiol level (n=5) was 29 pg/mL (19-209) with median fold increases from baseline of 17.9 (0.4-57.0) at wk4 and 8.1 (0.04 - 56.6) at wk24. Additional surgical and blood biomarker data will be presented at the meeting. Conclusions: ENDX (40 mg/day) exhibits promising antitumor activity for PM ER+/HER2- BC but with ENDX Css below target. Enrollment is ongoing to the 80 mg/day dose level. Citation Format: Matthew P. Goetz, Vera J. Suman, Heather Fraser, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Katie N. Hunt, Swaathi Jayaraman, James Jakub, Patricia Cronin, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah Buhrow, Joel Reid, Matthew Schellenberg, John Hawse, Steven Quay. Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT205.

17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment.

Abstract CT141: Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study

Abstract Introduction: Immunotherapy has not been proved to be efficacious in ER+/HER2- metastatic breast cancer. Our team has reported an effective combination of exemestane, gonadotropin releasing hormone agonist, and pembrolizumab in premenopausal ER+/HER2- MBC. Here we report the updates of the final results and biomarker associates of the study. Methods: Premenopausal ER+/HER2- MBC patients who failed no more than 2 lines of hormone therapy without chemotherapy for MBC were enrolled in a tertiary medical center in Taiwan (NCT02990845). The primary endpoint was progression-free survival (PFS) rate at 8 months. The secondary endpoints included overall response rate, overall survival (OS), progression-free survival (PFS), and other biomarkers. Pre-treatment (N=12) and post-treatment (N=5) tumor tissue were collected for biomarker analysis, including tumor-infiltrating lymphocyte(TIL), PD-L1 expression by immunohistochemical staining, tumor mutational burden, RNAseq, and IO360 analysis. Results: A total of 15 patients were enrolled in the study with 14 evaluable patients. The progression-free survival rate at 8 months was 64.3%. The median PFS and OS were 10.34 months and 39.56 months respectively. The overall response was 35.7%. TIL, tumor mutational burden, or PD-L1 expression were not associated with the response to the treatment. In the NanoString IO-360 analysis, increased expression of genes in the immune related signature was noted in the post-treatment samples as compared to the pre-treatment samples. The expression levels of MHC class II and T cell-related genes were upregulated in the post-treatment samples. Most of the immune cell populations are increased after pembrolizumab/exemestane/leuprolide treatment. CD56 dim NK cells, Th1 cells, and NK cells are the top 3 populations that are increased after treatment. Using CIBERSORT algorithms to analyze RNAseq data from pretreatment samples, dendritic cells (p=0.039) and NK cells (p=0.082) were associated with the responders versus non-responders in the study. Conclusion: In this final analysis, pembrolizumab, exemestane, and leuprolide remain an effective treatment for premenopausal ER+/HER2- MBC. Pembrolizumab, exemestane, and leuprolide treatment is associated with immune system activation, turning the tumor microenvironment from cold to hot in luminal disease. Citation Format: I-Chun Chen, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang, Yen-Shen Lu. Combination of hormone therapy, GnRH agonist, and immunotherapy enhance immune activation in premenopausal ER+/HER2- metastatic breast cancer patients: Results of biomarker analysis from a pilot phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT141.

FGF7/FGFR2-JunB signalling counteracts the effect of progesterone in luminal breast cancer.

We have recently demonstrated that fibroblast growth factor receptor 2 (FGFR2)‐mediated signalling alters progesterone receptor (PR) activity and response of oestrogen receptor α (ER)‐positive (ER+) breast cancer (BCa) cell lines to anti‐ER agents. Little is known about whether the crosstalk between ER and PR, shown to be modulated by the hormonal background, might also be affected by FGFR2. Here, PR‐dependent behaviour of ER+ BCa cells was studied in the presence of oestrogen (E2) and progesterone (P4) and/or FGF7. In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2‐promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER–PR complexes; and (d) reversed P4‐triggered deregulation of ER‐dependent genes. Analysis of clinical data demonstrated that the prognostic value of FGFR2 varied between patients with different menopausal status; that is, high expression of FGFR2 was significantly associated with longer progression‐free survival (PFS) in postmenopausal patients, whereas there was no significant association in premenopausal patients. FGFR2 was found to positively correlate with the expression of JunB proto‐oncogene, AP‐1 transcription factor subunit (JUNB), an ER‐dependent gene, only in premenopausal patients. Molecular analyses revealed that the presence of JunB was a prerequisite for FGFR2‐mediated abrogation of P4‐induced inhibition of cell growth. Our results demonstrate for the first time that the FGF7/FGFR2–JunB axis abolishes the modulatory effects of PR on ER‐associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR‐targeting therapeutic strategies.

Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor-positive breast cancer.

CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor–positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling–related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

Birth weight and the risk of overall breast cancer, premenopausal and postmenopausal breast cancer in adulthood: a dose-response meta-analysis of observational studies.

The effect of birth weight on breast cancer across different menopausal states remains unknown. The aim of this study was to systematically evaluate the association of birth weight with the risk of overall breast cancer (OBC) and premenopausal and postmenopausal breast cancer during adulthood. In parallel, the dose-response analyses were performed. Relevant studies were systematically searched from the PubMed, Embase, and the Cochrane Library databases from the inception to May 25, 2021, without language restrictions. All the results were pooled according to risk ratios (RRs). In total, 21 cohort studies comprising 1,139,032 participants were included. An increase in the birth weight was not associated with the risk of OBC and premenopausal and postmenopausal breast cancer. Compared with women having normal weight at birth, those with a high birth weight are likely to have an increased risk of invasive breast cancer (RR: 1.19, 95% confidence intervals: 1.03-1.38; I2: 28.6%). The dose-response analyses showed that the risk of premenopausal breast cancer increased significantly in unknown singleton status with birth weight over 2850 g (RR: 1.14 [1.02-1.30]). Similarly, postmenopausal breast cancer risk was increased in singleton births with birth weight over 3750 g (RR: 1.21 [1.00-1.47]). High weight at birth might be not significantly associated with the risk of OBC, premenopausal and postmenopausal breast cancer and ER+ and ER- breast cancer but is positively associated with the risk of invasive breast cancer, regardless of parity. Furthermore, with an increase in birth weight, the risk of postmenopausal breast cancer is likely to increase in the singleton births, whereas the risk of premenopausal breast cancer is likely to increase in unknown singleton status.

Awareness of the Causes Leading to Surgical Ablation of Ovarian Function in Premenopausal Breast Cancer-A Single-Center Analysis.

Background and Objectives: Ovarian surgical ablation (OSA) in estrogen receptor-positive (ER+) breast cancer is usually performed to halt ovarian function in premenopausal patients. Since alternative pharmacological therapy exists and few studies have investigated why surgery is still performed, we aimed to analyze the reasons for the use of OSA despite the remaining controversy. Materials and Methods: Premenopausal ER+ breast cancer patients treated at a tertiary center (2005–2011) were selected, and patients with germline mutations were excluded. Results: Seventy-nine patients met the inclusion criteria. Globally, the main reasons for OSA included: continued menstruation despite hormone therapy with or without ovarian medical ablation (OMA) (34.2%), patient informed choice (31.6%), disease progression (16.5%), gynecological disease requiring surgery (13.9%), and tamoxifen intolerance/contraindication (3.8%). In women aged ≥45 years, patient choice was significantly more frequently the reason for OSA (47.4% versus 17.1% (p = 0.004)). For those aged <45 years, salvation attempts were significantly more frequent as compared to older women (26.8% versus 5.3% (p = 0.01)). In 77.8% of women undergoing OSA with menstrual cycle maintenance, surgery was performed 1–5 years after diagnosis, while surgery was performed earlier (0–3 months after diagnosis) in patients undergoing OSA as an informed choice (56.0%), as a salvation attempt (53.8%), or due to gynecological disease (63.6%). The leading reason for OSA in women previously undergoing OMA was continued menstruation (60.0%). Conclusions: This study suggests a possible failure of pharmacological ovarian suppression and reinforces the need for shared decision-making with patients when discussing treatment strategies, although validation by further studies is warranted due to our limited sample size.

Abstract PS14-14: Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients

Abstract Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5 year survival rate for localized BC, yet metastatic BC continues to cause high mortality with a 5 year survival rate of 27%. Recent advances have been made in the treatment of primary BC, providing an opportunity to apply this positive momentum towards treating metastatic disease. Approximately 70% of BC metastases occur in the bone, with the majority of patients retaining estrogen receptor positive (ER+) disease. The BC tumor microenvironment (TME) in bone exhibits an osteolytic bone pathology of bone destruction and is composed of primarily four cellular groups including the cancer, immune, vascular and bone cells. These cellular constituents are uniquely responsive to estradiol (E2) and exhibit unique TMEs dependent on menopause status, when circulating E2 is lost. Both menopause and BC endocrine therapies induce an E2-deprived post-menopausal state in patients. However, studying the distinctions of pre- and post-menopausal BC patient TMEs is still necessary to understand how natural menopause status impacts non-treatment naïve ER+ BC that is already in a therapy induced menopausal state. In particular the full extent of the unique phenotypes harbored by pre- versus post-menopausal ER+ BC tumor induced bone disease (TIBD) remains unknown, and elucidation of these difference may identify novel mechanisms of TIBD. We investigated a cohort of demineralized formalin-fixed and paraffin-embedded (FFPE) pre- and post-menopausal lytic bone metastasis biopsies from non-treatment naïve ER+ BC patients. We utilized immunohistochemistry (IHC), NanoString nCounter gene expression panels and GeoMx Digital Spatial Profiling (DSP) to observe distinct TMEs in our archival biopsy cohort. IHC staining of pre- and post-menopausal samples displayed alterations to immune cell infiltration and composition. Differential gene expression analysis revealed enrichment of myeloid function in pre-menopausal patients compared to post-menopausal patients. Alterations to immune signaling pathways and cell profiles were also exhibited in pre-menopausal patients compared to post-menopausal patients. DSP analysis presented changes in both the tumor and microenvironment, and unique immune cell infiltration with checkpoint proteins in both pre-menopausal and post-menopausal ER+ BC bone metastases. The identification of these targetable markers unique to pre- and post-menopausal TIBD could provide new therapeutic strategies for ER+ BC patients with bone lesions. Thus, we propose that bone biopsies could be performed to guide selection for metastatic BC patients into appropriate therapeutic interventions, with pre- and post-menopausal patients receiving tailored treatments based on their distinct protein and RNA expression of available therapies. This personalized approach to treating metastatic disease could enhance patient quality of life and survival. Citation Format: Claire Ihle, Meredith Provera, Desiree Straign, Katy Zolman, Erin Smith, Adrie Van Bokhoven, Scott Lucia, Philip Owens. Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-14.

The Long and Winding Road for Breast Cancer Biomarkers to Reach Clinical Utility.

Tumor data from the ABCSG 5 trial of chemotherapy versus endocrine therapy for premenopausal ER+ breast cancer supports molecular subtyping by Ki-67 IHC as a prognostic marker. But while this tissue was handled uniformly, Ki-67 testing overall is unstandardized, complicating clinical utility. Increasing potential biomarkers herald more challenges in biomarker validation.See related article by Bago-Horvath et al., p. 5682.

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27–35 and 1–6; low oestradiol and low progesterone), W2 (days 7–16; high oestradiol and low progesterone) and W3 (days 17–26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3–2.4-fold; FDR 0.016–0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.

Abstract CS1-1: Adjuvant endocrine therapy for premenopausal ER+ breast cancer

Abstract Adjuvant therapy decisions for premenopausal ER+ve breast cancer are challenging. An analysis from TEXT found that therapy varied by geography.1 Approximately half the women with node negative tumors enrolled from North America received optional adjuvant chemotherapy, in addition to protocol ovarian suppression plus oral endocrine therapy, while only one quarter of women with node negative tumors enrolled from Italy received chemotherapy. For women with node positive tumors, the use of chemotherapy was almost universal (93%) in North America, while 27% enrolled from Italy did not receive chemotherapy. Use of multigene assays may reduce future use of chemotherapy in ER+ve breast cancer, however limited information exists for outcomes of young women with low risk assay results, treated with tamoxifen alone. Among 6,693 women enrolled in MINDACT, only 44 women were under age 35 with low genomic risk.2 Only 58 women aged 40 or under were included in the Tailor-X Recurrence Score 0-10 cohort and not all received tamoxifen alone.3 Chemotherapy may provide an indirect endocrine effect in premenopausal ER+ve breast cancer, due to suppression of ovarian estrogen production. The EBCTCG meta-analysis published in 1998 reported that 5 years of adjuvant tamoxifen was effective, regardless of age, menopausal status or chemotherapy.4 Adjuvant ovarian ablation is effective for women under 50 as a sole adjuvant therapy,5 but the value of ovarian suppression/ablation in premenopausal women with ER+ve tumors who also receive tamoxifen, with or without adjuvant chemotherapy, has been uncertain.6 SOFT randomized premenopausal women with hormone receptor-positive breast cancer to receive 5 years of tamoxifen or tamoxifen plus ovarian suppression or exemestane plus ovarian suppression.7 The initial results, after median 5.6 years follow-up, did not show a significant benefit from addition of ovarian suppression to tamoxifen in the overall premenopausal population. SOFT was stratified by use of prior chemotherapy and in the cohort who did not receive chemotherapy, women allocated tamoxifen alone had few recurrences and virtually no distant recurrences during the first 5 years. However, for patients in SOFT deemed at sufficient risk to receive chemotherapy and who remained premenopausal, the addition of ovarian suppression to tamoxifen did reduce risk of invasive recurrence during the first 5 years, and the use of exemestane with ovarian suppression further reduced recurrence. The joint analysis of TEXT and SOFT found that exemestane plus ovarian suppression significantly improved DFS compared with tamoxifen plus ovarian suppression.8 The absolute benefit of endocrine therapies that included ovarian suppression in SOFT and TEXT, as compared with tamoxifen alone, was most striking in women under age 35, although women with a high risk of recurrence from a combination of clinical-pathologic factors (composite risk) could also derive benefit.9

Long-Term Consequences of Extended Endocrine Strategies for Premenopausal Breast Cancer [11OP

INTRODUCTION: Breast cancer is the most common cancer among women in America, and gynecologists often encounter these women in their practice. After 5 years of adjuvant tamoxifen, women with ER+ breast cancer benefit from extended endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) is required before starting an AI, but there is concern about the long-term outcomes (osteoporosis, heart disease) and costs of OA. METHODS: A Markov Monte Carlo simulation model estimated the costs and benefits of extended endocrine strategies in a hypothetical cohort of premenopausal women with ER+ cancer: (1) no further treatment; (2) tamoxifen for 5 years; (3) OA followed by AI for 5 years (OA/AI). Effectiveness was measured in years of life expectancy gain. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the American population over a 40-year horizon. RESULTS: Tamoxifen for 5 more years yielded a higher average discounted life expectancy gain than OA/AI (16.57 vs. 16.34 years) at lower average cost ($2,976 vs. $10,150). For 18,000 ER+ premenopausal women diagnosed annually, the simulation estimated 12,526, 11,508, and 10,289 deaths after no further treatment, tamoxifen and OA/AI respectively, but another 2,139 deaths from long-term consequences of OA. According to sensitivity analyses, women had to be over 50.8 years of age before OA/AI became cost-effective. CONCLUSION: As extended endocrine therapy for premenopausal ER+ breast cancer, another 5 years of tamoxifen is more effective and less costly than ovarian ablation followed by 5 years of aromatase inhibitor.

Long-term consequences of ovarian ablation for premenopausal breast cancer.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03years) and less costly ($1566) than GnRHa-AI (17.66years, $93,692) or BSO-AI (17.63years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78years, $25,368) than tamoxifen alone (16.55years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.

Optimal endocrine therapy for breast cancer patients 45-50 years of age at diagnosis.

551Background: Aromatase inhibitors (AI) are superior to tamoxifen (TAM) in postmenopausal estrogen receptor positive (ER+) breast cancer patients. TAM is standard of care for premenopausal ER+ patients. The SOFT/TEXT trials showed, however, that ovarian function suppression combined with the AI exemestane significantly improves disease-free survival compared to TAM in premenopausal patients. Evidence on perimenopausal women at breast cancer diagnosis is scarce as they are usually excluded from studies. We therefore aim to provide evidence for the optimal treatment of ER+ breast cancer patients 45-50 years of age, using data from the population-based Netherlands Cancer Registry (NCR). Methods: All pre-menopausal Dutch women, without prior history of malignancy, diagnosed between 2004-2007 at age 45-50 years with an ER+, non-metastatic, primary invasive breast cancer for which they received chemotherapy and endocrine treatment, were identified through the NCR. Cox proportional hazards regression was used t...

Obesity, body fat distribution, and risk of breast cancer subtypes in African American women participating in the AMBER Consortium.

African American (AA) women are more likely than white women to be obese and to be diagnosed with ER- and triple-negative (TN) breast cancer, but few studies have evaluated the impact of obesity and body fat distribution on breast cancer subtypes in AA women. We evaluated these associations in the AMBER Consortium by pooling data from four large studies. Cases were categorized according to hormone receptor status as ER+, ER-, and TN (ER-, PR-, and HER2-) based on pathology data. A total of 2104 ER+ cases, 1070 ER- cases (including 491 TN cases), and 12,060 controls were included. Odds ratios (OR) and 95 % confidence intervals (CI) were computed using logistic regression, taking into account breast cancer risk factors. In postmenopausal women, higher recent (most proximal value to diagnosis/index date) BMI was associated with increased risk of ER+ cancer (OR 1.31; 95 % CI 1.02-1.67 for BMI ≥ 35 vs. <25 kg/m(2)) and with decreased risk of TN tumors (OR 0.60; 95 % CI 0.39-0.93 for BMI ≥ 35 vs. <25). High young adult BMI was associated with decreased premenopausal ER+ cancer and all subtypes of postmenopausal cancer, and high recent waist-to-hip ratio with increased risk of premenopausal ER+ tumors (OR 1.35; 95 % CI 1.01-1.80) and all tumor subtypes combined in postmenopausal women (OR 1.26; 95 % CI 1.02-1.56). The impact of general and central obesity varies by menopausal status and hormone receptor subtype in AA women. Our findings imply different mechanisms for associations of adiposity with TN and ER+ breast cancers.

Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer.

The purpose of this study is to determine if there are differences in the expression of estrogen-regulated genes (ERGs), proliferation-associated genes and the progesterone effector RANKL, in premenopausal ER+ breast cancer as a result of the major changes in hormone levels that occur through the menstrual cycle. Primary ER+ tumours from 174 patients were assigned to one of three menstrual cycle windows: W1 (days 27-35+1-6), W2 (days 7-16) and W3 (days 17-26). RNA expression of 42 genes, including 24 putative genes associated with plasma E2 levels, seven proliferation genes and RANKL was measured. Expression of PGR, TFF1, GREB1 and PDZK1 followed the previously reported pattern: a higher level in W2 compared to W1 while W3 had an intermediate value, mirroring changes in plasma estradiol. Of the other 20 ERGs, four (RUNX1, AGR2, SERPINA3 and SERPINA5) showed significant differences (p=0.009-0.049) in expression across the menstrual cycle. The expression of six of seven proliferation-associated genes varied across the cycle but differently from the ERGs, being 20-35% lower in W3 compared to W1 and W2 (p=0.004-0.031). Expression of RANKL was 2.5 to 3-fold highest in W3 (p=0.0001) and negatively correlated to the expression of the proliferation-associated genes (r=-0.37; p<0.0001). Expression of proliferation-associated genes and RANKL in ER+ breast tumours varies across the menstrual cycle showing a different rhythm to that of ERGs. This may affect the interpretation of gene expression profiles but may be exploitable as an endogenous test of endocrine responsiveness.

Abstract LB-285: Obesity and breast cancer subtypes in African American women participating in the AMBER Consortium

Abstract Introduction. Obesity has been shown to be associated with reduced risk in premenopausal women and increased risk in postmenopausal women, with evidence coming largely from studies in white women. African American (AA) women are more likely than white women to be obese and to have central obesity (measured as a high waist to hip ratio (WHR) or waist circumference). They are also more likely to be diagnosed with ER- and triple negative (TN) breast cancers, which tend to have poorer prognosis than ER+ tumors. There is growing evidence that risk profiles for these subtypes may differ. However, few studies have evaluated the impact of general and central obesity on breast cancer subtypes in AA women. Methods. We pooled data from three studies in AA women, the Black Women Health Study, the Carolina Breast Cancer Study, and the Women's Circle of Health Study, to evaluate the association of recent body mass index (BMI), young adult BMI (at age 18-21 y), and waist to hip ratio (WHR) with breast cancer subtypes. Cases were categorized according to hormone receptor subtype as ER+, ER-, and triple negative (TN: ER-, PR-, and HER2-) based on pathology reports or cancer registry data. A total of 1,809 ER+ cases, 1,024 ER- cases (which included 478 TN cases), and 9,593 controls were included in the analyses. Odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional polytomous or regular logistic regression, as appropriate, taking into account all major risk factors for breast cancer. Results. Recent BMI was inversely associated with postmenopausal ER- breast cancer (OR: 0.74; 95% CI: 0.53-1.02), and more strongly with tumors that were also PR- and HER2- (TN), (OR: 0.61; 95% CI: 0.39-0.97 for BMI≥35 vs. &amp;lt;25). For ER+, ORs were below one for pre-menopausal and above one for post-menopausal breast cancer, but confidence intervals included 1.0. However, among women who were thin as young adults (BMI&amp;lt;19.4, lowest tertile), recent high BMI (≥35) was associated with more than a twofold increase in risk of postmenopausal ER+ breast cancer (OR: 2.24; 95% CI 1.46-3.43, p for interaction: 0.02). Associations between recent BMI and ER- breast cancer did not differ by young-adult BMI. There was a suggestion of increased risk for high WHR (highest vs. lowest quartile) independent of BMI, which only approached statistical significance for premenopausal ER+ tumors (OR: 1.31; 95% CI: 0.98-1.75; p for trend: 0.05). In analyses of the joint effects of recent BMI and WHR, the association of WHR with ER+ tumors in postmenopausal women was strongest for women with normal BMI (OR: 1.61; 95% CI: 1.02-2.56), p for interaction: 0.05. Conclusion. Our results indicate the need to consider subtypes when evaluating the impact of general and central obesity on breast cancer and warrant the study of mechanisms underlying these complex associations. Citation Format: Elisa V. Bandera, Urmila Chandran, Chi-Chen Hong, Christine B. Ambrosone, Melissa Troester, Kathryn L. Lunetta, Lucile Adams-Campbell, Andrew Olshan, Julie R. Palmer, Lynn Rosenberg. Obesity and breast cancer subtypes in African American women participating in the AMBER Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-285. doi:10.1158/1538-7445.AM2014-LB-285

Do women younger than 40 treated in the hormone-therapy era benefit from a radiotherapy boost as a part of adjuvant breast radiotherapy?

72 Background: The EORTC 22881 trial showed a 10% reduction in local relapse with a radiotherapy boost (RTB) after breast conserving therapy (BCT) among women ≤40 years old. However no premenopausal patients received hormone therapy (HT) in this study. A policy change in December 1998 recommended the use of HT after chemotherapy for premenopausal ER positive women. A second policy change in December 2001 recommended an RTB after BCT for women ≤40 years old. The purpose of our study was to describe: 1)how the use of HT and RTB after BCT changed after practice guidelines were implemented in a population-based cancer care program; and 2) how local relapse rates (LRR) changed after these policy changes. Methods: A provincial database was used to analyse all women ≤ 40 years old referred for consideration of radiotherapy with margin negative stage 1 and 2 (≤3 nodes positive) breast cancer, treated with lumpectomy and whole breast radiotherapy. Cases were grouped into three eras according to policy transition with 3 month gaps: 1) Jan 1996-Sep 1998, 2) Jan 1999-Sep 2001, 3) Jan 2002 to Sep 2004. Changes in the use of HT and RTB over these eras were assessed. Eight year LR-free survival was calculated using the Kaplan-Meier method and the three eras compared using log rank tests. Multivariable analysis (MVA) was performed including era, size of tumour, nodal status (0 vs 1-3), grade, lymphovascular space invasion (LVI), and use of chemotherapy. Results: There were 130 eligible patients from Era 1, 145 patients from Era 2, and 140 patients from Era 3. ER status did not differ across eras. HT was used for ER positive patients in 13% of Era 1, 68% of Era 2, and 83% of Era 3 cases (p&lt;0.001). RTB was used in 40% of Era 1, 28% of Era 2, and 77% of Era 3 patients (p&lt;0.001). LRR at 8 years were 87.3% Era 1, 94.8 % Era 2, and 94.5% Era 3 (p=0.03). Era (used as surrogate for transitions in the use of HT and RTB) remained significant on MVA (0=0.008). Conclusions: Patterns of use of HT and RTB changed after policy changes. The benefit of adding a boost in women ≤40 years old shown by the EORTC was not observed after the introduction of routine HT at a population level.

Optimal management of the premenopausal patient with estrogen receptor-positive breast cancer.

Tamoxifen is the standard of care in the adjuvant treatment of premenopausal women with estrogen receptor-positive (ER+) breast cancer. Ovarian suppression (OS) is another method of endocrine therapy and has been shown to decrease the risk of recurrence and confer a survival advantage when used as the sole source of hormone therapy. However, there is no evidence that OS is superior to treatment with tamoxifen. Studies comparing OS with or without tamoxifen compared with chemotherapy have demonstrated comparable effects. There does not appear to be any additional benefit when OS is combined with chemotherapy, although there is a suggestion that there may be an effect in the subgroup of young women (aged younger than 40 years) who are least likely to experience chemotherapy-induced cessation of ovarian function. Interpretation of existing data is hampered by the lack of studies incorporating modern chemotherapy regimens and the absence of molecular analyses that would allow us to better define populations most likely to benefit from endocrine therapy. Last, the role of aromatase inhibitors (AI) in the premenopausal setting remains undefined. Two recent studies, SOFT and TEXT, aim to shed light on the effect of OS and AI in premenopausal ER+ breast cancer and are pending analysis.