Postmenopausal Early Breast Cancer Patients Research Articles

Pro-inflammatory cytokines increase temporarily after adjuvant treatment for breast cancer in postmenopausal women: a longitudinal study

BackgroundBreast cancer patients have an increased risk of cardiometabolic disease and for many patients, adjuvant therapy causes an altered lipid profile, insulin resistance and inflammation. Previous follow-up studies are inconclusive regarding the duration of therapy-induced inflammation. We examined the acute and persistent changes of adjuvant chemotherapy on inflammatory and metabolic health markers in breast cancer patients.MethodsPlasma levels of IL-6, IL-8, IL-10, IFN-γ, TNF-α, high-sensitivity C-reactive protein (hsCRP) and metabolic health parameters were analyzed before, shortly after and every six months up to two years after adjuvant chemotherapy treatment in 51 postmenopausal early breast cancer (EBC) patients, as well as in 41 healthy age- and BMI-matched controls. A target-specific multiplex assay was applied for cytokine measurements.ResultsBefore initiation of adjuvant therapy, plasma IL-8 levels were higher in EBC patients (31%, p = 0.0001). Also, a larger proportion of the patients had a hsCRP level above 2 mg/L (41%) compared to the controls (17%, Χ2 = 5.15, p = 0.023). Plasma levels of all five cytokines, but not hsCRP, were significantly increased after compared to before adjuvant chemotherapy (15–48% increase; all p ≤ 0.05). Already six months after ending chemotherapy treatment, all plasma cytokine levels were significantly reduced and close to pre-chemotherapy levels. Adjuvant chemotherapy caused a worsened lipid profile (increased triglycerides, lower HDL levels), insulin resistance and increased plasma insulin levels that remained high during the first year after chemotherapy.ConclusionPostmenopausal women with EBC have temporarily increased plasma levels of pro-inflammatory cytokines after adjuvant chemotherapy. Although transient, the therapy-induced increase in plasma cytokine levels, together with dyslipidemia and insulin resistance, may contribute to cardiometabolic risk in breast cancer patients treated with adjuvant chemotherapy.Trial registration The clinical trial (registration number NCT03784651) was registered on www.clinicaltrials.gov on 24 December 2018.

Abstract P2-02-06: Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Abstract Background. Adjuvant denosumab treatment improved bone-health related outcomes in early breast cancer (BC) patients with discordant survival results. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods. PubMed, CENTRAL, Scopus, Embase, clinicaltrials.gov and key oncological meetings websites were screened to identify potentially eligible RCTs based on the PICOs model: P) Participant: pre and postmenopausal early BC patients; I) Intervention: adjuvant denosumab; C) Comparator: placebo; O) Outcomes: Disease-free survival (DFS), Bone Metastasis-free survival (BMFS), Overall Survival (OS), fracture incidence and time to first fracture were adopted as survival endpoints, and Adverse Events, Serious Adverse Events, Osteonecrosis of the Jaw (ONJ) and Atypical Femur Fractures (AFF) as safety endpoints; S) Study design: phase III RCTs. Risk of bias was assessed with Cochrane Collaboration Risk of Bias Tool. Pooled hazard ratios (HR), risk ratios (RR), risk differences (RD) and respective confidence intervals (CI) were computed using both a fixed and a random effect model. Subgroup analyses based on menopausal status, hormone receptor and HER2 status and immunophenotype were performed. Results. Two phase III RCTs were included (ABCSG-18, D-CARE), for an overall population of 7929 early BC patients receiving denosumab or placebo. Denosumab addition to standard of care anticancer treatment showed no difference in DFS (HR 0.93; 95% CI 0.75-1.16, p=0.53), BMFS (HR 0.90; 95% CI 0.75-1.07, p=0.23) and OS (HR 0.92; 95% CI 0.72-1.17, p=0.49). In hormone receptor-positive/HER2 negative patients, denosumab significantly prolonged both DFS (HR 0.88; 95% CI 0.78-0.99, p=0.04) and BMFS (HR 0.83; 95% CI 0.71-0.97, p=0.02). No interaction was found between denosumab addition and menopausal status. Fracture incidence (RR 0.79; 95% CI 0.70-0.89, p< 0.01) and time to first fracture (HR 0.76; 95% CI 0.66-0.87, p< 0.01) were also improved with denosumab. No association between denosumab addition and overall toxicity was seen and no difference was observed in terms of ONJ and AFF between the 60mg every 6 months schedule and placebo (RD 0.001, 95% CI from -0.001 to 0.002, p=0.48) Conclusions. Findings from this meta-analysis validate the role of denosumab as a highly effective anti-resorptive agent. We provide robust evidence that its addition to standard anticancer treatment significantly improves survival outcomes in hormone receptor-positive/HER2 negative early BC patients, suggesting that the implementation of denosumab use in combination with endocrine therapy in this patient population should be reconsidered. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022332787. Citation Format: Luca Mastrantoni, Giovanna Garufi, Elena Di Monte, Noemi Maliziola, Mariangela Pasqualoni, Letizia Pontolillo, Sergio Pannunzio, Maria Chiara Cannizzaro, Armando Di Bello, Alessandra Fabi, Antonella Palazzo, Emilio Bria, Giampaolo Tortora, Armando Orlandi. Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. [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 P2-02-06.

Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12

BackgroundThe widespread adoption of adjuvant bisphosphonate therapy for postmenopausal early breast cancer (EBC) patients was based on results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis. Despite multiple regimens evaluated, there was no signal of varying efficacy with type, dose/dose intensity of bisphosphonate administration. We evaluated the effect of early treatment cessation using long-term outcome data from the ABCSG-12 trial. Patients and methodsABCSG-12 randomized 1803 hormone-receptor positive EBC patients on ovarian suppression between 1999 and 2006 to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, 2:2 factorial design). In the current study, we evaluated whether the number of zoledronate infusions had an impact on breast cancer-specific outcomes. We hypothesized that amongst patients who received at least one zoledronate infusion, the number of infusions had no effect on outcomes. Time-to-event endpoints were analysed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD analysis was restricted to patients who participated in the BMD sub-study. Results725 patients who received at least one zoledronate infusion were included in the time-to-event analysis. There was no statistically significant difference in disease-free or overall survival in the patients who received ≤6 zoledronate infusions (n = 170) compared to those who received ≥7 zoledronate infusions (n = 555). ConclusionsComparable to efforts to de-escalate treatment duration in metastatic bone disease, there was no evidence to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies are required.

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

The variant T allele of PvuII in ESR1 gene is a prognostic marker in early breast cancer survival

The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480–0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411–0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380–0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.

Predictive Factors Increasing the Risk of Radiation Toxicity in Patients with Early Breast Cancer.

Objectives:Radiation induces adverse events on healthy tissues which may be augmented by certain factors. This study aimed to assess patients; tumor and treatment-related factors which increase the risk of radiation-induced toxicity in breast cancer patients. Methods:This prospective study included postmenopausal early breast cancer patients treated at the clinical oncology department, Assiut University, Egypt between January 2015 and December 2018. Patients treated with mastectomy followed by conventional radiotherapy (25x 2 Gy) and either concurrent or sequential letrozole. Acute and late radiation toxicity was scored according to EORTC/RTOG and risk factors were analyzed. Results:A total of 75 patients were included in the study. After a median follow-up of 24 months, 12 patients had > grade 2 acute dermatitis, 5 patients had > grade 2 cardiac toxicity and 3 patients had > grade 2 lung toxicity. Multivariate analysis revealed that trastuzumab use was associated with a decrease risk of acute dermatitis (p= 0.01) but boost irradiation was significantly associated with increased risk of acute dermatitis (p= 0.01). Late toxicity > grade 2 was observed in 6 patients, 14 patients, and 2 patients for skin, heart, and lung respectively.Conclusion:The use of boost irradiation was associated with increased risk of acute dermatitis, in the contrary; the use of trastuzumab seemed to be protective as observed in this study.

Gene Expression Signatures of BRCAness and Tumor Inflammation Define Subgroups of Early-Stage Hormone Receptor-Positive Breast Cancer Patients.

Patients with estrogen receptor- and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors, gene expression analyses of 612 tumors was performed using the NanoString Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling, and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing. PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B, P = 0.04; HER2, P = 0.006; Basal, P = 0.008). In higher-risk patients, shorter EFS was associated with low androgen receptor [HR = 3.61; 95% confidence interval (CI), 1.72-7.56; P = 0.001] or high BRCAness signature expression (HR = 3.58; 95% CI, 1.19-10.7; P = 0.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR = 2.64; 95% CI, 1.31-5.34; P = 0.007). About 13%-15% of patients, enriched for high-grade, higher-risk subtypes (P ≤ 0.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited antitumor immune response. TIS scores were strongly associated with TIL numbers (P < 1e-30) but not with tumor mutation status. BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.

Development of a Prognostic Tool to Guide the Decision to Extend Adjuvant Aromatase Inhibitors for up to Ten Years in Postmenopausal Early Breast Cancer Patients

Simple SummaryPostmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitors (AIs) for five years. However, recurrences still occur at a steady rate over at least twenty years, and extending adjuvant AIs for up to ten years is an option. Our work focuses on a specific population of postmenopausal patients who have already received five years of adjuvant AIs. This population is at high risk of osteoporosis and extending AIs must be carefully decided in line with the potential benefit. In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AI treatment. The score it provides is available free of charge upon diagnosis and divides patients into two prognostic groups. Combining that score with comorbidities, bone mineral density, and patient motivation may help the decision-making process to recommend extending adjuvant AIs.Background: The selection of women with hormone receptor-positive (HR+) early breast cancer (EBC) at high risk of relapse after five years (yrs.) of adjuvant aromatase inhibitors (AIs) is crucial, as the benefit of extending AIs is counterbalanced by toxicity. We developed a clinicopathological tool to estimate the residual risk of relapse after five years of adjuvant AIs. Methods: The Institut de Cancérologie de l’Ouest (ICO) database was used to determine a prognostic score of post-five-year AI relapse. Cox regression models estimated our score’s prognostic performance. Results: In total, 1105 women were included. Median follow-up was 44 months (IQR = 21–70) post-AI treatment. From the Cox models, we designed a dichotomous prognostic score including the number of macrometastases, age (>70 yrs. vs. ≤70 yrs.), tumor size (≥T2 vs. not), and mitotic activity (≥2 vs. not). Overall, 77.5% of patients were classified as being at low risk and 22.5% at high risk of late recurrence. Low-risk patients had a five- to ten-year local or distant recurrence risk of 7.6% (95% CI, 5.4% to 10.6%) as compared with 26.9% (95% CI, 19.9% to 35.7%) for the high-risk roup. Conclusion: In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AIs.

206P - Effect of denosumab on low bone mineral density in postmenopausal Japanese early breast cancer patients receiving aromatase nhibitors: 36-month results

BackgroundAromatase inhibitors (AI) are standard as postoperative adjuvant therapy for hormone positive postmenopausal breast cancer. In recent years, the administration period tends to be longer, and bone loss which is a side effect has become a serious problem. We have already reported the effect of denosumab up to 24 months on postmenopausal early breast cancer patients with low bone mineral density (BMD) receiving AIs as adjuvant hormonal therapy. BMD in the lumber spine was found to increase, and the combination of denosumab revealed useful for blocking bone mineral loss in Japanese women receiving AIs. MethodsStudy design: A non-randomized, prospective study at three institutions was conducted in Japan. Patients administered 60mg of denosumab subcutaneously every 6 months. The BMD of the lumbar spine and bilateral femoral neck was measured at baseline and at 6, 12, 18, 24, 30 and 36 months. The levels of serum tartrate-resistant acid phosphatase isoform 5b (TRAP5b), bone alkaline phosphatase (BAP), albumin-corrected serum calcium concentration was measured at baseline and 1, 6, 12, 18, 24, 30 and 36 months. Patients: Postmenopausal women with early-stage hormone receptor-positive invasive breast cancer who were scheduled to receive an AI as adjuvant hormonal therapy or receiving AI adjuvant therapy were included in the analysis. We also included those who had completed a chemotherapy regimen ≥ 4 weeks before entering the study and patients with low BMD (lumbar spine, right femoral neck, and left femoral neck BMD: -2.5< T-score <-1.0). Endpoints: The primary endpoint was the change in percentage of the BMD of the lumbar spine (L1–L4) from baseline to 12 months. ResultsA total of 103 patients were enrolled. Seventy-three patients completed the study. At 36 months, the BMD of the lumbar spine increased by 8.8%. The BMD of the right and left femoral neck increased by 4.4% and 2.7%, respectively. Symptomatic clinical fractures did not occur in patients receiving AI and denosumab. ConclusionsAt 36 months, as with the data to the previous 24 months, in combination of denosumab for Japanese women receiving adjuvant AI treatment, an increase in BMD was noted. Clinical trial identificationUMIN-CTR, UMIN 000016173. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureT. Taguchi: Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Daiichi Sankyo Co., Ltd.; Research grant / Funding (institution): Eisai Co. Ltd. All other authors have declared no conflicts of interest.

The possible different roles of denosumab in prevention and cure breast cancer bone metastases: A 'hypothesis-generator' study from clinical practice.

The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with ‘luminal-like’ disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A ‘real life’ analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had ‘luminal-like’ disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous ‘luminal-like’ disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a ‘bone-related’ risk conditions for developing bone metastases must be considered with caution and surely needs further validations.

Abstract 3425: Exome-sequencing derived mutations of endocrine treated ER-positive early breast cancer

Abstract Anti-hormonal treatment of ER-positive early breast cancer with tamoxifen and/or aromatase inhibitors (AI) significantly improves patient outcome, however there is a lack of markers that predict the one third of treated patients who relapse or die. Although ER positive (luminal) tumors are known to be genetically highly diverse, the relevance of somatic mutations with regards to endocrine treatment outcome and course of the patients' disease is not fully understood. We conducted a prospective observational clinical trial for the investigation of treatment outcome determinants including 1219 tamoxifen and/or AI-treated postmenopausal ER-positive early breast cancer patients (DRKS00000605, recruitment between 2005-2010, median follow up 5.1 years). Of these, 40 tumors divided into 20 patients each with and without disease recurrence matched by prognostic variables (age, tumor size, grade, nodal status, treatment) were analyzed for their mutation pattern. We performed whole-exome sequencing of tumor and normal DNA (Agilent SureSelect, Illumina) for the identification of single nucleotide variants and small indels. Somatic mutations were identified following subtraction of germline single nucleotide polymorphisms (SNP), filtering based on raw-read quality parameters, in silico predicted biological function, and disease relatedness using the Ingenuity variant analysis software package (Qiagen). Clinical outcome associations were tested either on gene or on variant level. Somatic mutations with predicted deleterious effects were identified in 18 out of 40 known mutation-driver genes including PIK3CA, GATA3, MAP3K1, and TP53 (45%). Thirteen patients carried a mutation in the most frequently affected PIK3CA (32.5%). Of note, three out of four patients with a E542K mutation belonged to the breast cancer recurrence group, while 5 of 6 tumors with the H1047R mutation originated from patients without recurrence suggesting differential effects of these PIK3CA hotspot mutations. Common germline SNPs at IL17RB, ANK2, POM121, PGR, PTPRB, RAD51D, RFPLA4, and SUMO3 provided first hints for a possible association with relapse status (p&amp;lt;0.05). We will report on the extended genotype-outcome-correlations to further evaluate the relevance of somatic mutations for endocrine treatment outcome of early ER-positive breast cancer. Citation Format: Werner Schroth, Siarhei Kandabarau, Peter Fritz, Thomas Mürdter, Liza Bacchus, German Tamoxifen Study Group, Matthias Schwab, Hiltrud Brauch. Exome-sequencing derived mutations of endocrine treated ER-positive early breast cancer [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 3425.

Endocrine Treatment with 2 Years of Tamoxifen versus 2 Years of Exemestane in Postmenopausal Patients with High-Risk Early Breast Cancer and Persisting Circulating Tumor Cells - First Results of the SUCCESS C Endocrine Treatment Sub-Study

Background: Optimal choice and sequence of endocrine treatment following adjuvant chemotherapy in postmenopausal early breast cancer patients are still under discussion and treatment stratification factors are missing. Patients and Methods: Postmenopausal women with HER2-negative, hormone receptor-positive tumors and persisting circulating tumor cells (CTCs; assessed using the FDA-approved CellSearch® System, Janssen Diagnostics, LLC) after chemotherapy were randomized to 2 years of tamoxifen followed by 3 years of exemestane (tamoxifen-exemestane group, n = 54) or 5 years of exemestane (exemestane-only group, n = 54). CTCs were again assessed after the first 2 years of endocrine treatment. In addition, safety data were compared between the 2 groups. Results: The 2 groups were well-balanced with regard to baseline characteristics. The CTC clearance rate after 2 years was 89% in the exemestane-only group and 97% in the tamoxifen-exemestane group (exact Fisher test, p = 0.36). The safety profile showed good tolerability with few grade 3 or 4 adverse events in both groups. Conclusion: The similar CTC clearance rate after 2 years of endocrine therapy with exemestane or tamoxifen, and the safety profiles obtained may indicate comparable efficacy and tolerability of both endocrine treatment regimens. However, these results have to be confirmed by final survival and safety analysis.

Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1–2, node metastases (n = 0–3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

Aromatase inhibitors: A comprehensive review in mechanisms of action, side effects and treatment in postmenopausal early breast cancer patients

The best adjuvant treatment for hormone receptor-positive breast cancer, especially in the postmenopausal population, is not an unexceptionable decision and depends on several and many times unequal parameters. Apart from the mechanisms of action which are more or less the same among different agents, the two major factors for consideration are the potential side effects and treatment benefits of the selected drug. The last fifteen years have clearly shown that aromatase inhibitors (AIs) are significantly more effective than tamoxifen in preventing recurrence in this group of patients, but they seem to have no beneficial effect on overall survival. The analysis and results of major controlled randomized trials are taken into consideration every time we are called upon to select the best effective adjuvant treatment for well surgically-controlled early breast cancer in a postmenopausal woman. In the present review, we attempt a comprehensive review of the recent English literature in order to unfold the potent aspects for this decision.

Abstract P2-08-10: Validation of prediction of local recurrence (LR) by Prosigna® (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET)

Abstract Background: HR+EBC patients are routinely treated with both adjuvant radiation therapy (RT) and ET. RT is considered an important tool for achieving local control of disease. A limited number of biomarkers have been demonstrated to predict LR. In a previously performed retrospective analysis of a randomized trial, Prosigna (PAM50) risk of recurrence (ROR) score identified low risk patients with a local recurrence rate of 1.6% at 9.5yr median follow-up. In this study, we seek to validate the ability of ROR to predict LR in a comprehensive nationwide cohort from Denmark. Methods: Using the population based DBCG database primary FFPE tumor blocks and follow-up data were collected from all postmenopausal Danish women diagnosed from 2000-2003 with HR+EBC (N=2,722). Prosigna (PAM50) on the NanoString nCounter® Dx Analysis System assigned each patient an ROR score and associated risk group based on pre-specified cutoffs. Patients are also assigned an intrinsic subtype (Luminal A, Luminal B, Her2-Enriched, Basal-Like) based on gene expression. Univariate and multivariate analyses were performed to assess the ability of Prosigna (PAM50) to predict LR. Results: 48 local recurrences were observed with median follow-up of 9.25 yr. Continuous ROR was significantly associated with LR in univariate and multivariate models including node status (0, 1, 2, or 3 positive nodes), tumor size (≤2 vs.&amp;gt;2cm), grade (I, II, III, or unknown), age (≤65 vs.&amp;gt;65yr), and local treatment (mastectomy (MX), lumpectomy+RT, or MX+RT) (p=0.036 and p=0.049, respectively). Clinicopathologic variables were not significant in the multivariate model alone or in combination (p=0.85 for full model excluding ROR). Utilization of a pre-specified LR cutoff, hazard ratio (HR) and [95%CI, p-value] for high risk vs. low risk patients in a univariate analysis was 1.96 [1.11-3.46, p=0.0205] and 2.04 [1.08-3.83, p=0.0275] in the multivariate analysis. 10-year cumulative incidence of LR for low risk patients was 1.7% [1.1%-2.6%]. Similarly, 10-year cumulative incidence of LR for Luminal A patients was 1.7% [1.1%-2.6%]. 10-year cumulative incidence for high risk patients was 2.3% [1.3%-3.2%]. Conclusions: In a large population-based study of n=2,722 patients, Prosigna (PAM50) predicted LR over standard variables. These data validate a pre-specified cutoff separating patients at high and low risk of LR. Additional studies of Prosigna (PAM50) in RT-untreated populations are ongoing. Citation Format: Ole Eriksen J, Jensen M-B, Laenkholm A-V, Kibøll T, Bruun Rasmussen B, Knoop AS, Ferree S, Haffner T, Buckingham W, Schaper C, Ejlertsen B. Validation of prediction of local recurrence (LR) by Prosigna® (PAM50) in a Danish breast cancer cooperative group (DBCG) cohort of hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated to 5yr of endocrine therapy (ET). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-10.

Abstract P3-07-22: RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early breast cancer

Abstract Purpose It has been suggested that genetic polymorphisms in CYP19A1 gene were related to aromatase activity as well as circulating steroid hormone levels in postmenopausal women. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with clinical outcome for hormone therapy. Methods Genotyping for CYP19A1 polymorphism rs1008805 was performed on 287 women with HR-positive early breast cancer. Associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS). Results Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS, 5-year DFS rate. However, in postmenopausal women, rs1008805 genotypes were significantly associated with DFS and 5-years DFS rate (AA versus AG versus GG: 89.2 months versus 58.2 versus 32.7 months; 55.9% versus 47.8% versus 0%; P = 0.019). In addition, when the population was subgrouped into two cohorts, women carrying GG variant have a poorer DFS, 5-years DFS rate (GG versus AA or AG: 32.7 months versus 70.6 months; 0% versus 52.1%; HR, 3.613; 95% CI,1.380-9.457; P = 0.005). Furthermore, being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 3.439; 95% CI, 1.251-9.456; P = 0.017). However, there was no significant differences in DFS and 5-years DFS rate between women harbor the minor allele and those with the homozygous common allele (AG or GG versus AA: 52.4 months versus 89.2 months; 41.0% versus 52.9%; HR, 1.288; 95% CI, 0.705-2.353; P = 0.408). In addition, there were no differences between rs1008805 polymorphisms and DFS among premenopausal women. Conclusions The homozygous minor allele (GG) of CYP19A1 rs1008805 is significantly associated with worse clinical outcome of hormone therapy in postmenopausal HR-positive early breast cancer patients. If confirmed, genotyping for CYP19A1 polymorphisms rs1008805 may provide predictive information for better selection of endocrine treatment. Citation Format: Wang X, Shao X, Zheng Y, Shi L, Huang Y. RS1008805 polymorphism in CYP19A1 gene is related to the efficacy of hormone therapy in early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-22.

Abstract P4-10-05: Changes in metabolic syndrome components in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy

Abstract Purpose. We sought to determine the impact of (neo)adjuvant chemotherapy on metabolic syndrome (MetS) components and related anthropometric and metabolic biomarkers among premenopausal and postmenopausal early stage breast cancer patients. Methods. Eighty-six women with early stage (I-III) breast cancer who were free from clinically diagnosed MetS (defined as 3 out of 5 components of MetS) and were planning to undergo chemotherapy, enrolled in the study. Participants were tested for MetS (blood pressure; BP, waist circumference; WC, fasting blood glucose; FBG, high-density lipoprotein cholesterol; HDL-C, and triglycerides; TG), anthropometrics (body weight; BW, percent body fat; BF, fat mass; FM), lipid profile (total cholesterol; TC, low-density lipoprotein cholesterol; LDL-C), glucose metabolism (insulin, homeostatic model- insulin resistance; HOMA-IR, glycosylated hemoglobin; HbA1c), and inflammation (C-reactive protein; CRP) within one week before and following the completion of chemotherapy. Fasting (12-hour) venous blood samples of the antecubital vein were drawn to measure glucose, insulin, lipid profile (TC, HDL-C, LDL-C, and TRI), HbA1c, and CRP. Blood samples were analyzed at the City of Hope Clinical Pathology Laboratory. Insulin resistance was calculated using the HOMA index: [(fasting glucose (mg/dL) x fasting insulin (mg/dL)/405]. Height, BW, and BP measurements were obtained by the nursing staff during pre-chemotherapy physical exams. Body composition (BF and FM) was measured using a portable hand-held bioelectrical impedance device (Omron®; Hoffman Estates, IL). WC was measured, using a fabric measuring tape, as the distance around the waist using the umbilicus as the reference point. One-way analysis of covariance (ANCOVA) using SPSS version 18.0 was used to compare means adjusting for covariates such as age, race, type of chemotherapy, duration of chemotherapy, BMI at baseline, and menopausal status. Results. The majority of the 86 women enrolled were Caucasian (44%) or Hispanic (30%), nonsmoking (96%), employed (84%), and well-educated (90%), with a mean age of 48.2 years. Women were most commonly undergoing Cytoxan/Adriamycin + Taxol (42%) or Taxotere/Cytoxan (36%) chemotherapy regimens, lasting on average 15.3 (±2.7) weeks. Overall the population was sedentary, averaging 7.2 (±5.8) minutes of physical activity/week. Following chemotherapy, all MetS components and overall MetS score (out of 5) significantly increased (p&amp;lt;0.01). Additionally, BW, BF, FM, lipids (TC, LDL), glucose metabolism (HOMA-IR, insulin, HbA1c), and inflammation (CRP) significantly increased (p&amp;lt;0.01). Conclusion. In women without MetS, (neo)adjuvant chemotherapy negatively altered MetS components, related anthropometrics, and biomarkers of glucose metabolism and inflammation, within 12 -18 weeks. Studies that test the impact of lifestyle interventions, such as diet and exercise, should be explored in this population of breast cancer patients to reduce the onset of MetS. Citation Format: Dieli-Conwright CM, Wong L, Waliany S, Bernstein L, Salehian B, Mortimer JE. Changes in metabolic syndrome components in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-05.

Abstract 5483: CYP19A1 genetic variation is a potential predictor of outcome in ER-positive postmenopausal early breast cancer patients treated with tamoxifen

Abstract Tamoxifen is a selective estrogen receptor modulator which blocks estrogen from binding to the estrogen receptor (ER). Although estrogens are natural hormones vital for development, they are also critical growth factors responsible for cell proliferation and DNA synthesis, thus enhancing the growth of estrogen-responsive breast tumors. With breast cancer being the most frequent cancer in women, the carcinogenic effects of estrogen are mediated by ER which is expressed in approximately 75% of all tumors. Hence tamoxifen is commonly used to treat patients with ER-positive breast cancer. Our group has a long standing interest in the investigation of potential tamoxifen outcome predictors as up to 33% of treated patients relapse or dies at 15 years of follow up. Therefore it is crucial to determine which patient will benefit from tamoxifen or not. In a pilot study of 915 patients, we previously identified a single nucleotide polymorphism (SNP) at the aromatase gene (CYP19A1) which could potentially predict the outcome of postmenopausal patients treated with tamoxifen. Aromatase is a key enzyme in the estrogen biosynthesis pathway and in postmenopausal women, estrogen levels are low with the aromatase being responsible for estrogen synthesis from adipose tissue following the cessation of ovarian function. Therefore any alterations in aromatase function may affect the inhibitory capacity of tamoxifen for estrogen at the ER, resulting in variation of outcome in patients treated with tamoxifen. We hypothesized that genetic variation in CYP19A1 may influence aromatase expression and function, thus affecting the outcome of ER-positive postmenopausal early breast cancer patients treated with tamoxifen. Genotyping was conducted on 55,540 breast cancer patients from 50 studies with the custom Illumina Infinium array (iCOGS) by the Breast Cancer Association Consortium. More than 200,000 SNPs were genotyped of which 89 SNPs are located in the CYP19A1 genomic region. We included patients that are female with European ancestry, available follow up and vital status, invasive breast tumor, ascertained for their first tumor, stage I-III disease, postmenopausal, ER-positive, right truncation at 15 years of follow up, left censoring for study entry and those treated with tamoxifen. Furthermore, studies with less than 10 events for relapse or death were excluded leaving a total of 1313 patients for outcome analyses with distant metastasis-free survival as the endpoint. We identified rs7172156 being associated with poor outcome of which carriers of the minor A allele had a higher risk of distant metastasis or death (P = 0.007). Multivariate Cox regression stratified by study and adjusted for age, node status, tumor size and grade confirmed this observation (HR = 1.30, 95% CI 1.00-1.68, P = 0.049). Our data suggest that rs7172156 could be clinically relevant as a tamoxifen outcome predictor in early breast cancer. Citation Format: Wing-Yee Lo, Werner Schroth, Reiner Hoppe, Marjanka Schmidt, Montserrat Garcia-Closas, Paul Pharaoh, Per Hall, Douglas Easton, Peter Fasching, Hiltrud Brauch, in collaboration with the Breast Cancer Association Consortium. CYP19A1 genetic variation is a potential predictor of outcome in ER-positive postmenopausal early breast cancer patients treated with tamoxifen. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2015-5483

Abstract 5485: Coactivator PPARGC1B Ala203Pro polymorphism is linked with estrogen-related receptor function and breast cancer outcome

Abstract Background The estrogen-related receptors (ERRs) are orphan nuclear receptors (NRs) with high sequence similarity to the estrogen receptor (ER). Peroxisome proliferator-activated receptor gamma coactivator-1 beta (PERC) specifically activates ER and ERRs, thus providing a link with breast cancer growth. Here we functionally characterized a non-synonymous PERC polymorphism, rs7732671, previously associated with increased risk for familial breast cancer, and tested its clinical relevance for breast cancer progression. Methods A mammalian two-hybrid assay was used to identify protein interactions using full-length and truncated NR (ERα, ERRα, ERRγ) and PERC. PERC rs7732671 variant allele (649G&amp;gt;C_A203P) was created by site-directed mutagenesis. Expression of genes involved in cell glycolysis and/or direct ERR targets Eno1, PKM, LDHA and IDH3A, were analyzed in breast cancer cells and in breast tumors (N = 84). Cell supernatants were quantitated for lactate formation using liquid chromatography coupled mass spectrometry. PERC rs7732671 was genotyped in 896 postmenopausal early breast cancer patients treated with adjuvant tamoxifen and clinical outcome was analyzed using Kaplan-Meier and Cox regression analyses. Results Truncated PERC (aa129-426) containing the 649G&amp;gt;C_A203P variant did not interact with ERα, but ERRα and ERRγ ligand-binding domains were activated. The PERC129-426-C allele enhanced ERRα activity by 21% and ERRγ by 67%, compared to the PERC129-426-G major allele (P&amp;lt;0.005). Expression of ERR downstream genes Eno1, LDHA, IDH3A and lactate concentrations were increased in MCF7 and MDA-MB-231 overexpressing PERC-C as compared to PERC-G. In breast tumors, glycolytic or ERR target gene expression was increased in patients carrying the PERC-C allele. Patients carrying the PERC-C showed higher distant recurrence rates compared with patients of the G/G genotype (P = 0.01), which was confirmed in Cox regression adjusted to tumor size, nodal status, and grade (Hazard Ratio 2.06; 95% CI 1.26-3.38, P = 0.005 per C allele). Conclusion PERC rs7732671 variant 649C_203P enhances ERRα and ERRγ signaling independent of ER. Higher lactate concentrations in cells and increased ERR target gene expression in vitro and in patients with the PERC-C allele point to a modulation of aerobic glycolysis. The ERR/PERC axis is possibly linked with disease progression in breast cancer. Citation Format: Pilar H. Saladores, Reiner Hoppe, Wing-Yee Lo, Sibylle Cocciardi, Ute Hofmann, Ute Hamann, Peter Fasching, Marcus Schmidt, Hiltrud Brauch, Werner Schroth. Coactivator PPARGC1B Ala203Pro polymorphism is linked with estrogen-related receptor function and breast cancer outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5485. doi:10.1158/1538-7445.AM2015-5485

Validation of prediction of distant recurrence (DR) by Prosigna (PAM50) in subgroups of a Danish Breast Cancer Cooperative Group (DBCG) cohort of node-positive (N1), hormone receptor positive (HR+), postmenopausal early breast cancer (EBC) patients allocated 5yr of endocrine therapy (ET).

513 Background: N1, HR+ EBC patients are routinely treated with both ET and chemotherapy (CT). Identification of N1 patients with good outcome who may be spared CT remains an elusive goal. In a com...