Postmenopausal Breast Cancer Patients Research Articles

Evaluation of lipid profile in postmenopausal breast cancer patients and its association with serum level of thyroid hormones, vitamin D and estrogen

Evaluation of lipid profile in postmenopausal breast cancer patients and its association with serum level of thyroid hormones, vitamin D and estrogen

The relationship between homocysteine, coagulation dysfunction and breast cancer risk

Objective: To investigate the correlation of homocysteine (HCY) and coagulation function index with the risk of breast cancer and its clinicopathological characteristics. Methods: The HCY, coagulation function test index, and clinicopathological information of female breast cancer patients (333 cases) treated in Tianjin Medical University Cancer Hospital from January 2018 to December 2018 were collected, and female patients with benign breast (225 cases) were selected during the same period for the control group. The t-test was used to compare measurement data with normal distribution, D-Dimer data were distributed discreetly and described by median, non-parametric Mann-Whitney U test was used to compare the two groups. The chi-square test was used to compare enumeration data, and the Logistic regression analysis was used for the risk analysis. Results: The levels of HCY, fibrinogen (Fbg), protein C (PC), and median D-Dimer (D-D) in peripheral blood of breast cancer patients group [(13.26±5.24) μmol/L, (2.61±0.83) g/L, (117.55±19.67)%, and 269.68 ng/ml, respectively] were higher than those in the control group [(11.58±0.69) μmol/L, (2.49±0.49) g/L, (113.42±19.82)% and 246.98 ng/ml, respectively, P<0.05]. The prothrombin time (PT), PT(INR), α2-antiplasmin (α2-AP) levels [(10.19±0.63) s, 0.91±0.07 and (110.64±13.93)%, respectively] were lower than those in the control group [(10.58±0.65) s, 0.93±0.01 and (123.81±14.77) %, P<0.05]. The serum levels of PC and median D-D in premenopausal breast cancer patients [(112.57±17.86)% and 242.01 ng/ml, respectively] were higher than those in the control group [(105.31±22.31)% and 214.75 ng/ml, respectively, P<0.05]. The levels of PT(INR), α2-AP [0.91±0.07 and (111.29±12.54)%, respectively] were lower than those of the control group[0.98±0.15 and (120.17±16.35)%, respectively, P<0.05]. The levels of HCY and median D-D in postmenopausal breast cancer patients [(14.25±5.76) μmol/L and 347.53 ng/ml, respectively] were higher than those in the control group [(11.67±2.38) μmol/L and 328.28 ng/ml, P<0.05]. The levels of PT, PT(INR), antithrombin Ⅲ (AT-Ⅲ), α2-AP levels [(10.18±0.66) s, 0.87±0.09, (97.30±12.84)% and (110.13±14.96)%] were lower than those in the control group [(10.38±0.61) s, 0.90±0.08, (102.89±9.12)%, and (127.05±12.38)%, respectively, P<0.05]. The levels of α2-AP and median D-D in T2-4 stage breast cancer patients [(111.69±14.41)% and 289.25 ng/ml, respectively] were higher than those in Tis-1 stage patients [(108.05±12.37)% and 253.49 ng/ml, respectively, P<0.05]. The levels of PT, PT (INR), Fbg, AT-Ⅲ, α2-AP, median D-D [(10.62±0.63) s, 0.95±0.06, (3.04±1.52) g/L, (103.21±9.45)%, (118.72±14.77)% and 331.33 ng/ml, respectively] in breast cancer patients with lymph node metastasis were higher than those of patients without lymph node metastasis [(10.42±0.58) s, 0.93±0.06, (2.52±0.54) g/L, (95.20±13.63)%, (106.91±13.13)% and 263.38 ng/ml, respectively, P<0.05]. In non-menopausal breast cancer patients, the level of HCY [(12.63±4.41) μmol/L] in patients with T2-4 stage was higher than that of patients with Tis-1 stage [(10.70±3.49) μmol/L, P=0.010], and the level of thrombin time [(19.35±0.90) s] of patients with T2-4 stage was lower than that of patients with Tis-1 stage [(19.79±1.23) s, P=0.015]. The levels of PT(INR), Fbg, AT-Ⅲ, α2-AP [0.97±0.56, (3.37±2.34) g/L, (102.38±8.77)% and (120.95±14.06)%] in patients with lymph node metastasis were higher than those of patients without lymph node metastasis [0.94±0.05, (2.36±0.48) g/L, (94.56±14.37)% and (109.51±11.46)%, respectively, P<0.05]. Among postmenopausal breast cancer patients, the levels of AT-Ⅲ and α2-AP in T2-4 stage patients [(98.48±11.80)% and (111.84±15.35)%, respectively] were higher than those in patients with the Tis-1 stage [(94.12±14.98)% and (105.49±12.89)%, respectively, P<0.05]. The levels of AT-Ⅲ and α2-AP in N1-3 stage patients [(103.74±9.94)% and (117.29±15.23)%] were higher than those in N0 stage patients [(95.75±13.01)% and (108.39±14.42)%, P<0.05]. Conclusions: HCY and abnormal coagulation function are related to the risk of breast cancer, T stage and lymph node metastasis in breast cancer patients.

Changes in Vertebral Marrow Fat Fraction Using 3D Fat Analysis & Calculation Technique Imaging Sequence in Aromatase Inhibitor-Treated Breast Cancer Women.

Aromatase inhibitor (AI) is a cornerstone drug for postmenopausal women with estrogen receptor-positive early-stage breast cancer. Fat-bone interactions within the bone marrow milieu are growing areas of scientific interest. Although AI treatment could lead to deterioration of the skeleton, the association between AI medication and subsequent marrow adiposity remains elusive. A total of 40 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients who underwent treatment with adjuvant AIs and 40 matched controls were included. Marrow proton density fat fraction (PDFF) at the L1−L4 vertebral bodies using 3D Fat Analysis & Calculation Technique imaging (FACT) sequence at 3.0T, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and serum bone turnover biomarkers were determined at baseline and at 6 and 12 months. We found that, in comparison to baseline, an increase of type I collagen cross-linked telopeptide was detected at 12 months (P <0.05). From baseline to 12 months, the PDFF measured using FACT was greatly increased. At 12 months, the median percent change of PDFF (4.9% vs. 0.9%, P <0.05) was significantly different between the AI treatments and controls. The same trend was observed for the marrow PDFF at 6 months relative to the respective values at baseline. Although BMD values were significantly reduced after 12 months in AI-treated women, changes in BMD vs. baseline condition were not significantly different between the AI-treated and control groups [Δ BMD −1.6% to −1.8% vs. −0.3% to −0.6%, respectively, P > 0.05]. In the AI-treated group, Δ PDFF was associated with Δ BMD at the lumbar spine (r = −0.585, P < 0.001), but not in the controls. Taken together, over a 12-month period, spinal marrow fat content assessed with FACT sequence significantly increased in postmenopausal women with hormone-receptor-positive breast cancer receiving AI treatment.

Abstract 2693: The vitamin D3 metabolite, 24R,25(OH)3D3 is differentially tumorigenic in ER+ and ER- laryngeal cancer cells in vitro

Abstract Due to the high vitamin D3 levels associated with improved prognosis (but not incidence) in post-menopausal breast cancer patients with ER+ tumors, vitamin D3 supplementation has been used as potential therapeutics. 24R,25(OH)2D3, an active metabolite of vitamin D3, is known to protect cartilage cells through a membrane-initiated, p53-mediated pathway, suggesting that 24R,25(OH)2D3 may affect cancer cells through a similar mechanism. Our lab has shown that the effect of 24R,25(OH)2D3 on breast cancer cell growth is highly dependent on the expression levels of ERα isoforms, specifically ERα66. Understanding the mechanisms by which 24R,25(OH)2D3 affects tumor growth in breast cancer will aid in determining its therapeutic potential in another estrogen responsive cancer, laryngeal cancer. The goal of this study was to examine the effects of 24R,25(OH)2D3 on proliferation, apoptosis, and epithelial to mesenchymal transition (EMT) in laryngeal cancer cell lines. To assess the effect of 24R,25(OH)2D3 on cell growth, UM-SCC-12 (ERα66+) and UM-SCC-11A (ERα66-) cell lines were cultured on 96 well plates until 80% confluence. Cells were serum starved for 24 hours pretreatment and then treated with full media containing either vehicle, or 24R,25(OH)2D3 (10-9M, 10-8M, or 10-7M) for 15 minutes, at which time the media were replaced with fresh media. After 20 hours, cells were harvested for proliferation by EDU assay. For other experiments cells were treated with either vehicle, or 24R,25(OH)2D3 (10-9M, 10-8M, or 10-7M) for 15 minutes and after 24 hours, cells were assessed for apoptosis (TUNEL, P53) and metastasis (OPG/RANKL). 12 hours after treatment, cells were harvested for PCR and examined for gene expression of apoptotic markers (BAX, BCL2) and various metastatic markers (SNAI1, ERBB2). 24R,25(OH)2D3 decreased proliferation in ERα66- cells (UM-SCC-11A) with the 10-7M dosage. It also increased apoptotic markers (TUNEL, P53, BAX/BCL2 expression). EMT and metastatic markers (ERBB2, SNAI1 expression) as well as bone metastatic markers (OPG/RANKL) were reduced. Conversely, in ERα66+ cells (UM-SCC-12) 24R,25(OH)2D3 had the opposite effect, increasing proliferation with 10-7M 24R,25(OH)2D3 treatment as well as decreasing DNA fragmentation (TUNEL). Treatment with 24R,25(OH)2D3 increased total P53 content and had no effect on EMT, BAX/BCL2 or other metastatic markers (SNAI1, ERBB2, OPG, RANKL). These data show that 24R,25(OH)2D3 is functionally active in laryngeal cancer tumor regulation. Contrary to results shown in breast cancer in which 24R,25(OH)2D3 was pro-tumorigenic in ERα66- cells, 24R,25(OH)2D3 was anti-tumorigenic in ERα66- laryngeal cancer cells. While this difference may be a result of a difference in other aspects of the two ERα66- cell lines, these results provide evidence of the therapeutic potential of 24R,25(OH)2D3 in laryngeal cancer and its ERα66 dependent effect. Citation Format: Cydney D. Dennis, David Joshua Cohen, Barbara D. Boyan, Zvi Schwartz. The vitamin D3 metabolite, 24R,25(OH)3D3 is differentially tumorigenic in ER+ and ER- laryngeal cancer cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2693.

Estrogen and Progesterone Hormone Receptor Status in Pre-menopausal and Post-menopausal Women with Invasive Ductal Carcinoma in a Private Tertiary Hospital in Cebu City, Philippines: A Retrospective Study

Objective: This study was conducted to determine the difference of hormone receptor status between pre-menopausal and postmenopausal women diagnosed with invasive ductal carcinoma in the local setting. Methods: This retrospective descriptive study used data gathered from chart review of premenopausal and postmenopausal female patients diagnosed with invasive ductal carcinoma by tissue biopsy and underwent determination of hormone receptor status (estrogen and progesterone receptor) by immunohistochemical staining (ICA) using biopsy samples taken from June 2016 to December 2019 at Cebu Velez General Hospital, Cebu City. The significance of the difference in the hormone receptor status with menopausal status was analyzed using Fisher’s exact test. Results: Comparing the two groups, 25 (60%) of the pre-menopausal women and 37 (73%) of the post-menopausal women were determined as hormone sensitive, while 17 (40%) pre-menopausal women and 14 (27%) post-menopausal women were hormone resistant. The Fisher’s exact test did not detect a statistically significant difference in the hormone receptor status of pre-menopausal and post-menopausal breast cancer patients. Conclusion: There is no significant difference on the hormonal receptor status among pre-menopausal and post-menopausal women diagnosed with invasive ductal carcinoma. Thus, the need for hormone receptor status determination in these patients should be emphasized to aid in proper diagnosis, prognostication, and treatment planning. Key words: Hormone receptor status, menopausal status, invasive ductal carcinoma, immunohistochemical staining

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.

Adherence to adjuvant endocrine therapy assessed by data from prescription renewals and medical records from tamoxifen in Swedish patients with cytochrome P450 2D6 (CYP2D6) genotyped early breast cancer.

542 Background: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been suggested. The main aim of this study was to investigate the consistency between prescription refill data and reports from medical records on adherence to AET in early breast cancer. We also studied if there was an association between menopausal status, CYP2D6 activity, estimated risk for recurrence and adherence to AET. Methods: 1235 pre-and postmenopausal Swedish breast cancer patients operated 2006 – 2014, genotyped for CYP2D6, who initiated adjuvant tamoxifen treatment, were included in the study. Information on AET was retrospectively collected from both medical records and the Swedish Prescribed Drug Registry. Consistency was defined as dispensed doses of AET divided by AET intake documented in medical records. Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate (MPR) ≥ 80 %. Subgroup analyses were performed based on menopausal status, recurrence-risk and CYP2D6 activity. Results: In 84% of the patients the consistency of AET between the sources of information was within 80-125%. Consistency &lt; 80% was most frequent in premenopausal/high risk patients and CYP2D6 Poor Metabolizers (PM). Among 899 patients with at least 4.5 years follow up, adherence to tamoxifen was 72% according to prescription refill data, compared to 77% as reported by medical records. When including aromatase inhibitors adherence increased to 82% and 88%. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PM had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). Conclusions: Consistency between medical records and dispensing data on adherence was better than anticipated. Adherence to AET was good, 82% when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a reduced risk of side effects according to previous studies. Further work is needed to clarify the impact of CYP2D6 activity on adherence to tamoxifen.

The relationship of oncotype Dx Recurrence Score (RS) with Ki 67 in early stage breast cancer patients in a community based cancer center in rural central Nebraska.

e12566 Background: Oncotype Dx recurrence score (RS), is a prognostic and predictive test utilized for decision making in adjuvant therapy of 0-3 node/hormone receptor positive(HR+)/ HER-2-negative early breast cancer. Ki-67 is a marker of proliferating cells and is associated with prognosis and response. Immunohistological (IHC) assessment of Ki 67 expression is less expensive and with the approval of CDK inhibitors in the high risk adjuvant setting, it is increasingly being utilized in clinical decision making. A moderate to strong correlation between Ki67 and Oncotype Dx RS has been reported in the literature. We sought to examine the relationship of Ki 67 to Oncotype Dx RS in a community-based cancer center in rural central Nebraska. Methods: Forty-three consecutive postmenopausal breast cancer patients(pts) diagnosed and treated at our community based cancer center between 2020-2021 with T1–2 N0-1 M0, HR+, HER-2-negative disease were evaluated for histological type, tumor size, Nottingham grade, HR levels, Ki 67 expression (low &lt; 10%, intermediate 10 ≥ Ki67 &lt; 25 high ≥ 25), and Oncotype Dx RS(low &lt;16,intermediate 16⩽RS&lt;26), high ⩾26). Ki 67 and Oncotype Dx RS were treated as continuous variables to calculate a Pearson correlation coefficient. Results: Mean age at diagnosis was 59.4 years (range 48-89). Mean tumor diameter was 15.6 mm. 78.9% were intermediate histologic grade and 9.7% patients had lymph node involvement. Median expression of ER and PR were 90% (5-100) and 70% (0-100), respectively. The mean Ki 67 value was 17.5 (range 5-60 %), and mean Oncotype RS was 14.4 (range 4-34). There was a positive linear correlation between Ki 67 expression and Oncotype Dx RS (Pearson Correlation Coefficient=0.49, P-value &lt;0.001). The vast majority of high Ki 67 pts (80%) had high/intermediate Oncotype RS. All pts with low Ki 67 (100%) had low/intermediate RS. Conclusions: Our community based rural cancer center data support a linear, statistically significant, positive correlation between Ki 67 and Oncotype Dx RS in early stage 0-3 node/HR+ positive breast cancer pts. Increasing use of Ki 67 testing in different clinical settings will generate more data to better define this correlation.[Table: see text]

Associations Between Serum Reproductive Hormone Concentrations and Hormonal Receptor Status Among Postmenopausal Chinese Women With Breast Cancer: An Observational Study.

Background and ObjectivesReproductive hormones and receptors play crucial roles in breast cancer development and progression. The association between preoperative serum reproductive hormone levels and receptor status in postmenopausal women with breast cancer remains unclear. Therefore, this study investigated the relationship between serum reproductive hormone concentrations and patient characteristics and hormone receptor status among postmenopausal Chinese women with breast cancer.Materials and MethodsThe medical records of 352 postmenopausal breast cancer patients who underwent an operation between October 2007 and October 2010 at the Department of Breast Tumor Surgery of Zhejiang Cancer Hospital were retrospectively evaluated. Serum levels of reproductive hormones were measured before surgery by liquid-chromatography tandem mass spectrometry. Hormone receptor levels were measured by an immunohistochemical assay using a mouse monoclonal antibody. The associations between serum hormone concentrations and hormone receptors were investigated by analysis of covariance.ResultsIn this patient cohort, the serum level of luteinizing hormone (LH) declined with PMP duration. The median LH concentration was significantly higher in patients within 5 years of PMP than that in patients with PMP duration exceeding 5 years (23 vs. 18.32 mIU/ml, P <.0001). Significantly more patients with strong estrogen receptor (ER) or progesterone receptor (PR) expression had postmenopausal durations of less than 5 years compared to those with postmenopausal durations greater than 5 years (103 vs. 61 cases, P = .019; 93 vs. 46 cases, P = .0005). While most patients either lacked (97.1%) or co-expressed (84.3%) ER and PR, some patients expressed either ER or PR alone. ER and PR expression were negatively associated with receptor-tyrosine kinase erbB-2 (HER2) expression in postmenopausal patients with breast cancer. Meanwhile, increased ER and PR expression were associated with decreased serum levels of LH or follicle-stimulating hormone (FSH).ConclusionDecreased serum LH and FSH levels were associated with increased ER and PR expressions and decreased HER2 expression in postmenopausal patients with breast cancer.

Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature

PurposeGuidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making.MethodsIn the IKA trial, postmenopausal patients with non-metastatic breast cancer had been randomized between no or limited adjuvant tamoxifen treatment without receiving chemotherapy. For this secondary analysis, FFPE tumor material was obtained of ER+HER2− patients with 0–3 positive lymph nodes and tested for the 70-gene signature. Distant recurrence-free interval (DRFI) long-term follow-up data were collected. Kaplan–Meier curves were used to estimate DRFI, stratified by lymph node status, for the three predefined 70-gene signature risk groups.ResultsA reliable 70-gene signature could be obtained for 135 patients. Of the node-negative and node-positive patients, respectively, 20% and 13% had an ultralow-risk classification. No DRFI events were observed for node-negative patients with an ultralow-risk score in the first 10 years. The 10-year DRFI was 90% and 66% in the low-risk (but not ultralow) and high-risk classified node-negative patients, respectively.ConclusionThese survival analyses indicate that the postmenopausal node-negative ER+HER2− patients with an ultralow-risk 70-gene signature score have an excellent 10-year DRFI after surgery with a median of 1 year of endocrine treatment. This is in line with published results of the STO-3-randomized clinical trial and supports the concept that it is possible to reduce the duration of endocrine treatment in selected patients.

Influence of Autoantibodies to Estradiol and Progesterone on the Blood Serum Hormones Concentrations in Postmenopausal Healthy Women and Breast Cancer Patients

Background: It is known that antibodies to steroid hormones are associated with some human diseases (systemic lupus erythematosus, thrombosis, recurrent pregnancy loss, autoimmune dermatitis et al.). There were no any data about action of specific autoantibodies on the sex hormones in hormone-dependent cancer patients. Objectives: The purpose of this study was to investigate the probable links between estradiol (Es) and progesterone (Pg) levels and autoantibodies of A-class specific to these hormones (IgA-Es and IgA-Pg) in the blood serum of healthy women and breast cancer patients. Patients and Methods: There were examined 521 nearly diagnosed breast carcinoma patients from Regional Clinical Oncology Dispensary (Kemerovo, Russian Federation) and 143 healthy women from Kemerovo (Russian Federation). The serum concentration of Es and Pg were analyzed by competitive immunoassay using specific monoclonal antibodies. The serum IgA-Pg and IgA-Es were analyzed by solid-phase non-competitive immunoassay using Pg and Es conjugated with bovine serum albumin as adsorbed antigens. The data analysis was performed using software STATISTICA 8.0 (Stat Soft Inc., USA).Results: We discovered that low ratios Pg/Es&lt;4.3 were associated with breast cancer. Personal IgA-Pg/IgA-Es ratios negatively correlated with Es levels and positively correlated with Pg levels and Pg/Es ratios in compared groups. The influence of IgA-Pg/IgA-Es ratio on the hormones levels and their ratio in heathy women was more strong than in breast cancer patients. Conclusions: Our clinical results correspond to the known experimental data about influence of specific antibodies on the levels of steroid hormones in immunized animals. Human autoantibodies to Es and Pg could stimulate or inhibit promotion of carcinogenesis by influence on Pg/Es ratio depending on individual IgA-Pg/IgA-Es ratio.

A Presurgical-Window Intervention Trial of Isothiocyanate-Rich Broccoli Sprout Extract in Patients with Breast Cancer.

Dietary isothiocyanates (ITCs) from cruciferous vegetables have shown potent anti-breast cancer activities in preclinical models, but their anticancer effects in vivo in breast cancer patients remain elusive. A proof-of-principle, presurgical window of opportunity trial is conducted to assess the anticancer effects of dietary ITCs in breast cancer patients. Thirty postmenopausal breast cancer patients are randomly assigned to receive ITC-rich broccoli sprout extract (BSE) (200µmol ITC per day) or a placebo for 2 weeks. Expression of biomarkers related to ITCs functions are measured in breast cancer tissue specimens at pre- and post-interventions using immunohistochemistry staining. First morning urine samples are collected at both timepoints for proteomic analysis. Overall, the study shows high compliance (100%) and low toxicity (no grade 4 adverse event). Trends of increase in cleaved caspase 3 and tumor-infiltrating lymphocytes (TILs) and trends of decrease in Ki-67 and nuclear to cytoplasm ratio of estrogen receptor (ER)-α are observed in the BSE arm only, consistent with the significantly altered signaling pathways identified in urinary proteomic analysis. Anticancer activities of ITCs are observed in breast cancer patients, supporting the potential beneficial roles of ITC-containing cruciferous vegetables in breast cancer prognosis.

An aromatase inhibitor in combination with Zinc(II) phthalocyanine for targeted therapy of post-menopausal breast cancer

As a third-generation steroidal aromatase inhibitor, exemestane (EXE) has been clinically used for postmenopausal advanced breast cancer patients whose condition has progressed after treatment of tamoxifen. However, the further development and application of EXE was limited due to its low solubility and oral bioavailability, inevitable drug resistance and side effects. Based on the unique therapeutic advantages of photodynamic therapy (PDT), a novel aromatase-targeted photosensitizer EX-Pc was synthesized by the combination of EXE and the phthalocyanine photosensitizer. The compound EX-Pc still maintains the superior optical properties of the phthalocyanine photosensitizer upon the introduction of EXE and triethylene glycol chain. Meanwhile, the results of targeted uptake in vitro and in vivo indicated that EX-Pc exhibited high selectivity and affinity for breast cancer cells and tumor tissues, which have the overexpression of aromatase. More importantly, the compound EX-Pc exhibits significant photocytotoxicity and tumor regression ability on breast cancer cells and tumor. In addition, the compound EX-Pc shows negligible side effects and high biological safety. We believe that this is a potential strategy for the treatment of postmenopausal breast cancer.

Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial

BackgroundBetween 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AimTo present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. MethodsA total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8–9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. ResultsOverall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18–0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70–0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69–0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77–0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58–1.18]; nor secondary lung cancer HR: 1.44 [0.92–2.24], or other non-cancer related death HR: 1.15 [0.92–1.45]. ConclusionThe study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy.

This study aimed to evaluate the correlation of pre-treatment circulating reproductive hormones levels with pathological and survival outcomes in breast cancer patients received neoadjuvant chemotherapy (NAC). Information from 196 premenopausal and 137 postmenopausal breast cancer patients who received NAC were retrospectively analyzed. Treatment response to NAC, with odds ratios (OR) and 95% confidence intervals (95% CI) was estimated using logistic regression adjusted for key confounders. Survival outcomes with hazard ratios (HR) and 95% CI were estimated using Cox regression adjusted for key confounders. The Kaplan-Meier method was applied in the survival analysis. Premenopausal patients with lower testosterone levels (OR = 0.996, 95% CI 0.992-0.999, P = 0.026), and postmenopausal patients with higher follicle-stimulating hormone (FSH) levels (OR = 1.045, 95% CI 1.014-1.077, P = 0.005) were likely to achieve pathological complete response (pCR). In multivariate survival analysis, the lowest tertile (T) progesterone was associated with worse overall survival (OS) in premenopausal patients (T2 vs T1, HR = 0.113, 95% CI 0.013-0.953, P = 0.045; T3 vs T1, HR = 0.109, 95% CI 0.013-0.916, P = 0.041). Premenopausal patients with the lowest tertile progesterone exhibited worse 3-year OS compared with those with higher tertiles (72.9% vs 97.4%, log-rank, P = 0.007). Pre-treatment testosterone and FSH are significant independent predictors for pCR to NAC in premenopausal and postmenopausal patients, respectively. Low progesterone levels are correlated with worse OS in premenopausal patients. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer.

Clinical Treatment Score post-5 years as a predictor of late distant recurrence in hormone receptor-positive breast cancer: systematic review and meta-analysis.

The Clinical Treatment Score post-5 years (CTS5) integrates four clinicopathological variables to estimate the residual disease recurrence risk in hormone receptor-positive breast cancer patients who have been treated with five years of adjuvant endocrine therapy. This study aimed to determine the accuracy of the CTS5. A systematic review was performed in accordance with the PRISMA statement. Studies relevant for inclusion in the current review were identified from The Cochrane Library, EBSCO, Ovid, PubMed, and Embase. Six papers reported on 30 354 postmenopausal patients (age range 42 to 91 years). The pooled hazard ratio (HR) of distant recurrence relative to the low-risk CTS5 category was 5.41 (95% c.i. 4.50 to 6.51; P < 0.05) for the high-risk CTS5 category and 2.32 (95% c.i. 1.90-2.84; P < 0.05) for the intermediate CTS5 category. Three papers reported on 10 425 premenopausal patients (age range 18 to 54 years). The pooled HR of distant recurrence relative to the low-risk CTS5 category was 5.42 (95% c.i. 2.26 to 13.01; P < 0.05) for the high-risk CTS5 category and 2.82 (95% c.i. 1.35 to 5.88; P < 0.05) for the intermediate CTS5 category. Relative to high-risk postmenopausal patients, the mean observed 10-year distant recurrence risk for the high CTS5 category was 13.83 per cent, which differs significantly from the CTS5 estimation of 10-year distant recurrence risk (20.3 per cent, 95% c.i. 17.2 to 24; P = 0.000). The CTS5 can predict late distant recurrence risk in pre- and postmenopausal hormone receptor-positive breast cancer patients. CTS5 overestimates the risk for high-risk patients and thus, its use in these patients warrants caution.

Abstract PD3-09: Cd73 may influence zoledronate-induced b- and t-cell accumulation into triple-negative breast tumors

Abstract Background: CD73 is an ecto-5′-nucleotidase, which converts AMP to adenosine. In breast cancer, CD73 expression is associated with prognosis, treatment responses to anthracyclines and tumor immunity. Bisphosphonates (BP) inhibit osteoclast-mediated bone resorption. When given in the adjuvant setting, BPs increase survival among post-menopausal breast cancer patients. Since BPs also affect cells of the immune system, we hypothesized that CD73 expression may affect BP responses in triple negative breast cancer cells. Methods: Cell viability and IC50 BPs doses were determined by WST-8 kit. Apoptotic rate and cell cycle arrest were showed by FACS. The number of caspase3/7- positive cells was accessed by a red fluorescence emission via IncuCyteS3. The apoptosis-associated genes mRNA expression was determined by qPCR. To compare BP effect on TNBC tumoral responses in vivo, we used immune-competent mouse models of breast cancer. Tumors were stained by immunofluorescence and immunohistochemically.Results: Suppression of CD73 expression, but not of enzymatic activity significantly sensitized TNBC cells to nitrogen-containing BPs (n-BPs), especially to zoledronate in vitro. The stronger growth inhibitory effects of n-BPs in CD73-suppressed cells were associated with G1 cell cycle arrest and increased apoptosis, as compared with representative control cells in vitro. Zoledronate similarly inhibited both control and CD73-suppressed TNBC tumor growthin immune-competent mice. CD73 suppression in tumors led to the lower lung metastatic burden and metastases size. Zoledronate effect on increased apoptosis was similar in both groups, but significant in CD73-suppressed tumors. Impaired angiogenesis was shown by decreased CD34-positive cell number in CD73-suppressed tumors. Zoledronate significantly increased infiltration of CD45R/B220+ B cells and cytotoxic CD8+ T cells into CD73-suppressed tumors.Conclusions: Suppressed CD73 sensitizes TNBC cells to n-BP treatment, resulting inapoptosis activation and delayed proliferation in vitro. Zoledronate induces a more profound accumulation of CD45R/B220+ B cells and CD8+ T cells into TNBC tumors with the lack of CD73. Since tumor B-cell infiltration has been associated with favourable patient prognosis in breast cancer, the significance of this B-cell effect of zoledronate warrants further investigation. Citation Format: Nataliia Petruk, Arafat Siddiqui, Jorma Määttä, Jouko Sandholm, Katri Selander. Cd73 may influence zoledronate-induced b- and t-cell accumulation into triple-negative breast tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-09.

Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients.

ContextCurrently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography–tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone.MethodsInternal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods.ResultsThe measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment.ConclusionWe present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.

MAP3K1 SNP rs889312 potential risk and MAP3K9 SNP rs11628333 menopause dependent association for breast cancer

Abstract Objectives Breast cancer is the leading cause of mortality in today’s world. An alarming rise in cancer incidence has been observed in the South Asian region. The aberrant molecular mechanisms regulating cell proliferation and development contribute to cancer development. A better understanding of the detailed molecular mechanisms at genetic and epigenetic levels can help to treat breast cancer more efficiently. The present study is aimed to identify the possible association of MAP3K1 SNP rs889312 and MAP3K9 rs11628333 in breast cancer in the South Asian region. Methods Female breast cancer patients were recruited in the study. DNA was isolated from the blood samples collected from the patients. PCR-RFLP was used for genotyping, and data analysis was done by SPSS software. Results Genotyping data for MAP3K1 SNPrs889312 showed statistically significant association with breast cancer, while MAP3K9 SNPrs11628333 showed characteristic association of rare allele heterozygote’s and homozygotes in pre and post-menopausal patients, respectively. Conclusions The study concludes a strong association of the rs889312 with breast cancer in the Pakistani population and a characteristic association of unique genotypes TC and CC in pre- and post-menopausal breast cancer patients. These findings can provide a ready tool as a breast cancer marker in south Asian populations.

Combination of Endogenous Estradiol and Adipokine Leptin in Breast Cancer Risk and Prognosis Assessment in Postmenopausal Chinese Women

ObjectiveOur study aims to clarify the role of estradiol and leptin in breast cancer risk and prognostic assessment in postmenopausal Chinese women.DesignThe serum circulating estradiol and leptin level was detected by ELISA. Then the correlation between estradiol, leptin level, and clinical characteristics was analyzed using Fisher’s exact test. Next, the Kaplan-Meier model was used to analyze the association between estradiol, leptin, and prognosis of postmenopausal breast cancer patients in our cohort and the TCGA dataset.SettingThe study was conducted at the National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College.PatientsA total of 182 postmenopausal breast cancer patients and 111 healthy subjects from January 2010 to August 2010 were included in the analysis. Another 702 cases with breast cancer were retrieved from The Cancer Genome Atlas (TCGA) database for subsequent analysis.Main Outcome MeasureSerum circulating estradiol and leptin level.ResultsThe level of estradiol was significantly higher (P<0.001) but the level of leptin had no significant difference (P = 0.764) in postmenopausal breast cancer patients compared with healthy subjects. The level of estradiol and leptin was not significantly different between estrogen receptor (ER) positive and ER-negative groups (P>0.05). Estradiol was significantly correlated with tumor T stage (P = 0.002) and leptin was significantly associated with perineural invasion (P = 0.014). In addition, the disease-free survival of patients with a high level of estradiol was significantly shorter (P = 0.025) but leptin tended to be a protective factor for overall survival in TCGA analysis (P = 0.038).ConclusionCirculating estradiol and leptin played important roles in the risk of postmenopausal breast cancer even in low-estrogen nations with an independent expression of ER status. High circulating estradiol was a poor prognostic factor and leptin may be a protection signal in Chinese postmenopausal patients with breast cancer.