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The purpose of this investigation was to determine the effects of moderate intensity exercise training during peripuberty on nitrosomethylurea (NMU) induced mammary tumorigenesis and to assess the effects of this activity on mammary epithelial cell proliferation and mammary gland development in rats. Female Sprague Dawley rats were divided into two groups, sedentary and exercised. The rats were exercised five times per week from 21 to 50 days of age on a progressive treadmill training program with a final workload of 18 m/min at 15% incline for 60 min a day. At fifty days of age eight rats from each group were sacrificed to determine the effects of exercise on mammary gland labelling index and development scores. The remaining animals were given NMU at a concentration of 50 mg/kg body weight. The experiment was terminated 24 weeks post carcinogen administration, and cancer incidence, multiplicity, and latency were analyzed. The total tumor number per group was reduced by exercise (58 vs. 33 carcinomas p < 0.05). This corresponded to a significantly higher number of tumors/animal in the sedentary rats compared to those that were exercised prior to NMU administration. However latency period (124.9 ± 4.3 vs. 125.2 ± 6.4) and final incidence (68.9% vs. 61.5%) were not significantly different in sedentary vs. exercised rats. There were no significant differences in mammary gland developmental scores (4.1 ± 0.24 vs. 4.4 ± 0.26) or labelling index of mammary epithelial cells in either ducts or lobuloalveolar units (ductal 41.5 ± 4.7 vs. 39.4 ± 5.7; lobuloalveolar 38.5 ± 4.1 vs. 47.7 ± 5.7) between the two groups. The results of this study suggest that although exercise prior to carcinogen administration has an effect on mammary tumorigenesis, these effects do not appear to be related to exercise-induced changes in mammary gland development.

Information regarding the use of mammography by breast cancer survivors is limited. This study aimed at evaluating the compliance to surveillance mammography and/or clinical breast examination and the associated factors among patients living in northern Italy. A cancer registry-based cohort of 1304 patients living in the Health Care District of Forlì was followed up for 10 years. Eighty percent of patients had a mammogram and/or clinical breast examination during the first year after treatment. The proportion decreased to 67 % at 10 years of follow-up. Three demographic characteristics were independently associated with lower odds of having an annual mammogram and/or clinical breast examination: age at diagnosis [odds ratio (OR) 0.51, 95 % confidence interval (CI) 0.41–0.63 for patients aged 65–74 years; and OR 0.14, 95 % CI 0.11–0.18, for patients ≥75 years versus patients aged <64 year]; socio-economic status (OR 0.81, 95 % CI 0.65–1.00, for deprived patients versus patients of the reference class); and hospital travel time greater than 30 min (OR 0.44, 95 % CI 0.29–0.68 versus ≤15 min). With respect to clinical and disease characteristics, lower odds were observed for patients treated with mastectomy (OR 0.79, 95 % CI 0.65–0.97), for patients diagnosed with in situ breast cancer (OR 0.68, 95 % CI 0.46–0.99) as well as with stage II + breast cancer (OR 0.77, 95 % CI 0.63–0.94), and for patients with ≥3 Elixhauser comorbidities (OR 0.43, 95 % CI 0.26–0.71). Adherence to follow-up declined over time. Knowledge of associated factors may assist in improving access to care for breast cancer survivors.

To investigate the association between gut microbiome with breast tumor characteristics (receptor status, stage and grade) and known breast cancer risk factors. In a pilot cross-sectional study of 37 incident breast cancer patients, fecal samples collected prior to chemotherapy were analyzed by 16S ribosomal RNA (rRNA) gene-based sequencing protocol. Alpha diversity and specific taxa by tumor characteristics and breast cancer risk factors were tested by Wilcoxon rank sum test, and by differential abundance analysis, using a zero-inflated negative binomial regression model with adjustment for total counts, age and race/ethnicity. There were no significant alpha diversity or phyla differences by estrogen/progesterone receptor status, tumor grade, stage, parity and body mass index. However, women with human epidermal growth factor receptor 2 positive (HER2+) (n = 12) compared to HER2− (n = 25) breast cancer showed 12–23% lower alpha diversity [number of species (OTU) p = 0.033, Shannon index p = 0.034], lower abundance of Firmicutes (p = 0.005) and higher abundance of Bacteroidetes (p = 0.089). Early menarche (ages ≤ 11) (n = 11) compared with later menarche (ages ≥ 12) (n = 26) was associated with lower OTU (p = 0.036), Chao1 index (p = 0.020) and lower abundance of Firmicutes (p = 0.048). High total body fat (TBF) (> 46%) (n = 12) compared to lower (≤ 46%) TBF was also associated with lower Chao 1 index (p = 0.011). There were other significant taxa abundance differences by HER2 status, menarche age, as well as other tumor and breast cancer risk factors. Further studies are needed to identify characteristics of the human microbiome and the interrelationships between breast cancer hormone receptor status and established breast cancer risk factors.

Nền tảng: Bằng chứng gần đây cho thấy việc phát hiện bằng máy tính (CAD) có thể có tác động tiêu cực đến việc giải thích mammography - điều này đòi hỏi phải đánh giá kịp thời về CAD trong thực hành. Chúng tôi báo cáo một nghiên cứu hồi cứu về tác động gia tăng của CAD đối với độ chính xác của mammography kỹ thuật số toàn cảnh (DM) khi được áp dụng một cách tiềm năng trong đánh giá vú. Phương pháp: Đối tượng là tất cả những phụ nữ liên tiếp đến một trung tâm vú tự giới thiệu tại Florence giữa tháng 9 năm 2005 và tháng 1 năm 2007 (N = 3.425). DM được báo cáo không có và sau đó có CAD theo một giao thức tiêu chuẩn; tất cả mammogram được yêu cầu lại dựa trên đọc của bác sĩ chẩn đoán hình ảnh hoặc đọc của bác sĩ chẩn đoán hình ảnh sau khi xem CAD đều được triệu tập để đánh giá. Kết quả: Tỷ lệ yêu cầu lại tổng thể (RR) là 13,1% và 107 ca ung thư đã được chẩn đoán (90 ung thư xâm lấn, 8 DCIS, 9 ác tính trên tế bào học). Việc sử dụng CAD cho phép phát hiện thêm 5 ca ung thư (ba ung thư xâm lấn, một DCIS, một ác tính trên tế bào học) và gây ra một sinh thiết phẫu thuật lành tính bổ sung, với RR tương đối là 4,9% và RR gia tăng là 1,17%. Tỷ lệ phát hiện ung thư (CDR) của DM được giải thích với việc sử dụng CAD là 3,12% và không khác biệt đáng kể so với CDR 2,9% dựa trên DM mà không có CAD (χ2 = 3,2, P = 0,07). Kết luận: Trong khi sự gia tăng CDR với việc sử dụng CAD chỉ gần đạt ý nghĩa thống kê, thể hiện những lợi ích khiêm tốn về mặt tuyệt đối, số lượng ung thư gia tăng được phát hiện biện minh cho tỷ lệ yêu cầu lại gia tăng và sinh thiết phẫu thuật lành tính do việc sử dụng CAD gây ra. Trong bối cảnh lâm sàng của chúng tôi, những dữ liệu này gợi ý rằng lợi ích nhiều hơn là có hại khi sử dụng CAD kết hợp với DM, và chúng tôi sẽ tiếp tục sử dụng CAD với việc theo dõi liên tục các kết quả của bệnh nhân.

There are few studies of model-based survival projections using early empirical results for estimating long-term survival. Utilizing Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) data, a Markov model was generated to compare empirical results with those modeled beyond the empirical result time horizon in estrogen receptor (ER)-positive early-stage breast cancer (ESBC). Modeling 15-year survival based on 5- and 10-year EBCTCG data resulted in an average error estimate in breast cancer mortality of 0.75% [range −0.83 to 2.19%]. Although modeling life expectancy differences ranged from an underestimate of −7.93% to an overestimate of 12.64%, over the span of 15 years this corresponded to a loss of 18 days or a gain of 40 days of life. Reliable early survival data may be used to generate models that accurately estimate 15-year survival in ER-positive ESBC. Whether early survival data can be employed over the lifetime horizon remains to be demonstrated.

GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835 .

KX-01 is the first clinical Src inhibitor of the novel peptidomimetic class that targets the peptide substrate site of Src providing more specificity toward Src kinase. The present study was designed to evaluate the effects of KX-01 as a single agent and in combination with tamoxifen (TAM) on cell growth and apoptosis of ERα positive breast cancer in vitro and in vivo. Flow cytometry demonstrated that KX-01 induced cell cycle arrest in G2/M phase. Immunofluorescent staining for mitotic phase markers and TUNEL staining indicated that cells had arrested in the mitotic phase and mitotic arrested cells were undergoing apoptosis. KX-01 induced nuclear accumulation of cyclin B1, and activation of CDK1, MPM2, and Cdc25C that is required for progression past the G2/M checkpoint. Apoptosis resulted from activation of caspases 6, 7, 8, and 9. Combinational index analysis revealed that combinations of KX-01 with TAM resulted in synergistic growth inhibition of breast cancer cell lines. KX-01 combined with TAM resulted in decreased ERα phosphorylation at Src-regulated phosphorylation sites serines 118 and 167 that were associated with reduced ERα transcriptional activity. Orally administered KX-01 resulted in a dose dependent growth inhibition of MCF-7 tumor xenografts, and in combination with TAM exhibited synergistic growth inhibition. Immunohistochemical analysis revealed that combinational treatment reduced angiogenesis, and ERα signaling in tumors compared to either drug alone that may underlie the synergistic tumor growth inhibition. Combinations of KX-01 with endocrine therapy present a promising new strategy for clinical management of ERα positive breast cancer.