Pubertal high fat diet: effects on mammary cancer development

INTRODUCTION: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD. METHODS: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. RESULTS: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages. CONCLUSIONS: Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD

Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer

Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in cfDNA during neoadjuvant chemotherapy

Abstract S6-03: DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer

Abstract Background: DBCG 07-READ was designed to compare sequential EC followed by D with DC in patients with early, TOP2A normal breast cancer as a retrospective evaluation of the DBCG 89D trial suggested that these patients would not benefit from an anthracycline. Methods: This is a multicenter open-label randomized phase III trial. Three groups of women were eligible following completely resected unilateral invasive TOP2A normal (TOP2A gene to centromere 17 ratio of 0.8 to 2.0) breast cancer by mastectomy or breast conserving surgery in combination with axillary clearance or a negative sentinel node biopsy; 1: Age 18 to 39 years; 2: Age 40 to 75 years and estrogen receptor (ER) negative (&amp;lt;10% positive) and/or HER2 positive tumor; and 3: Age 40 to 59 years and ER ≥ 10% positive and either node positive, ductal carcinoma and grade II-III, or tumor size &amp;gt; 20 mm. Eligible patients were required to have a Charlson Comorbidity (CC) Index &amp;lt; 2 and to be without signs of distant metastasis. Patients were randomized to receive 6 cycles of DC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks or 3 cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) followed by 3 cycles of D (docetaxel 100 mg/m2) every 3 weeks. In case of a CC Index of 1 or 2 chemotherapy was administered at a reduced dose-intensity. Adjuvant endocrine treatment, trastuzumab and radiotherapy were administered according to the guidelines of the DBCG. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS) and distant disease-free survival (DDFS). Results: Between July 2008 and December 2012 we (12 DBCG centers) randomly assigned 2006 eligible patients to DC (N=1008) or EC-D (N=998). Patient and tumor characteristics were balanced by treatment groups. The median estimated potential follow-up is 5.4 years and the 5-year DFS was 88.0%; 95% CI 85.8 to 90.0 in the EC-D arm and 87.9%; 95% CI 85.7 to 89.9 in the DC arm. No significant difference in the risk of DFS events HR=1.03; 95% CI 0.80 to 1.32; p=0.84 or mortality HR=1.11; 95% 0.79 to 1.56; p=0.55 was observed in the intent to treat analysis. Patient-reported toxicity will be compared for the two chemotherapy regimens. Conclusion: The READ trial gives evidence to support no outcome benefit from anthracycline in patients with TOP2A normal ealy breast cancer. Citation Format: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-03.</jats:p

Primary prevention of cardiotoxicity in cancer patients treated with fluoropyrimidines: a randomized controlled trial

Abstract Background Fluoropyrimidines (FP) are the third most used chemotherapeutic drugs administered in solid tumors but have cardiotoxic side effects. We aimed to determine whether pre-chemotherapeutic cardiological assessment and management of cardiovascular risk factors could prevent FP-induced cardiotoxicity and if the coronary artery calcium (CAC) score was predictive of chest pain. Methods This was a randomized, controlled, single center trial of patients with various cancer types who were treated with FP and had no known ischemic heart disease. All patients had CAC score obtained by cardiac CT scan. Patients were randomized to pre-chemotherapeutic cardiological management or standard care. Cardiological management included risk reduction based on electro- and echocardiographic evaluation and blood samples. Primary composite endpoint included hospital admission for chest pain, acute coronary syndrome, coronary angiography intervention, or all-cause mortality. Secondary outcome was chest pain. Follow-up was 6 months. Data were analyzed using Kaplan–Meier survival function with log-rank test and ROC-analyses. Results Of the 192 patients included, the primary endpoint occurred in 9/95 (9.5%) patients in the intervention group and 15/97 (15.5%) patients in the control group (log-rank p = 0.19) with an incidence rate ratio (IRR) of 0.57 (95% CI [0.22 – 1.39]). Chest pain occurred in 6/95 (6.3%) patients in the intervention group and 13/97 (13.4%) in the control group, yielding an IRR of 0.44 (95% CI [0.14 – 1.23]). CAC score did not predict chest pain occurrence. Conclusions Cardiological management of cardiovascular risk factors prior to treatment with fluoropyrimidines resulted in half as many cardiotoxic events but the study did not reach statistical significance. Further studies are needed to investigate the optimal strategies to prevent fluoropyrimidine-induced cardiotoxicity in cancer patients. Trial registration ClinicalTrials.gov Identifyer NCT03486340