A Phase II randomized study of perioperative beta-blocker vs placebo on gene expression in newly diagnosed breast cancer

INTERVENTION: Arm 1:Propranolol Trade/Product/Code Name Deralin (Unregistered Trademark) Dosage form Tablet Presentation 40 mg tablet (red, film coated, marked PP/40, G on reverse) Route of administration Oral Formulation Propranolol hydrochloride Participants in the study will be given 7 days of pre‐operative Propranolol (or placebo equivalent) prior to and including the day of surgery and then will be titrated off Propranolol over two days in the postoperative period. Day AM dose PM dose ‐7 40mg 40mg ‐6 40mg 40mg ‐5 40mg 40mg ‐4* 80mg 80mg ‐3 80mg 80mg ‐2 80mg 80mg ‐1 80mg 80mg 0 80mg 40mg +1 40mg 40mg +2 40mg 40mg (0 = Day of surgery) Arm 2: Matched Placebo Compliance: Assessed through i) Second daily phone calls ii) Assessed pill return iii) Pill diary (for participants to self administer) iv) Quantification of propranolol dosing on day of surgery CONDITION: Breast cancer PRIMARY OUTCOME: Primary tumour gene expression (quantitative level: i.e. mRNA concentration within the cell sample) for each of 20,000 genes at baseline and at surgical resection. ; SECONDARY OUTCOME: Beck Anxiety Inventory at baseline and on the day of surgery ; ; Rather than a composite outcome, the Beck Anxiety Inventory is a questionnaire that provides a validated level of 'anxiety' through a scored questionnaire: 21 questions, each scored with 0, 1, 2 or 3 points. The scores within a patient at a particular time are summed, to be a total score ranging from 0 to 63. A score of 0‐7 indicates minimal, 8‐15 mild, 16‐25 moderate and 26‐63 severe anxiety. ANOVA will be used to assess whether there are differences in Beck Anxiety Inventory between groups, with p‐values reported. ; ; ; Inflammation‐relevant cytokines (IL‐1beta, IL‐2, IL‐6, IL‐10, IFN‐gamma, TNFalpha) and gene expression of cytokines at baseline and at surgery. ; ; Assessment: ; An interleukin arrays kit (multiplex ELISA) will be used to measure the stated plasma interleukins to compare baseline and day of surgery blood samples. Leukocyte gene expression (specifically conserved transcriptional response to adversity profile) at baseline and at surgery. ; ; Assessment: ; Total RNA will be extracted from the whole blood samples and then subjected to quality assurance assays to test suitable mass (by spectroscopy) and integrity (by Agilent Bioanalyzer RNA Integrity Score) for analysis, and subjected to microarray target synthesis and hybridization. This will be done in collaboration with the UCLA Neuroscience Genomics Core Laboratory using standard Illumina assay equipment and protocols. ; ; To assess the effect of beta blockade on: ; * Bradycardia (Heart Rate < 50bpm) ; ; This will be assessed using the patient's home blood pressure/heart rate monitoring device supplied to the patient. While in hospital, this will be measured using the hospital's pulse oximeter. To assess the effect of beta blockade on: ; * Perioperative labile blood pressure (Perceived by treating anaesthetist). To assess the effect of beta blockade on: ; * Symptoms of bronchial hyper‐reactivity. Specifically the report of wheezing, dry cough or sensation of shortness of breath. To assess the effect of beta blockade on: ; * Hypotension (Systolic blood pressure < 100mmHg) ; ; Assessment: ; INCLUSION CRITERIA: ‐ Written, informed consent; ‐ Female subjects with histologically‐confirmed breast cancer, who will undergo surgical excision at PMCC at least 7 days after enrollment; ‐ Age 18‐80 years old; ‐ World Health Organization ECOG performance status 0 or 1; ; Sphygmomanometer either at PMCC or a home blood pressure/heart rate monitoring device. Tumour markers of inflammation at baseline and at time of surgery: CD68, CD163 (M2) macrophage markers, neutrophil elastase, T cell markers (CD3, CD4, CD8), CD31 and VEGF angiogenesis markers, and D2‐40 lymphangiogenesis marker.