The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial

This is a protocol article on the MELODY trial. The objective of this double-blind randomized, placebo-controlled trial is to investigate whether daily treatment with 6 mg oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore to examine whether a specific clock-gene PER3 is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction

Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

Background: The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. Methods: Serum HER-2 was measured in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using the Bayer ADVIA Centaur assay. Tissue HER-2 was determined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC +3 or IHC +2 and FISH>2.0 were positive. Patients were considered to have positive serum HER-2 when at least two values were >15 ng/mL. Recurrence, progression and regression were diagnosed according to usual clinical practice. Serum HER-2 concentrations did not contribute to diagnostic decision-making or selection of treatment. Results: From January 2004 to January 2009, 149 patients were found to have positive serum HER-2. Of these, 35 were tissue HER-2 positive at surgery, 69 tissue-negative and 45 were not determined. Fifty-five of 149 that were serum HER-2 positive (37%, 95% CI: 29–45) had metastases. Among the 35 tissue-positive patients, 25 had recurrence in the form of metastases and there was good correlation between recurrence/progression and increase in serum HER-2 (p<0.0003). There was also a high correlation between effect of treatment and decline in serum HER-2 (p<0.0003). Of the 69 tissue-negative patients, 29 had recurrence in the form of metastases, and there was good correlation with serum HER-2 levels (p<0.000004). In this routine application of serum HER-2, the PPV for metastases recurrence detection in both tissue-positive and tissue-negative was 54 of 104 (52%, 95% CI: 42%–62%), in tissue-positive 25 of 35 (71%, 95% CI: 54%–85%), in tissue-negative 29 of 69 (42%, 95% CI: 30%–54%). The lead time of increases in serum HER-2 before recurrence could be determined in ten tissue-positive patients was 3–24 months (mean 11.3 months), when compared to standard clinical imaging methods. Conclusions: Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2 positive patients. Clin Chem Lab Med 2009;47:1117–23.Peer Reviewe

HER1-4 protein concentrations in normal breast tissue from breast cancer patients are expressed by the same profile as in the malignant tissue

Background: The epidermal growth factor receptor HER2 is overexpressed or amplified in 25%–30% of patients with breast cancer. The mechanism behind HER2 amplification is unknown, but may be a patho-physiological phenomenon caused by continuous stimulation and activation of the HER1-4 system. We have mapped the protein concentrations of HER1-4 in breast cancer tissue, autologous reference tissue, normal breast tissue and serum samples, to see whether non-cancer cells from these patients express a protein profile indicating general activation. Methods: Tissue samples from malignant and adjacent normal breast tissue (autologous reference tissue) were collected from 118 women consecutively admitted for surgical treatment of breast cancer. In addition, 26 samples of normal breast tissue were collected from healthy women having breast reduction surgery. The tissue samples were homogenized and the proteins extracted. The tissue and serum concentrations of HER1-4 were determined quantitatively using a commercially available enzyme linked immunosorbent assay (ELISA) method. Results: HER1 was down regulated in cancer tissue when compared to autologous reference tissue (p=8×10−6), while HER2 (p<10−7) and HER3 (p=3×10−5) were up regulated. Comparing autologous reference tissue with normal tissue showed down regulation of HER1 (p=0.122) and up regulation of HER2 (p=10−6), HER3 (p<10−7) and HER4 (p<10−7). Furthermore, we observed that correlations between the receptor combinations HER1-2, HER1-3 and HER1-4 were maintained from normal breast tissue to autologous reference breast tissue, but were lost in cancer tissue. Conclusions: We suggest that these findings indicate that breast cancer is a systemic disease where the HER1-4 system in autologous reference tissue is continuously activated, thus favoring the subsequent development of cancer. Clin Chem Lab Med 2009;47:977–84.Peer Reviewe

Effect of Melatonin on Sleep in the Perioperative Period after Breast Cancer Surgery:A Randomized, Double-Blind, Placebo-Controlled Trial

STUDY OBJECTIVES: To investigate whether administration of an oral dose of 6 mg melatonin before bedtime perioperatively in breast cancer surgery could change sleep outcomes measured by actigraphy. METHODS: This paper reports secondary outcomes from a double-blind, placebo-controlled, randomized clinical trial where patients received 6 mg melatonin (n = 27) or placebo (n = 21) approximately 60 minutes before bedtime 3 nights preoperatively until at least one week postoperatively. Participants were monitored in the entire period with actigraphy, and were instructed to complete visual analogue scale (VAS) for sleep, and the Karolinska Sleepiness Scale (KSS) each morning. RESULTS: Administration of 6 mg oral melatonin approximately 1 hour before bedtime resulted in significantly increased sleep efficiency and reduced wake after sleep onset for the entire 2-week postoperative period. No other significant differences for actigraphy determined sleep outcomes or subjective outcome parameters in the perioperative period were found between the groups. Overall, the patients sleep outcomes were within normal ranges and no participants had pathological sleep disturbances. CONCLUSIONS: Melatonin significantly changed sleep efficiency and wake after sleep onset after surgery, but had no effects on other objective sleep outcomes or on subjective sleep quality (VAS and KSS). CLINICAL TRIAL REGISTRATION: The trial was registered on www.clinicaltrials.gov (NCT01355523) before inclusion of the first patient. CITATION: Madsen MT, Hansen MV, Andersen LT, Hageman I, Rasmussen LS, Bokmand S, Rosenberg J, Gögenur I. Effect of melatonin on sleep in the perioperative period after breast cancer surgery: a randomized, double-blind, placebo-controlled trial. J Clin Sleep Med 2016;12(2):225–233

Effect of Melatonin on Cognitive Function and Sleep in relation to Breast Cancer Surgery:A Randomized, Double-Blind, Placebo-Controlled Trial

Background. Sleep disturbances and cognitive dysfunction are common in patients with breast cancer. Disturbed sleep leads to poor cognitive performance and exogenous melatonin may improve sleep and attenuate cognitive dysfunction. We hypothesized that melatonin would improve sleep and cognitive function after surgery. Methods. This study reports secondary endpoints from a randomized, double-blind, placebo-controlled trial. Women, 30–75 years, were randomized to 6mg oral melatonin/placebo for 3 months. We assessed postoperative cognitive dysfunction (POCD) with a neuropsychological test battery, sleep with a diary, and sleep quality with VAS. Results. 54 patients were randomized to melatonin (n=28) or placebo (n=26); 11 withdrew (10 placebo, 1 melatonin, P=0.002). The incidence of POCD was 0% (0/20) [95% CI 0.0%; 16.8%] in the placebo group and 0% (0/26) [95% CI 0.0%; 13.2%] in the melatonin group 2 weeks postoperatively (P=1.00) and 6.3% (1/16) [95% CI 0.0%; 30.2%] in the placebo group and 0% (0/26) [95% CI 0.0%; 13.2%] in the melatonin group 12 weeks postoperatively (P=0.38). Sleep efficiency was significantly greater in the melatonin group; mean difference was 4.28% [95% CI 0.57; 7.82] (P=0.02). The total sleep period was significantly longer in the melatonin group; mean difference was 37.0 min [95% CI 3.6; 69.7] (P=0.03). Conclusion. Melatonin increased sleep efficiency and total sleep time but did not affect cognitive function. The dropout rate was significantly lower in the melatonin group. This trial is registered with Clinicaltrials.gov NCT01355523

Male breast cancer: a nation-wide population-based comparison with female breast cancer

<p><b>Objective:</b> Describe prognostic parameters of Danish male breast cancer patients (MBCP) diagnosed from 1980–2009. Determine all-cause mortality compared to the general male population and analyze survival/mortality compared with Danish female breast cancer patients (FBCP) in the same period.</p> <p><b>Material and methods:</b> The MBCP cohort was defined from three national registers. Data was extracted from medical journals. Data for FBCP is from the DBCG database. Overall survival (OS) was quantified by Kaplan–Meier estimates. Standardized mortality ratios (SMRs) were calculated based on mortality rate among patients relative to the mortality rate in the general population. The association between SMR and risk factors were analyzed in univariate and multivariable Poisson regression models. Separate models for each gender were used for the analyses.</p> <p><b>Results:</b> We found a marked difference in OS for the two genders. For the total population of MBCP, 5- and 10-year survivals were 55.1% and 31.7%, respectively. For FBCP, the corresponding figures were 76.8% and 59.3%. Median age at diagnosis for FBCP was 61 years and 70 years for MBCP. By applying SMR, the difference in mortality between genders equalized and showed pronounced age-dependency. For males <40 years, SMR was 9.43 and for females 19.56 compared to SMR for males 80 + years (0.95) and females 80 + years (0.89). During the period 1980–2009, the risk of dying gradually decreased for FBCP (<i>p</i> < .0001). The risk 1980–1984 was 35% higher than 2005–2009 (RR 1.35). Although the risk of dying for MBCP was also lowest in 2005–2009, there was no clear tendency (<i>p</i> = .1439). The risk was highest in 1990–1994 (RR =2.48).</p> <p><b>Conclusion:</b> We found better OS for FBCP than for MBCP. But SMR showed similar mortality rate for the two genders, except for very young FBCP, who had higher SMR. Furthermore, significantly improved survival over time for FBCP was observed, with no clear tendency for MBCP.</p

Male breast cancer: a nation-wide population-based comparison with female breast cancer

Objective: Describe prognostic parameters of Danish male breast cancer patients (MBCP) diagnosed from 1980–2009. Determine all-cause mortality compared to the general male population and analyze survival/mortality compared with Danish female breast cancer patients (FBCP) in the same period. Material and methods: The MBCP cohort was defined from three national registers. Data was extracted from medical journals. Data for FBCP is from the DBCG database. Overall survival (OS) was quantified by Kaplan–Meier estimates. Standardized mortality ratios (SMRs) were calculated based on mortality rate among patients relative to the mortality rate in the general population. The association between SMR and risk factors were analyzed in univariate and multivariable Poisson regression models. Separate models for each gender were used for the analyses. Results: We found a marked difference in OS for the two genders. For the total population of MBCP, 5- and 10-year survivals were 55.1% and 31.7%, respectively. For FBCP, the corresponding figures were 76.8% and 59.3%. Median age at diagnosis for FBCP was 61 years and 70 years for MBCP. By applying SMR, the difference in mortality between genders equalized and showed pronounced age-dependency. For male