Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review.

BACKGROUND AND AIM: The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations. METHODS: Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review. RESULTS: Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

Rest-activity rhythm in breast cancer survivors: an update based on non-parametric indices.

Recently we evaluated by actigraphy the rest-activity circadian rhythm (RAR) in breast cancer (BC) survivors at 5 years from primary diagnosis, as well as in a control group with similar age and body mass index (BMI). RAR, analyzed by Cosinor method, resulted significantly different in BC survivors compared to healthy subjects: BC survivors showed lower values of MESOR and Amplitude (A), while acrophase (φ) was similar in the two groups. Now, using non-parametric methods we have detected Interdaily Stability (IS), Intradaily Variability (IV), nocturnal activity (L5), and daily activity (M10) on the same sample of previous study: 15 BC survivors at 5 years from the primary diagnosis (mean age = 56.7 ± 6.6 yrs; mean BMI = 24.5 ± 3.8 Kg/m2) and 13 healthy controls (mean age = 54.4 ± 7.2 yrs; mean BMI = 25.2 ± 2.8 Kg/m2). The non-parametric indices showed that in BC-group IV was significantly higher than in Ctrl-group (0.86 vs. 0.65 a.u. in BC and Ctrl, respectively; p <.01), while L5 (11.27 vs. 34.41 a.c. in BC and Ctrl, respectively; p <.0001) and M10 (326.82 vs. 428.07 a.c. in BC and Ctrl, respectively; p <.01) were significantly lower compared to Ctrl-group. The data suggest that BC patients need constant clinical assessment of RAR characteristics along the years following the primary diagnosis. The analysis of RAR in all its components, parametric and non-parametric, is important to detect alterations in the sleep-wake cycle and can be useful for developing new strategies for health protection, such as structured and tailored physical activity programs, to improve circadian activity level in order to raise the quality of life in BC survivors.

Effect of aerobic exercise intervention on markers of insulin resistance in breast cancer women.

Insulin may affect breast cancer (BC) risk and prognosis. Exercise reduces insulin in obese BC survivors. We designed a randomised controlled trial to test the effect of an aerobic exercise intervention (AEI) on insulin parameters and body composition in non-obese BC women without insulin resistance. Thirty-eight BC women were randomised into an intervention group (IG = 18) or control group (CG = 20). IG participated in a structured AEI for 3 months, while CG received only the Word Cancer Research Fund/American Institute Cancer Research (WCRF/AICR) recommendation to be physically active. Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, metabolic parameters and body composition were collected at baseline and after the AEI. IG reduced insulin and HOMA-IR index by 15% and 14%, while CG increased these parameters (+12% and +16%). Insulin changed differently over time in the two randomised groups (pinteraction  = .04). The between-group differences in the change of insulin (IG = -1.2 µU/ml versus CG = +0.8 µU/ml) and HOMA-IR index (IG = -0.26 versus CG = +0.25) were respectively significant (p = .04) and non-significant (p = .06). IG significantly improved lower limb muscle mass in comparison with CG (p = .03). A structured AEI may improve insulin, HOMA-IR index and body composition in non-obese BC survivors without insulin resistance.

Rest-activity circadian rhythm and sleep quality in patients with binge eating disorder.

Recent findings suggest that altered rest-activity circadian rhythms (RARs) are associated with a compromised health status. RARs abnormalities have been observed also in several pathological conditions, such as cardiovascular, neurological, and cancer diseases. Binge eating disorder (BED) is the most common eating disorder, with a prevalence of 3.5% in women and 2% in men. BED and its associate obesity and motor inactivity could induce RARs disruption and have negative consequences on health-related quality of life. However, the circadian RARs and sleep behavior in patients with BED has been so far assessed only by questionnaires. Therefore, the purpose of this study was to determine RARs and sleep parameters by actigraphy in patients with BED compared to a body mass index-matched control group (Ctrl). Sixteen participants (eight obese women with and eight obese women without BED diagnosis) were recruited to undergo 5-day monitoring period by actigraphy (MotionWatch 8®, CamNtech, Cambridge, UK) to evaluate RARs and sleep parameters. In order to determine the RARs, the actigraphic data were analyzed using the single cosinor method. The rhythmometric parameters of activity levels (MESOR, amplitude and acrophase) were then processed with the population mean cosinor. The Actiwatch Sleep Analysis Software (Cambridge Neurotecnology, Cambridge, UK) evaluated the sleep patterns. In each participant, we considered seven sleep parameters (sleep onset: S-on; sleep offset: S-off; sleep duration: SD; sleep latency: SL; movement and fragmentation index: MFI; immobility time: IT; sleep efficiency: SE) calculated over a period of five nights. The population mean cosinor applied to BED and Ctrl revealed the presence of a significant circadian rhythm in both groups (p < 0.001). The MESOR (170.0 vs 301.6 a.c., in BED and Ctrl, respectively; p < 0.01) and amplitude (157.66 vs 238.19 a.c., in BED and Ctrl, respectively p < 0.05) differed significantly between the two groups. Acrophase was not different between BED and Ctrl, as well as all sleep parameters. Both groups displayed a low level of sleep quality (SE 80.7% and 75.7% in BED and Ctrl, respectively). These data provided the first actigraphy-based evidence of RARs disruption and sleep behavior disorder in patients with BED. However, while sleep disorders could be reasonably ascribed to overweight/obesity and the related lower daily physical activity, RARs disruption in this pathology should be ascribed to factors other than reduced physical activity. The circadian timing approach can represent a novel potential tool in the treatment of patients with eating disorders. These data provide exploratory evidence of behavioral association in a small population of patients that, if confirmed in a wider number of subjects and across different populations, may lead to a revision and enhancement of interventions in BED patients.

A randomized controlled trial of diet and physical activity in BRCA mutation carriers.

High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). Furthermore, insulin and markers of insulin resistance, such as abdominal obesity, high blood glucose, high serum testosterone and metabolic syndrome, may affect both BC incidence and prognosis. We hypothesized that all these factors might be relevant also for hereditary BC, due to a deleterious mutation of BRCA genes. Epidemiological observation suggested that weight, energy intake (usually associated with higher bio-availability of growth factors) and physical activity may be relevant in BRCA mutation carriers. Mechanistic studies hypothesized a functional interaction between BRCA genes and the IGF-I system. We have provided some evidence that high serum levels of IGF-I are associated with a significantly increased penetrance. We are recruiting a larger cohort of BRCA mutation carriers in order to test potential modulators of penetrance and prognosis. Within this cohort, we have planned a randomized controlled trial to test whether moderate calorie and protein restriction, together with physical activity, decrease IGF-I. Eligible study subjects are women with or without BC, aged 18-70, with a proven deleterious BRCA mutation, and without metastases. All the women will receive recommendations for the dietary prevention of cancer. The women will be then randomized into an active life-style intervention group and into a control group that will receive only the baseline recommendations. We expect to significantly reduce IGF-I in the intervention group. This trial and the subsequent cohort follow-up might open up primary prevention options for genetic BC.

Postmenopausal breast cancer, androgens, and aromatase inhibitors.

Recent data can help to better define the long debated relationship between androgens and breast cancer (BC) after menopause. We reviewed the available literature data on: the origin of androgens after menopause, the association between circulating androgens and BC incidence and recurrence, the relationship between circulating and intratumoral hormones, the prognostic significance of the presence of androgen receptors (ARs) in the different BC subtypes, the androgen effect on BC cell lines, and the relationship between androgens and aromatase inhibitors. Epidemiological, clinical, and preclinical data on the role of androgens and of ARs on estrogen receptor (ER)-negative BC are somewhat controversial. However, most preclinical studies suggest that activated ARs, when present, have a proliferative effect, particularly in HER2 expressing cell lines, due to the cross-talk between AR and HER2 pathways. As regards ER-positive BC, epidemiological studies associate androgen levels with increased incidence and risk of recurrences, whilst clinical studies associate the AR positivity with a better prognosis. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also anti-proliferative, because AR activation restrains ER activity. The relative increase of androgenic action that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs), could contribute to their therapeutic efficacy in AR-positive cases. Available data, although defining a complex picture, suggest that circulating androgen levels are clinically relevant, particularly when AIs are used.

Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects.

Understanding the complexity of cancer and of the underlying regulatory networks provides a new paradigm that tackles cancer development and treatment through a system biology approach, contemporarily acting on various intersecting pathways. Cancer cell metabolism is an old pathogenetic issue that has recently gained new interest as target for therapeutic approaches. More than 70 years ago, Warburg discovered that malignant cells generally have altered metabolism with high rates of glucose uptake and increased glycolysis, even under aerobic condition. Observational studies have provided evidence that impaired metabolism, obesity, hyperglycemia and hyperinsulinemia may have a role in cancer development, progression and prognosis, and actually diabetic and obese patients have increased cancer risk. On the other hand, caloric restriction has been shown to prolong life span and reduce cancer incidence in several animal models, having an impact on different metabolic pathways. Metformin, an antidiabetic drug widely used for over 40 years, mimics caloric restriction acting on cell metabolism at multiple levels, reducing all energy-consuming processes in the cells, including cell proliferation. By overviewing molecular mechanisms of action, epidemiological evidences, experimental data in tumor models and early clinical study results, this review provides information supporting the promising use of metformin in cancer prevention and treatment.

Preventing weight gain during adjuvant chemotherapy for breast cancer: a dietary intervention study.

Adjuvant chemotherapy significantly decreases recurrences and improves survival in women with early breast cancer (BC). However, the side effects of chemotherapy include weight gain, which is associated with poorer prognosis. We have previously demonstrated that by means of a comprehensive dietary modification which aims at lowering insulin levels it is possible to reduce body weight and decrease the bioavailability of insulin, sex hormones and the growth factors linked to BC risk and prognosis. We are now going to present a randomized controlled study of adjuvant diet in BC patients undergoing chemotherapy. The diet was designed to prevent weight gain during chemotherapy treatment. Women of any age, operated for invasive BC, scheduled for adjuvant chemotherapy and without evidence of distant metastases, were randomized into a dietary intervention group and a control group. The intervention implied changing their usual diet for the whole duration of chemotherapy, following cooking classes and having lunch or dinner at the study centre at least twice per week. 96 BC patients were included in the study. The women in the intervention group showed a significant reduction in their body weight (2.9 kg on average), compared with the controls. They also significantly reduced body fat mass, waist and hip circumferences, biceps, underscapular and suprailiac skinfolds, compared with the women in the control group. Our results support the hypothesis that dietary intervention during adjuvant chemotherapy for BC is feasible and may prevent weight gain.

[HACCP (Hazard Analysis and Critical Point system) at a catering service: checklist and microbiological examination]. / HACCP in una mensa collettiva: checklist e controlli microbiologici.

The A.A. carried out a survey on the functioning of a catering service in Rome. The risk analysis assessment was performed by means of a checklist that collected systematically all data about the environment, the operators, the food and the catering process. The results of the microbiological analysis carried out in the CCP's showed that the general conditions of the catering service were not satisfactory, but also indicated the validity of the checklist used. This method showed a high predictive value and can be useful to improve the application of the HACCP system.

[Glucagon test for Doppler sonography measurement of portal flow in chronic HCV infections] / Il test al glucagone nello studio eco-Doppler del flusso portale nell'infezione cronica da HCV.

Purpose - To evaluate whether Doppler sonography measurement of portal flow velocity (PFV) after glucagon injection can be useful in assessing the severity of liver damage in chronic HCV infection. Methods - Forty-five patients (32 males and 13 females; mean age 54.1 14.8 years) with biochemical (raised serum ALT levels), virological (positive serum HCV RNA test) and histological (liver biopsy) evidence of chronic HCV infection were included in the study. According to hepatitis staging (degree of liver fibrosis), as assessed by Knodell histological activity index, patients were divided into three groups: group 1 (n.=17), with no or mild fibrosis (fibrosis score: 0-1); group 2 (n.=11), with severe fibrosis (score: 3); and group 3 (n.=17), with liver cirrhosis (score: 4). For sonographic measurements of PFV, a Doppler ultrasound multi-purpose equipment and a convex 3.5 MHz probe were used. All patients were examined after an 8-hour fast, in supine position, 10 min before (baseline), as well as 5 and 10 min after, intravenous administration of 1 mg of glucagon chloride (Novo Nordisk). Statistical analysis was performed by ANOVA test, Bonferroni t test and Spearman rank correlation test. Results - No significant differences were found in mean basal PFV of group 1 (19.4 2.4 cm/sec), group 2 (20.1 3.6 cm/sec) and group 3 (17.5 3.7 cm/sec) (p > 0.05). Five minutes after glucagon injection, all the three groups showed a significant increase in PFV (25.6 4.8,23.7 4.0 and 19.5 5.0 cm/sec, respectively; p < 0.05 vs baseline). The peak increase in PFV after glucagon injection was significantly higher in group 1 (7.9 3.7 cm/sec; 40.7% of basal value) than in group 2 (4.5 3.9 cm/sec; 22.4%) (p < 0.05) and in group 3 (2.7+2.3 cm/sec; 15.4%) (p < 0.05). A significant (p< 0.001) inverse correlation was also found between the patients fibrosis scores and peak increments of PFV induced by glucagon. Conclusions - In some patients with chronic HCV infection, Doppler sonography measurement of PFV after glucagon injection can be useful, in combination with other non invasive ultrasound investigations, both in staging of liver disease and in monitoring the progression of liver histological damage.