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Background Healthy lifestyle, including caloric restriction, balanced diet and physical activity, is important in primary and secondary prevention of breast cancer (BC). It is known that Mediterranean diet reduces metabolic syndrome and insulin resistance that are associated with increased risk of BC onset and recurrence. Physical activity decreases BMI, blood concentrations of testosterone, estrogens, insulin, its resistance and strengthens anti-inflammatory pathways against tumor cells. Since January 2014, at our Institution we promoted a project named “Lifestyle Program” for high risk BC patients underwent to primary surgery. Here we presented the results of 12 months of “Lifestyle Program”. Patients and methods Since January 2014 we have prospectively enrolled all high risk patients between 18 and 70 years treated to our department for invasive early-stage breast cancer (stage I-III). High risk has been defined by one or more of the following inclusion criteria: body mass index (BMI) > 25, diagnosis of metabolic syndrome, increased level of blood testosterone and/or insulin. All high risk patients receive a periodical personalized educational intervention by a physiatrist for physical activity and by a nutritionist for a mediterranean diet low in animals fat and enriched of fibers, fruits and vegetables. All patients underwent to screening for anxiety and depression through HADS questionnaire scores. All data were analyzed by Chi-square test assuming statistical significance at p25 in 94.9% of pts at baseline vs 63.2% after 12 months of lifestyle; p=110 mg/dl in 23.5% of pts at baseline vs 10.2% at 12 months; p=27 uU/ml in 20.6% of pts at baseline vs 2.9% after 12 months; p1,2 ng/ml in 17.6% of pts at baseline vs 4.1% at 12 months; p200 mg/dl in 46.9% of pts at baseline vs 35.7% at 12 months; p170 mg/dl in 13.3% of pts at baseline vs 10.2% at 12 months; p Citation Format: Mirco Pistelli, Valentina Natalucci, Lucia Bastianelli, Laura Scortichini, Veronica Agostinelli, Filippo Merloni, Agnese Savini, Marianna Capecci, Maria Gabriella Ceravolo, Roberta Serrani, Maurizio Ricci, Marina Taus, Albano Nicolai, Elena Barbieri, Rossana Berardi. Assessing the impact of 12 months lifestyle interventions on breast cancer secondary prevention: A modeling approach [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-03.

Background:RAR-related Orphan Receptor C (RORC) is a DNA-binding transcription factor and the key transcription factor responsible for differentiation of T helper 17 cells. TheRORCgene plays a role in lymphoid organogenesis, thymopoiesis, and lymph node organogenesis. The aim of our study was to determine the possible role ofRORCin the development of lymphatic system malformations by combining data from the scientific literature and next-generation sequencing ofRORCin lymphedema patients negative for known causative genes. Methods and Results:We sequencedRORCin 235 lymphedema patients negative for known lymphedema-associated genes. We found two probands carrying nonsenseRORCvariants. Conclusions:We show thatRORCis important for normal function of the lymphatic system and that a rare variant with a possible causative effect may imply predisposition for lymphedema.

Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.

Background The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. Methods We used next‐generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Results Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants—p.(Leu590His) and p.(Gly106Asp)—indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema., Background: The PROX1 gene is a specific marker expressed in a subpopulation of endothelial cells that by budding and sprouting give rise to the murine lymphatic system. It plays a critical role in embryo development and functions as a key regulatory protein in neurogenesis and the development of many organs, including the lymphatic system. Methods and Results: We used NGS to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then tested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Two of 235 probands were found to carry rare missense heterozygous variants in PROX1. In silico analysis suggested that the overall protein structure was somehow altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions: Our results suggest that PROX1 is a possible candidate for predisposition to lymphedema.

Background We developed a Next‐Generation‐Sequencing (NGS) protocol to screen the most frequent genetic variants related to lymphedema and a group of candidate genes. The aim of the study was to find the genetic cause of lymphedema in the analyzed patients. Methods We sequenced a cohort of 246 Italian patients with lymphatic malformations. In the first step, we analyzed genes known to be linked to lymphedema: 235 out of 246 patients tested negative for the most frequent variants and underwent testing for variants in a group of candidate genes, including the NOTCH1 gene, selected from the database of mouse models. We also performed in silico analysis to observe molecular interactions between the wild‐type and the variant amino acids and other protein residues. Results Seven out of 235 probands, five with sporadic and two with familial lymphedema, were found to carry rare missense variants in the NOTCH1 gene. Conclusions Our results propose that NOTCH1 could be a novel candidate for genetic predisposition to lymphedema., Background: We developed a Next‐Generation‐Sequencing (NGS) protocol to screen the most frequent genetic variants related to lymphedema, including a group of candidate genes.Methods and Results: We sequenced a cohort of 246 Italian patients with lymphatic malformations. In the first step, we analyzed genes known to be linked to lymphedema: 235 out of 246 patients tested negative for the most frequent variants and underwent testing for variants in a group of candidate genes, including the NOTCH1 gene, selected from the database of mouse models. The aim of the study was to define the genotype of these patients, in order to explore the role of the candidate gene NOTCH1 in lymphedema.We studied lymphatic malformations related to NOTCH1 variants. We also performed in silico analysis to observe molecular interactions between the wild‐type and the variant amino acids and other protein residues. Seven out of 235 probands, five with sporadic and two with familial lymphedema, were found to carry rare missense variants in the NOTCH1 gene.Conclusions: Our results propose that NOTCH1 could be a novel candidate for genetic predisposition to lymphedema.

Background ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation. Objective The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema. Methods and Results We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins. Conclusions Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.

Background. ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation. Objective. The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema. Methods and Results. We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins. Conclusions. Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.

Simple Summary High body mass index (BMI) is correlated with an increased production of hormones (estrogens, insulin, testosterone, leptin), and pro-inflammatory cytokines, which have been associated with breast cancer (BC) risk and recurrence. Regular physical activity (PA) decreases BMI and blood concentrations of testosterone, estrogens, insulin and pro-inflammatory cytokines. Moreover, the Mediterranean diet (MD) reduces obesity, metabolic syndrome (MS) and insulin resistance, which are all associated with increased risk of BC onset and recurrence. Despite the accumulating evidence of the detrimental effect of physical inactivity and overweight on BC recurrence, weight control and PA counseling are not yet current practice. The principal aim of the lifestyle intervention is to promote weight loss through diet and physical activity in overweight and/or high-risk breast cancer survivors. Moreover, implementing a “lifestyle interventions program” in clinical practice can lead to improvements in psychophysical well-being and favor the correction of cardiovascular risk factors and compliance with endocrine therapy, potentially translating into a prognostic advantage. Abstract A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

// Daniela Tavian 1 , Sara Missaglia 1 , Paolo E. Maltese 2 , Sandro Michelini 3 , Alessandro Fiorentino 3 , Maurizio Ricci 4 , Roberta Serrani 4 , Michael A. Walter 5,6 and Matteo Bertelli 2 1 Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of the Sacred Heart, Milan, Italy 2 MAGI Non-Profit Human Medical Genetics Institute, Rovereto (TN), Italy 3 Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy 4 Medicina Riabilitativa, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Torrette, Italy 5 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada 6 Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada Correspondence to: Daniela Tavian, email: // Keywords : primary lymphedema, distichiasis, Foxc2 gene mutations, transcription factor, gain of function, Pathology Section Received : December 21, 2015 Accepted : May 22, 2016 Published : June 02, 2016 Abstract Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema.

Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.