Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application. METHODS: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs. RESULTS: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. CONCLUSION: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs.

Ipsilateral Breast Tumor Reappearance and Contralateral Breast Cancer after Primary Breast Cancer Treatment: A Comprehensive Retrospective Study of 15,168 Patients.

OBJECTIVE: The aim of this retrospective study was to assess the risk factors for developing ipsilateral breast tumor reappearance (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. METHODS: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (from June 1994 to December 2006). Clinicopathological features, follow-up, and survival at 15 years were considered for statistical analysis. RESULTS: Significant associations of increased risk for IBTR were verified with metastatic axillary lymph nodes (HR 1.37 [1.15-1.62], p = 0.0004), high tumor grade G2 (HR 1.35 [1.05-1.74], p = 0.02) and G3 (HR 1.35 [1.01-1.79], p = 0.04), luminal B (HR 1.51 [1.25-1.82], p < 0.0001), and HER2-positive (HR1.66 [1.14-2.41], p = 0.008) and triple-negative subtype (HR 1.54 [1.07-2.21], p = 0.02). Older age (HR 1.44 [1.08-1.91], p = 0.01) and positive family history (HR 1.85 [1.47-2.32], p < 0.0001) were risk factors for contralateral BC. Significant protective factors for IBTR were hormonotherapy (HR 0.71 [0.59-0.85], p = 0.0003), chemotherapy (HR 0.72 [0.60-0.87], p = 0.001), and radiotherapy (HR 0.73 [0.61-0.87], p = 0.0005). Hormonotherapy was also confirmed as a protective factor for contralateral second BC (HR 0.43 [0.30-0.60], p < 0.0001). CONCLUSIONS: We classified factors for IBTR and contralateral BC in high- and low-risk groups. In the high-risk group, breast surgery still remains more important than in the low-risk group, which seems to benefit more from adjuvant treatments.

Physical activity and/or dietary intervention in overweight or obese breast cancer survivors: results of the InForma randomized trial.

PURPOSE: This study aimed to test the efficacy of a 6-month intervention on weight loss in a group of overweight or obese breast cancer (BC) survivors. We promoted adherence to a healthy diet or/and to increase physical activity, making use of a step counter device. Here we present results regarding the change in anthropometric measures and blood parameters. METHODS: 266 women treated for BC with a BMI ≥ 25 kg/m2 were randomized to a 6-month intervention into four arms: Dietary Intervention (DI); Physical Activity Intervention (PAI); Physical Activity and Dietary Intervention (PADI); Minimal Intervention (MI). Women were offered individualized counseling by a dietitian, a physiotherapist and a psychologist. Participants were followed up for an additional 18 months. RESULTS: 231 women completed the 6-month intervention and 167 completed the additional 18-month follow-up. Respectively, 37.5% and 36.7% of women included in the DI and PADI arm reached the objective of the trial (weight reduction > 5%). Significant weight and circumferences decrease was observed at 6-month in the four arms. Weight decrease was more pronounced in the DI (-4.7% ± 5.0%) and PADI (-3.9% ± 4.5%) arms, persisted over time (at 12 and 24 months), where counseling was mainly focused on the dietic component. The intervention had an effect on the glucose level with a significant reduction in whole population (-0.9 ± 11.7 p-value 0.02) and most pronounced in the PADI arm (-2.4 ± 7.8 p-value 0.03). CONCLUSIONS: Lifestyle intervention mainly focused on the dietetic component and making use of a step counter improved body weight, circumferences and glucose levels. IMPLICATIONS FOR CANCER SURVIVORS: A personalized approach yields a potential clinical benefit for BC survivors.

Ductal carcinoma in situ and intraoperative partial breast irradiation: Who are the best candidates? Long-term outcome of a single institution series.

AIMS: To report the long-term outcome of a single institution series of pure ductal carcinoma in situ (DCIS) treated with accelerated partial irradiation using intraoperative electrons (IOERT). METHODS: From 2000 to 2010, 180 DCIS patients, treated with quadrantectomy and 21 Gy IOERT, were analyzed in terms of ipsilateral breast recurrences (IBRs) and survival outcomes by stratification in two subgroups. The low-risk group included patients who fulfilled the suitable definition according to American Society of Radiation Oncology (ASTRO) Guidelines (size ≤2.5 cm, grade 1-2 and surgical margins ≥3 mm) (Suitable), while the remaining ones formed the high-risk group (Non-Suitable). RESULTS: Eighty-four and 96 patients formed the Suitable and Non-Suitable groups, respectively. In the whole population, the cumulative incidence of IBR at 5, 7 and 10 years was 19%, 21%, and 25%, respectively. In the Suitable group, the cumulative incidence of IBR remained constant at 11% throughout the years, while in the Non-Suitable group increased from 26% at 5 years to 36% at 10 years (p < 0.0001). When hormonal positivity and HER2 absence of expression were added to the selection of the Suitable group, the cumulative incidence of IBR dropped and stabilized at 4% at 10 years. None died of breast cancer. In the whole population, 5-year and 10-year overall survival rate was 98% and 96.5%, respectively, without any difference between the two groups. CONCLUSIONS: The overall and by group IBR rates were high and stricter criteria are required for acceptable local control for Suitable DCIS. Because of the concerns raised, IOERT should not be used in clinical practice.

Promoting weight loss through diet and exercise in overweight or obese breast cancer survivors (InForma): study protocol for a randomized controlled trial.

BACKGROUND: Most women with breast cancer experience a progressive weight gain during and after treatment. Obesity is associated with an increased risk of recurrence, contralateral breast cancer, and death. Physical activity after cancer diagnosis has been reported to have positive effects on body composition and quality of life. We present the protocol of the InForma study, a trial testing the efficacy of an intervention on weight loss (≥5 % of the baseline body weight) in a group of overweight or obese breast cancer survivors. METHODS/DESIGN: This is a four-arm randomized controlled trial. Patients will receive a 6-month intervention and be followed for a further 18 months. Intervention is designed to improve adherence to a healthy diet and/or to increase physical activity, taking advantage of a wrist-based activity monitor. Participants will be recruited among overweight or obese breast cancer patients treated at the European Institute of Oncology, after completion of eventual adjuvant chemotherapy and/or radiotherapy. It is envisaged that 260 patients will be randomized into four arms: Dietary Intervention; Physical Activity Intervention; Physical Activity and Dietary Intervention; and Less Intensive Intervention. Women will be offered individualized counseling consisting of face-to face discussion and phone calls in addition to group meetings. A motivational interviewing approach will be used to encourage health behavior change. All participants will be given a pedometer device to monitor their physical activity. Participants' dietary intake will be repeatedly assessed using a validated food frequency questionnaire. Participants' quality of life and anxiety will be assessed with the Functional Assessment of Cancer Therapy-Breast and the State-Trait Anxiety Inventory questionnaires. Blood samples will be collected at baseline and follow-up visits to assess lipid and hormone profiles. Body composition will be repeatedly assessed using bioelectrical impedance vector analysis for identifying changes of fat and fat-free mass. Women allocated to the less intensive intervention arm will be considered as the control group. DISCUSSION: While there is a rising concern about the role of obesity in cancer recurrence and survival, this trial with its multi-arm design, motivational approach and use of a pedometer device will provide important insights regarding the most effective approach in promoting weight control in breast cancer survivors. TRIAL REGISTRATION: ISRCTN53325751 (registration date: 16 October 2015); ClinicalTrials.gov NCT02622711 (registration date: 2 December 2015).

Long-term side effects and cosmetic outcome in a pool of breast cancer patients treated with intraoperative radiotherapy with electrons as sole treatment.

AIMS: To evaluate late toxicity and cosmetic outcome after intraoperative radiotherapy using electrons (ELIOT) as sole treatment modality in early breast cancer patients. METHODS: A total of 119 patients selected randomly among 1200 cases was analyzed. Late toxicities were documented using the LENT-SOMA scoring system, cosmesis was evaluated with the Harvard scale, and a numeric rating scale was used to assess symptoms. RESULTS: After a median follow-up of 71 months, grade II fibrosis was observed in 38 patients (31.9%) and grade III fibrosis in 7 patients (5.9%). Postoperative complications (12.6%) did not correlate with late toxicity. Physicians and patients scored cosmesis as excellent or good in 84% and 77.3% of the cases, respectively. Patient satisfaction was higher than 90%. CONCLUSIONS: In the study, ELIOT gives low and acceptable long-term toxicity. A longer follow-up and a larger number of patients are needed to confirm these promising results.