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The dissertation is focused on the evaluation of a Docetaxel-based sequential regimen as adjuvant therapy of breast cancer. Docetaxel is among the most active chemotherapeutic agents for breast cancer. With Taxit 216 trial, we aimed to assess the efficacy of adding docetaxel in a block-sequential fashion to a regimen with doxorubicin followed by CMF in the adjuvant therapy for node-positive early stage breast cancer (ESBC). Patients were randomized to arm A (epirubicin 120 mg/m2 for 4 cycles then cyclophosphamide, methotrexate and 5-fluorouracil [CMF] for 4 cycles), or arm B (4 cycles of docetaxel 100 mg/m2 administered after the fourth epirubicin cycle and before the first CMF cycle). Treatment allocation was performed, in our Institution, by a computer program using a minimization algorithm. Stratification factors were: center, lymph node involvement (1 to 3, 4 to 9, >10), estrogen receptor status (negative/positive/unknown), menopausal status (pre/post). The primary end-point was invasive disease-free survival (IDFS). Secondary end-points were recurrence-free survival (RFS), overall survival (OS) and toxicity. The study was designed to detect a hazard ratio of 0.70, assuming an a of 0.05 (two-sided), a power of 0.80 and an expected DFS in arm A of 0.65 at 5 years. This required 480 patients per arm and 250 events. Final results are reported according to the standardized system for efficacy end points (STEEP system). Between July 1998 and July 2002, 972 patients were randomized (486 in each arm). At a median follow-up of 62 months, 278 IDFS events were recorded. Five-year IDFS was 74% in arm B vs 68% in arm A (P = 0.13), with a hazard ratio (HR) of 0.82 (95% confidence interval [CI] = 0.64–1.03). RFS was significantly better for arm B than for arm A (76% vs 69%; P = 0.0332) with a HR of 0.75 (95% CI = 0.59–0.96). There was a significant improvement in OS, with an estimated five-year OS of 90% in arm B and 85% in arm A (P = 0.0168; HR = 0.67, 95% CI = 0.48–0.94). This benefit comes at the cost of increased but acceptable toxicity. We demonstrated, with the results of the Taxit 216 phase III trial, that incorporating docetaxel into a block-sequential epirubicin–CMF regimen significantly reduces the risk of recurrence and death in patients with nodepositive ESBC.

Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

The partner and localizer of BRCA2 (PALB2) is a major BRCA2 binding partner that participates in homologous recombination repair in response to DNA double-strand breaks. Germline alterations of the PALB2 gene have recently been associated with a high risk of developing breast cancer. We investigated a 37-year-old Caucasian woman with breast cancer and family history of breast cancer using targeted next generation sequencing. A novel heterozygous deletion involving exons 5 and 6 was found in the PALB2 gene, and resulted in the production of a truncated PALB2 protein. These findings expand the mutational spectra of PALB2-associated breast cancer, and may improve the mutation-based screening and genetic diagnosis of breast cancer.

Aim The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor–positive (HR+) tumours. Patients and methods In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3–4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. ( NCT00412022 )

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Weight gain and metabolic changes have been related to survival of early breast cancer patients (EBC). ‘’However, factors influencing metabolism post-diagnosis are not fully understood. We measured anthropometric [body mass index (BMI), body weight, waist and hip circumferences, and waist-to-hip ratio] and metabolic (levels of insulin, glucose, H1Ac, total, HDL, and LDL cholesterol, triglycerides, and the homeostasis model assessment score [HOMA]) parameters in 433 pre- and post-menopausal women with EBC at diagnosis and 3, 6, 9, 12, and 24 months thereafter. At diagnosis, compared with post-menopausal women, pre-menopausal patients were more likely to be leaner and to have a lower BMI, smaller waist and hip circumferences, and waist-to-hip ratio. They had also lower glucose, HbA1c, and triglyceride levels and a lower HOMA score. Furthermore, they were more likely to have an estrogen- and/or progesterone-positive tumor and a higher proliferating breast cancer. During the first two post-diagnosis years, all women showed a significant increase of weight (+0.72 kg/year, P

// Giuseppe Buono 1, * , Anna Crispo 2, * , Mario Giuliano 1, 3 , Carmine De Angelis 1 , Francesco Schettini 1 , Valeria Forestieri 1 , Rossella Lauria 1 , Matilde Pensabene 1 , Michelino De Laurentiis 4 , Livia Silvia Adriana Augustin 2, 5 , Alfonso Amore 4 , Massimiliano D’Aiuto 4 , Raffaele Tortoriello 4 , Antonello Accurso 6 , Ernesta Cavalcanti 2 , Gerardo Botti 2 , Maurizio Montella 2 , Sabino De Placido 1 and Grazia Arpino 1 1 Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy 2 Unit of Epidemiology, National Cancer Institute, G. Pascale Foundation, Naples, Italy 3 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA 4 Breast Unit, National Cancer Institute, G. Pascale Foundation, Naples, Italy 5 Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Canada 6 Department of Gastroenterology, Endocrinology and Surgery, University of Naples Federico II, Naples, Italy * These authors contributed equally to this work Correspondence to: Grazia Arpino, email: grazia.arpino@unina.it Keywords: breast cancer; obesity; diabetes; combined variables; outcome Received: August 19, 2017 Accepted: November 16, 2017 Published: December 05, 2017 ABSTRACT Background: Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods: Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test. Results: At diagnosis, obese and diabetic patients were more likely to be older ( p < 0.0001) and post-menopausal ( p < 0.0001) and to have a tumor larger than 2 cm ( p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival ( p = 0.01) and overall survival ( p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for disease-free survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival. Conclusions: At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cancer.

BACKGROUND: Recent studies of the correlation between breast cancer (BC) and vitamin D yielded contrasting results. Although preclinical and clinical evidence has implicated vitamin D in BC prevention and outcome, little is known about the link between vitamin D and specific BC histologically defined subtypes. In the attempt to clarify this association we correlated vitamin D levels with BC characteristics. PATIENTS AND METHODS: We enrolled 220 pre- and postmenopausal women with early BC in this prospective observational trial. Data on the patients' clinical and specific BC pathological characteristics were collected and related to vitamin D levels, stratified in deficient (< 20 ng/mL), insufficient (20-30 ng/mL), and sufficient (> 30 ng/mL). BC subtypes were defined according to the 14th St Gallen Breast Cancer Conference. RESULTS: Deficient vitamin D levels were correlated with Grade 3 (P = .015) and node-positive (P = .043) BC, and with a higher body mass index (P = .017). Insufficient vitamin D levels were associated with estrogen receptor expression in the primary tumor (P = .033). Vitamin D levels were unrelated to the histological molecular subtypes of BC. CONCLUSION: Deficient vitamin D levels were correlated with more aggressive disease, namely, node-positive high grade BC, and with obesity. Should our findings be confirmed in larger prospective studies, nutritional programs designed to reduce body weight, and vitamin D supplementation might be considered a BC prevention strategy.

Background Male breast cancer (MBC) is rare. Given the paucity of randomized trials, treatment is generally extrapolated from female breast cancer guidelines. Methods This is a retrospective analysis of all male patients presenting with MBC at the Department of Oncology at University Federico II of Naples between January 1989 and January 2014. We recorded the following data: baseline characteristics (age, height, weight, body mass index, risk factors, family history), tumor characteristics (side affected, stage, histotype, hormonal and HER2 status, and Ki-67 expression), treatment (type of surgery, chemotherapy, endocrine therapy, and/or radiotherapy), BRCA1/2 mutation status (if available), other tumors, and long-term survival. Results Forty-seven patients were analyzed. Median age was 62.0 [55.0–72.0]. Among risk factors, obesity and family history of breast cancer were associated with 21 % and 30 % of MBC cases, respectively. The majority of tumors were diagnosed at an early stage: stage I (34.0 %) and stage II (44.7 %). Infiltrating ductal carcinoma was the most frequent histologic subtype (95.8 %). Hormone receptors were generally positive (88.4 % of cases were Estrogen receptor [ER] positive and 81.4 % Progesteron receptor [PgR] positive). Human epidermal growth factor receptor 2 (HER2) was positive in 26.8 % of cases; 7.0 % of MBCs were triple negative. The tumor had high proliferation index (Ki67 ≥ 20 %) in 64.7 %. Surgery was predominantly mastectomy (85.1 %), whereas quadrantectomy was performed in 14.9 % of patients. Adjuvant chemotherapy was administered to 70.7 % of patients, endocrine therapy to 90.2 %, trastuzumab to 16.7 % and radiotherapy to 32.6 %. BRCA status was available for 17 patients: 10 wild-type, 1 BRCA1 carrier, 5 BRCA2 carriers, 1 unknown variant sequence. The overall estimated long-term survival was about 90 % at 5 years, 80 % at 10 years and 70 % at 20 years. Patients carrying a BRCA mutation had a significantly lower survival than patients with wild-type BRCA (p = 0.04). Conclusions Long-term survival was high in MBC patients referred to our clinical unit. Survival was poorer in BRCA-mutated patients than in patients with wild-type BRCA.

Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes.

Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p

Purpose We conducted a meta-analysis of randomized trials that evaluated the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer (EBC). We aimed to determine whether this approach improves disease-free survival (DFS) and overall survival (OS) and whether benefits are maintained across relevant patient subgroups. Methods Studies were retrieved by searching the PubMed database and the proceedings of major conferences. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model. Results Thirteen studies were included in the meta-analysis (N = 22,903 patients). The pooled HR estimate was 0.83 (95% CI, 0.79 to 0.87; P < .00001) for DFS and 0.85 (95% CI, 0.79 to 0.91; P < .00001) for OS. Risk reduction was not influenced by the type of taxane, by estrogen receptor (ER) expression, by the number of axillary metastases (N1 to 3 v N4+), or by the patient's age/menopausal status. Sensitivity analysis showed that taxanes given in combination with anthracyclines, unlike sequential administration, did not significantly improve OS. However, the test for interaction showed that HR did not differ between the two schedules (P = .54). Taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS and 3% for OS. Conclusion The addition of a taxane to an anthracycline-based regimen improves the DFS and OS of high-risk EBC patients. The DFS benefit was independent of ER expression, degree of nodal involvement, type of taxane, age/menopausal status of patient, and administration schedule.

BACKGROUND: Several analyses suggest an increase of brain metastases in HER2 over-expressing breast cancers treated with trastuzumab as compared to historical series of unselected patients. PATIENTS AND METHODS: We analyzed the incidence of central nervous system (CNS) metastases in 78 patients with HER2 over-expressing breast cancer treated with trastuzumab between July 2000 and June 2006 at the Oncology Department of University Federico II in Naples. We also characterized and compared patients with and without CNS involvement. RESULTS: The median follow-up was 35.3 months (95\%CI 26.3-44); median overall survival was 56 months (95\%CIs 46-nr); 5 patients showed CNS involvement before trastuzumab therapy while 31 developed CNS metastases during trastuzumab treatment. The median overall survival after CNS metastases was 25.4 months (95\%CIs 15.2-nr); patients with CNS lesions showed worse overall survival than patients without CNS lesions (39.1 vs. 75 months, p = 0.005). CONCLUSION: CNS metastases are common events in patients with metastatic HER2 over-expressing breast cancer treated with trastuzumab; the impact on survival is detrimental even if survival after CNS metastases is longer than historical reports. Appropriate investigation of the role of CNS imaging screening and the prophylactic treatment strategies for CNS represents a priority research in this setting.

This paper describes a rare occurrence of primary lymphoma of the liver in a young female and demonstrates the possibility of making the correct diagnosis by ultrasonically guided fine needle aspiration biopsy. A 32-year old female suffering from upper abdominal pain, hepatomegaly, nausea, anorexia and weight loss for almost 2 months was admitted to our Department. After a clinical and instrumental (lab exams, ultrasonography, computed tomography) evaluation, we reached the correct diagnosis of hepatic primary non-Hodgkin's lymphoma by means of ultrasonically guided fine needle aspiration biopsy. Two weeks after hospitalization the patient was treated with 8 cycles of CHOP chemotherapy and then with alpha-2b interferon immunotherapy. The hepatic ultrasonography and CT abdominal scan showed the complete absence of the lymphomatous lesions 36 months later. Up to February 1998, the patient was well and led a normal life. We conclude that the CHOP chemotherapy plus interferon immunotherapy were effective and well tolerated with a complete response 38 months following diagnosis.