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Sammichele di Bari, Italy

Farolfi A.,Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori | Scarpi E.,Unit of Biostatistics and Clinical Trials | Rocca A.,Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori | Mangia A.,Functional Biomorphology Laboratory | And 12 more authors.
European Journal of Cancer | Year: 2015

Aim To evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC). Patients and methods The relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin → cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF → epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size. Results At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02-1.30, p = 0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p = 0.043): 8-year OS 88% (95% CI 85-90) for patients with a TTC <7 weeks and 78% (95% CI 68-87) for the other group. Conclusions Our results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC. © 2015 Elsevier Ltd. Source

Mazzotta A.,Functional Biomorphology Laboratory | Partipilo G.,Functional Biomorphology Laboratory | de Summa S.,Molecular Genetic Laboratory | Giotta F.,Medical Oncology Unit | And 2 more authors.
Tumor Biology | Year: 2015

Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) plays important roles in DNA damage response pathways and is often overexpressed in various human tumors. Currently, the use of PARP inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. The aim was to investigate the clinicopathological and prognostic significance of PARP1 in BC patients. The PARP1 and breast cancer susceptibility gene 1 (BRCA1) protein expressions were evaluated in 114 BCs by immunohistochemistry. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Our results showed that nuclear PARP1 expression was significantly associated with peritumoral vascular invasion (P = 0.046), chemotherapeutic treatment (P = 0.026), oestrogen receptor (ER; P = 0.013), human epidermal growth factor receptor 2 (HER2; P = 0.003) and BRCA1 (P < 0.001) expression. Survival analyses showed a significant association with clinical outcome in the subgroup of ER-negative patients (P = 0.017 for DFS and P = 0.048 for OS) and in the subgroup of patients treated with chemotherapeutic agents (P = 0.042 for DFS and P = 0.046 for OS). A significant correlation was also found for DFS in patients characterized by tumors without peritumoral vascular invasion (P = 0.022). More importantly, multivariate analyses revealed that high nuclear PARP1 expression was associated with decreased DFS (P = 0.012) and OS (P = 0.026). In conclusion, PARP1 expression may be used as an independent prognostic factor in BC patients. In addition, this study demonstrated that high PARP1 expression may represent a marker of poorer prognosis both for patients with worse clinical outcome and in less aggressive clinical conditions. © 2015 International Society of Oncology and BioMarkers (ISOBM) Source

Paradiso A.,Experimental Medical Oncology | Scarpi E.,Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori | Malfettone A.,Functional Biomorphology Laboratory | Addati T.,Istituto Tumori Giovanni Paolo | And 4 more authors.
Cell Death and Disease | Year: 2013

Our purpose was to investigate whether Na+/H+ exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(+)/ER(+) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (Po0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients. © 2013 Macmillan Publishers Limited All rights reserved. Source

Partipilo G.,Functional Biomorphology Laboratory | Simone G.,Istituto Tumori Giovanni Paolo | Scattone A.,Istituto Tumori Giovanni Paolo | Scarpi E.,Unit of Biostatistics and Clinical Trials | And 2 more authors.
International Journal of Cancer | Year: 2016

Understanding the expression of proteins involved in DNA damage response could improve knowledge of the pathways that contribute to familial and sporadic breast cancer (BC). We aimed to assess the different roles of BRCA1, poly(ADP-ribose) polymerase-1 (PARP1), BRCT-repeat inhibitor of hTERT expression (BRIT1) and novel SWItch 5 (SWI5) expression in 130 sporadic and 73 familial BC samples, by immunohistochemistry. In the sporadic group, negative nuclear BRCA1 (nBRCA1) expression was associated with positive PgR (p=0.037). Negative association was found between nBRCA1 expression and HER2 (p=0.001). In the familial group, nBRCA1 expression was associated with ER (p=0.002). Reduced nBRCA1 expression was associated with higher histological grade and positive Ki67 both in sporadic (p=0.0010, p=0.047) and familial groups (p<0.001, p=0.001). Nuclear PARP1 (nPARP1) expression was associated with histological grade (p=0.035) and positive PgR (p=0.047) in sporadic cases. High cytoplasmic and low nuclear BRIT1 (cBRIT1 and nBRIT1) expression were associated with high histological grade in the familial group (p=0.013, p=0.025). Various statistical associations between the protein expressions were observed in the sporadic group, while in familial group only few associations were found. Univariate analyses showed that nPARP1 expression is able to discriminate between sporadic and familial tumors (OR 2.80, p=0.002). Multivariate analyses proved that its overexpression is an independent factor associated with a high risk of sporadic tumor (OR 2.96, p=0.017). Our findings indicate that nPARP1 expression is an independent factor for sporadic BCs and PARP1 inhibitors could be a promising therapy for different phenotypes. What's new? Genetic mutations that alter mechanisms of DNA repair and genomic maintenance potentially heighten individual susceptibility to cancer. In the present study, this relationship was examined in the context of familial and sporadic breast cancer. Nuclear expression of PARP1, a protein involved in DNA repair, was found to serve as an independent factor for sporadic breast cancer. Meanwhile, nBRCA1 expression was associated with aggressive tumor phenotypes, with potentially important roles in the pathogenesis of both familial and sporadic malignancy. The findings highlight the complexities of aberrant DNA repair in breast cancer and the therapeutic potential of PARP1 inhibition. © 2015 UICC. Source

Schirosi L.,Functional Biomorphology Laboratory | De Summa S.,Molecular Genetic Laboratory | Tommasi S.,Molecular Genetic Laboratory | Paradiso A.,Experimental Medical Oncology | And 4 more authors.
Oncotarget | Year: 2015

Familial breast cancer (BC) is a heterogeneous disease with variable prognosis. The identification of an immunoprofile is important to predict tumor behavior for the routine clinical management of familial BC patients. Using immunohistochemistry on tissue microarrays, we studied 95 familial BCs in order to analyze the expression of some biomarkers involved in different pathways. We used unsupervised hierarchical clustering analyses (HCA), performed using the immunohistochemical score data, to define an immunoprofile able to characterize these tumors. The analyses on 95 and then on a subset of 45 tumors with all biomarkers contemporarily evaluable, revealed the same biomarker and patient clusters. Focusing on the 45 tumors we identified a group of patients characterized by the low expression of estrogen receptor (P = 0.009), progesterone receptor (P < 0.001), BRCA1 (P = 0.005), nuclear Na+/H+ exchanger regulatory factor 1 (NHERF1) (P = 0.026) and hypoxia inducible factor-1 alpha (P < 0.001), and also by the higher expression of MIB1 (P = 0.043), cytoplasmic NHERF1 (P = 0.004), cytoplasmic BRCT-repeat inhibitor of hTERT expression (P = 0.001), vascular endothelial growth factor (VEGF) (P = 0.024) and VEGF receptor-1 (P = 0.029). This immunoprofile identified a more aggressive tumor phenotype associated also with a larger tumor size (P = 0.012) and G3 grade (P = 0.006), confirmed by univariate and multivariate analyses. In conclusion, the clinical application of HCA of immunohistochemical data could allow the assessment of prognostic biomarkers to be used simultaneously. The 10 protein expression panel might be used to identify the more aggressive tumor phenotype in familial BC and to direct patients towards a different clinical therapy. Source

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