A. Pagliacci

Pancreatic cancer: progress in cancer therapy.

Pancreatic cancer continues to be a highly lethal disease. In fact the overall 5-year survival rate is less than 4% and has hardly improved over the past two decades. Surgery is the only potential curative treatment, but the majority of patients have an unresectable disease at the diagnosis. After the demonstration in 1997 that gemcitabine could lead to an improvement in clinical benefit and overall survival this chemotherapy agent became the standard of care for advanced pancreatic cancer patients. Several authors tried to improve results obtained with single agent gemcitabine by exploring the activity of novel chemotherapy on biologically targeted agents in combination with gemcitabine. Unfortunately, global findings were often disappointing with only a marginally significant survival benefit. New treatment strategies and a more careful evaluation of innovative therapies are clearly needed for this disease. In this review we will focus on treatment strategies both in resectable and advanced pancreatic cancer.

Androgen Receptor Expression in Early Triple-Negative Breast Cancer: Clinical Significance and Prognostic Associations

Background: Triple-negative breast cancers (TNBC) are characterized by aggressive tumour biology resulting in a poor prognosis. Androgen receptor (AR) is one of newly emerging biomarker in TNBC. In recent years, ARs have been demonstrated to play an important role in the genesis and in the development of breast cancer, although their prognostic role is still debated. In the present study, we explored the correlation of AR expression with clinical, pathological and molecular features and its impact on prognosis in early TNBC. Patients and Methods: ARs were considered positive in case of tumors with >10% nuclear-stained. Survival distribution was estimated by the Kaplan Meier method. The univariate and multivariate analyses were performed. The difference among variables were calculated by chi-square test. Results: 81 TNBC patients diagnosed between January 2006 and December 2011 were included in the analysis. Slides were stained immunohistochemically for estrogen and progesterone receptors, HER-2, Ki-67, ALDH1, e-cadherin and AR. Of the 81 TNBC samples, 18.8% showed positive immunostaining for AR, 23.5% and 44.4% of patients were negative for e-cadherin and ALDH1, respectively. Positive AR immunostaining was inversely correlated with a higher Ki-67 (p < 0.0001) and a lympho-vascular invasion (p = 0.01), but no other variables. Univariate survival analysis revealed that AR expression was not associated with disease-free survival (p = 0.72) or overall survival (p = 0.93). Conclusions: The expression of AR is associated with some biological features of TNBC, such as Ki-67 and lympho-vascular invasion; nevertheless the prognostic significance of AR was not documented in our analysis. However, since ARs are expressed in a significant number of TNBC, prospective studies in order to determine the biological mechanisms and their potential role as novel treatment target.

Pre-treatment neutrophil to lymphocyte ratio may be a useful tool in predicting survival in early triple negative breast cancer patients

BackgroundThere is a growing body of evidence that immune response plays a large role in cancer outcome. The neutrophil to lymphocyte ratio (NLR) has been used as a simple parameter of systemic inflammation in several tumors. The purpose was to investigate the association between pre-treatment NLR, disease-free survival and overall survival in patients with early triple negative breast cancer (TNBC).MethodsWe reviewed the records of patients with stage I-III TNBC at our Institution from 2006 to 2012. The association between pre-treatment NLR and survival was analyzed. The difference among variables was calculated by chi-square test. DFS and OS were estimated using Kaplan-Meier method. Cox analysis was performed to analyze clinical parameters for their prognostic relevance.ResultsA total of 90 patients were eligible. There was no significant correlation among pre-treatment NLR and various clinical pathological factors. Patients with NLR higher than 3 showed significantly lower DFS (p = 0.002) and OS (p = 0.009) than patients with NLR equal or lower than 3. The Cox proportional multivariate hazard model revealed that higher pre-treatment NLR was independently correlated with poor DFS and OS, with hazard ratio 5.15 (95% confidence interval [CI] 1.11-23.88, p = 0.03) and 6.16 (95% CI 1.54-24.66, p = 0.01) respectively.ConclusionOur study suggests that pre-treatment NLR may be associated with DFS and OS patients with early TNBC. Further validation and a feasibility study are required before it can be considered for clinical use.

Paclitaxel and Bevacizumab in First Line-Treatment Patients with HER-2 Negative Advanced Breast Cancer: Who could Benefit?

Background: Angiogenesis is essential for tumor growth and development of metastases in human breast cancer. Randomized studies have shown that bevacizumab (inhibitor of VEGF) combined with taxane-based regimens increases response rates and prolongs Progression-Free Survival (PFS) of patients with Metastatic Breast Cancer (MBC). However predictive or prognostic markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed. In this retrospective analysis, we investigated the impact of traditional clinical and pathological features in order to identify the subgroups of patients who derive the greatest benefit from antiangiogenic-agents. Patients and methods: Retrospectively, we included consecutive patients treated with bevacizumab (10 mg/Kg on days 1 and 15) and paclitaxel (90 mg/m2, on days 1, 8 and 15) as first-line treatment for HER2-negative MBC at our Institution between June 2007 and December 2012. Results: 33 patients were included. Median age was 50 years (31-68). 78. 8%, 12.1% and 9.1% of patients had luminal B, triple negative and luminal A breast cancer, respectively. 66. 6% of patients had visceral disease. The overall response rate was 31.2%. Median PFS and overall survival (OS) were 7.7 months (range 1. 9-14.0 months) and 95.2 months (range 11.6-205.8 months), respectively. Univariate analysis highlighted a statistically significant relationship between PFS to the first line and the following factors: relapse-free survival (RFS 12 months; p<0,001), disease control rate (p=0,001), Ca15. 3 reduction of more than 50% from baseline (p=0,03), reduction of LDH from baseline (p=0,02). No significant relationship resulted between PFS and the biological characterization of neoplasia, age, receptor status, Ki-67, nodal status at diagnosis, having carried out a previous (neo) adjuvant chemotherapy (with or without taxane), having visceral disease at time of relapse, the histological evidence of lymph-vascular invasion. At multivariate analysis, RFS was the only confirmed independent prognostic factor (p=0.01; HR=0. 18; 95% CI 0. 04-0.73). Conclusion: Our results confirmed the efficacy and the acceptable toxicity profile of bevacizumab plus paclitaxel as first-line regimen for MBC. RFS may be a useful tool in the clinical practice to select HER-2 negative MBC which may obtain a better prognosis administering this particular regimen.

Phosphorylated mTOR is associated to androgen receptor expression in early triple-negative breast cancer

The significance of phosphorylated mTOR (p-mTOR) expression is unknown in triple-negative breast carcinoma (TNBC). The aims of the present study were to assess the expression of p-mTOR in early TNBC and to evaluate possible correlations between androgen receptor (AR) expression, clinicopathological parameters and disease outcome. Between January 2009 and December 2013, all consecutive patients who were diagnosed and completed the treatment of invasive TNBC at our institution were eligible for this analysis. Patients with stage IV disease were excluded. The evaluation of p-mTOR immunohistochemical staining was semi-quantitatively considering both the percentage of positive tumor cells (range, 0-100%) and staining intensity (range, 0-3+). Ninety-eight TNBC patients were included. Approximately 33% of cases were p-mTOR positive and there was no association between positive immunostaining for p-mTOR and DFS (p=0.74) and OS (p=0.81). p-mTOR positivity was associated with small tumor size (p=0.03) and AR expression (p=0.04). High expression of p-mTOR may drive tumor proliferation in almost one third of TNBC. The biological association between mTOR activation and AR pathway suggests that there may exist a subgroup of TNBC in which the combination of both AR antagonism and mTOR inhibition should have a synergistic effect on cell growth and tumor progression.

342PBASELINE NEUTROPHIL TO LYMPHOCYTE RATIO CORRELATES WITH TUMOR STAGE IN LOCALLY ADVANCED BREAST CANCER PATIENTS

ABSTRACT Aim: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancers (BC). Based on previous studies high-lightening the potential role of baseline neutrophil to lymphocyte ratio (NLR) in predicting survival and mortality of patients with early breast cancer (BC), we aimed to investigate the association between pre-therapeutic NLR as a predictive marker for the pathologic response to NAC in patients with locally advanced breast cancer. Methods: We reviewed the records of consecutive patients undergoing NAC for locally advanced BC (stage I-III) following surgery at our Institution between January 2007 and December 2012. The NLR was measured before NAC and the pathologic responses to NAC were evaluated. NLR is calculated as absolute neutrophil count divided by absolute lymphocyte count. The cut-off value of 3 was decided as the maximum (sensitivity + specificity) point according to receiver operating characteristics curves. The difference among variables was calculated by chi-square test. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan-Meier method. Results: A total of 86 patients were eligible for analysis: 56% of patients showed higher pre-treatment NLR. Median age at diagnosis was 50 years (range 28-75). Patients with higher pretherapeutic NLR showed a significant association with lobular histology (12.8% vs 1.1; p = 0.01), pre-NAC lymph node involvement (48.8% vs 29%; p = 0.04) and deaths (15.1% vs 3.5%; p = 0.04). 25.6% of patients had a pathological complete response (pCR) to NAC. There was no significant correlation between pCR and NLR (p = 0.7). Breast cancers with negative Her-2 status or positive progesterone receptor, were less likely to have a pCR to NAC (p = 0.0002 and p = 0.02, respectively). Univariate survival analysis revealed that NLR was not associated with DFS (p = 0.42) or OS (p = 0.13). Conclusions: Our results show that baseline NLR may play a potential role to assess tumor staging in locally advanced BC. Although baseline high pre-treatment NLR did not showed to be related with pCR, the trend of these patient with high pre-treatment NLR was worse than whom with lower NLR. In this setting, further validation and a feasibility study are required before it can be considered for clinical use. Disclosure: All authors have declared no conflicts of interest.

Chemotherapy and Radiotherapy in Pancreatic Cancer

Pancreatic cancer continues to be a highly lethal disease, with approximately 37,000 estimated new cases in the USA in 2007 in both sexes, representing the fourth leading cause of cancer death [1]. Surgery remains the only treatment with a curative potential for local disease, but only 15–20% of patients have resectable disease at the time of diagnosis [2], and the median survival of radically resected patients is approximately 20 months, with a 2-year survival rate ranging from 20 to 40%. Adjuvant chemotherapy or radiotherapy has been assessed in several trials in an attempt to improve patients’ prognosis.