Chiara Pellei

Neoadjuvant therapy in pancreatic cancer: an emerging strategy.

Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths among men and women, being responsible for 6% of all cancer-related deaths. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. In recent years, increasing evidences support the use of neoadjuvant strategies in pancreatic cancer in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC in order to allow early treatment of micrometastatic disease, tumour regression, and reduced risk of peritoneal tumour implantation during surgery. Furthermore, neoadjuvant treatment allows evaluation of tumour response and increases patients compliance. However, most evidences in this setting come from retrospective analysis or small case series and in many studies chemotherapy or chemoradiation therapies used were suboptimal. Currently, prospective randomized trials using the most active chemotherapy regimens available are trying to define the real benefit of neoadjuvant strategies compared to conventional adjuvant strategies. In this review, the authors examined available data on neoadjuvant treatment in patients with resectable pancreatic cancer as well as in patients with borderline resectable or locally advanced PDAC and the future directions in this peculiar setting.

Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer

In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal–epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.

Toll like receptors and pancreatic diseases: From a pathogenetic mechanism to a therapeutic target

Toll-like receptors (TLRs) mediate interactions between environmental stimuli and innate immunity. TLRs play a major role in the development of numerous pancreatic diseases, making these molecules attractive as potential therapeutic targets. TLR2, TLR7 and TLR9 are involved in the initiation of type 1 diabetes mellitus (T1DM), whereas TLR2 and TLR4 play a major role in the onset of type 2 diabetes mellitus (T2DM). Furthermore, TLRs cause derangements in several tumor suppressor proteins (such as p16, p21, p27, p53 and pRb), induce STAT3 activation and promote epithelial-mesenchymal transition as well as oncogene-induced senescence. In this review we will focus on the contribution of TLRs in pancreatic disease including cancer and we describe recent progress in TLR-modulation for the treatment of these patients.

Chromium Exposure and Germinal Embryonal Carcinoma: First Two Cases and Review of the Literature

The aim of the study was to determine the potential role of occupational exposures to chromium (Cr) in the onset of extragonadal germinal embryonal carcinoma. The first two cases of workers in a company with Cr exposure are reported. The published scientific literature regarding the topic in peer-reviewed journals including MEDLINE and CancerLit databases was extensively reviewed. Two young patients who were coworkers in the same company, exposed to Cr, developed extragonadal germinal embryonal carcinomas. One of them also developed angiosarcoma of the mediastinum. To the best of our knowledge these are the first two cases of germinal embryonal carcinoma in patients with occupational exposure to Cr.

Lgr5 expression, cancer stem cells and pancreatic cancer: results from biological and computational analyses

AIMS To determine the relationship between Lgr5 and other stemness markers and pathologic features in pancreatic ductal adenocarcinoma (PDAC) samples. MATERIALS & METHODS In 69 samples, Lgr5 was analyzed by qRT-PCR together with a panel of 29 genes. Bioinformatic analysis was carried out to identify a possible pathway regulating Lgr5 expression in PDAC. RESULTS Lgr5 expression was not associated with the expression of tested cancer stem cell markers. Moreover, it was not an independent predictor of survival neither at univariate analysis (p = 0.21) nor at multivariate analysis (p = 0.225). CONCLUSION Based on the lack of correlation between Lgr5 and tested cancer stem cell markers, Lgr5 does not seem to be a potential stemness marker or prognostic factor in PDAC.

Prognostic factors in advanced pancreatic cancer patients receiving second line chemotherapy: a single institution experience

Background: First-line chemotherapy in pancreatic ductal cancer has been shown to improve the survival and quality of life, while there is still no consensus concerning the role and the optimal regimen for second-line chemotherapy. The aim of our study was to identify prognostic factors that could predict which patients may receive benefit from second-line treatment. Methods: Data regarding 144 patients, with progressive disease after first-line chemotherapy and measurable or evaluable disease, who received second-line chemotherapy were collected. The regimens included capecitabine, 5-fluorouracil (5-FU) or 5-FU based combinations, gemcitabine or gemcitabine-based combinations, nab-paclitaxel or taxanes. Prognostic variables examined were gender, ECOG PS, stage of disease, metastatic localization, presence or absence of peritoneal involvement, surgery on the primary tumor, age, hemoglobin levels (Hb), neutrophil-lymphocyte ratio (NLR), carbohydrate antigen 19-9 (Ca 19-9), lactate dehydrogenase (LDH), sodium (Na+) levels, mono-chemotherapy vs. combination therapy and PFS after first line chemotherapy. Results: The median OS was 5.26 months (95% CI, 4.01–6.84 months) while median PFS was 2.76 months (95% CI, 2.50–3.22 months). At multivariate analysis, three clinical-laboratoristic features (ECOG PS, CA 19-9 value and LDH value) resulted significant independent prognostic factors for OS, with a hazard ratio (HR) respectively of 1.94 (95% CI, 1.18–3.19), 2.99 (95% CI, 1.37–6.54; P=0.006) and 2.10 (95% CI, 1.08–4.04; P=0.029). No significant impact on prognosis was observed for the other variables. Conclusions: This study confirms the role of CA 19-9 in second line setting and highlights the potential role of LDH, as a prognostic relevant factor in this disease. Main limitation of the study is the small percentage of patients treated in first line with intensified regimens such as FOLFIRINOX or gemcitabine and nab-paclitaxel.

Developments in the management of advanced soft-tissue sarcoma – olaratumab in context

Lartruvo® (olaratumab) is a fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that inhibits platelet-derived growth factor receptor alpha (PDGFRα). The antitumor activity of olaratumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in cancer cell lines, including glioblastoma and leiomyosarcoma cells. It represents the first-in-class antibody to be approved by regulatory authorities for the treatment of advanced soft-tissue sarcomas (STSs) in combination with doxorubicin, based on the results of the Phase Ib/II trial by Tap et al. The median progression-free survival (PFS), which was the primary end point of the study, was improved for patients treated with olaratumab plus doxorubicin compared to those treated with doxorubicin monotherapy (6.6 vs 4.1 months, respectively; HR 0.672, 95% CI 0.442–1.021, p=0.0615). Moreover, final analysis of overall survival (OS) showed a median OS of 26.5 months with olaratumab plus doxorubicin vs 14.7 months with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30–0.71, p=0.0003). In October 2016, olaratumab was admitted in the Accelerated Approval Program by the US Food and Drug Administration (FDA) for use in combination with doxorubicin for the treatment of adult patients with STSs. In November 2016, the European Medicines Agency (EMA) granted conditional approval for olaratumab in the same indication under its Accelerated Assessment Program. A double-blind, placebo-controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943) is being performed in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The study is ongoing, but enrollment is closed. The purpose of this review was to evaluate the rationale of olaratumab in the treatment of advanced STSs and its emerging role in clinical practice.

710PCLINICAL OUTCOME OF ELDERLY (>70Y) ADVANCED PANCREATIC CANCER PATIENTS RECEIVING CHEMOTHERAPY

ABSTRACT Aim: Pancreatic cancer is a disease seen predominantly in elderly patients (pts). However, no standards of care exist for >70y patients. We aimed at evaluating the outcome of elderly pts treated with chemotherapy for pancreatic cancer and the presence of prognostic factors in this subpopulation. Methods: We reviewed the clinical records of patients with PDAC aged ≥70y treated with chemotherapy in four Italian Oncology Units from January 2005 to April 2014. Survival estimates were quantified using Kaplan Meier curves. Tumor stage, ECOG-Performance Status (PS), pre-treatment CEA and CA 19-9, hemoglobin (Hb), neutrophil, lymphocyte and platelet count as well as LDH were included in the Cox analysis to investigate their prognostic significance. Results: 178 pts were included in this analysis. Median age was 74 years (range 70-88); 97 pts (54.5%) were males; 128 pts (71.9%) had metastatic disease. Median overall survival (OS) was 5.6 months. Median first-line PFS was 3.2 months. Folfirinox was the first-line in 10 pts (5.6%); 90 pts (50.6%) were treated with gemcitabine alone, 78 pts (43.8%) gemcitabine-based doublets, without differences in terms of OS (p = 0.07). Forty-five pts (25.2%) were treated with second-line chemotherapy; median OS of 4.2 months and a PFS of 2.2 months No differences in terms of OS and PFS were found between mono (23 pts) vs combined (22 pts) second-line chemotherapy (p = 0.42). Only 7 pts (3.9%) underwent third-line chemotherapy, with an OS of 8.1 months and a PFS of 1.7 months. At multivariate analysis, ECOG-PS ≥ 2 (p = 0.004) and lymphocyte count (p = 0.04) were independent prognostic factors for OS. Furthermore, ECOG-PS ≥ 2 (p = 0.04), Hb (p = 0.03), lymphocyte (p = 0.01) and neutrophil counts (p = 0.04) were significantly associated with PFS. Conclusions: Chemotherapy appears to have a similar activity in elderly patients as compared to younger patients with pancreatic cancer. However, combined chemotherapy does not occur to be more effective than monotherapy. Disclosure: All authors have declared no conflicts of interest.

698PCOX-2 STATUS MODULATES THE ACTIVATION OF HEDGEHOG PATHWAY AND CONSEQUENTLY THE EXPRESSION OF STEM CELL MARKERS IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA

ABSTRACT Aim: Inflammation is a key driver in the development of pancreatic ductal adenocarcinoma (PDAC). Cyclooxygenase-2 (COX-2) and Interleukin (IL)-6 are key modulators of inflammation and act as a potential link between chronic pancreatitis and subsequent carcinogenesis. In this study, we analyzed the association between COX-2 and IL-6 status and the expression of Hedgehog signaling pathway and stem cell markers and their relationship with the clinico-pathological features and prognosis of PDAC patients. Methods: The expressions of COX-2 and IL-6 were examined using immunohistochemistry in 79 resection specimens of PDAC. The expression of the Hedgehog components SHH, IHH, DHH, SMO, PTCH1, PTCH2, and stem cell markers CD24, CD44, OCT3/4 and PROM1 were analyzed by qRT-PCR. The correlation among gene expression levels was performed by the Pearson product moment correlation method. Survival analysis was conducted via Kaplan-Meier product-limit method. Results: 49 patients (62%) had COX-2+ tumors, while 37 patients (47%) had IL-6+ tumors. SHH (p = 0.001), IHH (p = 0.011) and SMO (p = 0.040) were significantly more expressed in patients COX-2+. In addition, IHH was significantly more expressed in patients with IL-6+ tumors (p = 0.040). CD44 expression was associated with DHH (rho = 0.742), IHH (rho = 0.826) and SMO (rho = 0.899). PROM1 expression was associated with DHH (rho = 0.772), IHH (rho = 0.847) and SMO (rho = 0.915). T stage was higher in patients with COX-2+ (p = 0.020), whereas no associations were found between COX-2 and node involvement (p = 0.071) or grading (p = 0.273) as well as between IL-6 expression and the clinico-pathological characteristics of these patients. No significant differences in terms of survival were found based on COX-2 or IL-6 status. Conclusions: Taken together, our data suggest for a model in which COX-2 expression modulates the activation of the Hedgehog pathway and, subsequently, the expression of stemness markers. These data may lead to a better characterization of patients to include in clinical trials in order to develop future therapeutic strategies. Disclosure: All authors have declared no conflicts of interest.

709PSINGLE-AGENT OR DOUBLETS AS SECOND-LINE CHEMOTHERAPY AFTER FOLFIRINOX IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC CANCER

ABSTRACT Aim: FOLFIRINOX represents an active regimen in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) patients (pts) with good performance status (PS). Currently, there are no accepted standard regimens in second-line therapy for patients with disease progression and data about efficacy of chemotherapy after FOLFIRINOX failure are lacking. Methods: We retrospectively investigated clinical and laboratory characteristics (including blood count, LDH, CEA and CA19.9) of PDAC pts treated between June 2011 and April 2014 in four Italian institutions with either doublet or single agent as second-line therapy after FOLFIRINOX failure. Survival estimates were quantified using Kaplan Meier curves, and differences between groups were compared with the log-rank test. Results: Among 96 pts treated with FOLFIRINOX as first-line chemotherapy, 50 pts received second-line treatment (52%). Median age at diagnosis was 60 years (range 36-76); 66 pts were males (72%). PDAC was locally advanced in 15 (30%) and metastatic in 35 pts (70%). Patients who received second line single agent (gemcitabine, docetaxel or nab-paclitaxel) or doublets (gemcitabine with either abraxane, capecitabine, cisplatin or docetaxel) were 24 (48%) and 26 (52%), respectively. According to RECIST criteria, 2 pts achieved PR (4%), 10 (20%) SD for ≥9 wks and 38 (76%) PD. Median progression-free survival (PFS) was 2.7 months and median overall survival (OS) was 3.4 months. No differences were found in terms of OS (5.0 vs 3.1, p = 0.489) or PFS (4.0 vs 2.7 p = 0.182) between patients treated with single-agent or doublets as second-line. At multivariate analysis, ECOG ≥ 2 was the only independent prognostic factor for worst OS (p = 0.002) and PFS (p = 0.020). Conclusions: Our findings suggest that the choice of second line therapy in patients treated with first-line FOLFIRINOX should be carefully evaluated. ECOG ≥ 2 was significantly associated with poor prognosis, while pre-treatment CA 19-9, LDH, Hb, neutrophil and platelet counts were not prognostic factors for OS, although these data should be confirmed in perspective studies. Disclosure: All authors have declared no conflicts of interest.