Mirco Pistelli

Clinical Evidence for Three Distinct Gastric Cancer Subtypes: Time for a New Approach

Background Recently, a new classification for gastric cancer (GC) has been proposed, based on Laurens histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. Patients and Methods Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. Results A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). Conclusions Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients.

Role of maspin in cancer

Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis.Further studies in these directions are necessary to better define the therapeutic implication of maspin.

5-fluorouracil pharmacogenomics: still rocking after all these years?

The 5-fluorouracil (5-FU) metabolic pathway is mainly dependent on the activity of several intracellular enzymes. Among them, four in particular; thymidylate synthase, methylenetetrahydrofolate reductase, dihydropyrimidine dehydrogenase and thymidine phosphorylase are considered the key points in determining sensitivity or resistance to this drug. These enzymes are needed to metabolize the drug in its active form (thymidylate phosphorylase) or to drop the concentration of the active drug in the cell (dihydropyrimidine dehydrogenase) or both (thymidylate synthase and methylenetetrahydrofolate reductase). Several different studies have tried to investigate the relationship between the presence of mutations in these enzymes and a reduced/improved activity of treatment based on 5-FU or its derivatives. In this article, we will focus on the often contradictory results of these studies.

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.

Toward molecularly selected chemotherapy for advanced gastric cancer: State of the art and future perspectives

In the last few years therapeutic options for gastric cancer patients have slowly, but constantly expanded following the introduction of both new chemotherapy agents and innovative indications for treatment. Along with the medical therapy also our knowledge of the molecular mechanisms underlying this disease has progressively improved. However although the available treatment options have undoubtedly increased no clear definitive indications can be made for a standard chemotherapy regimen and we are still unable to accurately select the appropriate treatment for the appropriate patient. Many molecular determinants of response/toxicity to chemotherapy agents have been identified, but only few of them seem to possess the necessary potential for a subsequent application in the clinical practice. Some of these factors have also been indicated as a therapeutic target for a novel class of anti-cancer compounds. This systematic review will analyse available data about these factors with the aim to constitute a starting point for future research.

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.

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.

Novel Perspectives for the Treatment of Gastric Cancer: From a Global Approach to a Personalized Strategy

Although recent advances have been made, surgery still remains the mainstay of any curative treatment for gastric cancer patients, with radical gastrectomy representing the procedure of choice. However, patients with locally advanced disease show high rates of locoregional or distant recurrence even after potentially curative resections. According to global results presented in the setting of locally advanced resectable gastric carcinoma, perioperative chemotherapy may be considered a valuable option. On the other hand, clinical trials for advanced gastric cancer seem to suggest that a limit in efficacy has been reached for standard chemotherapy. Interesting data are expected from the development of targeted agents that, similarly to other cancer sites, showed appealing results in gastric cancer as well. Along with new effective therapeutic opportunities, better clinical and molecularly driven patient selection will represent the cornerstone of the global care for these patients.

Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer

Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.