Rafael Sirera

The Role of Tumor Stroma in Cancer Progression and Prognosis: Emphasis on Carcinoma-Associated Fibroblasts and Non-small Cell Lung Cancer

Maintenance of both normal epithelial tissues and their malignant counterparts is supported by the host tissue stroma. The tumor stroma mainly consists of the basement membrane, fibroblasts, extracellular matrix, immune cells, and vasculature. Although most host cells in the stroma possess certain tumor-suppressing abilities, the stroma will change during malignancy and eventually promote growth, invasion, and metastasis. Stromal changes at the invasion front include the appearance of carcinoma-associated fibroblasts (CAFs). CAFs constitute a major portion of the reactive tumor stroma and play a crucial role in tumor progression. The main precursors of CAFs are normal fibroblasts, and the transdifferentiation of fibroblasts to CAFs is driven to a great extent by cancer-derived cytokines such as transforming growth factor-&bgr;. During recent years, the crosstalk between the cancer cells and the tumor stroma, highly responsible for the progression of tumors and their metastasis, has been increasingly unveiled. A better understanding of the host stroma contribution to cancer progression will increase our knowledge about the growth promoting signaling pathways and hopefully lead to novel therapeutic interventions targeting the tumor stroma. This review reports novel data on the essential crosstalk between cancer cells and cells of the tumor stroma, with an emphasis on the role played by CAFs. Furthermore, it presents recent literature on relevant tumor stroma- and CAF-related research in non-small cell lung cancer.

The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer.

In addition to malignant neoplastic cells, cancer tissues also include immune cells, fibroblasts, and endothelial cells, including an abundant collection of growth factors, proangiogenic mediators, cytokines, chemokines, and components of the extracellular matrix. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. Between immune cells and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has both tumor-promoting and -inhibiting roles. In non-small cell lung cancer (NSCLC), there is a marked infiltration of different types of immune cells, and the distribution, tissue localization, and cell types are significantly associated with progression and survival. Cancer immunotherapy has seen a significant progress during the last decade. An increased understanding of the mechanisms by which lung cancer cells escape the immune system, and the recognition of the key tumor antigens and immune system components in tumor ignorance have led to the development of several lung cancer vaccines. As the NSCLC prognosis in general is dismal, one may hope that future immunotherapy may be an effective adjunct to standard therapy, reversing immunologic tolerance in the tumor microenvironment. This review reports on the tumor stroma and in particular tumor-suppressing and -promoting roles of the immune system. Furthermore, it presents recent literature on relevant immune cell-related research in NSCLC.

Circulating DNA is a useful prognostic factor in patients with advanced non-small cell lung cancer

Background: Circulating DNA is observed at higher concentrations in patients with lung cancer than in controls. Qualitative and quantitative analysis of circulating DNA is a promising noninvasive tool. Our aim was to prospectively study the association between the catalytic subunit of telomerase (human telomerase reverse transcriptase [hTERT]) in plasma and clinical variables and survival in a large-scale non-small cell lung cancer (NSCLC) study. Methods: Four hundred forty-six patients with stages IIIB and IV NSCLC with a median follow-up of 9.7 months (range, 0.5–45) were analyzed. Blood samples were collected before therapy start (cisplatin/docetaxel). Quantification of baseline circulating DNA was determined as the amount of free hTERT in plasma, by using real-time quantitative polymerase chain reaction. Results: Patients with hTERT ≤49.8 ng/ml (median value) had a median time to progression (TTP) of 6.3 months compared with 4.9 for hTERT more than 49.8 ng/ml (p = 0.001). Overall survival (OS) was significantly higher (10.9 versus 9.3 months) at lower hTERT levels (p = 0.012). When calculations were done using hTERT as continuous variable, we did not observe independent significant differences. Thus, there is an apparent discrepancy in p values when hTERT is considered as a continuous versus dichotomized variable. There was a tendency to differentiate median hTERT levels with respect to response rates (complete response + partial response: 33.1 versus stable disease + progressive disease: 50.7 ng/ml, p = 0.12), but other clinical variables such as age, gender, performance status, stage, histology, and number of metastatic locations were not associated with hTERT. In multivariate analysis, hTERT was an independent prognostic variable for both TTP (hazard ratio: 1.44, p < 0.001) and OS (hazard ratio: 1.33, p = 0.007). Conclusions: In advanced NSCLC, high pretreatment circulating hTERT level is an independent poor prognostic marker for TTP and OS. Circulating DNA is a noninvasive marker, which may help to improve the prognostic profile of these patients.

Combined VEGF-A and VEGFR-2 concentrations in plasma: Diagnostic and prognostic implications in patients with advanced NSCLC

INTRODUCTION The vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFR) play an important role in tumor angiogenesis. Increased expression of angiogenic factors in tumors or in blood is associated with poor prognosis. The aim of this study was to investigate the role of VEGF-A and soluble VEGFR-2 (sVEGFR-2) as biomarkers in advanced non-small-cell lung cancer (NSCLC). METHODS We studied 432 patients with advanced NSCLC (stages IIIB-IV) treated with cisplatin and docetaxel and 89 healthy age-matched controls. Blood samples were collected before chemotherapy, and VEGF-A and sVEGFR-2 levels were determined by ELISA. RESULTS VEGF-A and sVEGFR-2 levels were higher in NSCLC patients than in the controls, but VEGF-A behaves as a better diagnostic biomarker. There were no significant associations between VEGF-A and sVEGFR-2 concentrations and clinical characteristics, such as ECOG-PS, gender, stage, histology, metastases, and treatment response. A patient subgroup characterized by a combination of high VEGF-A and low sVEGFR-2 levels exhibited the worst patient prognoses in terms of TTP and OS. CONCLUSIONS VEGF-A and sVEGFR-2 levels were significantly higher in patients than in the controls. A combination of VEGF-A and sVEGFR-2 can be used as an independent prognostic biomarker in advanced NSCLC.

The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients.

BACKGROUND Qualitative analysis of circulating DNA in the blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of KRAS mutations at codon 12 and several clinical variables in advanced non-small cell lung cancer (NSCLC) patients. METHODS We examined 308 stage IIIB and IV NSCLC patients who were treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. The KRAS mutational status was determined by an RT-PCR method that is based on allelic discrimination. RESULTS The median age of the patients was 60 years [31-80], 84% were male, 98% had a performance status of 0-1 and 84% of the patients were in stage IV. The histological subtypes were as follows: 30% squamous cell carcinoma (SCC), 51% adenocarcinoma (ADC) and 19% others. Of the 277 response-evaluated patients, 1% achieved a complete response (CR), 26% achieved a partial response (PR), 34% had stable disease (SD) and 39% had progressive disease (PD). Additionally, 27 (8.8%) patients had KRAS mutations; 26 had a KRAS codon 12 TGT mutation, and 1 had a codon 12 GTT mutation. Plasmatic KRAS mutations were found in patients presenting SCC or ADC. Patients with KRAS mutations in plasma DNA had a median progression free survival (PFS) of 5.77 months [3.39-8.14], whereas for patients with wild-type (wt) KRAS, the PFS was 5.43 months [4.65-6.22] (p=0.277). The median overall survival (OS) in KRAS-mutated patients was 9.07 months [4.43-13.70] vs 10.03 months [8.80-11.26] in wt patients (p=0.514). CONCLUSIONS In advanced NSCLC patients, there were no significant differences between patients with or without KRAS mutations in plasma-free DNA with respect to the baseline characteristics, response rates, PFS or OS.

Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.

IntroductionMalnutrition is a common problem in cancer patients. Its incidence varies according to disease stage (between 15 and 90%) and is considered a possible prognostic factor for therapeutic response and survival. It is also one of the causes contributing to the increase in morbidity and mortality in patients. Tumor cachexia is defined as a nutritional defect caused by tumor growth in the patient and presents as a significant weight loss. This weight loss is mainly caused by a degradation of skeletal muscle proteins.ConclusionThe ubiquitin–proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.

Importance of quality of life in patients with non-small-cell lung cancer.

The therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC) are palliative. Therefore, the quality of life in oncology is considered as an endpoint in clinical trials, and several scales have been accepted for its measurement in parallel with other clinical determinations. However, its use in clinical practice is hindered by various obstacles that need to be overcome. In this article we examine the concept of the quality of life in patients with NSCLC, as well as giving an evaluation and interpretation of the results of various clinical trials. We describe the new technological methods used in daily clinical practice to measure the quality of life.

Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer

Prostate cancer is the second most diagnosed cancer in males in the world. Plasma quantification of prostate-specific antigen substantially improved the early detection of prostate cancer, but still lacks the required specificity. Clinical management of prostate cancer needs advances in the development of new non-invasive biomarkers, ameliorating current diagnosis and prognosis and guiding therapeutic decisions. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. These miRNAs are expressed in the cells and are also present in cell-derived extracellular vesicles such as exosomes. Exosomes have been shown to act as mediators for cell to cell communication because of the regulatory functions of their content. High levels of exosomes are found in several body fluids from cancer patients and could be a potential source of non-invasive biomarkers. In this review, we summarize the diagnostic and prognostic utility of exosomal miRNAs in prostate cancer.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

INTRODUCTION The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. AREAS COVERED This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. EXPERT OPINION Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations.

Chemotherapy-Induced Neutropenia Does Not Correlate With DNA Repair Gene Polymorphisms and Treatment Efficacy in Advanced Non–Small-Cell Lung Cancer Patients

BACKGROUND Platinum doublets are standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether neutropenia is: (1) an indicator for treatment efficacy, or (2) associated with specific polymorphisms. PATIENTS AND METHODS Four hundred ninety-four patients, treated with cisplatin-docetaxel were retrospectively analyzed. Relative dose intensity (RDI) was assessed for both drugs. Neutrophil counts were assessed only on Day 21 of each cycle. Genotyping was performed for 4 different polymorphisms in ERCC1, XRCC3, XPD-23, and XPD-10. RESULTS The median overall survival was 9 months. The mean RDI was 0.94 for cisplatin and 0.93 for docetaxel. Four hundred three patients received ≥ 3 cycles of chemotherapy, and 239 received ≥ 6 cycles. Thirty-one percent developed neutropenia, and 19% had Grade (G)3-4 neutropenia. RDI was lower in patients with neutropenia (G1-4; 0.87-0.93) when compared with those without (G0; 0.94-0.95; P < .02). Male patients (P = .02) had inferior survival when compared with female patients, and ECOG (Eastern Cooperative Oncology Group) 1-2 patients (P < .001) had worse survival when compared with ECOG 0. There was no significant survival difference with respect to Grade of neutropenia (G0, 8.7 vs. G1-2, 11.6 vs. G3-4, 9.6 months; P = .41). In ECOG 0 patients, survival was significantly better for neutropenic G1-4 (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.31-0.96; P = .034) when compared with non-neutropenic (G0) patients. No association was observed between examined polymorphisms and neutropenia. CONCLUSION RDI was significantly higher in patients who did not develop neutropenia during treatment, but as the nadir period was not explored in our study, the low occurrence of neutropenia in our cohort is considered underestimated. There was no significant survival difference with respect to grade of neutropenia. Finally, none of the examined single nucleotide polymorphisms (SNPs) were associated with the presence of neutropenia, disease characteristics, response rates, or survival.