Special Issue "Prognostic and Predictive Factors in Colorectal Cancer"

Guest Editor
Dr. Alessandro Lugli
Institute of Pathology, University of Bern, 3010 Bern, Switzerland
E-Mail:
Phone: +41 31 632 99 58
Fax: +41 31 632 49 95
Interests: gastrointestinal and liver tumors; tumor diagnosis and staging; prognostic and predictive biomarkers

Dear Colleagues,

Colorectal cancer (CRC) is one of the most common malignant diseases worldwide. Based on the chromosomal instability (CIN) and serrated pathways, CRC can be subdivided into mismatch-repair proficient (85%) and deficient (15%) tumors. In 2007, Jeremy Jass proposed a new molecular classification of CRC including KRAS, BRAF, mismatch-repair, CpG Island Methylator Phenotype (CIMP) and O-6-methylguanine-DNA methyltransferase (MGMT) status. According to the UICC/AJCC tumor extent, lymph node and distant metastasis, lymphatic and vascular invasion are considered the essential prognostic factors. Although several recent studies have proposed different histomorphological, immunohistochemical and molecular biomarkers to improve stratification of CRC patients into prognostic subgroups, there are no officially established additional prognostic and predictive factors included in the pre- and postoperative management of non-metastatic CRC. Due to the implementation of anti-EGFR therapy for metastatic CRC patients in the last years, predictive factors such as the KRAS mutational status are now included in the therapeutic assessment. This special issue of Cancers will include original contributions or review articles that focus on the prognostic and predictive value of molecular, immunohistochemical and histomorphological biomarkers to help improve the clinical management of CRC patients.

Dr. Alessandro Lugli
Guest Editor

Submission

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• TNM classification
• prognostic factors
• predictive factors
• KRAS
• BRAF
• CIMP
• MGMT
• mismatch repair status
• molecular biomarkers
• immunohistochemistry
• histomorphological factors

Type of Paper: Article
Title: The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor A Gene in Colorectal Cancer
Author: Torben Frøstrup Hansen
Affiliation: Department of Oncology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark; E-Mail: torben.hansen@slb.regionsyddanmark.dk
Abstract: The objective of the present study was to investigate the prognostic importance of haplotypes in the VEGF-A gene in patients with CRC. The study included a total of 486 patients surgically resected for stage II and III CRC, divided into two independent cohorts. Three SNPs in the VEGF-A gene were analysed by PCR. Haplotypes were estimated using the PHASE program. All 3 SNPs were significantly related to survival. A haplotype combination present in approximately 30% demonstrated a significant relationship with poor survival and remained an independent prognostic marker after multivariate analysis. Validation was provided by consistent findings in a second and independent cohort.

Type of Paper: Article
Title: Detection of up to 65% of the Preneoplastic Lesions in Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1
Author: Pablo Steinberg ^1,2
Affiliation: ¹ Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany
² Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany;
E-Mail: Pablo.Steinberg@tiho-hannover.de
Abstract: In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signalling pathways was used to analyze 20 colorectal hyperplastic polyp and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned precancerous lesions carrying at least one of the four above-mentioned genes in a mutated form. CTNNB1 and B-RAF were screened by PCR-single-strand conformation polymorphism analysis, K-RAS by restriction fragment length polymorphism analysis and the APC gene mutation cluster region (codons 1243-1567) by direct DNA sequencing. Whereas APC mutations were only detected in 10% of the hyperplastic polyps, 34% of the adenomas showed alterations in APC. Twenty percent of the hyperplastic polyps and 14% of the adenomas carried a mutated K-RAS gene. B-RAF was found to be mutated in 50% of the hyperplastic polyps and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in hyperplastic polyps. With the new primer panel it could be shown that 65% of the hyperplastic polyps and 61% of the adenomas carried at least one out of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (this study) and neoplastic lesions (a previous study) of the human colon and rectum the new primer panel might also be suited to efficiently detect genetic alterations in stool DNA of patients with colorectal cancer in a non-invasive manner.

Type of Paper: Review
Title: Intratumoral Immune Reaction: A Novel Paradigm for Cancer
Author: Jerome Galon
Affiliation: INSERM U872, Integrative Cancer Immunology Team, Cordeliers Research Center, 75006 Paris, France; E-Mail: jerome.galon@crc.jussieu.fr
Abstract: To date the anatomic extent of tumor (TNM classifications) has been by far the most important factors to predict the prognosis of cancer patients. However, the impact of immune responses and tumor escape on patient prognosis in human cancer is poorly understood. We showed that tumors from human colorectal cancer with a high density of infiltrating memory and effector memory T-cells (TEM) are less likely to disseminate to lymphovascular and perineural structures and to regional lymph-nodes (New Engl J Med 2005). We showed that the combination of immune parameters associating the nature, the density, the functional orientation and the location of immune cells within the tumor was essential to accurately define the impact of the local host immune reaction on patients prognosis (Science 2006). We proposed to define these immune criteria as “immune contexture”. Investigation of the primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response. We described four major immune coordination profiles within primary tumors depending on the balance between tumor escape and immune coordination. Analysis of patients with early-stage colorectal cancer confirmed the major role of cyotoxic effector T cells in predicting the prognosis of the patients (J Clin Oncol 2009). In conclusion, the density and the immune-cell location within the tumor have a prognostic value that is superior of those of the TNM classifications. Tumor invasion is statistically dependent on the host-immune reaction.

Type of Paper: Article
Title: The Role of Tumour Stroma in Colorectal Invasion and Metastasis
Author: John Conti
Affiliation: Infection, Inflammation and RepairDivision, Southampton University, E Level, South Block, Southampton General Hospital, Mailpoint 811, Tremona Road, Southampton SO16 6YD, UK; E-Mail: jaconti1@soton.ac.uk
Abstract: Colorectal cancer (CRC) is a major cause of mortality in western society with a 5-yr survival of approximately 50%. Metastasis to the liver and lungs is the principal cause of death and occurs in up to 25% of patients at presentation.  Despite advances in available techniques for treating metastases, the majority of patients remain incurable and existing adjuvant therapies such as chemotherapy are only of limited effectiveness. Understanding the molecular mechanisms underlying the metastatic process may allow us to identify those at greatest risk of recurrence and discover new tumour targets to prevent disease progression. It is now apparent that tumour stroma plays an important role in promoting tumour progression. A pronounced desmoplastic reaction was associated with a reduced immune response and has been shown to be an independent poor prognostic indicator in CRC and cancer recurrence. Determining the cause(s) and effect(s) of this stromal response will further our understanding of tumour cell/stromal interactions, and will help us identify prognostic indicators for patients with CRC. This will not only allow us to target our existing treatments more effectively, we also aim to identify novel and more specific therapeutic targets for the treatment of CRC which will add to our current therapeutic options.

Type of Paper: Article 
Title: Significance of Levels of Cytokeratin Fragment M65 and Cytokines Il6, Il8 And Il17a In Bone Marrow (Bm) Aspirates of Colorectal Cancer Patients
Authors: U. Olszewski, C. Ausch, V. Buxhofer and G. Hamilton
Affiliation: Ludwig Boltzmann Cluster of Translational Oncology, Vienna, Austria
Abstract: Introduction: Soluble cytokeratin (CK) fragments and inflammatory cytokines in BM aspirates of colorectal cancer patients are expected to indicate presence of tumor cells and response of the host, respectively. The present study investigated the relation of IL6, IL8, and IL17A and the CK18 fragment M65 in BM samples to biopsy status and prognosis. Methods: BM aspirates were obtained immediately prior to tumor surgery as well as one and two years thereafter, respectively. M65 was quantified using the M65® ELISA (Peviva, Bromma, Sweden) kit and cytokines by Biolegend ELISA assays (San Diego, CA, USA). Results: 16/66 patients revealed tumor-positive BM aspirates, and 10/46 evaluable patients relapsed within five years. M65 levels exhibited no relation to positive biopsies, relapses or methylation status of MGMT, respectively. In contrast, IL17A concentrations of BM aspirates were elevated in non-relapsed versus relapsed as well as MGMT-wildtype versus MGMT-methylated patients. Due to large individual variations, IL6 and IL8 levels of BM showed no significant differences between these groups of patients. Conclusion: M65 levels of BM samples of colorectal cancer patients exhibited no correlation with micrometastases or disease recurrence, respectively. However, patients showing disease-free survival revealed increases of IL17A in BM aspirates, possibly indicating immune response to tumor cells.

Type of Paper: Review
Title: Prognostically Significant Histopathological Features in Colorectal Cancer
Author: John Schofield
Affiliation: Department of Cellular Pathology, Preston Hall Hospital, Maidstone, Kent ME20 7NH, UK; E-Mail: john.schofield@nhs.net
Abstract: Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumour size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as the presence of lymphovascular invasion and lymph node involvement are well known factors that influence outcome. Our understanding of these factors has improved in the past few years with factors such as tumour budding, lymphocytic infiltration being recognized as important.  A number of molecular and genetic markers such as K-Ras, BRAF and microsatellite instability are also important and correlate with histological features in some patients. This review summarizes our current understanding of the main histopathological factors that affect prognosis of colorectal cancer.

Type of Paper: Review
Title: Prognostic and Predictive Factors in Locally Advanced Rectal Cancer: State of the Art and Future Perspectives
Author: Rossana Berardi
Affiliation: Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I - GM Lancisi - G Salesi, Via Conca 71, 60126 Ancona, Italy; E-Mail: r.berardi@univpm.it
Abstract: In Western countries, colorectal cancer is the third commonest cancer in terms of incidence and mortality. The management of rectal cancer has undergone and continues to undergo significant evolutions. In the last two decades, new multimodality strategies have been developed. Multimodality treatments have improved the prognosis of locally advanced rectal cancer with local recurrences decreasing from 40 to <10% and overall survival increasing from 50 to 75% in the last 40 years. The ability to predict tumour response before treatment may significantly impact the selection of patients for preoperative combined-modality therapy as well as potentially modify postoperative treatment plans. Therefore the present review will analyse the new molecular targets that could be involved in predicting response and prognosis.

Type of Paper: Review
Title: Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic?
Authors: Masaki Shibayama ¹, Matthias Maak ², Ulrich Nitsche ², Keigo Gohda ¹, Hideki Ishihara ¹, Helmut Friess ², Robert Rosenberg ² and Klaus-Peter Janssen ²
Affiliations ¹ Sysmex Corporation, Central research laboratories, Kobe, Japan; E-Mail: Shibayama.Masaki@sysmex.co.jp (M.S.)
² Chirurgische Klinik, Klinikum rechts der Isar der TUM, München, Germany; E-Mails: maak@chir.med.tu-muenchen.de (M.M.); nitsche@chir.med.tu-muenchen.de (U.N.); friess@chir.med.tu-muenchen.de (H.F.); rosenberg@chir.med.tu-muenchen.de (R.R.)
klaus-peter.janssen@lrz.tum.de (K.-P.J.)
Abstract: Cancers of the colon and rectum, which rank among the most frequent human tumors, are currently treated by surgical resection in locally restricted tumor stages. However, disease recurrence and formation of local and distant metastasis frequently occur even in cases with early tumor stages and successful curative resection of the primary tumor (R0). Recent technological advances in molecular diagnostic analysis have lead to a wealth of knowledge about the changes in gene transcription in all stages of colorectal tumors. Differential gene expression, or transcriptome analysis, has been proposed by many groups to predict disease recurrence, clinical outcome, and also response to therapy, in addition to the well-established UICC/AJCC tumor staging system.. However, the clinical usability of gene expression profiling as reliable and robust prognostic tool that allows evidence-based clinical decisions is currently under debate. In this review, we will discuss the most recent data on the prognostic significance and potential clinical application of array-based gene expression analysis in colorectal cancer.
Keywords: colorectal cancer; transcriptome; metastasis; prognosis; therapy prediction

Type of Paper: Review
Title:Predictive Factors of Rectal Cancer Response to Neoadjuvant Radiochemotherapy
Author: Gaya Spolverato ¹, Salvatore Pucciarelli ¹, Roberta Bertorelle ², Donato Nitti ¹ and Anita De Rossi ²
Affiliations:¹ Section of Surgery, Department of Oncological  and Surgical Sciences, University of Padova, Italy
² Section of Oncology, Department of Oncological  and Surgical Sciences, University of Padova, Italy; E-Mail: anita.derossi@unipd.it (A.D.R.)
Abstract: Background locally advanced rectal cancer (LARC) is currently treated with pre-operative chemoradiation (pCRT). The response toneoadjuvant treatment is not uniform and there is no effective method of predicting the response. It’s clinically relevant to identify patients who have a higher likelihood of responding to pCRT, because patients with a priori resistant tumors could be spared exposure to radiation or DNAdemaging drugs that are associated with adverse effects. Aim The aim of this review was to highlight predictive markers of response to pCRT for rectal cancer.
Materials and methods A systematic search of PubMed was conducted with combination of the following terms: “rectal”, “predictive”, “radiochemotherapy”. Articles were hand searched for those of relevance. Results We distinguished three classes of factors that have a role in prediction of response to pCRT: biological, clinical, and imaging indices. The most important biomarkers are: thymidylate synthase (TS), epithelial growth factor receptor (EGFR), p53, p21, Ki-67 and bcl-2/bax. Polymorphisms in TS-DNA have a predictive value; EGFR is a predictor of response when evaluated for polymorphisms and quantitatively. P53 , Ki-67 and bcl-2/bax are not useful in predicting response. P21 need to be further evaluated. Gene expression of thousand of genes using microarray generate interesting results that may lead to the further exploration of genes. Clinical factors such as pre-CRT serum CEA levels are associated with tumor response to pCRT. In terms of molecular imaging, % SUV predict complete pathological response in patients with rectal cancer treated with pCRT. Conclusions Currently there are no predictors of response with a clinical utility. Global gene sequencing and evaluation of biomarkers in larger prospective trial are required to guide the therapeutic strategy.