Special Issue "Prognostic and Predictive Factors in Colorectal Cancer"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 February 2011)

Special Issue Editor

Guest Editor
Dr. Alessandro Lugli

Deputy Chief Pathologist, Head, Division of Clinical Pathology, Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland
Fax: +41 31 632 49 95
Interests: gastrointestinal and liver tumors; tumor diagnosis and staging; prognostic and predictive biomarkers

Special Issue Information

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

Keywords

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

Published Papers (12 papers)

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Research

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Open AccessArticle The Role of Tumour Stroma in Colorectal Cancer Invasion and Metastasis
Cancers 2011, 3(2), 2160-2168; doi:10.3390/cancers3022160
Received: 23 February 2011 / Revised: 5 April 2011 / Accepted: 6 April 2011 / Published: 26 April 2011
Cited by 8 | PDF Full-text (408 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer (CRC) is a major cause of mortality in western society with a 5-year 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 [...] Read more.
Colorectal cancer (CRC) is a major cause of mortality in western society with a 5-year 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. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessArticle The Prognostic Impact of p53 Expression on Sporadic Colorectal Cancer Is Dependent on p21 Status
Cancers 2011, 3(1), 1274-1284; doi:10.3390/cancers3011274
Received: 19 January 2011 / Revised: 28 February 2011 / Accepted: 4 March 2011 / Published: 11 March 2011
Cited by 1 | PDF Full-text (238 KB) | HTML Full-text | XML Full-text
Abstract
The prognostic value of p53 and p21 expression in colorectal cancer is still under debate. We hypothesize that the prognostic impact of p53 expression is dependent on p21 status. The expression of p53 and p21 was immunohistochemically investigated in a prospective cohort of 116 patients with UICC stage II and III sporadic colorectal cancer. The results were correlated with overall and recurrence-free survival. The mean observation period was 51.8 ± 2.5 months. Expression of p53 was observed in 72 tumors (63%). Overall survival was significantly better in patients with p53-positive carcinomas than in those without p53 expression (p = 0.048). No differences were found in recurrence-free survival (p = 0.161). The p53+/p21− combination was seen in 68% (n = 49), the p53+/p21+ combination in 32% (n = 23). Patients with p53+/p21− carcinomas had significantly better overall and recurrence-free survival than those with p53+/p21+ (p < 0.0001 resp. p = 0.003). Our data suggest that the prognostic impact of p53 expression on sporadic colorectal cancer is dependent on p21 status. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessArticle Detection of up to 65% of Precancerous Lesions of the Human Colon and Rectum by Mutation Analysis of APC, K-Ras, B-Raf and CTNNB1
Cancers 2011, 3(1), 91-105; doi:10.3390/cancers3010091
Received: 24 October 2010 / Revised: 7 December 2010 / Accepted: 20 December 2010 / Published: 29 December 2010
Cited by 1 | PDF Full-text (268 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially precancerous [...] Read more.
In the present study a recently conceived 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signaling pathways was used to analyze 20 colorectal serrated lesions and 41 colorectal adenoma samples and to determine the percentage of each of the above-mentioned potentially 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. APC mutations were only detected in 10% of the serrated lesions but in 34% of the adenomas. Twenty percent of the serrated lesions and 14% of the adenomas carried a mutated K-Ras. B-Raf was found to be mutated in 50% of the serrated lesions and in 22% of the adenomas. CTNNB1 was altered in 12% of the adenomas, but not in serrated lesions. By using the above gene marker panel it could be shown that 65% of the serrated lesions and 61% of the adenomas carried at least one of the four genes in a mutated form. Based on its excellent performance in detecting mutations in sporadic preneoplastic (in this study) and neoplastic lesions (in a previous study) of the human colon and rectum, this primer combination might also be suited to efficiently and non-invasively detect genetic alterations in stool DNA of patients with early colorectal cancer. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Figures

Open AccessArticle The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor A Gene in Colorectal Cancer
Cancers 2010, 2(3), 1405-1418; doi:10.3390/cancers2031405
Received: 24 May 2010 / Revised: 23 June 2010 / Accepted: 25 June 2010 / Published: 28 June 2010
Cited by 6 | PDF Full-text (228 KB) | HTML Full-text | XML Full-text
Abstract
New prognostic markers in patients with colorectal cancer (CRC) are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene has been proposed. 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 486 patients surgically resected for stage II and III CRC, divided into two independent cohorts. Three SNPs in the VEGF-A gene were analyzed by polymerase chain reaction. Haplotypes were estimated using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible for this effect, was present in approximately 30% of the patients and demonstrated a significant relationship with poor survival, and it remained an independent prognostic marker after multivariate analysis, hazard ratio 2.46 (95% confidence interval 1.49–4.06), p < 0.001. Validation was provided by consistent findings in a second and independent cohort. Haplotype combinations call for further investigation. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)

Review

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Open AccessReview Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic?
Cancers 2011, 3(3), 2858-2869; doi:10.3390/cancers3032858
Received: 10 May 2011 / Revised: 23 June 2011 / Accepted: 27 June 2011 / Published: 7 July 2011
Cited by 9 | PDF Full-text (112 KB) | HTML Full-text | XML Full-text
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 successful [...] Read more.
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 successful curative resection of the primary tumor (R0). Recent technological advances in molecular diagnostic analysis have led 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 clinico-pathological factors. However, the clinical usability of gene expression profiling as a 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 genome wide expression analysis in colorectal cancer. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Review of Histopathological and Molecular Prognostic Features in Colorectal Cancer
Cancers 2011, 3(2), 2767-2810; doi:10.3390/cancers3022767
Received: 10 March 2011 / Revised: 14 June 2011 / Accepted: 15 June 2011 / Published: 23 June 2011
Cited by 10 | PDF Full-text (575 KB) | HTML Full-text | XML Full-text
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 tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well [...] Read more.
Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumor 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 tumor budding, lymphocytic infiltration being recognized as important. Likewise the prognostic significance of resection margins, particularly circumferential margins has been appreciated in the last two decades. A number of molecular and genetic markers such as KRAS, 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. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview The Role of High Frequency Dynamic Threshold (HiDT) Serum Carcinoembryonic Antigen (CEA) Measurements in Colorectal Cancer Surveillance: A (Revisited) Hypothesis Paper
Cancers 2011, 3(2), 2302-2315; doi:10.3390/cancers3022302
Received: 25 January 2011 / Revised: 22 April 2011 / Accepted: 4 May 2011 / Published: 11 May 2011
Cited by 4 | PDF Full-text (194 KB) | HTML Full-text | XML Full-text
Abstract
Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits [...] Read more.
Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits the potential role of serum carcinoembryonic antigen (CEA) in follow-up. A comprehensive review of the literature (1978–2008) demonstrates that the initial promise of serum CEA as an effective surveillance tool has been tarnished through perpetuation of poorly designed studies. Specific limitations included: testing CEA as only an ‘add-on’ diagnostic tool; lack of standardization of threshold values; use of static thresholds; too low measurement frequency. Major changes in localizing imaging techniques and treatment of metastatic CRC further cause a decrease of clinical applicability of past trial outcomes. In 1982, Staab hypothesized that the optimal benefit of serum CEA as a surveillance tool is through high-frequency triage using a dynamic threshold (HiDT). Evidence supporting this hypothesis was found in the biochemical characteristics of serum CEA and retrospective studies showing the superior predictive value of a dynamic threshold. A multi-centred randomized phase III study optimizing the usage of HiDT against resectability of recurrent disease is commencing recruitment in the Netherlands. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Predictive Factors of the Response of Rectal Cancer to Neoadjuvant Radiochemotherapy
Cancers 2011, 3(2), 2176-2194; doi:10.3390/cancers3022176
Received: 11 March 2011 / Revised: 8 April 2011 / Accepted: 11 April 2011 / Published: 26 April 2011
Cited by 8 | PDF Full-text (310 KB) | HTML Full-text | XML Full-text
Abstract
Locally advanced rectal cancer is currently treated with pre-operative radiochemotherapy (pRCT), but the response is not uniform. Identification of patients with higher likelihood of responding to pRCT is clinically relevant, as patients with resistant tumors could be spared exposure to radiation or [...] Read more.
Locally advanced rectal cancer is currently treated with pre-operative radiochemotherapy (pRCT), but the response is not uniform. Identification of patients with higher likelihood of responding to pRCT is clinically relevant, as patients with resistant tumors could be spared exposure to radiation or DNA-damaging drugs that are associated with adverse side effects. To highlight predictive biomarkers of response to pRCT, a systematic search of PubMed was conducted with a combination of the following terms: “rectal”, “predictive”, “radiochemotherapy”, “neoadjuvant”, “response” and “biomarkers”. Genetic polymorphisms in epithelial growth factor receptor (EGFR) and thymidylate synthase (TS) genes, the expression of several markers, such as EGFR, bcl-2/bax and cyclooxygenase (COX)-2, and circulating biomarkers, such as serum carcinoembryonic antigen (CEA) level, are promising as predictor markers, but need to be further evaluated. The majority of the studies did not support the predictive value of p53, while the values of Ki-67, TS and p21 is still controversial. Gene expression profiles of thousands of genes using microarrays, microRNA studies and the search for new circulating molecules, such as human telomerase reverse transcriptase mRNA and cell-free DNA, are providing interesting results that might lead to the identification of new useful biomarkers. Evaluation of biomarkers in larger, prospective trials are required to guide therapeutic strategies. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Prognostic Value of Colorectal Cancer Biomarkers
Cancers 2011, 3(2), 2080-2105; doi:10.3390/cancers3022080
Received: 18 February 2011 / Revised: 21 March 2011 / Accepted: 23 March 2011 / Published: 19 April 2011
PDF Full-text (280 KB) | HTML Full-text | XML Full-text
Abstract
Despite the large amount of data in cancer biology and many studies into the likely survival of colorectal cancer (CRC) patients, knowledge regarding the issue of CRC prognostic biomarkers remains poor. The Tumor-Node-Metastasis (TNM) staging system continues to be the most powerful [...] Read more.
Despite the large amount of data in cancer biology and many studies into the likely survival of colorectal cancer (CRC) patients, knowledge regarding the issue of CRC prognostic biomarkers remains poor. The Tumor-Node-Metastasis (TNM) staging system continues to be the most powerful and reliable predictor of the clinical outcome of CRC patients. The exponential increase of knowledge in the field of molecular genetics has lead to the identification of specific alterations involved in the malignant progression. Many of these genetic alterations were proposed as biomarkers which could be used in clinical practice to estimate CRC prognosis. Recently there has been an explosive increase in the number of putative biomarkers able to predict the response to specific adjuvant treatment. In this review we explore and summarize data concerning prognostic and predictive biomarkers and we attempt to shed light on recent research that could lead to the emergence of new biomarkers in CRC. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Biomarkers in Advanced Colorectal Cancer: Challenges in Translating Clinical Research into Practice
Cancers 2011, 3(2), 1844-1860; doi:10.3390/cancers3021844
Received: 27 February 2011 / Accepted: 25 March 2011 / Published: 1 April 2011
PDF Full-text (170 KB) | HTML Full-text | XML Full-text
Abstract
The growing number of therapeutic agents and known molecular targets in oncology makes the study and clinical use of biomarkers imperative for improving response and survival, reducing toxicity and ensuring economic sustainability. Colorectal cancer, among others, is at the forefront of development [...] Read more.
The growing number of therapeutic agents and known molecular targets in oncology makes the study and clinical use of biomarkers imperative for improving response and survival, reducing toxicity and ensuring economic sustainability. Colorectal cancer, among others, is at the forefront of development of predictive and prognostic biomarkers; however, the difficulty lies in translating potential biomarkers garnered from retrospective analyses in small numbers of patients to generalizable and affordable biomarkers used worldwide. This review outlines the progress made in prognostic and predictive biomarkers in advanced colorectal cancer (ACRC) from the early use of carcinoembryonic antigen (CEA) to the KRAS mutation and beyond. Future challenges are to incorporate standardized and validated methods preferentially during early phases of drug development linked with sophisticated biostatistical support. New trial designs focusing on biomarkers will be essential not only for better understanding of mechanisms of action, but also to make confident ‘go or no-go’ decisions. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Predictive and Prognostic Factors in Colorectal Cancer: A Personalized Approach
Cancers 2011, 3(2), 1622-1638; doi:10.3390/cancers3021622
Received: 23 January 2011 / Revised: 13 March 2011 / Accepted: 18 March 2011 / Published: 29 March 2011
Cited by 8 | PDF Full-text (396 KB) | HTML Full-text | XML Full-text
Abstract
It is an exciting time for all those engaged in the treatment of colorectal cancer. The advent of new therapies presents the opportunity for a personalized approach to the patient. This approach considers the complex genetic mechanisms involved in tumorigenesis in addition [...] Read more.
It is an exciting time for all those engaged in the treatment of colorectal cancer. The advent of new therapies presents the opportunity for a personalized approach to the patient. This approach considers the complex genetic mechanisms involved in tumorigenesis in addition to classical clinicopathological staging. The potential predictive and prognostic biomarkers which have stemmed from the study of the genetic basis of colorectal cancer and therapeutics are discussed with a focus on mismatch repair status, KRAS, BRAF, 18qLOH, CIMP and TGF-β. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
Open AccessReview Regulatory T Cells in Colorectal Cancer: From Biology to Prognostic Relevance
Cancers 2011, 3(2), 1708-1731; doi:10.3390/cancers3021708
Received: 4 February 2010 / Revised: 13 March 2011 / Accepted: 21 March 2011 / Published: 29 March 2011
Cited by 3 | PDF Full-text (273 KB) | HTML Full-text | XML Full-text
Abstract
Regulatory T cells (Tregs) were initially described as "suppressive" lymphocytes in the 1980s. However, it took almost 20 years until the concept of Treg-mediated immune control in its present form was finally established. Tregs are obligatory for self-tolerance and defects within their [...] Read more.
Regulatory T cells (Tregs) were initially described as "suppressive" lymphocytes in the 1980s. However, it took almost 20 years until the concept of Treg-mediated immune control in its present form was finally established. Tregs are obligatory for self-tolerance and defects within their population lead to severe autoimmune disorders. On the other hand Tregs may promote tolerance for tumor antigens and even hamper efforts to overcome it. Intratumoral and systemic accumulation of Tregs has been observed in various types of cancer and is often linked to worse disease course and outcome. Increase of circulating Tregs, as well as their presence in mesenteric lymph nodes and tumor tissue of patients with colorectal cancer de facto suggests a strong involvement of Tregs in the antitumor control. This review will focus on the Treg biology in view of colorectal cancer, means of Treg accumulation and the controversies regarding their prognostic significance. In addition, a concise overview will be given on how Tregs and their function can be targeted in cancer patients in order to bolster an inherent immune response and/or increase the efficacy of immunotherapeutic approaches. Full article
(This article belongs to the Special Issue Prognostic and Predictive Factors in Colorectal Cancer)
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