Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

In this article, the authors review the current status of biomarker research in the adjuvant treatment of colon cancer, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

Abstract

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

Related collections

Most cited references 130

Record: found
Abstract: found
Article: not found

Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

Rafael Amado, Michael Wolf, Marc Peeters … (2008)

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

0 comments Cited 803 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genetic instabilities in human cancers.

C Lengauer, K Kinzler, B Vogelstein (1998)

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

0 comments Cited 726 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

Andrea Bild, Guang Yao, Jeffrey Chang … (2006)

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

0 comments Cited 673 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Oncologist

Journal ID (iso-abbrev): Oncologist

Journal ID (pmc): oncologist

Journal ID (hwp): theoncologist

Journal ID (publisher-id): The Oncologist

Title: The Oncologist

Publisher: AlphaMed Press (Durham, NC, USA )

ISSN (Print): 1083-7159

ISSN (Electronic): 1549-490X

Publication date (Print): April 2010

Publication date (Electronic): 29 March 2010

Volume: 15

Issue: 4

Pages: 390-404

Affiliations

[1] ^aDigestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium;

[2] ^bDepartment of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA;

[3] ^cDepartment of Pathology, Lausanne University, Lausanne, Switzerland;

[4] ^dKeck School of Medicine, University of Southern California, Los Angeles, California, USA;

[5] ^eMedical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA;

[6] ^fDepartment of Urology and

[7] ^gDepartment of Surgery, University of California, San Francisco, CA, USA;

[8] ^hDepartment of Pharmacology & Toxicology, University of Utah, Salt Lake City, Utah, USA;

[9] ⁱDepartment of Pathology, Virginia Mason Medical Center, Seattle, Washington, USA;

[10] ^jAlmac Diagnostics, Cambridge, Massachusetts, USA;

[11] ^kSchool of Molecular Medical Sciences, University of Nottingham, Nottingham, UK;

[12] ^lDepartment of Pathology, Leiden University Medical Center, Leiden, The Netherlands;

[13] ^mCancer Research UK, London Research Institute, Royal Marsden Hospital, London, UK;

[14] ⁿMolecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK;

[15] ^oSwiss Institute of Bioinformatics, Lausanne, Switzerland;

[16] ^pDepartment of Surgical and Morphological Science, University of Genova, Genova, Italy;

[17] ^qOncosurgery, University Hospital of Geneva, Geneva, Switzerland

Author notes

Correspondence: Sabine Tejpar, M.D., Ph.D., Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, B - 3000 Leuven, Belgium. Telephone: 32-16-344218; Fax: 32-16-344419; E-mail: sabine.tejpar@ 123456uz.kuleuven.ac.be

Disclosures: Sabine Tejpar: None; Monica Bertagnolli: Honoraria: Pfizer; Fred Bosman: Research funding/contracted research: Pfizer; Heinz-Joseph Lenz: Intellectual property rights/inventor/patent holder: Abraxis; Research funding/contracted research: Genentech, ImClone, Roche, BMS, Merck, Pfizer; Ownership interest: Responsegenetics; Levi Garraway: Consultant/advisory role: Novartis; Research funding/contracted research: Novartis; Frederic Waldman: None; Robert Warren: Research funding/contracted research: NCCN; Andrea Bild: None; Denise Collins-Brennan: None; Hejin Hahn: None; D. Paul Harkin: Employment/leadership position: Almac Diagnostics; Ownership interest: Almac Diagnostics; Richard Kennedy: Employment/leadership position: Almac Diagnostics; Mohammad Ilyas: None; Hans Morreau: None; Vitali Proutski: None; Charles Swanton: None; Ian Tomlinson: None; Mauro Delorenzi: None; Roberto Fiocca: Research funding/contracted research: Pfizer; Eric Van Cutsem: Research funding/contracted research: Pfizer; Arnaud Roth: Honoraria: Pfizer.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

Article

Publisher ID: 3590874

DOI: 10.1634/theoncologist.2009-0233

PMC ID: 3227961

PubMed ID: 20350999

SO-VID: 6e385d69-6149-469d-84d3-f0074c38b231

License:

available online without subscription through the open access option.

History

Date received : 28 September 2009

Date accepted : 22 February 2010

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.