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Chromosomal Copy Number Alterations Are Associated with Persistent Lymph Node Metastasis After Chemoradiation in Locally Advanced Rectal Cancer

Chen, Zhenbin Ph.D.1; Liu, Zheng Ph.D.2; Deng, Xutao Ph.D.2; Warden, Charles M.A.2; Li, Wenyan B.A.1; Garcia-Aguilar, Julio M.D., Ph.D.1

Diseases of the Colon & Rectum: June 2012 - Volume 55 - Issue 6 - p 677–685
doi: 10.1097/DCR.0b013e31824f873f
Original Contribution

BACKGROUND: Lymph node metastasis is an important indicator of oncologic outcome for patients with rectal cancer. Identifying predictive biomarkers of lymph node metastasis could therefore be clinically useful.

OBJECTIVE: The aim of this study was to assess whether chromosomal copy number alterations can assist in predicting persistent lymph node metastasis in patients with locally advanced rectal cancer treated with preoperative chemoradiation therapy.

DESIGN: This is a nonrandomized, prospective phase II study.

SETTING: This study took place in a multi-institutional setting.

PATIENTS: Ninety-five patients with stage II (cT3-4, cN0) or stage III (any cT, cN1-2) rectal cancer were included.

INTERVENTION: Patients were treated with preoperative chemoradiation therapy followed by total mesorectal excision. Pretreatment biopsy tumor DNA and surgical margin control DNA were extracted and analyzed by oligonucleotide array-based comparative genomic hybridization. Chromosomal copy number alterations were correlated with persistent lymph node metastasis. Finally, a model for predicting persistent lymph node metastasis was built.

MAIN OUTCOME MEASURES: The primary outcomes assessed were whether chromosomal copy number alterations are associated with persistent lymph node metastasis in patients with rectal cancer and the accuracy of oligonucleotide array-based comparative genomic hybridization for predicting lymph node metastasis.

RESULTS: Twenty-five of 95 (26%) patients had lymph node metastasis after chemoradiation. Losses of 28 chromosomal regions, most notably in chromosome 4, were significantly associated with lymph node metastasis. Our predictive model contained 65 probes and predicted persistent lymph node metastasis with 68% sensitivity, 93% specificity, and positive and negative predictive values of 77% and 89%. The use of this model accurately predicted lymph node status (positive or negative) after chemoradiation therapy in 82 of 95 patients (86%).

LIMITATIONS: The patient cohort was not completely homogeneous, which may have influenced their clinical outcome. In addition, although we performed rigorous, statistically sound internal validation, external validation will be important to further corroborate our findings.

CONCLUSIONS: Copy number alterations can help identify patients with rectal cancer who are at risk of lymph node metastasis after chemoradiation.

1Department of Surgery, City of Hope, Duarte, California

2Bioinformatics Core, Department of Molecular Medicine, City of Hope, Duarte, California

Funding/Support: This study was supported by the National Institutes of Health, National Cancer Institute R01 Grant CA090559 (to J.G.A.).

Financial Disclosures: None reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (www.dcrjournal.com)

ClinicalTrials.gov identifier NCT00335816.

Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Vancouver, BC, Canada, May 14 to 18, 2011. Awarded Best Rectal Cancer Poster provided by Richard Wolf Medical Instruments Corporation in memory of Dr Gerhard F. Buess.

Correspondence: Julio Garcia-Aguilar, M.D., Ph.D., Department of Surgery, City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010. E-mail: jgarcia-aguilar@coh.org

© The ASCRS 2012