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Value of Primary Tumor Gene Signatures in Colon Cancer When National Quality Standards are Adhered to: Preliminary Results of an International Prospective Multicenter Trial

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The purpose of this study was to determine if gene signatures are informative in colon cancer (CC) when National Quality Standards (NQS) are adhered to. Several studies have demonstrated the prognostic potential of gene signatures in primary CC. This has never been evaluated prospectively with adherence to NQS.

Methods

This was a prospective, international, multicenter trial. Eligibility criteria were: no distant metastasis, ≥12 lymph nodes (LNs), and no adjuvant chemotherapy for LN-negative CC. RNA from frozen tumor samples was considered reliable if RNA Integrity Number >9. Using an Agilent whole human genome array, 44,000 genes were analyzed in primary tumors for differential gene expression (DGE). ANOVA applied at 2-fold expression level was performed in at least 8 experiments to obtain the DGEs.

Results

Molecular analysis was completed in 113 of 128 patients. With median follow-up of 27 months, 11.5 % recurred within 3 years after surgery. Significant DGE was identified in recurrent tumors reflected by upregulation (UR) in cellular proliferation and by downregulation (DR) in prodifferentiating panel of 9 genes, independent of T or N classification. By multivariate analysis 3-year disease-free survival was 12.5 % in the UR/DR group versus 93.4 % in the non-UR/DR group (p < .0001; HR = 24.2; 95 % CI 4.8–120.4).

Conclusions

This is the first prospective trial to evaluate gene signatures in CC with adherence to a 12-node minimum quality standard. Certain molecular pathways may be prognostically relevant if both surgery and pathology are standardized, regardless of T or N classification. Careful consideration should be made to include surgical quality measures when planning clinical trials to evaluate the true effect of molecular markers in CC.

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Acknowledgment

Thanks to Tiffany Felix, Dr. Alix Norris, the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the Bon Secours Virginia Foundation.

Disclosure

The authors have no financial or commercial interest related to this research. The financial and material support from this project originated from NIH R01 Grant (5RO1CA090848), United States Military Cancer Institute (USMCI), and the California Oncology Research Institute (CORI). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Cancer Institute or the National Institutes of Health.

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Authors and Affiliations

  1. John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA

    Anton J. Bilchik MD, PhD

  2. David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA

    Anton J. Bilchik MD, PhD, Zev A. Wainberg MD, Dennis J. Slamon MD, PhD & David Chen MD

  3. California Oncology Research Institute, Santa Monica, CA, USA

    Anton J. Bilchik MD, PhD

  4. United States Military Cancer Institute, Washington, DC, USA

    Anton J. Bilchik MD, PhD, Aviram Nissan MD, Mladjan Protic MD & Alexander Stojadinovic MD

  5. Hadassah Medical Center, Jerusalem, Israel

    Aviram Nissan MD

  6. Translational Oncology Research Labs, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

    Zev A. Wainberg MD, Dennis J. Slamon MD, PhD & Hsiao-Wang Chen MS

  7. University of Novi Sad, Novi Sad, Serbia

    Mladjan Protic MD, Itzhak Avital MD & Alexander Stojadinovic MD

  8. Bon Secours Cancer Institute, Richmond, VA, USA

    Itzhak Avital MD & Alexander Stojadinovic MD

  9. Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Alexander Stojadinovic MD

  10. Department of Medicine, Statistics Core, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA

    Myung Sim PhD & David Elashoff PhD

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  1. Anton J. Bilchik MD, PhD
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  2. Zev A. Wainberg MD
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  3. Aviram Nissan MD
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  4. Dennis J. Slamon MD, PhD
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  8. David Chen MD
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Correspondence to Anton J. Bilchik MD, PhD.

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Bilchik, A.J., Wainberg, Z.A., Nissan, A. et al. Value of Primary Tumor Gene Signatures in Colon Cancer When National Quality Standards are Adhered to: Preliminary Results of an International Prospective Multicenter Trial. Ann Surg Oncol 22, 535–542 (2015). https://doi.org/10.1245/s10434-014-4013-y

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