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Original Investigation |

Expression of HLA Class I Antigen, Aspirin Use, and Survival After a Diagnosis of Colon Cancer

Marlies S. Reimers, MD1; Esther Bastiaannet, PhD1,2; Ruth E. Langley, MD3; Ronald van Eijk, PhD4; Ronald L. P. van Vlierberghe, BSc1; Valery E. P. Lemmens, PhD5; Myrthe P. P. van Herk-Sukel, PhD6; Tom van Wezel, PhD4; Riccardo Fodde, PhD7; Peter J. K. Kuppen, PhD1; Hans Morreau, MD4; Cornelis J. H. van de Velde, MD1; Gerrit Jan Liefers, MD1
[+] Author Affiliations
1Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
2Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
3Medical Research Council Clinical Trials Unit, University College, London, England
4Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
5Comprehensive Cancer Centre South, Eindhoven Cancer Registry, Eindhoven, the Netherlands
6PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands
7Department of Experimental Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
JAMA Intern Med. 2014;174(5):732-739. doi:10.1001/jamainternmed.2014.511.
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Importance  Use of aspirin (which inhibits platelet function) after a colon cancer diagnosis is associated with improved overall survival. Identifying predictive biomarkers of this effect could individualize therapy and decrease toxic effects.

Objective  To demonstrate that survival benefit associated with low-dose aspirin use after a diagnosis of colorectal cancer might depend on HLA class I antigen expression.

Design, Setting, and Participants  A cohort study with tumor blocks from 999 patients with colon cancer (surgically resected between 2002 and 2008), analyzed for HLA class I antigen and prostaglandin endoperoxide synthase 2 (PTGS2) expression using a tissue microarray. Mutation analysis of PIK3CA was also performed. Data on aspirin use after diagnosis were obtained from a prescription database. Parametric survival models with exponential (Poisson) distribution were used to model the survival.

Main Outcomes and Measures  Overall survival.

Results  The overall survival benefit associated with aspirin use after a diagnosis of colon cancer had an adjusted rate ratio (RR) of 0.53 (95% CI, 0.38-0.74; P < .001) when tumors expressed HLA class I antigen compared with an RR of 1.03 (0.66-1.61; P = .91) when HLA antigen expression was lost. The benefit of aspirin was similar for tumors with strong PTGS2 expression (0.68; 0.48-0.97; P = .03), weak PTGS2 expression (0.59; 0.38-0.97; P = .02), and wild-type PIK3CA tumors (0.55; 0.40-0.75; P < .001). No association was observed with mutated PIK3CA tumors (0.73; 0.33-1.63; P = .44).

Conclusions and Relevance  Contrary to the original hypothesis, aspirin use after colon cancer diagnosis was associated with improved survival if tumors expressed HLA class I antigen. Increased PTGS2 expression or the presence of mutated PIK3CA did not predict benefit from aspirin. HLA class I antigen might serve as a predictive biomarker for adjuvant aspirin therapy in colon cancer.

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Figure 1.
Representative Images of Immunohistochemical Staining for HLA Class I Antigen Expression (HCA2 and HC10) and Prostaglandin Endoperoxide Synthase 2 (PTGS2)

Staining performed according to standard protocols, as detailed in the Methods section. A, HC10-negative tumor. B, HC10-positive tumor. C, HCA2-negative tumor. D, HCA2-positive tumor. E, Tumor with weak PTGS2 expression. F, Tumor with strong PTGS2 expression. G, Enlarged view of sample in F. See the Tissue Microarray Production and Immunohistochemistry subsection of the Methods section for details of the immunohistochemical staining methods used. Original magnifications ×20 (A-F) and ×40 (G).

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Figure 2.
Curves for Overall Survival in Patients With Colon Cancer According to Aspirin Use After Diagnosis or Nonuse of Aspirin After Diagnosis and HLA Class I Antigen Expression

A, Overall survival among patients with loss of HLA class I antigen in tumor sections. B, Overall survival among patients with expression of HLA class I antigen in tumor sections.

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