Although previous research has shown that taking low dose aspirin after being diagnosed with colon cancer improves patient outcome, the reasons why this happens remained, so far, unknown.

Now, new research shows that aspirin improves outcome in patients whose tumour cells express a specific protein known as Human Leukocyte Antigen class I (HLA class I), a cell-surface protein produced by a collection of genes involved in the functioning of the immune system. The outcomes of the study have been presented at the 2013 European Cancer Congress (ECC2013) being held in Amsterdam, The Netherlands, September 27 – October 1, 2013.

Effect on blood clothing
The results mean that HLA class I could be used in the future to predict whether or not a patient would benefit from aspirin. The findings also suggest that aspirin?s role in improved patient survival could be explained by the interaction of the body?s immune system with the effect of aspirin on platelets – cell fragments in the blood that are involved in clotting.

Marlies Reimers, MD, a PhD student, in the Department of Surgery, LUMC – Leiden University Medical Center, Leiden, The Netherlands, said: ?We think that platelets are involved in cancer spreading to other parts of the body by shielding tumor cells in the bloodstream so that they cannot be recognized by the immune system and can finally colonize distant organs. Aspirin could help to ?unmask? those tumor cells by attacking platelet formation, so that the immune cells can detect and eliminate them.?

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Reimers and her colleagues used tissue microarray technology [2] to investigate the pattern of protein expression in colon cancer patients whose aspirin use after cancer diagnosis was known and who were registered with the Eindhoven Cancer Registry between 1998 and 2007. The researchers studied 999 colon cancers to look at HLA class I expression, and expression of the COX-2 enzyme. They also extracted DNA from 663 tumors to look for mutations in the PIK3CA gene. Both COX-2 expression and PIK3CA mutations are known to be involved in the onset of cancer.

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Improving survival
They found that low dose (80mg a day) aspirin use after diagnosis improved survival only in patients with tumors expressing HLA class I; if these patients used aspirin they were half as likely to die during the average four years of follow-up as patients with tumours expressing HLA class I that did not use aspirin. This effect of aspirin was not seen in patients without HLA class I expression. ?Therefore, HLA class I might serve as a predictive biomarker to help identify patients who would benefit from aspirin therapy after diagnosis,? Reimers noted.

?Our results showed that there was no difference in the effect of aspirin in relation to COX-2 expression and PIK3CA mutation,? she added.

No difference in survival benefit
Until now it was assumed that COX-2 expression or PIK3CA gene mutation played a role in the effectiveness of aspirin use. However, Reimers explained,?When we stratified our analyses for COX-2 expression and PIK3CA mutation status, we did not see differences in survival benefit. For example, patients with aspirin use after diagnosis with strong COX-2 expressing tumors had the same survival benefit as tumors with weak COX-2 expression.?

Reimers and her colleagues believe their results suggest that aspirin may be acting on two different pathways in colon cancer. One pathway in the preventive setting and the other through the control of metastasis ? the spread of cancer to other parts of the body from its primary site.

?The first pathway is through PIK3CA mutations and COX-2 expression in the tumors, which seem to show more effect in the preventive setting. Studies of hereditary colorectal cancers have shown that aspirin can help to prevent the onset of cancer by limiting the formation of polyps in the bowel, which are often the forerunners of cancer, and that this is linked to PIK3CA mutations and COX-2 expression, she said.

?The second pathway, revealed by our results today, is more involved in metastasis, by influencing the platelets in the bloodstream. Although speculative, it may be that the interaction of platelets with HLA positive tumour cells circulating in the blood promotes the metastatic potential of these cells. Aspirin interferes with this interaction, thereby decreasing the risk of metastatic disease and colon cancer-related death.?

Larger studies required
The researchers say that more evidence from larger studies and clinical trials is required to support their findings. Some randomised clinical trials have started in the UK and one in Asia ? a multi-centre prospective randomized controlled phase III trial of aspirin use in colorectal cancer patients, called the ASCOLT study.[3]

Enhancing the effects of the immune system
Commenting on the results of the study, Peter Naredi, MD, Chair of the Department of surgery, Sahlgrenska University Hospital, Gothenburg, Sweden and a member of the Board of Directors of the European CanCer Organisation (ECCO), said: ?The results presented by Reimers and colleagues are very interesting. The idea that aspirin can enhance the effect of our immune system and that we might be able to identify those cancer patients who best benefit from it, is worth further studies. Ongoing placebo-controlled randomised trials evaluating the effect of aspirin in colorectal cancer can hopefully strengthen the evidence that aspirin is useful in patients with HLA class 1 expression.?[3]

For more information:
[1]Abstract no: 2183: COX-2 expression influences the prognostic effect of aspirin use after diagnosis in colon cancer patients?. Gastrointestinal Malignancies ? Colorectal Cancer II, poster discussion session, 11.30 a.m. CEST, Monday 30 September 2013, RAI Auditorium.
[2] Tissue microarray technology involves using a punching instrument to precisely place up to 1,000 tissue samples in a paraffin block for analysis of multiple components.

Clinical Trials
[3] NCT00565708 – Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers (ASCOLT) [Study Record Detail]

Educational Book
The Educational Book from ECC 2013 is published as a supplement to the European Journal of Cancer. [Download]

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