HLA Determines Response to Aspirin in Colon Cancer

Roxanne Nelson

October 01, 2013

Aspirin use appears to improve outcomes in patients with colorectal cancer, but the exact mechanism of action has been unclear. Now, researchers might have figured out at least part of the puzzle, and the results could lead to a way to identify patients most likely to benefit from aspirin use.

New data, presented here at the European Cancer Congress 2013, show that aspirin improves outcomes in patients with colorectal cancer whose tumors express human leukocyte antigen (HLA) class I genes.

"Low-dose aspirin was associated with a survival benefit in HLA-expressing tumors only," said study author Marlies Reimers, MD, a PhD student in the Department of Surgery at Leiden University Medical Center in the Netherlands, during a press briefing.

"Therefore, HLA might serve as a predictive biomarker to help identify patients who might benefit from aspirin therapy after diagnosis," she explained. "We believe there might be tumor cell to platelet signaling involved, and that HLA is needed for this signaling and for metastasis."

Protective Effect on Colon Cancers

Aspirin use has been associated with a lower risk for colon cancer, especially hereditary forms of the disease, and for polyp formation. In addition, previous studies have shown that aspirin use after diagnosis is associated with a survival advantage in colon cancer patients, the researchers note.

The reasons for this protective effect are not clear, but Dr. Reimers and colleagues surmised that it could be related to selective inhibition of cyclooxygenase (COX)-2.

Approximately 70% of all colon cancers express COX-2, which is related to tumorigenesis and might, therefore, influence the effect of aspirin on prognosis. In addition, activating mutations of PIK3CA oncogenes are frequently found in colorectal cancer.

Previous research has shown that platelets are involved in the spread of cancer through the bloodstream, Dr. Reimers explained. The fact that aspirin inhibits platelets might explain the protective effect, she added.

Pharmacologic data indicate that low-dose aspirin almost exclusively inhibits platelets, and platelets are thought to protect tumor cells from elimination by the immune system. "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," she explained. "Aspirin could help to unmask those tumor cells by attacking platelet formation so that the immune cells can detect and eliminate them."

Patterns of Protein Expression

Dr. Reimers and colleagues investigated 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 from 1998 to 2007. The study population consisted of 999 patients who were registered in the community pharmacy database of the PHARMO record linkage system.

The team used cancer tissue microarrays to look at the expression of HLA class I genes and the COX-2 enzyme. They also extracted DNA from 663 tumors to look for mutations in the PIK3CA gene.

They found that the use of low-dose aspirin (80 mg a day) after a cancer diagnosis improved survival only in patients with tumors expressing HLA class I genes. In fact, HLA class I patients who used aspirin were half as likely to die during the average 4-year follow-up period than those who did not use aspirin.

The protective effect of aspirin was not seen in patients with tumors not expressing HLA class I genes.

Dr. Reimers noted that when the analysis was stratified for COX-2 expression and PIK3CA mutation status, no differences were seen in survival benefit.

More Studies Needed

These results are very interesting, said Peter Naredi, MD, professor of surgery and chair of the Department of Surgery at Sahlgrenska University Hospital in Gothenburg, Sweden.

"The idea that aspirin can enhance the effect of our immune system and that we might be able to identify cancer patients who best benefit from it is worth further study," he said in a statement. It is hoped that "ongoing placebo-controlled randomized trials evaluating the effect of aspirin in colorectal cancer can strengthen the evidence that aspirin is useful in patients with HLA class I expression."

The authors have disclosed no relevant financial relationships.

European Cancer Congress 2013 (ECCO-ESMO-ESTRO): Abstract 2183. Presented September 30, 2013.

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