Clues Found to Aspirin's Benefit in Colon Cancer
Clues Found to Aspirin's Benefit in Colon Cancer
03/10/2013
Aspirin's survival benefit in colon cancer correlated with the drug's antiplatelet activity but was not associated with a common tumor mutation or an enzyme linked to cancer etiology and pathogenesis, an analysis of 1,000 tumor samples showed.
Low-dose aspirin after colon cancer diagnosis was associated with 47% better survival in patients whose tumors expressed human leukocyte antigen class I (HLA-I, a marker of platelet activation and aggregation, in addition to immunologic activity). Aspirin use did not correlate with PI3KA mutation or expression of cyclooxygenase-2 (COX-2).
The results suggest that aspirin's protective effect in colon cancer relates to inhibition of platelet activity associated with tumor migration and metastasis, Marlies Reimers, MD, of Leiden University Medical Center in the Netherlands, reported here at the European Cancer Congress.
"HLA class I might serve as a predictive biomarker to help identify patients who would benefit from aspirin therapy after diagnosis of colon cancer," Reimers said during an ECC press briefing.
The results do not rule out an effect of aspirin on PI3KA or COX-2, she added. However, randomized clinical trials are needed to confirm the association between HLA-I expression and survival in colon cancer. Such a trial is underway in Asia.
"It's still too early to say 'Give all the patients aspirin,'" said Reimers.
Multiple studies have demonstrated a favorable association between aspirin use and survival in colorectal cancer, particularly tumors involving the colon. Several mechanisms have been postulated to explain the effect, but none has been definitively proven.
COX-2 expression and PIK3CA mutation are involved in cancer progression. Additionally, aspirin inhibits platelet activation and aggregation, suggesting another potential mechanism for aspirin's favorable effect on colon cancer survival.
"Platelets are thought to protect tumor cells in the blood from elimination by the immune system," said Reimers. "The aspirin benefit might depend on expression of HLA-I on the surface of tumor cells, which elicits an immune reaction."
To examine the effects of low-dose aspirin on colon tumors, Dutch investigators analyzed data for 999 colon cancer patients whose medical records established aspirin use and survival. Tumor specimens from all patients were evaluated for HLA-I and COX-2 expression. In a subset of 663 patients, tumor specimens also were analyzed for PIK3CA mutations.
The results showed that low-dose (80 mg/day) aspirin after colon cancer diagnosis reduced the likelihood of colon cancer mortality by half during 4 years of follow-up. Patients whose tumors did not express HLA class I protein derived no benefit from aspirin therapy.
The data showed no interaction between aspirin use and PI3KCA mutation or COX-2 expression, said Reimers. For example, patients whose tumors exhibited strong COX-2 expression had survival similar to that of patients whose tumors had weak COX-2 expression.
Evidence from previous studies had implicated PI3KCA and COX-2 in the risk of colon cancer death.
The results suggest aspirin acts on two different platelet-related pathways associated with colon cancer, one involving colon cancer prevention and the other involving inhibition of cancer's ability to spread from the primary site to other parts of the body.
"Our results relate to the second pathway, which is more involved in metastasis," said Reimers. "Although speculative, it may be that the interaction of platelets with HLA-positive tumor 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."
Laboratory tests to establish HLA-I expression status are simpler, more widely available, and less expensive compared with assays for PI3KCA mutation and COX-2 expression. Even so, Reimers reiterated, routine testing of colon tumors for HLA-I expression is not yet warranted.
In response to a question, Reimers acknowledged that clinical trials to evaluate HLA-I expression, low-dose aspirin, and colon cancer survival would have to overcome certain pragmatic issues. For example, low-dose aspirin is available without prescription in many parts of the world, which would allow patients in clinical trials to take aspirin on their own, regardless of treatment assignment.
The issue would be less problematic in the Netherlands, where low-dose aspirin is available only by prescription, although standard-dose aspirin is sold over the counter.
The concept that aspirin's beneficial effect on colon cancer survival relates to influence on immunologic activity is both novel and intriguing, according to Peter Naredi, MD, of Sahlgrenska University Hospital in Gothenburg, Sweden. The data reported by Reimers support continued investigation of the concept, including randomized trials to test the hypothesized effect.
Source: MedPage Today: http://www.medpagetoday.com/MeetingCoverage/ECC/42035