Low Levels of Protein May Predict Risk of Pancreatic Cancer

BOSTON, Aug. 16 -- A previously unsuspected independent risk factor for pancreatic cancer may be a low level of plasma insulin-like growth factor binding protein-1 (IGFBP-1), found researchers here.

IGFBP-1 is a downstream target of insulin and inhibits insulin-like growth factor I (IGF-I) activity. Because IGF-I has growth-promoting effects on pancreatic cancer cells, and elevated fasting serum insulin has been linked to pancreatic cancer risk, the investigators looked to see whether prediagnostic plasma levels of IGFBP-1 are associated with pancreatic cancer risk.

The finding that IGFBP-1 seemed to be a pancreatic cancer risk factor emerged from a prospective, case-control study with 573 participants reported in the Aug. 15 issue of Cancer Research by a team led by Brian Wolpin, M.D., of the Dana-Farber Cancer Institute.

The 144 cases and 429 controls, matched for date of birth, smoking status, and fasting status, came from the Health Professionals Follow-up Study, the Nurses' Health Study, the Physicians' Health Study, and the Women's Health Initiative, said Dr. Wolpin and colleagues.

The investigators collected blood samples from the 573 participants and measured circulating IGFBP-1. The measurements were repeated four or more years later.

Study participants in the lowest quartile of IGFBP-1 were more than twice as likely to develop pancreatic cancer as were those participants with higher levels of plasma IGFBP-1. The influence of IGFBP-1 increased with time since blood collection.

Specifically, participants in the lowest quartile for IGFBP-1 who were diagnosed with pancreatic cancer eight or more years after blood draw had nearly 3.5 times the risk for developing pancreatic cancer as those participants in the upper quartiles.

Participants in the lowest quartile of plasma IGFBP-1 had a relative risk of 2.07 for pancreatic cancer, compared with their counterparts with higher levels of plasma IGFBP-1 (95% CI 1.26-3.39). These findings held even after researchers adjusted for plasma insulin growth factor-1, C-peptide and IGFBP-3; suggesting an independent effect of IGFBP-1 on pancreatic cancer risk.

The adjusted relative risk for participants diagnosed with pancreatic cancer eight or more years after blood collection was 3.47 (95% CI 1.48-8.14). Overall, only patients in the lowest quartile for IGFBP-1 were found to have an increased risk for pancreatic cancer.

Moreover, the study found that the effect of IGFBP-1 was strongest among those participants who never smoked cigarettes (RR 3.30; 95% CI, 1.48-7.48). The influence of low IGFBP-1 also seemed to be greater among participants with higher plasma levels of C-peptide. The study findings also held in participants with diabetes and were not affected by the time between a participant's last meal and the time of the blood draw.

IGFBP-1 is known to decline in response to obesity and a sedentary lifestyle, two suspected risk factors for pancreatic cancer. Although the exact mechanism by which IGFBP-1 may affect pancreatic cancer risk is not known, the researchers speculated that higher amounts of IGFBP-1 are able to absorb more insulin growth factor, leaving less available to encourage pancreatic cancer cell growth.

They also suggested that IGFBP-1 may have some anti-cancer properties of its own. Previous research has linked low levels of plasma IGFBP-1 to a risk of colorectal and endometrial cancer, but not postmenopausal breast cancer or lung cancer.

"Further studies of the interaction of insulin and the IGF axis in pancreatic cancer are needed to better understand the mechanism by which anthropometric factors and plasma levels of insulin and IGFBP-1 alter the risk for this highly lethal malignancy," the study authors concluded.