Gloria M. Petersen: Toward Pancreatic Cancer Prevention

Over the last few years, we hear of progress in the War on Cancer, with declines in incidence and mortality overall, and significant progress against many of the top cancers. One cancer, however, that has been an enduring enigma to biomedical research has been pancreatic cancer. No reliable screening tests or cures are available. Among the leading cancers, it has the worst survival and is the least studied. The incidence and mortality rate statistics have remained largely unchanged since 1973, and the 5-year survival rate has been less than 4% for decades.

At the same time, pancreatic cancer has been increasing in frequency. The American Cancer Society estimates that in 2008 there will be 37,170 new cases of pancreatic cancer and 34,290 deaths. (1) This means that over 20% more new cases will be diagnosed this year as compared to five years earlier, even as the U.S. incidence rate holds steady. As health care professionals are aware, more Americans in coming years are expected to continue developing this cancer as the "baby-boom" generation ages, because the median age at diagnosis is around 70 years. The high mortality rate of pancreatic cancer is primarily due to the advanced stage at diagnosis in the majority of cases: by the time of diagnosis, eighty percent of pancreatic cancers are no longer localized to the pancreas.

If we are to make inroads in the early detection and prevention of pancreatic cancer, it is essential to understand its causes. Epidemiology presents a set of strategies to illuminate this understanding. A variety of studies have examined different suspected risk factors, including diet, occupation, physical activity, anthropometrics, hormones, cigarette smoking, prior chronic diseases, medications, genetics, and so on. Several factors that have consistently been associated with an increased risk (around two- to three-fold that of the general population risk) of pancreatic cancer include cigarette smoking, high usual adult body mass index, and a family history of pancreatic cancer. (2,3) Other studies have shown that certain diseases, such as chronic pancreatitis and diabetes mellitus, are risk factors. (4) Interestingly, in a small proportion of cases, diabetes may be caused by the tumor itself. Observations that over 70% of pancreatic cancer patients present at the time of diagnosis with elevated fasting blood glucose or diabetes have led to further studies suggesting that the tumor may induce diabetes up to three years prior to the pancreatic cancer diagnosis. (5,6) This presents a promising opportunity for earlier intervention; research is ongoing.

Family history studies have offered an important line of research focused on understanding and discovering the genetic basis of pancreatic cancer. The hope is that genetic testing for pancreatic cancer could identify high risk individuals who would be recommended for more vigilant evaluation, and to whom future preventive strategies could be targeted. Research in this area has provided new insights. While about 90% of pancreatic cancer patients report no family history of pancreatic cancer, familial aggregation in the remaining 10% of patients is thought to be due to genetic susceptibility or shared family environment and exposures, or a combination of both. Studies have also shown that the age at which pancreatic cancer occurs among members of familial pancreatic cancer kindreds may be younger than the nonfamilial patients, around 5 to 6 years younger on average (3), and certain types of cancers that cluster in families (breast, ovarian, colorectal cancers or melanoma) may also be associated with younger age at diagnosis in these families. (7) It has also been observed that risk increases with the number of blood relatives affected with pancreatic cancer in a kindred.

There is now ample evidence that there is etiologic heterogeneity in pancreatic cancer (i.e., there are multiple causes). As an example, among the patients who have familial clustering of pancreatic cancer, there are several hereditary conditions which have known genes identified, and that are associated with increased risk of pancreatic cancer among family members (Table 1). While these known conditions account for around 1% of all pancreatic cancers, they also constitute the best opportunity at present for families that can be offered services in cancer genetic risk assessment clinics. Risk assessment and genetic testing are currently feasible, but should be accompanied by careful genetic counseling. (8) Once a genetic mutation carrier has tested positive for any of these genes, there still remains a challenge as to next steps. There are no clear evidence-based guidelines for screening or managing high risk individuals or genetic mutation carriers for the prevention of pancreatic cancer, although anecdotal experiences and small clinical studies give us some perspective on the potential benefits and hazards. (9,10)

There still remains a sizable proportion of pancreatic cancer families that are not explained by known genes. There is ongoing research to characterize the role of genes in these and the nonfamilial patients. There are presently two major initiatives funded by the National Cancer Institute: PACGENE3 is searching for families which contain two or more members affected with pancreatic cancer which will be studied by linkage analysis, and PanScan is pooling data and biospecimens on thousands of patients to conduct a genomewide scan.

The prospects for prevention of pancreatic cancer are guardedly optimistic. There are multiple initiatives to identify genes, to better identify those who are at risk, and to more effectively screen these individuals. Interventions to prevent cancer in those found to be at risk can then follow.

References

1. American Cancer Society. Cancer Facts and Figures 2008. Atlanta, GA. (view PDF)
2. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Practice & Research Clinical Gastroenterology 20:197-209, 2006.
3. Petersen GM, de Andrade M, Goggins M, Hruban RH, Bondy M, Korczak JF, Gallinger S, Lynch HT, Syngal S, Rabe KG, Seminara D, Klein AP. Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium. Cancer Epidemiology Biomarkers and Prevention 15:704-10, 2006.
4. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta- analysis. JAMA. 1995;273(20):1605-9.
5. Chari ST, Leibson CL, Rabe KG, Ransom JE, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: A population-based study. Gastroenterology 129:504-11, 2005.
6. Chari St, Leibson CL, Rabe KG, Timmons LJ, Ransom J, de Andrade M, Petersen GM. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134:95-101, 2008.
7. McWilliams RR, Bamlet WR, Rabe KG, Olson JE, de Andrade M, Petersen GM. Association of family history of specific cancers with a younger age of onset of pancreatic adenocarcinoma. Clin Gastroenterol Hepatol.4:1143-7, 2006.
8. Lindor NM, McMaster ML, Lindor CJ, Greene MH. Pancreatic cancer, hereditary. In Concise Handbook of Familial Cancer Susceptibility Syndromes, 2nd edition. Journal of the National Cancer Institute Monographs, No. 38, pp. 66-67, 2008.
9. Canto MI, Goggins M, Hruban RH, Petersen GM, Giardiello FM, Yeo C, Fishman EK, Brune K, Axilbund J, Griffin C, Ali s, Richman J, Jagannath S, Kantsevoy SV, Kalloo AN. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clini Gastroenterol Hepatol 4:766-781, 2006.
10. Brand RE, Lerch MM, Rubenstein WS, Neoptolemos JP, Whitcomb DC, Hruban RH, Brentnall TA, Lynch HT, Canto MI, et al. Advances in counseling and surveillance of patients at risk for pancreatic cancer. Gut 56:1460-9, 2007.