Serum autoantibodies to pancreatic cancer antigens as biomarkers of pancreatic cancer in a San Francisco Bay Area case–control study

Pancreatic cancer is among the most fatal cancers diagnosed in adult men and women in the U.S. Each year a similar number of newly diagnosed pancreatic cancer cases and deaths occur and the number of new cases continues to increase (1). Recently published data suggest that pancreatic cancer develops slowly over many years (2); however, most patients are diagnosed with late stage disease that is refractory to current therapies. Vague and non-specific symptoms that are consistent with other benign gastrointestinal conditions are likely to contribute to the typically late diagnosis. Increasing age, smoking, diabetes, obesity, heavy alcohol consumption, family history and several rare genetic syndromes are known risk factors for pancreatic cancer but explain little of the disease incidence. Pancreatic cancer, like brain cancers and lymphoma is clearly associated with allergies and allergic conditions (3-6), indicative of an interaction between the immune system and the cancer. Currently used biomarkers, CA19-9 and CEA, have high false-positive rates for pancreatic cancer and while new imaging technologies are helpful they tend to identify more advanced disease. Biomarkers are critically needed to better understand the etiology of this disease, to identify new therapeutic targets and to develop early detection tests to reduce incidence and improve patient prognosis. Identification of sensitive and specific biomarkers that can be screened using biospecimens obtained through minimally invasive methods (i.e. peripheral blood) has been challenging. Autoantibodies to tumor-associated antigens (TAAs) have been reported for a number of other cancers [ovarian (7-9), breast (10), lung (11), hepatocellular (12), colorectal(13-15)]. Originally explored for development of immunogenic cancer vaccines, autoantibodies to TAAs have more recently been studied for their potential as biomarkers for cancer screening as they may be present in serum months to years before the cancer is symptomatic (16). Specific autoantibodies have been associated with several cancers or with non-cancer conditions whereas others have shown promise as biomarkers for specific types of cancer (17). Further data show that because cancer is a heterogeneous disease, and those with cancer respond to their own tumors in an individual, HLA-restricted fashion, the frequency of specific autoantibodies to TAAs is only about 30% (18). In addition to their potential role as diagnostic markers, there is some evidence to suggest that autoantibodies to tumor-associated antigens may be useful prognostic or clinical indicators for cancer including ovarian, lung and breast(19-22). While poor clinical response and reduced survival in platinum resistant/refractory ovarian cancer was observed for patients with high serum anti-MUC1 antibody levels(22), separate studies showed improved survival or clinical prognosis with detectable serum autoantibodies to p53 in serous ovarian cancer patients(20), to endostatin in metastatic breast cancer patients(21) and to alpha-2-glycoprotein 1, zinc (AZGP1, a protein overexpressed in smokers) in early stage lung adenocarcinoma patients(19). Further, results also suggest that a specific marker may be useful for diagnosis, prognosis, or both diagnosis and prognosis, emphasizing the importance of separately evaluating serum autoantibodies for use in diagnostic and prognostic biomarker panels. Given the current evidence, a panel of autoantibodies will be needed to provide the level of sensitivity and specificity necessary for an effective screening tool. Recent intensive screens for autoantibodies to pancreatic cancer have produced several candidates; we selected 3 promising biomarkers [CTDSP1(23), MAPK9 (8), NR2E3 (8)] to explore their association with pancreatic cancer and pancreatic cancer survival in our San Francisco Bay Area population-based epidemiological case-control study.