The movement to relate gene profiles and protein expression to tumor aggressiveness is as active in pancreatic cancer as in other more common tumors, according to studies presented at the 2011 Gastrointestinal Cancers Symposium, held January 20–22 in San Francisco. Two investigations in particular correlated biomarkers with outcomes after surgery and/or chemoradiation.

S100A2 and A4 Related to Poor Prognosis

Aberrant expression of two calcium-binding proteins stratifies pancreatic cancer into distinct prognostic groups and can be incorporated into nomograms to better select patients for treatment, Australian investigators reported.¹

Surgery provides the only potential for cure in pancreatic cancer, but there are no means of predicting who will benefit preoperatively. “Defining clinically and biologically relevant phenotypes in other cancers has led to substantial improvements in overall outcomes, but none have been defined for pancreatic cancer,” said David Chang, MD, of the Cancer Research Program at the Garvan Institute of Medical Research in Sydney, Australia, who is part of a team led by Professor Andrew Biankin.

Dr. Chang and colleagues evaluated the expression of two biologically relevant proteins, S100A4 and S100A2,² which are known to be related to metastatic potential, chemoresistance, and poor-prognosis cancer phenotypes. They associated the expression of these proteins with survival in a cohort of 372 patients who underwent surgical resection for pancreatic cancer and incorporated this information, along with clinicopathologic variables, into a nomogram to guide decision-making.

“A preoperative nomogram using only variables that could be measured preoperatively, such as tumor size and molecular biomarkers, predicted survival better than nomograms derived from using clinicopathologic variables, which are only determined after examination of the resected specimen,” said Dr. Chang. “Integration of S100A4 and S100A2 stratified the cohort into three distinct prognostic groups.”

Patients who lacked aberrant expression of both markers had a median survival of 34.3 months after pancreatectomy, compared with 15.6 months for those who were S100A2-negative but S100A4-positive and just 11.9 months for the S100A2-positive subset (P < .0001, see Fig. 1).

“The development and application of such nomograms in routine clinical practice has the potential to improve patient selection and, as a consequence, overall outcomes for pancreatic cancer,” Dr. Chang concluded. The investigators are now refining means of assessing biomarker status preoperatively, to put this information into clinical use.

RecQ1 A159C Polymorphism Associated with Survival

RecQ1, a DNA helicase, has been implicated in cancer and chromosome instability, and its depletion results in mitotic catastrophe and mitotic death in cancer cells. The RecQ1 A159C polymorphism was associated with a significantly reduced overall survival in patients with resectable pancreatic cancer.³

The study included 154 patients with resected pancreatic cancer enrolled on the Radiation Therapy Oncology Group (RTOG) 9704 trial of fluorouracil (5‑FU)-based chemoradiation, preceded and followed by 5-FU or gemcitabine. Investigators evaluated the association between genotype (RecQ1 A159 AA, AC, and CC) and overall survival, and found the AA genotype to be protective.

The RecQ1 variant AC/CC genotype carriers were more likely to have node-positive disease than the AA carriers (P = .03) and more likely to die (P = .032). Carriers of this allele had a 52% increased risk of death, compared to AA. Risk was increased by 57% for AC carriers (P = .027) and by 49% for CC carriers (P = .11), compared with the AA genotype, reported Donghui Li, PhD, of The University of Texas MD Anderson Cancer Center, Houston. The RecQ1 effect (AA vs AC/CC) is more definitive for patients on the 5-FU arm than for patients on the gemcitabine arm, she added.

“Our results suggest that the RecQ1 A159C genotype is a prognostic or predictive factor for patients with resectable pancreatic cancer who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation,” Dr. Li commented.

“The value of the current study is that it confirmed our previous finding that the RecQ1 A159C variant was associated with significantly reduced overall survival in patients with resectable pancreatic cancer,” Dr. Li told The ASCO Post. “The current study was conducted in patients with resected pancreatic cancer. So the chemoradiation was given before surgery in our previous study but after surgery in the current study, and the genotype effect was the same,” she noted. ■

References

1. Chang DK, Colvin EK, Scarlett CJ, et al: A molecular prognostic nomogram for resectable pancreatic cancer. Gastrointestinal Cancers Symposium. Abstract 154. Presented January 21, 2011.

2. Biankin AV, Kench JG, Colvin EK, et al: Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer. Gastroenterology 137:558-68, 568 e1-11, 2009

3. Li D, Moughan J, Crane CH, et al: Association of RecQ1 A159C polymorphism with overall survival of patients with resected pancreatic cancer: A replication study in RTOG 9704. Gastrointestinal Cancers Symposium. Abstract 156. Presented January 21, 2011.