High Nuclear Hypoxia-Inducible Factor 1 Alpha Expression Is a Predictor of Distant Recurrence in Patients With Resected Pancreatic Adenocarcinoma

Abstract

Purpose Nuclear Hypoxia-Inducible Factor 1 Alpha (HIF1a) is involved in tumor response to microenvironmental stress and may initiate development of micrometastases and chemoradiation resistance. The goal of this analysis was to evaluate HIF1a expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) following pancreatic adenocarcinoma (PAC) resection. Materials/Methods Tissue specimens were collected from 98 patients with PAC who underwent resection without neoadjuvant therapy between January 2000 and December 2011. LR was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. DR was defined as radiographically or pathologically confirmed recurrent disease in other sites. IHC staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF1a overall expression score was defined as high percentage and intensity staining and score>1.33. Univariate analysis was performed for HIF1a score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results Median follow-up time for all patients was 16.3 months. 8 (8%) patients demonstrated isolated LR, 26 (26.5%) patients had isolated DR, and 13 patients had both LR and DR. 53 (54%) patients had high HIF1a expression and 45 (46%) patients had low HIF1a expression. High HIF1a expression was significantly associated with DR (p=0.03) and low HIF1a expression was significantly associated with isolated LR (p=.03). On multivariate logistic regression analysis, high HIF1a was the only significant predictor of DR (OR=2.46 [95% CI 1.06–5.72]; p=.03). In patients with a known recurrence, a HIF1a score ≥ 2.5 demonstrated a specificity of 100% for DR. Conclusions High HIF1a expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. HIF1a expression may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.

Distal pancreatectomy with celiac axis resection: what are the added risks?

“…The ability to predict patterns of failure based on tumour biology remains a major challenge in defining patients who would benefit from such an aggressive surgical approach. Previous reports have demonstrated that the loss of SMAD4 and the increased expression of nuclear hypoxia‐inducible factor 1 α (HIF‐1 α ) are important predictors for distant failure in patients undergoing resection of pancreatic adenocarcinoma . More recently, new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2) have been discovered, and patterns of variation in chromosomal structure based on whole‐genome sequencing have facilitated the classification of PDACs into four subtypes: stable, locally rearranged, scattered and unstable .…”

“…Previous reports have demonstrated that the loss of SMAD4 and the increased expression of nuclear hypoxia-inducible factor 1a (HIF-1a) are important predictors for distant failure in patients undergoing resection of pancreatic adenocarcinoma. 29,30 More recently, new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2) have been discovered, and patterns of variation in chromosomal structure based on whole-genome sequencing have facilitated the classification of HPB PDACs into four subtypes: stable, locally rearranged, scattered and unstable. 31 While the implications of these findings are broad, their clinical utility in selecting patients that would benefit from a more aggressive surgical approach remains to be seen.…”

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

“…Importantly, recurrence can occur at the primary tumor site even after tumor resection with histopathologically confirmed complete margins 5 . As previously reported, microscopic tumors can survive and resume growth if the tumor microenvironment (TME) is suitably modulated by angiogenic activity, intratumoral hypoxia, and recruitment of tumor‐infiltrating regulatory T‐cells (Tregs) 6‐8 . Therefore, therapeutically targeting the TME could prove an effective strategy to prevent relapse or delay tumor growth after surgery.…”

EGLN Inhibition Reduces Gastrointestinal Radiation Toxicity and Improves Survival in a Murine Model of Locally Advanced Pancreatic Cancer

“…Thus, with better systemic treatments, durable local control through dose-escalated radiation may become even more critical in this patient population. Incorporating predictive and prognostic molecular (3,(43)(44)(45)(46)(47)(48) as well as radiomic biomarkers (49) into the clinical translation of these studies will help guide clinical decision making and determine patients most likely ot benefit from doseescalated radiation therapy. Thus, our finding that intestinal radioprotection by EGLN inhibition enables potentially definitive radiation treatments for LAPC effective should justify clinical trials to test this paradigm for our patients who would otherwise have no options for long-term local control.…”