High proliferation is independently associated with disease progression in metastatic pancreatic adenocarcinoma
Authors: S. Temraz, M. Salim Hammoud, I. Makki, S. Nassif, M. Charafeddine, D. Mukherji, A. Shamseddine
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer is an aggressive disease with a 5-year survival rate below 5%. It involves genomic alterations like mutated tumor suppressor gene p53 (TP53) and overexpressed Ki-67. We investigated the expression of Ki67 and p53 in metastatic pancreatic adenocarcinomas and analyzed their relationship with progression free survival (PFS).We also correlated their expression with PFS in two different groups of patients: gemcitabine-based treated patients (GT) versus FOLFIRINOX treated (FT) patients. Methods: This is a retrospective study done at the American University of Beirut Medical Center (AUBMC) in which we included the medical records of sixty one patients diagnosed with metastatic pancreatic cancer over a period extending from May 2000–November 2013. Patients proved to have a stage IV pancreatic adenocarcinoma, with available tissue blocks, demographic, clinical and survival data were included in this study. Pancreatectomy and biopsy specimen slides were reviewed for immunohistochemistry (IHC) staining of both p53 and Ki67. Ki-67 proliferation index was determined using the following method: 1-the tumor area was screened and foci with the highest nuclear staining were selected; 2-these foci were further subdivided into quadrants and examined at 400x magnification; 3- tumor nuclei were counted in each quadrant, and the percentage of tumor nuclei with positive staining was determined. P53 staining results were noted as an overall estimate of positive tumor nuclei, throughout the entire tumor area in the stained section. All data were collected and analyzed using the SPSS v.23.0 statistical package. Results: The mean of Ki-67 and P53 were significantly higher in the patients who had disease progression (31.0 vs 8.2, p < 0.001 and 46.9 vs 16.2; p < 0.001, respectively). The estimated cutoff value calculated by the ROC curve of Ki-67 was 12.5 and that of P53 was 15. In the overall study population, patients who had Ki67 and p53 levels greater than their corresponding cut off value had a significantly shorter PFS (Ki67 >12.5, p = 0.048; p53>15, p = 0.048). This effect was more prominent in the GT group compared to FT group. Multivariate analysis proved that Ki67 remained significantly associated with disease progression: for every one-unit increase in Ki-67 the progression risk will be increased by 1.017 times, controlling for other variables including grade, age, and P53. Ca19-9 levels were significantly higher in patients with a progressing disease (8885.3 vs 1714.4; p = 0.016). Moreover, 58% was identified by the ROC curve as the cutoff value after which there is an increased likelihood of the progression of the disease. Patients who had a decrease in CA19-9 levels 6-8 weeks after chemotherapy of > 58% had significantly longer PFS (p = 0.027). This effect was also more prominent in the GT group compared to FT group. Conclusion: Our study highlights the negative impact of high P53 and Ki67 expression on PFS in patients with metastatic pancreatic cancer. Ki-67 is an independent prognostic factor for PFS especially in the GT group.