Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. - PubMed - NCBI
JAMA Oncol. 2017 Nov 2. doi: 10.1001/jamaoncol.2017.3420. [Epub ahead of print]
Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.
Qian ZR1,2,
Rubinson DA1,
Nowak JA2,3,
Morales-Oyarvide V1,
Dunne RF4,
Kozak MM5,
Welch MW1,
Brais LK1,
Da Silva A1,2,
Li T2,
Li W2,
Masuda A2,
Yang J2,
Shi Y2,
Gu M2,
Masugi Y2,
Bui J5,
Zellers CL1,
Yuan C1,6,
Babic A1,
Khalaf N7,
Aguirre A1,
Ng K1,
Miksad RA8,
Bullock AJ8,
Chang DT5,
Tseng JF9,
Clancy TE10,
Linehan DC11,
Findeis-Hosey JJ12,
Doyle LA3,
Thorner AR1,13,
Ducar M3,13,
Wollison B13,
Laing A13,
Hahn WC1,13,
Meyerson M1,3,13,14,
Fuchs CS1,
Ogino S1,2,6,15,
Hornick JL3,
Hezel AF4,
Koong AC16,
Wolpin BM1.
Abstract
IMPORTANCE:
Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. OBJECTIVE:
To evaluate the alterations of the 4 main driver genes in pancreatic adenocarcinoma and patient outcomes after cancer resection. DESIGN, SETTING, AND PARTICIPANTS:
This study analyzed protein expression and DNA alterations for the KRAS, CDKN2A, SMAD4, and TP53 genes by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors in 356 patients with resected pancreatic adenocarcinoma who were treated at the Dana-Farber/Brigham and Women's Cancer Center (October 26, 2002, to May 21, 2012), University of Rochester Medical Center (March 1, 2006, to November 1, 2013), or Stanford Cancer Institute (September 26, 1995, to May 22, 2013). Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HRs) and 95% CIs and adjustment for age, sex, tumor characteristics, institution, and perioperative treatment. Data were collected September 9, 2012, to June 28, 2016, and analyzed December 17, 2016, to March 14, 2017. MAIN OUTCOMES AND MEASURES:
The DFS and OS among patients with resected pancreatic adenocarcinoma. RESULTS:
Of the 356 patients studied, 191 (53.7%) were men and 165 (46.3%) were women, with a median (interquartile range [IQR]) age of 67 (59.0-73.5) years. Patients with KRAS mutant tumors had worse DFS (median [IQR], 12.3 [6.7 -27.2] months) and OS (20.3 [11.3-38.3] months) compared with patients with KRAS wild-type tumors (DFS, 16.2 [8.9-30.5] months; OS, 38.6 [16.6-63.1] months) and had 5-year OS of 13.0% vs 30.2%. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had a median (IQR) OS of 15.3 (9.8-32.7) months. Patients whose tumors lacked CDKN2A expression had worse DFS (median, 11.5 [IQR, 6.2-24.5] months) and OS (19.7 [10.9-37.1] months) compared with patients who had intact CDKN2A (DFS, 14.8 [8.2-30.5] months; OS, 24.6 [14.1-44.6] months). The molecular status of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS (HR, 1.33; 95% CI, 1.02-1.75; P = .04). Patients had worse DFS and OS if they had a greater number of altered driver genes. Compared with patients with 0 to 2 altered genes, those with 4 altered genes had worse DFS (HR, 1.79 [95% CI, 1.24-2.59; P = .002]) and OS (HR, 1.38 [95% CI, 0.98-1.94; P = .06]). Five-year OS was 18.4% for patients with 0 to 2 gene alterations, 14.1% for those with 3 alterations, and 8.2% for those with 4 alterations. CONCLUSIONS AND RELEVANCE:
Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.
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