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JAMA Oncol. 2018 Mar 8;4(3):e173420. doi: 10.1001/jamaoncol.2017.3420. Epub 2018 Mar 8.

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
2
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
4
Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
5
Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.
6
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
7
Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts.
8
Department of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
9
Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
10
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
11
Department of Surgery, University of Rochester Medical Center, Rochester, New York.
12
Department of Pathology, University of Rochester Medical Center, Rochester, New York.
13
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts.
14
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
15
Division of Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
16
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

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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