TY - JOUR
T1 - Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma
AU - Qian, Zhi Rong
AU - Rubinson, Douglas A.
AU - Nowak, Jonathan A.
AU - Morales-Oyarvide, Vicente
AU - Dunne, Richard F.
AU - Kozak, Margaret M.
AU - Welch, Marisa W.
AU - Brais, Lauren K.
AU - Da Silva, Annacarolina
AU - Li, Tingting
AU - Li, Wanwan
AU - Masuda, Atsuhiro
AU - Yang, Juhong
AU - Shi, Yan
AU - Gu, Mancang
AU - Masugi, Yohei
AU - Bui, Justin
AU - Zellers, Caitlin L.
AU - Yuan, Chen
AU - Babic, Ana
AU - Khalaf, Natalia
AU - Aguirre, Andrew
AU - Ng, Kimmie
AU - Miksad, Rebecca A.
AU - Bullock, Andrea J.
AU - Chang, Daniel T.
AU - Tseng, Jennifer F.
AU - Clancy, Thomas E.
AU - Linehan, David C.
AU - Findeis-Hosey, Jennifer J.
AU - Doyle, Leona A.
AU - Thorner, Aaron R.
AU - Ducar, Matthew
AU - Wollison, Bruce
AU - Laing, Angelica
AU - Hahn, William C.
AU - Meyerson, Matthew
AU - Fuchs, Charles S.
AU - Ogino, Shuji
AU - Hornick, Jason L.
AU - Hezel, Aram F.
AU - Koong, Albert C.
AU - Wolpin, Brian M.
N1 - Funding Information:
Funding/Support: This study was funded in part by a grant from the Department of Medical Oncology translational research grant program of the Dana-Farber Cancer Institute (Dr Qian); grant K07 CA148894 from the National Institutes of Health (Dr Ng); grant R35 CA197735 from the National Cancer Institute (Dr Ogino); grants from the Hale Center for Pancreatic Cancer Research, the Perry S. Levy Fund for Gastrointestinal Cancer Research, and the Pappas Family Research Fund for Pancreatic Cancer, as well as grants R01 CA124908 and P50 CA127003 from the National Institutes of Health (Dr Fuchs); funding from MyBlueDots (Dr Koong); and grants from the Hale Center for Pancreatic Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, the Pancreatic Cancer Action Network, the Noble Effort Fund, the Peter R. Leavitt Family Fund, the Wexler Family Fund, and Promises for Purple, as well as grant CA130288 from the US Department of Defense and grant U01 CA210171 from the National Institutes of Health/National Cancer Institute (Dr Wolpin).
Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2018/3
Y1 - 2018/3
N2 - 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 gens resected nancreatic adenocrcinoma.
AB - 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 gens resected nancreatic adenocrcinoma.
UR - http://www.scopus.com/inward/record.url?scp=85047468710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047468710&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2017.3420
DO - 10.1001/jamaoncol.2017.3420
M3 - Article
C2 - 29098284
AN - SCOPUS:85047468710
VL - 4
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 3
M1 - e173420
ER -
