Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma

Zhi Rong Qian, Douglas A. Rubinson, Jonathan A. Nowak, Vicente Morales-Oyarvide, Richard F. Dunne, Margaret M. Kozak, Marisa W. Welch, Lauren K. Brais, Annacarolina Da Silva, Tingting Li, Wanwan Li, Atsuhiro Masuda, Juhong Yang, Yan Shi, Mancang Gu, Yohei Masugi, Justin Bui, Caitlin L. Zellers, Chen Yuan, Ana BabicNatalia Khalaf, Andrew Aguirre, Kimmie Ng, Rebecca A. Miksad, Andrea J. Bullock, Daniel T. Chang, Jennifer F. Tseng, Thomas E. Clancy, David C. Linehan, Jennifer J. Findeis-Hosey, Leona A. Doyle, Aaron R. Thorner, Matthew Ducar, Bruce Wollison, Angelica Laing, William C. Hahn, Matthew Meyerson, Charles S. Fuchs, Shuji Ogino, Jason L. Hornick, Aram F. Hezel, Albert C. Koong, Brian M. Wolpin

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 gens resected nancreatic adenocrcinoma.

Original languageEnglish
Article numbere173420
JournalJAMA oncology
Volume4
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1
Externally publishedYes

Fingerprint

Adenocarcinoma
Disease-Free Survival
Survival
Genes
Neoplasms
p16 Genes
p53 Genes
Sex Characteristics
Paraffin
Formaldehyde
Biomarkers
Immunohistochemistry
Outcome Assessment (Health Care)
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Qian, Z. R., Rubinson, D. A., Nowak, J. A., Morales-Oyarvide, V., Dunne, R. F., Kozak, M. M., ... Wolpin, B. M. (2018). Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA oncology, 4(3), [e173420]. https://doi.org/10.1001/jamaoncol.2017.3420

Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. / Qian, Zhi Rong; Rubinson, Douglas A.; Nowak, Jonathan A.; Morales-Oyarvide, Vicente; Dunne, Richard F.; Kozak, Margaret M.; Welch, Marisa W.; Brais, Lauren K.; Da Silva, Annacarolina; Li, Tingting; Li, Wanwan; Masuda, Atsuhiro; Yang, Juhong; Shi, Yan; Gu, Mancang; Masugi, Yohei; Bui, Justin; Zellers, Caitlin L.; Yuan, Chen; Babic, Ana; Khalaf, Natalia; Aguirre, Andrew; Ng, Kimmie; Miksad, Rebecca A.; Bullock, Andrea J.; Chang, Daniel T.; Tseng, Jennifer F.; Clancy, Thomas E.; Linehan, David C.; Findeis-Hosey, Jennifer J.; Doyle, Leona A.; Thorner, Aaron R.; Ducar, Matthew; Wollison, Bruce; Laing, Angelica; Hahn, William C.; Meyerson, Matthew; Fuchs, Charles S.; Ogino, Shuji; Hornick, Jason L.; Hezel, Aram F.; Koong, Albert C.; Wolpin, Brian M.

In: JAMA oncology, Vol. 4, No. 3, e173420, 01.03.2018.

Research output: Contribution to journalArticle

Qian, ZR, Rubinson, DA, Nowak, JA, Morales-Oyarvide, V, Dunne, RF, Kozak, MM, Welch, MW, Brais, LK, Da Silva, A, Li, T, Li, W, Masuda, A, Yang, J, Shi, Y, Gu, M, Masugi, Y, Bui, J, Zellers, CL, Yuan, C, Babic, A, Khalaf, N, Aguirre, A, Ng, K, Miksad, RA, Bullock, AJ, Chang, DT, Tseng, JF, Clancy, TE, Linehan, DC, Findeis-Hosey, JJ, Doyle, LA, Thorner, AR, Ducar, M, Wollison, B, Laing, A, Hahn, WC, Meyerson, M, Fuchs, CS, Ogino, S, Hornick, JL, Hezel, AF, Koong, AC & Wolpin, BM 2018, 'Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma', JAMA oncology, vol. 4, no. 3, e173420. https://doi.org/10.1001/jamaoncol.2017.3420
Qian, Zhi Rong ; Rubinson, Douglas A. ; Nowak, Jonathan A. ; Morales-Oyarvide, Vicente ; Dunne, Richard F. ; Kozak, Margaret M. ; Welch, Marisa W. ; Brais, Lauren K. ; Da Silva, Annacarolina ; Li, Tingting ; Li, Wanwan ; Masuda, Atsuhiro ; Yang, Juhong ; Shi, Yan ; Gu, Mancang ; Masugi, Yohei ; Bui, Justin ; Zellers, Caitlin L. ; Yuan, Chen ; Babic, Ana ; Khalaf, Natalia ; Aguirre, Andrew ; Ng, Kimmie ; Miksad, Rebecca A. ; Bullock, Andrea J. ; Chang, Daniel T. ; Tseng, Jennifer F. ; Clancy, Thomas E. ; Linehan, David C. ; Findeis-Hosey, Jennifer J. ; Doyle, Leona A. ; Thorner, Aaron R. ; Ducar, Matthew ; Wollison, Bruce ; Laing, Angelica ; Hahn, William C. ; Meyerson, Matthew ; Fuchs, Charles S. ; Ogino, Shuji ; Hornick, Jason L. ; Hezel, Aram F. ; Koong, Albert C. ; Wolpin, Brian M. / Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. In: JAMA oncology. 2018 ; Vol. 4, No. 3.
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title = "Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma",
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 gens resected nancreatic adenocrcinoma.",
author = "Qian, {Zhi Rong} and Rubinson, {Douglas A.} and Nowak, {Jonathan A.} and Vicente Morales-Oyarvide and Dunne, {Richard F.} and Kozak, {Margaret M.} and Welch, {Marisa W.} and Brais, {Lauren K.} and {Da Silva}, Annacarolina and Tingting Li and Wanwan Li and Atsuhiro Masuda and Juhong Yang and Yan Shi and Mancang Gu and Yohei Masugi and Justin Bui and Zellers, {Caitlin L.} and Chen Yuan and Ana Babic and Natalia Khalaf and Andrew Aguirre and Kimmie Ng and Miksad, {Rebecca A.} and Bullock, {Andrea J.} and Chang, {Daniel T.} and Tseng, {Jennifer F.} and Clancy, {Thomas E.} and Linehan, {David C.} and Findeis-Hosey, {Jennifer J.} and Doyle, {Leona A.} and Thorner, {Aaron R.} and Matthew Ducar and Bruce Wollison and Angelica Laing and Hahn, {William C.} and Matthew Meyerson and Fuchs, {Charles S.} and Shuji Ogino and Hornick, {Jason L.} and Hezel, {Aram F.} and Koong, {Albert C.} and Wolpin, {Brian M.}",
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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.

PY - 2018/3/1

Y1 - 2018/3/1

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.

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