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Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma
Open accessAbstract
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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“SMAD4 is a tumor suppressor gene, and reported results about the prognostic value of SMAD4 have been inconsistent39,60–62.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [39]
In the citing paper
“This is consistent with a previous study of 356 patients with resected PDAC, which reported that those with KRAS mutations had worse disease-free survival (DFS) (median 12.3 months) and OS (median 20.3 months) compared with those with wildtype KRAS (DFS 16.2 months and OS 38.6 months), and particularly poor outcomes were observed in patients with KRASG12D mutation (median OS 15.3 months)39.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [39]
In the citing paper
“Patients with resected PDAC and somatic CDKN2A loss had worse survival (median DFS 11.5 and OS 19.7) compared to patients with wildtype CDKN2A (median DFS 14.8 and median OS 24.6)39.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [39]
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“Furthermore, increasingnumbersofpatientsare receivingchemotherapy and radiation before surgical resection to rapidly initiate therapyagainstmicrometastaticdisease andselect out those patientswith early disease progression unlikely to benefit fromsurgery.(14) In the future,molecular assessmentofpancreatic cancermayhelp…”
BackgroundWhole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
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SMAD4 Gene Mutations Are Associated with Poor Prognosis in Pancreatic Cancer
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Cited by
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Molecular subtypes of pancreatic cancer
Collisson, E. A., Bailey, P., Chang, D. K., & Biankin, A. V. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0109-y · Cited by 892
Self-citationRole of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer
Buscail, L., Bournet, B., & Cordelier, P. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0245-4 · Cited by 721
Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data
Connor, A. A., & Gallinger, S. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00418-1 · Cited by 369
Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot
Ullman, N. A., Burchard, P. R., Dunne, R. F., & Linehan, D. C. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02616 · Cited by 311
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Metadata
- Authors
- Qian, Z. R., Rubinson, D. A., Nowak, J. A., Morales-Oyarvide, V., Dunne, R. F., Kozak, M. M., Welch, M. W., Brais, L. K., Da Silva, A., Li, T., Li, W., Masuda, A., Yang, J., Shi, Y., Gu, M., Masugi, Y., Bui, J., Zellers, C. L., Yuan, C., Babic, A., Khalaf, N., Aguirre, A., Ng, K., Miksad, R. A., Bullock, A. J., Chang, D. T., Tseng, J. F., Clancy, T. E., Linehan, D. C., Findeis-Hosey, J. J., Doyle, L. A., Thorner, A. R., Ducar, M., Wollison, B., Laing, A., Hahn, W. C., Meyerson, M., Fuchs, C. S., Ogino, S., Hornick, J. L., Hezel, A. F., Koong, A. C., & Wolpin, B. M.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- University of Rochester Medicine (US)
- Stanford Cancer Institute (US)
- Dana-Farber Cancer Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Broad Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Wolpin, Brian M.
- ORCID
- Qian, Zhi Rong
- Rubinson, Douglas A.
- Nowak, Jonathan A.
- Dunne, Richard F.
- Kozak, Margaret M.
- Brais, Lauren K.
- Li, Tingting
- Li, Wanwan
- Masuda, Atsuhiro
- Yang, Juhong
- Shi, Yan
- Gu, Mancang
- Masugi, Yohei
- Bui, Justin
- Yuan, Chen
- 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
- Hahn, William C.
- Meyerson, Matthew
- Fuchs, Charles S.
- Ogino, Shuji
- Hornick, Jason L.
- Hezel, Aram F.
- Koong, Albert C.
- Wolpin, Brian M.
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-03-08
- Volume
- 4
- Issue
- 3
- Pages
- e173420
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC5844844
- OpenAlex
- W2767007332
- Cited by
- 260
- References
- 15
- Citations by year
- 2026: 17 · 2025: 31 · 2024: 38 · 2023: 47 · 2022: 49 · 2021: 28 · 2020: 24 · 2019: 19 · 2018: 7
- FWCI
- 6.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pancreatic Cancer Action Network
- National Institutes of Health (UL1TR001102, UL1TR001863)
- National Cancer Institute (P50CA127003, R01CA124908, R35CA197735, K07CA148894, U01CA176058, U01CA199253, K08CA218420, U01CA210171)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic cancer surgery, driver gene alterations, KRAS mutation, CDKN2A, SMAD4, TP53, disease-free survival, overall survival, prognostic factors, protein expression, DNA alterations, recurrence, postoperative adjuvant therapy, neoadjuvant therapy, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, tumor-infiltrating neutrophils, tumor-infiltrating T cells, tumor-infiltrating B cells, tumor-infiltrating plasma cells, tumor-infiltrating dendritic cells, tumor-infiltrating NK cells, tumor-infiltrating Treg cells, tumor-infiltrating myeloid cells
- MeSH terms
- Adenocarcinoma, Aged, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Pancreatectomy, Pancreatic Neoplasms, Prognosis, Proto-Oncogene Proteins, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Survival Analysis, Treatment Outcome, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, High-Throughput Nucleotide Sequencing
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