The Evolutionary Origins of Recurrent Pancreatic Cancer

• Published in: Cancer discovery Vol. 10; no. 6; pp. 792 - 805
• Main Authors: Sakamoto, Hitomi, Attiyeh, Marc A, Gerold, Jeffrey M, Makohon-Moore, Alvin P, Hayashi, Akimasa, Hong, Jungeui, Kappagantula, Rajya, Zhang, Lance, Melchor, Jerry P, Reiter, Johannes G, Heyde, Alexander, Bielski, Craig M, Penson, Alexander V, Gönen, Mithat, Chakravarty, Debyani, O'Reilly, Eileen M, Wood, Laura D, Hruban, Ralph H, Nowak, Martin A, Socci, Nicholas D, Taylor, Barry S, Iacobuzio-Donahue, Christine A
• Format: Journal Article
• Language: English
• Published: United States 01.06.2020
• Subjects: Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - secondary; Evolution, Molecular; Exome Sequencing; Humans; Neoplasm Metastasis - genetics; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-19-1508

Surgery is the only curative option for stage I/II pancreatic cancer; nonetheless, most patients will experience a recurrence after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer, we performed whole-exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate MAPK/ERK and PI3K-AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment-induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In 1 patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer. SIGNIFICANCE: The biological features or clinical vulnerabilities of recurrent pancreatic cancer after pancreaticoduodenectomy are unknown. Using whole-exome sequencing we find that recurrent disease has a distinct genomic landscape, intermetastatic genetic heterogeneity, diverse clonal origins, and higher mutational burden than found for treatment-naïve disease. . .