Abstract 2910: Inter metastatic genetic heterogeneity is a characteristic feature of recurrent pancreatic cancer
Authors: Hitomi Sakamoto, Alvin Makohon-Moore, Marc Attiyeh, Liguo Zhang, Christine A. Iacobuzio-Donahue
Journal: Cancer Research (2017)

Abstract Pancreatic cancer (PDA) is a 4th leading cause of cancer death with an overall 5-year survival of 8%. Surgical resection remains the only option for cure but only 10-15% of newly diagnosed patients are eligible. While surgery clearly provides a survival benefit compared to those patients who do not undergo potentially curative resection, the vast majority of patients will recur in the pancreatic remnant, liver, lungs, and/or peritoneum. Thus, there is an unmet need to better understand the fundamental features of recurrent disease. To explore the fundamental genomic features of recurrent PDA, patients were selected from participating Gastrointestinal Cancer Rapid Medical Donation Program (GICRMDP). 10 patients who underwent surgical resection; 8 patients had a whipple procedure, 2 patients had a distal pancreatectomy and each patient received a different type of chemotherapy after surgery, was evaluated. We performed 250x whole exome sequencing (WES) of 82 unique samples from these 10 patients, using frozen samples from autopsy and FFPE tissues from matching surgical specimen. In addition to the treatment naïve primary tumor, one or more samples of the local recurrence and multiple metastases were studied. The mean depth of coverage for all samples was 317x. Copy number variations were assessed by FACETs. MSK-IMPACT was performed for orthogonal validation of a subset of variants. We found that compared to the treatment naïve resected tumor, recurrent disease contained novel mutations in genes associated with MAPK and PI3K signaling. The most common mutational signature was Signature 1 followed by Signature 3. All patients who received a platinum drug as a form of therapy had a greater proportion of Signature 3 and 9 mutations in the recurrent disease than the primary tumor. Phylogenetic studies revealed that recurrent disease is the result of three patterns: 1) dissemination of disease to distant organs before surgery was performed, 2) dissemination of disease after surgery from residual microscopic disease in the pancreatic remnant, or 3) development of a second primary tumor in the remnant pancreas. This third scenario was identified in one of six additional patients studied by IMPACT. We conclude that recurrent pancreatic cancer is multifactorial, and at least two of these scenarios could be eliminated by total pancreatectomy, thereby increasing the rate of cure by surgical resection. Our study serves as a window to an understanding of the clonal dynamics of recurrent pancreatic cancer. Citation Format: Hitomi Sakamoto, Alvin Makohon-Moore, Marc Attiyeh, Liguo Zhang, Christine A. Iacobuzio-Donahue. Inter metastatic genetic heterogeneity is a characteristic feature of recurrent pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2910. doi:10.1158/1538-7445.AM2017-2910