Pancraetic cancer is a highly letal malignancy. Up to 40% of patients found unresectable at exploratory laparoscopy/tomy and more than one third of eventually resected patients will need a vascular resection in order to achieve a radical pancreatectomy, of those barely a half of specimens will confirm an histological invasion. Clinical preoperative staging is inaccurate in predicting resectability but unfortunately whether patients should undergo neoadjuvant therapy or surgery first relies on weak bases.
Liquid biopsy provides an non-invasive signature of the tumor. Analyzing mutations on cell-free nucleic acids gives translational information on tumor biology and therefore on its clinico-pathological features and likely on its progression. In order to better stage patients candidated to pancreatectomy for ductal adenocarcinoma of the pancreas, we aim to find a non-invasive signature of vascular invasion by analyzing key-genes mutations on cell-free DNA. This pilot study will led to a wider multicentric validation study.
Liquid biopsy provides an non-invasive signature of the tumor. Analyzing mutations on cell-free nucleic acids gives translational information on tumor biology and therefore on its clinico-pathological features and likely on its progression. Pancreatic cancer progression has long been studied. What is clear is that activating K-RAS mutations are an early event in most lesions, followed by inactivating mutations in CDKN2A, TP53 and SMAD4 [9]. K-RAS mutations have been associated to a worse overall survival in particular when found in peripheral blood by liquid biopsy [10]. CDKN2A mutations have been associated to lymphatic invasion and widespread metastatic recurrence [11]. TP53 mutations have been associated to poor differentiation and locoregional recurrence [11]. Finally SMAD4 mutations have been associated to portal vein invasion, perineural invasion and lymph vessel invasion [12]. Those data have been validated on samples of the tumor and thus usually on specimens since only 53,3% of ultrasound guided biopsies provides enough material for histopathology and/or immunohistochemistry [13]. As seen in previous studies, the concordance between plasma and primary tumor is as high as 100% in pancreatic cancer [14].
The study of those mutations on liquid biopsy would provide non-invasive informations on preoperative staging and therefore a more accurate therapeutic planning.
REFERENCES
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10. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Kinugasa H, Nouso K, Miyahara K, Morimoto Y, Dohi C, Tsutsumi K, Kato H, Matsubara T, Okada H, Yamamoto K. Cancer 2015 Jul 1;121(13):2271-80.
11. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, Yachida S. Ann Surg 2013 Aug;258(2):336-46.
12. SMAD4 expression predicts local spread and treatment failure in resected pancreatic cancer. Yamada S, Fujii T, Shimoyama Y, Kanda M, Nakayama G, Sugimoto H, Koike M, Nomoto S, Fujiwara M, Nakao A, Kodera Y. Pancreas 2015 May;44(4):660-4.
13. Randomized trial comparing a side-port needle and standard needle for EUS-guided histology of pancreatic lesions. Ishiwatari H, Hayashi T, Kawakami H, Isayama H, Hisai H, Itoi T, Ono M, Kawakubo K, Yamamoto N, Tanaka M, Itokawa F, Oshiro H, Sonoda T, Hasegawa T; Japan EZ Port Study Group. Gastrointest Endosc. 2016 Oct;84(4):670-8.
14. JD COHEN ET AL. SCIENCE 10.1126/SCIENCE.AAR3247 (2018)