Predictive Value of Transcriptome-based OncoTreat/Oncotarget and Organoid Testing in Metastatic Pancreatic Cancer.

Pancreatic cancer is burdened by a survival of barely 10% at 5 years. About 80% of new cases do not qualify for surgery due to either locally-advanced or metastatic disease. In patients with good performance status (PS), palliative first-line treatments mainly consist of combination regimens, such as FOLFIRINOX, modified FOLFIRINOX or Gemcitabine-Abraxane. For subjects with a poor PS, instead, guidelines recommend single-agent infusions (e.g. Gemcitabine, Capecitabine or 5-FU alone). Nevertheless, upon disease progression therapeutic options are still scarce and with limited sustained efficacy. Overall survival in metastatic pancreatic cancer ranges between 9.1 and 13.5 months, while progression-free survival under either FOLFIRINOX or Gemcitabine-Abraxane spans between 5.5 and 6.4 months. This timespan reduces even further when standard second-line regimens must be initiated upon disease progression. Nowadays, genomic and transcriptomic analysis are crucial tools in cancer research that enable the identification of genetic mutations and alterations that drive the development and progression of cancer. By studying the changes in the DNA and RNA sequences of cancer cells, researchers can gain insights into the underlying molecular mechanisms of cancer and identify potential therapeutic targets. Genomic analysis can identify specific mutations or alterations that are present in cancer cells, while transcriptomic analysis can reveal changes in gene expression that may be linked to disease progression or response to treatment. These analyses are an essential component for the development of precision medicine approaches, which aim to tailor cancer treatment to the individual genetic profile of each patient. PDOs can replicate in vitro the biological, genetic and molecular aspects of the primary tumour. Some of their advantages include their rapid growth compared to xenografts, the possibility to perform high-throughput drug screening, and their direct application to precision oncology by predicting best therapies. In this study they will be used as an in vitro comparator of the molecular tests to the clinical course of the patient. Overall, combining genomic and transcriptomic analysis with PDO technology in cancer research might lead to exponential capacity to provide oncologic patients with extremely tailored and effective cancer treatments in the future. For HIPANC-002 these tests are being evaluated as non-interventional investigational IVD's. Test results are not to be used for protocol mandated therapy decisions.

Sex

All

Minimum age

18 Years

Inclusion criteria:

* Informed Consent as documented by signature
* Patients older than 18 years
* Patients with metastatic pancreatic ductal adenocarcinoma
* At least one lesion amenable for surgical excisional biopsy
* ECOG Performance status 0-2
* Radiologically measurable disease
* Life expectancy \> 3 months
* Absolute leucocyte count \>1.5 G/l, platelets \>100 G/l
* Serum creatinine \<1.5 times of the upper limit of normal or Clearance \>50ml/min (according to the CKD-EPI formula)

Exclusion criteria:

* Known allergies or intolerance to one or more compounds present in one of the first line or second line regimens
* Concomitant need for full anticoagulation that cannot be interrupted or bridged prior to tissue biopsy
* ECOG PS \>2
* Heart failure (NYHA class III-IV)
* Severe or uncontrolled concurrent illness
* Active viral infection from HIV, HBV or HCV, even if under antiretroviral treatment
* Myocardial infarction within the previous 6 months
* Patients who are pregnant or breastfeeding

• RESULTMorikawa T, Yoshida M. A useful testing strategy in phase III trials: combined test of superiority and test of equivalence. J Biopharm Stat. 1995 Nov;5(3):297-306. doi: 10.1080/10543409508835115. PMID 8580930
• RESULTDindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae. PMID 15273542
• RESULTPaluri RK, Kasi A, Young C, Posey JA. Second-line treatment for metastatic pancreatic cancer. Clin Adv Hematol Oncol. 2020 Feb;18(2):106-115. PMID 32558804
• RESULTEttrich TJ, Seufferlein T. Systemic Therapy for Metastatic Pancreatic Cancer. Curr Treat Options Oncol. 2021 Oct 19;22(11):106. doi: 10.1007/s11864-021-00895-4. PMID 34665339
• RESULTZhang XW, Ma YX, Sun Y, Cao YB, Li Q, Xu CA. Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. Target Oncol. 2017 Jun;12(3):309-321. doi: 10.1007/s11523-017-0486-5. PMID 28353074
• RESULTNguyen KT, Gamblin TC, Geller DA. World review of laparoscopic liver resection-2,804 patients. Ann Surg. 2009 Nov;250(5):831-41. doi: 10.1097/SLA.0b013e3181b0c4df. PMID 19801936
• RESULTStrassburg CP, Manns MP. Approaches to liver biopsy techniques--revisited. Semin Liver Dis. 2006 Nov;26(4):318-27. doi: 10.1055/s-2006-951599. PMID 17051446
• RESULTVasciaveo A, Arriaga JM, de Almeida FN, Zou M, Douglass EF, Picech F, Shibata M, Rodriguez-Calero A, de Brot S, Mitrofanova A, Chua CW, Karan C, Realubit R, Pampou S, Kim JY, Afari SN, Mukhammadov T, Zanella L, Corey E, Alvarez MJ, Rubin MA, Shen MM, Califano A, Abate-Shen C. OncoLoop: A Network-Based Precision Cancer Medicine Framework. Cancer Discov. 2023 Feb 6;13(2):386-409. doi: 10.1158/2159-8290.CD-22-0342.