Molecular treatment stratification in second-line treatment of pancreatic adenocarcinoma: PePaCaKa-001
Authors: M. Kordes, M. Löhr, L. Malgerud, S. Kaduthanam, J.-E. Frödin, M. Karimi, J. Yachnin, C. Fernadez Moro, S. Ghazi, R. Heuchel, V. Wirta, C. Hülsewig, K. Stecker, M. Del Chiaro, A. Östman, L. Engstrand, S. Brock, M. Gustafsson-Liljefors
Journal: Annals of Oncology (2018)

Background: Pancreatic cancer (PDAC) is highly resistant to cytotoxic chemotherapy and several trials of molecularly targeted drugs have failed. However, some tumors with specific somatic mutations respond to targeted therapy and patients might profit from treatment stratified by genetic biomarker profiles. Methods: We used MH Guide, a proprietary data tool, to annotate somatic mutation in PDAC patients who had received ≥ 1st line palliative therapy. A molecular tumor board (MTB) interpreted suggestions and matched consecutive therapies including off-lable use of any EMA-approved drug to biomarker profiles. Frequency of clinically relevant markers was the primary outcome. Secondary outcomes were choice of therapy, clinical outcomes and AE. Results: We enrolled 39 patients, analyzed 35 samples and had valid results from 31 tumors. The most common mutations were KRAS (n = 24), TP53 (n = 17), SMAD4 (n = 2), BRCA1/2 (n = 4; 3 germline), CDKN2A (n = 9), ATM (n = 6; 3 LOF), APC (n = 4), and MSH3 (n = 15, 1 germline). MH Guide suggested off-label treatment in 28 cases: PARP-inhibitors (n = 26), MEK/RAF inhibitors (n = 20), CDK inhibitors (n = 9), other kinase inhibitors (n = 3), mTOR inhibitors (n = 2). Common toxicity markers were: Platinum (XRCC1 n = 16; 5 homozygous, TPMT n = 1; MUTYH n = 3), paclitaxel (CYP2C8 n = 2), gemcitabine (CDA n = 4; 1homozygous), 5-FU (DPYD n = 1), doxorubicin (G6PD n = 1), docetaxel (GSTP1 n = 2), sunitinib (ABCG2 n = 2), irinotecan (ERCC2, n = 6; 5 homozygous, UGT1A1 n = 1). Three patients deceased before MTB decision and 8 prior to treatment, 5 patients were not eligible for active treatment. Seven patients received targeted treatment: Olaparib (n = 6, 1 still on treatment), palbociclib (n = 1) and remained median 84 days (range 18 – 114) on treatment. Four patients received cytotoxic chemotherapy according to MTB decision (among them one without positive markers) and in four cases cytotoxic therapy was used despite a molecularly targeted suggestion. Conclusions: Unbiased evidence-based molecular stratification of pre-treated patients with PDAC is feasible in a clinical setting. Disease progression and tissue availability are major challenges. Conclusions on clinical outcomes are limited by the study size. Clinical trial identification: NCT02767700. Legal entity responsible for the study: Karolinska University Hospital. Funding: Molecular Health GmbH (Data analysis). Disclosure: M. Kordes: Travel Grant from Molecular Health GmbH. M. Löhr: Consultant or advisory role: Molecular Health GmbH, Pharmcyte. Stock in Centogene AG. Horaria: Abbott, Mylan, Nordmark. Travel Grant: Abbott, Pharmcyte, Molecular Health GmbH. S. Kaduthanam, C. Hülsewig, K. Stecker, S. Brock: Employee of Molecular Health GmbH. J-E. Frödin: Travel grant: Amgen. All other authors have declared no conflicts of interest.