engleski

The role of PARP inhibitors in the treatment of metastatic pancreatic cancer

Introduction: Treatment options for patients with metastatic pancreatic cancer are limited. They are based on systemic chemotherapy whose effects are short limited and eventually pancreatic cancer becomes resistant to conventional therapy. The causes of pancreatic cancer vary and, in many cases, remain unknown. It includes many changes, like inactivation of tumor suppressor genes and mutation of genes which are included in DNA damage repair pathways like BRCA 1 and BRCA 2. Therefore, inhibition of PARP mediated pathway in patients with BRCA1 or BRCA2 mutation represents an important therapeutic option for these patients. The phase III POLO trial showed that maintenance treatment with the poly (ADP ribose) polymerase (PARP) inhibitor olaparib improved progression- free survival vs placebo (7.4 months vs. 3.8 months) among patients with germline BRCA-mutant metastatic pancreatic cancer that had not progressed during first-line platinumbased chemotherapy. Case study: We present interesting case from every day clinical practice. 75year old female was admitted in February 2017. to Department of Internal medicine UHC Zagreb due to severe abdominal pain. After comprehensive diagnostic assessment she was diagnosed with metastatic pancreatic adenocarcinoma. After seeing an oncologist, the patient started combination chemotherapy treatment with gemcitabine and nab- paclitaxel. Until May 2018. she was administrated with 11 cycles of chemotherapy and was regularly evaluated every three months with serum levels of the tumor marker and abdominal, pelvic and thoracic CT scans. Due to progression of liver metastasis in May 2018. she started with second- line chemotherapy with oxaliplatin and capecitabine. Also, Next generation sequencing (NGS) of tumor tissue was performed. From June to December of 2018. six cycles of chemotherapy have been administrated. Control evaluation in December 2018. showed stable disease and NGS results detected somatic mutations in BRCA1 gene. Due to results of NGS patient received maintenance therapy with PARP inhibitor talazoparib from medication donation program. Talazoparib was administrated from February 2019. until April 2020. with occasional disruptions due to thrombocytopenia and neutropenia, in total of 14 months which was significantly longer than median Progression- free survival in POLO trial. Control evaluation showed significantly progression of disease and active anti-cancer treatment was no longer indicated. In July 2020. the patient passed away from complications of progression of primary disease. Conclusion: All proposed molecular mechanisms in pancreatic cancer pathogenesis are still unknown. Additional polygenic tumor sequencing is the future of pancreatic cancer treatment. It is necessary to determine mutational status of BRCA1/2 genes from peripheral blood because standard treatment with PARP inhibitors in this moment requires detection of germ line mutation from peripheral blood. The case we presented shows that it is possible to achieve much longer over-all survival in patients with pancreatic cancer with combination of conventional and target therapy based on new generation sequencing analysis. Younger patients as well as the patients with positive family history for pancreatic cancer should be target group for genetic testing of BRCA1/2 mutations.

metastatic pancreatic cancer ; PARP inhibitors

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