Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: A scoping review

•Genomic alterations in PDAC represent potential targeting opportunities to individualize therapy.•Attempts to target key somatic driver mutations in PDAC have been unsuccessful.•DNA-damage repair gene mutations confer vulnerability to platinum agents and PARP-inhibitors.•Microsatellite unstable PDA...

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Vydané v:	Cancer treatment reviews Ročník 75; s. 27 - 38
Hlavní autori:	Singh, Ritu R., Goldberg, Johanna, Varghese, Anna M., Yu, Kenneth H., Park, Wungki, O'Reilly, Eileen M.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Netherlands Elsevier Ltd 01.05.2019
Predmet:	Animals Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics DNA damage repair DNA Repair - drug effects DNA Repair - genetics Genomic alteration (GA) Genomics - methods Germline mutation Humans Microsatellite instability Mismatch repair (MMR) Pancreatic ductal adenocarcinoma (PDAC) Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Somatic mutation Somatic mutation Mismatch repair (MMR) DNA damage repair Pancreatic ductal adenocarcinoma (PDAC) Genomic alteration (GA) Germline mutation Microsatellite instability
ISSN:	0305-7372, 1532-1967, 1532-1967
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Shrnutí:	•Genomic alterations in PDAC represent potential targeting opportunities to individualize therapy.•Attempts to target key somatic driver mutations in PDAC have been unsuccessful.•DNA-damage repair gene mutations confer vulnerability to platinum agents and PARP-inhibitors.•Microsatellite unstable PDAC (1%) can benefit from checkpoint point inhibitor therapy.•The KRAS wild-type subset of PDAC (5%) is enriched for actionability, e.g., ALK, NTRK, NRG-1 fusions and others. Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23
ISSN:	0305-7372 1532-1967 1532-1967
DOI:	10.1016/j.ctrv.2019.03.003