Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer - the MetAction study.

Autor:	Ree AH; Department of Oncology, Akershus University Hospital, Lørenskog, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Nygaard V; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway., Boye K; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, Oslo, Norway., Heinrich D; Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Dueland S; Department of Oncology, Oslo University Hospital, Oslo, Norway., Bergheim IR; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway., Johansen C; Department of Oncology, Akershus University Hospital, Lørenskog, Norway., Beiske K; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Pathology, Oslo University Hospital, Oslo, Norway., Negård A; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Radiology, Akershus University Hospital, Lørenskog, Norway., Lund-Iversen M; Department of Pathology, Oslo University Hospital, Oslo, Norway., Nygaard V; Department of Core Facilities, Oslo University Hospital, Oslo, Norway., Hovig E; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.; Centre for Bioinformatics, University of Oslo, Oslo, Norway.; Norwegian Cancer Genomics Consortium, Oslo, Norway., Nakken S; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.; Norwegian Cancer Genomics Consortium, Oslo, Norway.; Centre for Cancer Cell Reprogramming, University of Oslo, Oslo, Norway., Nasser S; Department of Radiology, Akershus University Hospital, Lørenskog, Norway., Julsrud L; Department of Radiology, Oslo University Hospital, Oslo, Norway., Reisse CH; Department of Radiology, Oslo University Hospital, Oslo, Norway., Ruud EA; Department of Radiology, Akershus University Hospital, Lørenskog, Norway., Kristensen VN; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway., Flørenes VA; Department of Pathology, Oslo University Hospital, Oslo, Norway., Geitvik GA; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway., Lingjærde OC; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway.; Centre for Bioinformatics, University of Oslo, Oslo, Norway., Børresen-Dale AL; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway., Russnes HG; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway.; Department of Pathology, Oslo University Hospital, Oslo, Norway., Mælandsmo GM; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.; Institute for Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway., Flatmark K; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Tumor Biology, Oslo University Hospital, Oslo, Norway.; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Acta oncologica (Stockholm, Sweden) [Acta Oncol] 2020 Jul; Vol. 59 (7), pp. 733-740. Date of Electronic Publication: 2020 Mar 25.
DOI:	10.1080/0284186X.2020.1742377
Abstrakt:	Background: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014-2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016-2019). Material and methods: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints. Results: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2-3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment. Conclusions: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity versus resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies. ClinicalTrials.gov, identifier: NCT02142036.
Databáze:	MEDLINE
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