Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial (NCT01856296) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P < 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.
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The availability of the data is described in the Nature Research Reporting Summary. Detailed clinical and biological information for each patient is available in Supplementary Table 4; further biological data are available at www.winconsortium.org, containing: (1) tumor mutations data in XML format; and (2) expression data in a table format (providing information about tumor versus normal fold change and tumor intensity alone for all of the cases for which mRNA was analyzed). The BAM and XML files for normal tissue are deposited in dbGaP with a controlled access mechanism for private information.
No custom code or mathematical algorithm was used. Statistical analysis was performed using standard software including SAS and R.
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Dr John Mendelsohn, President Emeritus of The University of Texas, MD Anderson Cancer Center, Director of Sheikh Khalifa Bin Zayad Al Nahyan Institute for Personalized Cancer Therapy (IPCT), Houston, TX, USA, Chairman of the WIN Association—WIN Consortium, Villejuif, France, and co-author of the Letter died on 7 January 2019. Dr Mendelsohn was a brilliant scientist and visionary, an optimist and a truly inspirational leader. The WINTHER study was one of his very last projects. The research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007–2013 under grant agreement no. 306125). This work was funded in part by the ARC Foundation for Cancer Research (France), Pfizer Oncology, Lilly France SAS and Novartis Pharmaceuticals Corporation. This work was also funded in part by The Fero/J.P. Morgan Private Bank Clinical Oncology Research Grant, the National Cancer Institute grant P30 P30-CA023100 (R.K.), the Israeli Science Foundation grant 1188/16 (E.R.), Instituto Salud Carlos III—Programa Rio Hortega Contract grant CM15/00255 (I.B.), the Canadian Institutes for Health Research (grant MOP-142281 to W.H.M.) and the Canadian Cancer Society (grant 703811 to W.H.M.).
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Nature Reviews Clinical Oncology (2019)