Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers
Yuxuan Wang, Lu Li, Christopher Douville, Joshua D Cohen, Ting-Tai Yen, Isaac Kinde, Karin Sundfelt, Susanne K Kjær, Ralph H Hruban, Ie-Ming Shih, Tian-Li Wang, Robert J Kurman, Simeon Springer, Janine Ptak, Maria Popoli, Joy Schaefer, Natalie Silliman, Lisa Dobbyn, Edward J Tanner, Ana Angarita, Maria Lycke, Kirsten Jochumsen, Bahman Afsari, Ludmila Danilova, Douglas A Levine, Kris Jardon, Xing Zeng, Jocelyne Arseneau, Lili Fu, Luis A Diaz Jr, Rachel Karchin, Cristian Tomasetti, Kenneth W Kinzler, Bert Vogelstein, Amanda N Fader, Lucy Gilbert, Nickolas Papadopoulos, Yuxuan Wang, Lu Li, Christopher Douville, Joshua D Cohen, Ting-Tai Yen, Isaac Kinde, Karin Sundfelt, Susanne K Kjær, Ralph H Hruban, Ie-Ming Shih, Tian-Li Wang, Robert J Kurman, Simeon Springer, Janine Ptak, Maria Popoli, Joy Schaefer, Natalie Silliman, Lisa Dobbyn, Edward J Tanner, Ana Angarita, Maria Lycke, Kirsten Jochumsen, Bahman Afsari, Ludmila Danilova, Douglas A Levine, Kris Jardon, Xing Zeng, Jocelyne Arseneau, Lili Fu, Luis A Diaz Jr, Rachel Karchin, Cristian Tomasetti, Kenneth W Kinzler, Bert Vogelstein, Amanda N Fader, Lucy Gilbert, Nickolas Papadopoulos
Abstract
We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
Conflict of interest statement
Competing interests: Under agreements between the Johns Hopkins University (JHU), Genzyme, Sysmex Inostics, Qiagen, Invitrogen, and Personal Genome Diagnostics, B.V., K.W.K., N.P., and L.A.D. are entitled to a share of the royalties received by the university on the sales of products related to genes and technologies described in this manuscript. B.V., K.W.K., N.P., and L.A.D. are cofounders of Personal Genome Diagnostics and PapGene Inc., are members of the Scientific Advisory Boards of Sysmex Inostics, Personal Genome Diagnostics, and PapGene Inc., and own Personal Genome Diagnostics and PapGene Inc. stock, which is subject to certain restrictions under JHU policy. I.K. is a cofounder and chief scientific officer of PapGene Inc. The company has licensed previously described technologies related to the work described in this paper. The terms of these arrangements are managed by the JHU in accordance with its conflict of interest policies. Part of the technology described in U.S. Patent 20150292027 (Papanicolaou Test for Ovarian and Endometrial Cancers) was applied in this study. Y.W., K.W.K., N.P., C.T., and B.V. are inventors on a patent application on the use of biomarker combinations for the detection of gynecologic cancers. This application will be submitted by the JHU and managed in accordance with its conflict of interest policies. Y.W., K.W.K., N.P., B.V., R.K., I.K., L.D., and C D. are inventors of technologies that are related to those described in this paper and that are associated with equity or royalty payments to the inventors. The terms of these arrangements are being managed by JHU in accordance with its conflict of interest policies. L.G. is listed as a co-inventor on U.S. Provisional Patent application no. 62/656,525 (Uterine Brush and Sample Collection Kit, and Method of Collecting Endometrial Cells from the Uterus) that partially describes the intrauterine sampling method outlined in this paper.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Source: PubMed