Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes

Valeriy Domenyuk; Zoran Gatalica; Radhika Santhanam; Xixi Wei; Adam Stark; Patrick Kennedy; Brandon Toussaint; Symon Levenberg; Jie Wang; Nianqing Xiao; Richard Greil; Gabriel Rinnerthaler; Simon P. Gampenrieder; Amy B. Heimberger; Donald A. Berry; Anna Barker; John Quackenbush; John L. Marshall; George Poste; Jeffrey L. Vacirca; Gregory A. Vidal; Lee S. Schwartzberg; David D. Halbert; Andreas Voss; Daniel Magee; Mark R. Miglarese; Michael Famulok; Günter Mayer; David Spetzler

doi:10.1038/s41467-018-03631-z

Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes

Valeriy Domenyuk, Zoran Gatalica, Radhika Santhanam, Xixi Wei, Adam Stark, Patrick Kennedy, Brandon Toussaint, Symon Levenberg, Jie Wang, Nianqing Xiao, Richard Greil, Gabriel Rinnerthaler, Simon P. Gampenrieder, Amy B. Heimberger, Donald A. Berry, Anna Barker, John Quackenbush, John L. Marshall, George Poste, Jeffrey L. VacircaGregory A. Vidal, Lee S. Schwartzberg, David D. Halbert, Andreas Voss, Daniel Magee, Mark R. Miglarese, Michael Famulok, Günter Mayer, David Spetzler

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Abstract

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.

Original language	English (US)
Article number	1219
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03631-z
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Domenyuk, V., Gatalica, Z., Santhanam, R., Wei, X., Stark, A., Kennedy, P., Toussaint, B., Levenberg, S., Wang, J., Xiao, N., Greil, R., Rinnerthaler, G., Gampenrieder, S. P., Heimberger, A. B., Berry, D. A., Barker, A., Quackenbush, J., Marshall, J. L., Poste, G., ... Spetzler, D. (2018). Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes. Nature communications, 9(1), Article 1219. https://doi.org/10.1038/s41467-018-03631-z

Domenyuk, V, Gatalica, Z, Santhanam, R, Wei, X, Stark, A, Kennedy, P, Toussaint, B, Levenberg, S, Wang, J, Xiao, N, Greil, R, Rinnerthaler, G, Gampenrieder, SP, Heimberger, AB, Berry, DA, Barker, A, Quackenbush, J, Marshall, JL, Poste, G, Vacirca, JL, Vidal, GA, Schwartzberg, LS, Halbert, DD, Voss, A, Magee, D, Miglarese, MR, Famulok, M, Mayer, G & Spetzler, D 2018, 'Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes', Nature communications, vol. 9, no. 1, 1219. https://doi.org/10.1038/s41467-018-03631-z

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abstract = "Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.",

author = "Valeriy Domenyuk and Zoran Gatalica and Radhika Santhanam and Xixi Wei and Adam Stark and Patrick Kennedy and Brandon Toussaint and Symon Levenberg and Jie Wang and Nianqing Xiao and Richard Greil and Gabriel Rinnerthaler and Gampenrieder, {Simon P.} and Heimberger, {Amy B.} and Berry, {Donald A.} and Anna Barker and John Quackenbush and Marshall, {John L.} and George Poste and Vacirca, {Jeffrey L.} and Vidal, {Gregory A.} and Schwartzberg, {Lee S.} and Halbert, {David D.} and Andreas Voss and Daniel Magee and Miglarese, {Mark R.} and Michael Famulok and G{\"u}nter Mayer and David Spetzler",

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AU - Gatalica, Zoran

AU - Santhanam, Radhika

AU - Wei, Xixi

AU - Stark, Adam

AU - Kennedy, Patrick

AU - Toussaint, Brandon

AU - Levenberg, Symon

AU - Wang, Jie

AU - Xiao, Nianqing

AU - Greil, Richard

AU - Rinnerthaler, Gabriel

AU - Gampenrieder, Simon P.

AU - Heimberger, Amy B.

AU - Berry, Donald A.

AU - Barker, Anna

AU - Quackenbush, John

AU - Marshall, John L.

AU - Poste, George

AU - Vacirca, Jeffrey L.

AU - Vidal, Gregory A.

AU - Schwartzberg, Lee S.

AU - Halbert, David D.

AU - Voss, Andreas

AU - Magee, Daniel

AU - Miglarese, Mark R.

AU - Famulok, Michael

AU - Mayer, Günter

AU - Spetzler, David

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N2 - Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.

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Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes

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