Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

Sean P. Pitroda; Nikolai N. Khodarev; Lei Huang; Abhineet Uppal; Sean C. Wightman; Sabha Ganai; Nora Joseph; Jason Pitt; Miguel Brown; Martin Forde; Kathy Mangold; Lai Xue; Christopher Weber; Jeremy P. Segal; Sabah Kadri; Melinda E. Stack; Sajid Khan; Philip Paty; Karen Kaul; Jorge Andrade; Kevin P. White; Mark Talamonti; Mitchell C. Posner; Samuel Hellman; Ralph R. Weichselbaum

doi:10.1038/s41467-018-04278-6

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

Sean P. Pitroda, Nikolai N. Khodarev, Lei Huang, Abhineet Uppal, Sean C. Wightman, Sabha Ganai, Nora Joseph, Jason Pitt, Miguel Brown, Martin Forde, Kathy Mangold, Lai Xue, Christopher Weber, Jeremy P. Segal, Sabah Kadri, Melinda E. Stack, Sajid Khan, Philip Paty, Karen Kaul, Jorge AndradeKevin P. White, Mark Talamonti, Mitchell C. Posner, Samuel Hellman, Ralph R. Weichselbaum

Research output: Contribution to journal › Article › peer-review

150 Scopus citations

Abstract

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

Original language	English (US)
Article number	1793
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04278-6
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-04278-6

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Pitroda, S. P., Khodarev, N. N., Huang, L., Uppal, A., Wightman, S. C., Ganai, S., Joseph, N., Pitt, J., Brown, M., Forde, M., Mangold, K., Xue, L., Weber, C., Segal, J. P., Kadri, S., Stack, M. E., Khan, S., Paty, P., Kaul, K., ... Weichselbaum, R. R. (2018). Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nature communications, 9(1), [1793]. https://doi.org/10.1038/s41467-018-04278-6

Pitroda, SP, Khodarev, NN, Huang, L, Uppal, A, Wightman, SC, Ganai, S, Joseph, N, Pitt, J, Brown, M, Forde, M, Mangold, K, Xue, L, Weber, C, Segal, JP, Kadri, S, Stack, ME, Khan, S, Paty, P, Kaul, K, Andrade, J, White, KP, Talamonti, M, Posner, MC, Hellman, S & Weichselbaum, RR 2018, 'Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis', Nature communications, vol. 9, no. 1, 1793. https://doi.org/10.1038/s41467-018-04278-6

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title = "Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis",

abstract = "The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.",

author = "Pitroda, {Sean P.} and Khodarev, {Nikolai N.} and Lei Huang and Abhineet Uppal and Wightman, {Sean C.} and Sabha Ganai and Nora Joseph and Jason Pitt and Miguel Brown and Martin Forde and Kathy Mangold and Lai Xue and Christopher Weber and Segal, {Jeremy P.} and Sabah Kadri and Stack, {Melinda E.} and Sajid Khan and Philip Paty and Karen Kaul and Jorge Andrade and White, {Kevin P.} and Mark Talamonti and Posner, {Mitchell C.} and Samuel Hellman and Weichselbaum, {Ralph R.}",

note = "Funding Information: This work was supported in part by the Virginia and D.K. Ludwig Fund for Cancer Research, as well as generous gifts from The Foglia Foundation and Mr. and Mrs. Vincent Foglia (R.R.W.). The funding sources had no role in the study design, collection/ analysis/interpretation of data, writing of the report, or decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are also grateful to Dr. Philip Connell, Dr. Michael Spiotto and Dr. Ainhoa Arina for their careful reviews of the manuscript and MaryAnn Regner for her assistance in performing MSI analysis. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04278-6",

language = "English (US)",

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T1 - Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

AU - Pitroda, Sean P.

AU - Khodarev, Nikolai N.

AU - Huang, Lei

AU - Uppal, Abhineet

AU - Wightman, Sean C.

AU - Ganai, Sabha

AU - Joseph, Nora

AU - Pitt, Jason

AU - Brown, Miguel

AU - Forde, Martin

AU - Mangold, Kathy

AU - Xue, Lai

AU - Weber, Christopher

AU - Segal, Jeremy P.

AU - Kadri, Sabah

AU - Stack, Melinda E.

AU - Khan, Sajid

AU - Paty, Philip

AU - Kaul, Karen

AU - Andrade, Jorge

AU - White, Kevin P.

AU - Talamonti, Mark

AU - Posner, Mitchell C.

AU - Hellman, Samuel

AU - Weichselbaum, Ralph R.

N1 - Funding Information: This work was supported in part by the Virginia and D.K. Ludwig Fund for Cancer Research, as well as generous gifts from The Foglia Foundation and Mr. and Mrs. Vincent Foglia (R.R.W.). The funding sources had no role in the study design, collection/ analysis/interpretation of data, writing of the report, or decision to submit the paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors are also grateful to Dr. Philip Connell, Dr. Michael Spiotto and Dr. Ainhoa Arina for their careful reviews of the manuscript and MaryAnn Regner for her assistance in performing MSI analysis. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

AB - The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

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JO - Nature Communications

JF - Nature Communications

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M1 - 1793

ER -

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

Abstract

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