Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

Alvaro Lassaletta; Michal Zapotocky; Matthew Mistry; Vijay Ramaswamy; Marion Honnorat; Rahul Krishnatry; Ana Guerreiro Stucklin; Nataliya Zhukova; Anthony Arnoldo; Scott Ryall; Catriona Ling; Tara McKeown; Jim Loukides; Ofelia Cruz; Carmen De Torres; Cheng Ying Ho; Roger J. Packer; Ruth Tatevossian; Ibrahim Qaddoumi; Julie H. Harreld; James D. Dalton; Jean Mulcahy-Levy; Nicholas Foreman; Matthias A. Karajannis; Shiyang Wang; Matija Snuderl; Amulya Nageswara Rao; Caterina Giannini; Mark Kieran; Keith L. Ligon; Maria Luisa Garre; Paolo Nozza; Samantha Mascelli; Alessandro Raso; Sabine Mueller; Theodore Nicolaides; Karen Silva; Romain Perbet; Alexandre Vasiljevic; Cécile Faure Conter; Didier Frappaz; Sarah Leary; Courtney Crane; Aden Chan; Ho Keung Ng; Zhi Feng Shi; Ying Mao; Elizabeth Finch; David Eisenstat; Bev Wilson; Anne Sophie Carret; Peter Hauser; David Sumerauer; Lenka Krskova; Valerie Larouche; Adam Fleming; Shayna Zelcer; Nada Jabado; James T. Rutka; Peter Dirks; Michael D. Taylor; Shiyi Chen; Ute Bartels; Annie Huang; David W. Ellison; Eric Bouffet; Cynthia Hawkins; Uri Tabori

doi:10.1200/JCO.2016.71.8726

Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, Ofelia Cruz, Carmen De Torres, Cheng Ying Ho, Roger J. Packer, Ruth Tatevossian, Ibrahim Qaddoumi, Julie H. HarreldJames D. Dalton, Jean Mulcahy-Levy, Nicholas Foreman, Matthias A. Karajannis, Shiyang Wang, Matija Snuderl, Amulya Nageswara Rao, Caterina Giannini, Mark Kieran, Keith L. Ligon, Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, Alessandro Raso, Sabine Mueller, Theodore Nicolaides, Karen Silva, Romain Perbet, Alexandre Vasiljevic, Cécile Faure Conter, Didier Frappaz, Sarah Leary, Courtney Crane, Aden Chan, Ho Keung Ng, Zhi Feng Shi, Ying Mao, Elizabeth Finch, David Eisenstat, Bev Wilson, Anne Sophie Carret, Peter Hauser, David Sumerauer, Lenka Krskova, Valerie Larouche, Adam Fleming, Shayna Zelcer, Nada Jabado, James T. Rutka, Peter Dirks, Michael D. Taylor, Shiyi Chen, Ute Bartels, Annie Huang, David W. Ellison, Eric Bouffet, Cynthia Hawkins, Uri Tabori

Laboratory Medicine and Pathology

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

109 Scopus citations

Abstract

Purpose: BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods: A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results: BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion: BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Original language	English (US)
Pages (from-to)	2934-2941
Number of pages	8
Journal	Journal of Clinical Oncology
Volume	35
Issue number	25
DOIs	https://doi.org/10.1200/JCO.2016.71.8726
State	Published - Sep 1 2017

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1200/JCO.2016.71.8726

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Lassaletta, A., Zapotocky, M., Mistry, M., Ramaswamy, V., Honnorat, M., Krishnatry, R., Stucklin, A. G., Zhukova, N., Arnoldo, A., Ryall, S., Ling, C., McKeown, T., Loukides, J., Cruz, O., De Torres, C., Ho, C. Y., Packer, R. J., Tatevossian, R., Qaddoumi, I., ... Tabori, U. (2017). Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. Journal of Clinical Oncology, 35(25), 2934-2941. https://doi.org/10.1200/JCO.2016.71.8726

Lassaletta, A, Zapotocky, M, Mistry, M, Ramaswamy, V, Honnorat, M, Krishnatry, R, Stucklin, AG, Zhukova, N, Arnoldo, A, Ryall, S, Ling, C, McKeown, T, Loukides, J, Cruz, O, De Torres, C, Ho, CY, Packer, RJ, Tatevossian, R, Qaddoumi, I, Harreld, JH, Dalton, JD, Mulcahy-Levy, J, Foreman, N, Karajannis, MA, Wang, S, Snuderl, M, Rao, AN, Giannini, C, Kieran, M, Ligon, KL, Garre, ML, Nozza, P, Mascelli, S, Raso, A, Mueller, S, Nicolaides, T, Silva, K, Perbet, R, Vasiljevic, A, Conter, CF, Frappaz, D, Leary, S, Crane, C, Chan, A, Ng, HK, Shi, ZF, Mao, Y, Finch, E, Eisenstat, D, Wilson, B, Carret, AS, Hauser, P, Sumerauer, D, Krskova, L, Larouche, V, Fleming, A, Zelcer, S, Jabado, N, Rutka, JT, Dirks, P, Taylor, MD, Chen, S, Bartels, U, Huang, A, Ellison, DW, Bouffet, E, Hawkins, C & Tabori, U 2017, 'Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas', Journal of Clinical Oncology, vol. 35, no. 25, pp. 2934-2941. https://doi.org/10.1200/JCO.2016.71.8726

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title = "Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas",

abstract = "Purpose: BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods: A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results: BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion: BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.",

author = "Alvaro Lassaletta and Michal Zapotocky and Matthew Mistry and Vijay Ramaswamy and Marion Honnorat and Rahul Krishnatry and Stucklin, {Ana Guerreiro} and Nataliya Zhukova and Anthony Arnoldo and Scott Ryall and Catriona Ling and Tara McKeown and Jim Loukides and Ofelia Cruz and {De Torres}, Carmen and Ho, {Cheng Ying} and Packer, {Roger J.} and Ruth Tatevossian and Ibrahim Qaddoumi and Harreld, {Julie H.} and Dalton, {James D.} and Jean Mulcahy-Levy and Nicholas Foreman and Karajannis, {Matthias A.} and Shiyang Wang and Matija Snuderl and Rao, {Amulya Nageswara} and Caterina Giannini and Mark Kieran and Ligon, {Keith L.} and Garre, {Maria Luisa} and Paolo Nozza and Samantha Mascelli and Alessandro Raso and Sabine Mueller and Theodore Nicolaides and Karen Silva and Romain Perbet and Alexandre Vasiljevic and Conter, {C{\'e}cile Faure} and Didier Frappaz and Sarah Leary and Courtney Crane and Aden Chan and Ng, {Ho Keung} and Shi, {Zhi Feng} and Ying Mao and Elizabeth Finch and David Eisenstat and Bev Wilson and Carret, {Anne Sophie} and Peter Hauser and David Sumerauer and Lenka Krskova and Valerie Larouche and Adam Fleming and Shayna Zelcer and Nada Jabado and Rutka, {James T.} and Peter Dirks and Taylor, {Michael D.} and Shiyi Chen and Ute Bartels and Annie Huang and Ellison, {David W.} and Eric Bouffet and Cynthia Hawkins and Uri Tabori",

note = "Publisher Copyright: {\textcopyright} 2017 by American Society of Clinical Oncology.",

year = "2017",

month = sep,

day = "1",

doi = "10.1200/JCO.2016.71.8726",

language = "English (US)",

volume = "35",

pages = "2934--2941",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "25",

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TY - JOUR

T1 - Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

AU - Lassaletta, Alvaro

AU - Zapotocky, Michal

AU - Mistry, Matthew

AU - Ramaswamy, Vijay

AU - Honnorat, Marion

AU - Krishnatry, Rahul

AU - Stucklin, Ana Guerreiro

AU - Zhukova, Nataliya

AU - Arnoldo, Anthony

AU - Ryall, Scott

AU - Ling, Catriona

AU - McKeown, Tara

AU - Loukides, Jim

AU - Cruz, Ofelia

AU - De Torres, Carmen

AU - Ho, Cheng Ying

AU - Packer, Roger J.

AU - Tatevossian, Ruth

AU - Qaddoumi, Ibrahim

AU - Harreld, Julie H.

AU - Dalton, James D.

AU - Mulcahy-Levy, Jean

AU - Foreman, Nicholas

AU - Karajannis, Matthias A.

AU - Wang, Shiyang

AU - Snuderl, Matija

AU - Rao, Amulya Nageswara

AU - Giannini, Caterina

AU - Kieran, Mark

AU - Ligon, Keith L.

AU - Garre, Maria Luisa

AU - Nozza, Paolo

AU - Mascelli, Samantha

AU - Raso, Alessandro

AU - Mueller, Sabine

AU - Nicolaides, Theodore

AU - Silva, Karen

AU - Perbet, Romain

AU - Vasiljevic, Alexandre

AU - Conter, Cécile Faure

AU - Frappaz, Didier

AU - Leary, Sarah

AU - Crane, Courtney

AU - Chan, Aden

AU - Ng, Ho Keung

AU - Shi, Zhi Feng

AU - Mao, Ying

AU - Finch, Elizabeth

AU - Eisenstat, David

AU - Wilson, Bev

AU - Carret, Anne Sophie

AU - Hauser, Peter

AU - Sumerauer, David

AU - Krskova, Lenka

AU - Larouche, Valerie

AU - Fleming, Adam

AU - Zelcer, Shayna

AU - Jabado, Nada

AU - Rutka, James T.

AU - Dirks, Peter

AU - Taylor, Michael D.

AU - Chen, Shiyi

AU - Bartels, Ute

AU - Huang, Annie

AU - Ellison, David W.

AU - Bouffet, Eric

AU - Hawkins, Cynthia

AU - Tabori, Uri

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Purpose: BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods: A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results: BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion: BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

AB - Purpose: BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods: A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results: BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion: BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

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DO - 10.1200/JCO.2016.71.8726

M3 - Article

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AN - SCOPUS:85029215323

SN - 0732-183X

VL - 35

SP - 2934

EP - 2941

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 25

ER -

Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas

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