RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Filippo Pietrantonio, F. Di Nicolantonio, A. B. Schrock, J. Lee, F. Morano, G. Fucà, P. Nikolinakos, A. Drilon, J. F. Hechtman, J. Christiansen, K. Gowen, G. M. Frampton, P. Gasparini, D. Rossini, C. Gigliotti, S. T. Kim, M. Prisciandaro, J. Hodgson, A. Zaniboni, V. K. Chiu & 16 others M. Milione, R. Patel, V. Miller, A. Bardelli, L. Novara, L. Wang, S. M. Pupa, G. Sozzi, J. Ross, M. Di Bartolomeo, A. Bertotti, S. Ali, L. Trusolino, A. Falcone, F. de Braud, C. Cremolini

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P=0.052), with ECOG PS 1-2 (90% versus 50%, P=0.02), right-sided (55% versus 32%, P=0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P=0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

Original languageEnglish
Pages (from-to)1394-1401
Number of pages8
JournalAnnals of Oncology
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Colorectal Neoplasms
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Patient Rights
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Control Groups
Mutation
N-methylsuccinimide
Therapeutics

Keywords

  • Colorectal cancer
  • Gene fusions
  • MSI-high
  • Prognosis
  • RET
  • Targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Pietrantonio, F., Di Nicolantonio, F., Schrock, A. B., Lee, J., Morano, F., Fucà, G., ... Cremolini, C. (2018). RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. Annals of Oncology, 29(6), 1394-1401. https://doi.org/10.1093/annonc/mdy090

RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. / Pietrantonio, Filippo; Di Nicolantonio, F.; Schrock, A. B.; Lee, J.; Morano, F.; Fucà, G.; Nikolinakos, P.; Drilon, A.; Hechtman, J. F.; Christiansen, J.; Gowen, K.; Frampton, G. M.; Gasparini, P.; Rossini, D.; Gigliotti, C.; Kim, S. T.; Prisciandaro, M.; Hodgson, J.; Zaniboni, A.; Chiu, V. K.; Milione, M.; Patel, R.; Miller, V.; Bardelli, A.; Novara, L.; Wang, L.; Pupa, S. M.; Sozzi, G.; Ross, J.; Di Bartolomeo, M.; Bertotti, A.; Ali, S.; Trusolino, L.; Falcone, A.; de Braud, F.; Cremolini, C.

In: Annals of Oncology, Vol. 29, No. 6, 01.06.2018, p. 1394-1401.

Research output: Contribution to journalArticle

Pietrantonio, F, Di Nicolantonio, F, Schrock, AB, Lee, J, Morano, F, Fucà, G, Nikolinakos, P, Drilon, A, Hechtman, JF, Christiansen, J, Gowen, K, Frampton, GM, Gasparini, P, Rossini, D, Gigliotti, C, Kim, ST, Prisciandaro, M, Hodgson, J, Zaniboni, A, Chiu, VK, Milione, M, Patel, R, Miller, V, Bardelli, A, Novara, L, Wang, L, Pupa, SM, Sozzi, G, Ross, J, Di Bartolomeo, M, Bertotti, A, Ali, S, Trusolino, L, Falcone, A, de Braud, F & Cremolini, C 2018, 'RET fusions in a small subset of advanced colorectal cancers at risk of being neglected', Annals of Oncology, vol. 29, no. 6, pp. 1394-1401. https://doi.org/10.1093/annonc/mdy090
Pietrantonio, Filippo ; Di Nicolantonio, F. ; Schrock, A. B. ; Lee, J. ; Morano, F. ; Fucà, G. ; Nikolinakos, P. ; Drilon, A. ; Hechtman, J. F. ; Christiansen, J. ; Gowen, K. ; Frampton, G. M. ; Gasparini, P. ; Rossini, D. ; Gigliotti, C. ; Kim, S. T. ; Prisciandaro, M. ; Hodgson, J. ; Zaniboni, A. ; Chiu, V. K. ; Milione, M. ; Patel, R. ; Miller, V. ; Bardelli, A. ; Novara, L. ; Wang, L. ; Pupa, S. M. ; Sozzi, G. ; Ross, J. ; Di Bartolomeo, M. ; Bertotti, A. ; Ali, S. ; Trusolino, L. ; Falcone, A. ; de Braud, F. ; Cremolini, C. / RET fusions in a small subset of advanced colorectal cancers at risk of being neglected. In: Annals of Oncology. 2018 ; Vol. 29, No. 6. pp. 1394-1401.
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title = "RET fusions in a small subset of advanced colorectal cancers at risk of being neglected",
abstract = "Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P=0.052), with ECOG PS 1-2 (90{\%} versus 50{\%}, P=0.02), right-sided (55{\%} versus 32{\%}, P=0.013), previously unresected primary tumors (58{\%} versus 21{\%}, P < 0.001), RAS and BRAF wild-type (100{\%} versus 40{\%}, P < 0.001) and MSI-high (48{\%} versus 7{\%}, P < 0.001). Notably, 11 (26{\%}) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95{\%} CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95{\%} CI, 1.25-7.07; P=0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.",
keywords = "Colorectal cancer, Gene fusions, MSI-high, Prognosis, RET, Targeted therapy",
author = "Filippo Pietrantonio and {Di Nicolantonio}, F. and Schrock, {A. B.} and J. Lee and F. Morano and G. Fuc{\`a} and P. Nikolinakos and A. Drilon and Hechtman, {J. F.} and J. Christiansen and K. Gowen and Frampton, {G. M.} and P. Gasparini and D. Rossini and C. Gigliotti and Kim, {S. T.} and M. Prisciandaro and J. Hodgson and A. Zaniboni and Chiu, {V. K.} and M. Milione and R. Patel and V. Miller and A. Bardelli and L. Novara and L. Wang and Pupa, {S. M.} and G. Sozzi and J. Ross and {Di Bartolomeo}, M. and A. Bertotti and S. Ali and L. Trusolino and A. Falcone and {de Braud}, F. and C. Cremolini",
year = "2018",
month = "6",
day = "1",
doi = "10.1093/annonc/mdy090",
language = "English",
volume = "29",
pages = "1394--1401",
journal = "Annals of Oncology",
issn = "0923-7534",
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}

TY - JOUR

T1 - RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

AU - Pietrantonio, Filippo

AU - Di Nicolantonio, F.

AU - Schrock, A. B.

AU - Lee, J.

AU - Morano, F.

AU - Fucà, G.

AU - Nikolinakos, P.

AU - Drilon, A.

AU - Hechtman, J. F.

AU - Christiansen, J.

AU - Gowen, K.

AU - Frampton, G. M.

AU - Gasparini, P.

AU - Rossini, D.

AU - Gigliotti, C.

AU - Kim, S. T.

AU - Prisciandaro, M.

AU - Hodgson, J.

AU - Zaniboni, A.

AU - Chiu, V. K.

AU - Milione, M.

AU - Patel, R.

AU - Miller, V.

AU - Bardelli, A.

AU - Novara, L.

AU - Wang, L.

AU - Pupa, S. M.

AU - Sozzi, G.

AU - Ross, J.

AU - Di Bartolomeo, M.

AU - Bertotti, A.

AU - Ali, S.

AU - Trusolino, L.

AU - Falcone, A.

AU - de Braud, F.

AU - Cremolini, C.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P=0.052), with ECOG PS 1-2 (90% versus 50%, P=0.02), right-sided (55% versus 32%, P=0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P=0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

AB - Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P=0.052), with ECOG PS 1-2 (90% versus 50%, P=0.02), right-sided (55% versus 32%, P=0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P=0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

KW - Colorectal cancer

KW - Gene fusions

KW - MSI-high

KW - Prognosis

KW - RET

KW - Targeted therapy

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U2 - 10.1093/annonc/mdy090

DO - 10.1093/annonc/mdy090

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JO - Annals of Oncology

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