PMID- 29370427
OWN - NLM
STAT- MEDLINE
DCOM- 20190215
LR  - 20190215
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Linking)
VI  - 109
IP  - 12
DP  - 2017 Dec 1
TI  - ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.
LID - 10.1093/jnci/djx089 [doi]
AB  - Background: ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal
      cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing
      rearrangements who benefited from anti-ALK, ROS, and TrkA-B-C therapies have been
      reported previously. Here we aimed at characterizing the clinical and molecular
      landscape of ALK, ROS1, and NTRK rearranged mCRC. Methods: Clinical features and 
      molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK
      rearranged tumors were compared with those of a cohort of 319 patients not
      bearing rearrangements by means of Fisher's exact, chi2 test, or Mann-Whitney
      test as appropriate. Overall survival curves were estimated with the Kaplan-Meier
      method and compared using the log-rank test. A Cox proportional hazard model was 
      adopted in the multivariable analysis. Deep molecular and immunophenotypic
      characterizations of rearranged cases, including those described in The Cancer
      Genome Atlas database, were performed. All statistical tests were two-sided.
      Results: Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements
      more frequently occurred in elderly patients (P = .02) with right-sided tumors (P
      < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P <
      .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter
      overall survival (15.6 months, 95% confidence interval [CI] = 0.0 to 20.4 months)
      than negative patients (33.7 months, 95% CI = 28.3 to 42.1 months), both in the
      univariate (hazard ratio [HR] = 2.17, 95% CI = 1.03 to 4.57, P < .001) and
      multivariable models (HR = 2.33, 95% CI = 1.10 to 4.95, P = .02). All four
      evaluable patients with rearrangements showed primary resistance to
      anti-epidermal growth factor receptor agents. Frequent association with
      potentially targetable RNF43 mutations was observed in MSI-high rearranged
      tumors. Conclusions: ALK, ROS1, and NTRK rearrangements define a new rare subtype
      of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and 
      BRAF wild-type status may help to identify patients bearing these alterations.
      While sensitivity to available treatments is limited, targeted strategies
      inhibiting ALK, ROS, and TrkA-B-C provided encouraging results.
CI  - (c) The Author 2017. Published by Oxford University Press. All rights reserved.
      For Permissions, please e-mail: journals.permissions@oup.com.
FAU - Pietrantonio, Filippo
AU  - Pietrantonio F
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Di Nicolantonio, Federica
AU  - Di Nicolantonio F
AD  - Department of Oncology, University of Torino, Candiolo, Italy.
AD  - Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
FAU - Schrock, Alexa B
AU  - Schrock AB
AD  - Foundation Medicine, Inc., Cambridge, MA.
FAU - Lee, Jeeyun
AU  - Lee J
AD  - Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu,
      Seoul, Korea.
FAU - Tejpar, Sabine
AU  - Tejpar S
AD  - Molecular Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven,
      Belgium.
FAU - Sartore-Bianchi, Andrea
AU  - Sartore-Bianchi A
AD  - Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
FAU - Hechtman, Jaclyn F
AU  - Hechtman JF
AD  - Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Christiansen, Jason
AU  - Christiansen J
AD  - Ignyta Inc., San Diego, CA.
FAU - Novara, Luca
AU  - Novara L
AD  - Department of Oncology, University of Torino, Candiolo, Italy.
FAU - Tebbutt, Niall
AU  - Tebbutt N
AD  - Austin Health, Melbourne VIC, Australia.
FAU - Fuca, Giovanni
AU  - Fuca G
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Antoniotti, Carlotta
AU  - Antoniotti C
AD  - Azienda Ospedaliero, Universitaria Pisana, Pisa, Italy.
AD  - University of Pisa, Pisa, Italy.
FAU - Kim, Seung Tae
AU  - Kim ST
AD  - Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu,
      Seoul, Korea.
FAU - Murphy, Danielle
AU  - Murphy D
AD  - Ignyta Inc., San Diego, CA.
FAU - Berenato, Rosa
AU  - Berenato R
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Morano, Federica
AU  - Morano F
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Sun, James
AU  - Sun J
AD  - Foundation Medicine, Inc., Cambridge, MA.
FAU - Min, Bosun
AU  - Min B
AD  - Ignyta Inc., San Diego, CA.
FAU - Stephens, Philip J
AU  - Stephens PJ
AD  - Foundation Medicine, Inc., Cambridge, MA.
FAU - Chen, Marissa
AU  - Chen M
AD  - Ignyta Inc., San Diego, CA.
FAU - Lazzari, Luca
AU  - Lazzari L
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Miller, Vincent A
AU  - Miller VA
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Shoemaker, Robert
AU  - Shoemaker R
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Amatu, Alessio
AU  - Amatu A
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Milione, Massimo
AU  - Milione M
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Ross, Jeffrey S
AU  - Ross JS
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Siena, Salvatore
AU  - Siena S
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Bardelli, Alberto
AU  - Bardelli A
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Ali, Siraj M
AU  - Ali SM
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Falcone, Alfredo
AU  - Falcone A
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - de Braud, Filippo
AU  - de Braud F
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori,
      Milan, Italy.
FAU - Cremolini, Chiara
AU  - Cremolini C
AD  - Azienda Ospedaliero, Universitaria Pisana, Pisa, Italy.
AD  - University of Pisa, Pisa, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (ROS1 protein, human)
RN  - EC 2.7.10.1 (Receptor, trkA)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anaplastic Lymphoma Kinase/*genetics
MH  - Biomarkers, Tumor/*genetics
MH  - Colorectal Neoplasms/*genetics/pathology/therapy
MH  - Combined Modality Therapy
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Expression Regulation, Neoplastic
MH  - *Gene Rearrangement
MH  - Humans
MH  - Liver Neoplasms/*genetics/pathology/therapy
MH  - Lung Neoplasms/genetics/pathology/therapy
MH  - Lymphatic Metastasis
MH  - Male
MH  - Middle Aged
MH  - Peritoneal Neoplasms/genetics/pathology/therapy
MH  - Prognosis
MH  - Protein-Tyrosine Kinases/*genetics
MH  - Proto-Oncogene Proteins/*genetics
MH  - Receptor, trkA/*genetics
MH  - Survival Rate
MH  - Young Adult
EDAT- 2018/01/26 06:00
MHDA- 2019/02/16 06:00
CRDT- 2018/01/26 06:00
PHST- 2017/01/05 00:00 [received]
PHST- 2017/04/11 00:00 [accepted]
PHST- 2018/01/26 06:00 [entrez]
PHST- 2018/01/26 06:00 [pubmed]
PHST- 2019/02/16 06:00 [medline]
AID - 3860155 [pii]
AID - 10.1093/jnci/djx089 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2017 Dec 1;109(12). pii: 3860155. doi: 10.1093/jnci/djx089.