ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-re...

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Veröffentlicht in:	Clinical cancer research Jg. 19; H. 15; S. 4273
Hauptverfasser:	Gainor, Justin F, Varghese, Anna M, Ou, Sai-Hong Ignatius, Kabraji, Sheheryar, Awad, Mark M, Katayama, Ryohei, Pawlak, Amanda, Mino-Kenudson, Mari, Yeap, Beow Y, Riely, Gregory J, Iafrate, A John, Arcila, Maria E, Ladanyi, Marc, Engelman, Jeffrey A, Dias-Santagata, Dora, Shaw, Alice T
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.08.2013
Schlagworte:	Adult Aged Aged, 80 and over Anaplastic Lymphoma Kinase Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Crizotinib Drug Resistance, Neoplasm - genetics ErbB Receptors - genetics Female Gene Expression Regulation, Neoplastic - drug effects Gene Rearrangement Humans Immunohistochemistry In Situ Hybridization, Fluorescence Male Middle Aged Mutation Protein Kinase Inhibitors - administration & dosage Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) Pyrazoles - administration & dosage Pyridines - administration & dosage ras Proteins - genetics Receptor Protein-Tyrosine Kinases
ISSN:	1078-0432, 1557-3265, 1557-3265
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Abstract	Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers. We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing. Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.
AbstractList	Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers.PURPOSEAnaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers.We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib.EXPERIMENTAL DESIGNWe reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib.Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing.RESULTSScreening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing.Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.CONCLUSIONSFunctional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib. Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers. We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing. Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.
Author	Awad, Mark M Gainor, Justin F Ou, Sai-Hong Ignatius Ladanyi, Marc Shaw, Alice T Iafrate, A John Katayama, Ryohei Yeap, Beow Y Arcila, Maria E Kabraji, Sheheryar Engelman, Jeffrey A Varghese, Anna M Mino-Kenudson, Mari Riely, Gregory J Dias-Santagata, Dora Pawlak, Amanda
Author_xml	– sequence: 1 givenname: Justin F surname: Gainor fullname: Gainor, Justin F organization: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA – sequence: 2 givenname: Anna M surname: Varghese fullname: Varghese, Anna M – sequence: 3 givenname: Sai-Hong Ignatius surname: Ou fullname: Ou, Sai-Hong Ignatius – sequence: 4 givenname: Sheheryar surname: Kabraji fullname: Kabraji, Sheheryar – sequence: 5 givenname: Mark M surname: Awad fullname: Awad, Mark M – sequence: 6 givenname: Ryohei surname: Katayama fullname: Katayama, Ryohei – sequence: 7 givenname: Amanda surname: Pawlak fullname: Pawlak, Amanda – sequence: 8 givenname: Mari surname: Mino-Kenudson fullname: Mino-Kenudson, Mari – sequence: 9 givenname: Beow Y surname: Yeap fullname: Yeap, Beow Y – sequence: 10 givenname: Gregory J surname: Riely fullname: Riely, Gregory J – sequence: 11 givenname: A John surname: Iafrate fullname: Iafrate, A John – sequence: 12 givenname: Maria E surname: Arcila fullname: Arcila, Maria E – sequence: 13 givenname: Marc surname: Ladanyi fullname: Ladanyi, Marc – sequence: 14 givenname: Jeffrey A surname: Engelman fullname: Engelman, Jeffrey A – sequence: 15 givenname: Dora surname: Dias-Santagata fullname: Dias-Santagata, Dora – sequence: 16 givenname: Alice T surname: Shaw fullname: Shaw, Alice T
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/23729361$$D View this record in MEDLINE/PubMed
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Snippet	Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports...
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SubjectTerms	Adult Aged Aged, 80 and over Anaplastic Lymphoma Kinase Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Crizotinib Drug Resistance, Neoplasm - genetics ErbB Receptors - genetics Female Gene Expression Regulation, Neoplastic - drug effects Gene Rearrangement Humans Immunohistochemistry In Situ Hybridization, Fluorescence Male Middle Aged Mutation Protein Kinase Inhibitors - administration & dosage Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) Pyrazoles - administration & dosage Pyridines - administration & dosage ras Proteins - genetics Receptor Protein-Tyrosine Kinases
Title	ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer
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