BACKGROUND: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. PATIENTS AND METHODS: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. RESULTS: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. CONCLUSION: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. CLINICAL TRIAL INFORMATION: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).
BACKGROUND: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. PATIENTS AND METHODS: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. RESULTS: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. CONCLUSION: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. CLINICAL TRIAL INFORMATION: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).
Authors: Dongfang Tang; Hongliang Liu; Yuchen Zhao; Danwen Qian; Sheng Luo; Edward F Patz; Li Su; Sipeng Shen; David C ChristianI; Wen Gao; Qingyi Wei Journal: Am J Cancer Res Date: 2020-08-01 Impact factor: 6.166
Authors: Alexander Drilon; Romel Somwar; Biju P Mangatt; Henrik Edgren; Patrice Desmeules; Anja Ruusulehto; Roger S Smith; Lukas Delasos; Morana Vojnic; Andrew J Plodkowski; Joshua Sabari; Kenneth Ng; Joseph Montecalvo; Jason Chang; Huichun Tai; William W Lockwood; Victor Martinez; Gregory J Riely; Charles M Rudin; Mark G Kris; Maria E Arcila; Christopher Matheny; Ryma Benayed; Natasha Rekhtman; Marc Ladanyi; Gopinath Ganji Journal: Cancer Discov Date: 2018-04-02 Impact factor: 39.397
Authors: Jacques Cadranel; Stephen V Liu; Michaël Duruisseaux; Eva Branden; Yasushi Goto; Benjamin A Weinberg; Christoph Heining; Richard F Schlenk; Parneet Cheema; Martin R Jones; Alexander Drilon; Domenico Trombetta; Lucia Anna Muscarella; Khaled Tolba; Valerie Gounant; Agnieszka Cseh; Flavio Solca; Janessa J Laskin; Daniel J Renouf Journal: Oncologist Date: 2020-09-23
Authors: Alexander Drilon; Michael Duruisseaux; Ji-Youn Han; Masaoki Ito; Christina Falcon; Soo-Ryum Yang; Yonina R Murciano-Goroff; Haiquan Chen; Morihito Okada; Miguel Angel Molina; Marie Wislez; Philippe Brun; Clarisse Dupont; Eva Branden; Giulio Rossi; Alexa Schrock; Siraj Ali; Valérie Gounant; Fanny Magne; Torsten Gerriet Blum; Alison M Schram; Isabelle Monnet; Jin-Yuan Shih; Joshua Sabari; Maurice Pérol; Viola W Zhu; Misako Nagasaka; Robert Doebele; D Ross Camidge; Maria Arcila; Sai-Hong Ignatius Ou; Denis Moro-Sibilot; Rafael Rosell; Lucia Anna Muscarella; Stephen V Liu; Jacques Cadranel Journal: J Clin Oncol Date: 2021-06-02 Impact factor: 50.717