PURPOSE: There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). PATIENTS AND METHODS: HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS). RESULTS: Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). CONCLUSION: Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.
PURPOSE: There is increasing recognition of the existence of intratumoral heterogeneity of the humanepidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). PATIENTS AND METHODS: HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS). RESULTS: Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). CONCLUSION: Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.
Authors: Alastair I Bartlett; Jane Starcyznski; Tammy Robson; Alex Maclellan; Fiona M Campbell; Cornelis J H van de Velde; Annette Hasenburg; Christos Markopoulos; Caroline Seynaeve; Daniel Rea; John M S Bartlett Journal: Am J Clin Pathol Date: 2011-08 Impact factor: 2.493
Authors: Mitch Dowsett; Steve R Ebbs; J Michael Dixon; Anthony Skene; Clive Griffith; Irene Boeddinghaus; Janine Salter; Simone Detre; Margaret Hills; Susan Ashley; Stephen Francis; Geraldine Walsh; Ian E Smith Journal: J Clin Oncol Date: 2005-03-14 Impact factor: 44.544
Authors: Ruhul M Quddus; James C Sung; Cunxian Zhang; Terese Pasqueriello; Meryle Eklund; Margaret M Steinhoff Journal: Breast Cancer Date: 2005 Impact factor: 4.239
Authors: James T Mascarello; Arthur R Brothman; Keri Davison; Gordon W Dewald; Marille Herrman; Danette McCandless; Jonathan P Park; Diane L Persons; Kathleen W Rao; Nancy R Schneider; Gail H Vance; Linda D Cooley Journal: Arch Pathol Lab Med Date: 2002-12 Impact factor: 5.534
Authors: Edith A Perez; Monica M Reinholz; David W Hillman; Kathleen S Tenner; Matthew J Schroeder; Nancy E Davidson; Silvana Martino; George W Sledge; Lyndsay N Harris; Julie R Gralow; Amylou C Dueck; Rhett P Ketterling; James N Ingle; Wilma L Lingle; Peter A Kaufman; Daniel W Visscher; Robert B Jenkins Journal: J Clin Oncol Date: 2010-08-09 Impact factor: 44.544
Authors: Gail H Vance; Todd S Barry; Kenneth J Bloom; Patrick L Fitzgibbons; David G Hicks; Robert B Jenkins; Diane L Persons; Raymond R Tubbs; M Elizabeth H Hammond Journal: Arch Pathol Lab Med Date: 2009-04 Impact factor: 5.534
Authors: Naser Davarzani; Lindsay C Hewitt; Matthew D Hale; Veerle Melotte; Matthew Nankivell; Gordon G A Hutchins; David Cunningham; William H Allum; Ruth E Langley; Shahab Jolani; Heike I Grabsch Journal: Dis Esophagus Date: 2020-08-03 Impact factor: 3.429
Authors: Angela N Bartley; Mary Kay Washington; Christina B Ventura; Nofisat Ismaila; Carol Colasacco; Al B Benson; Alfredo Carrato; Margaret L Gulley; Dhanpat Jain; Sanjay Kakar; Helen J Mackay; Catherine Streutker; Laura Tang; Megan Troxell; Jaffer A Ajani Journal: Am J Clin Pathol Date: 2016-11-14 Impact factor: 2.493
Authors: Harry H Yoon; William R Sukov; Qian Shi; Christopher A Sattler; Anne E Wiktor; Robert B Diasio; Tsung-Teh Wu; Robert B Jenkins; Frank A Sinicrope Journal: Cancer Date: 2013-10-21 Impact factor: 6.860
Authors: Daniel V T Catenacci; Wei-Li Liao; Lei Zhao; Emma Whitcomb; Les Henderson; Emily O'Day; Peng Xu; Sheeno Thyparambil; David Krizman; Kathleen Bengali; Jamar Uzzell; Marlene Darfler; Fabiola Cecchi; Adele Blackler; Yung-Jue Bang; John Hart; Shu-Yuan Xiao; Sang Mee Lee; Jon Burrows; Todd Hembrough Journal: Gastric Cancer Date: 2015-11-18 Impact factor: 7.370