Sandeep Kumar1, Amanjit Bal2, Ashim Das1, Ishita Loriya3, Siddhant Khare3, Shalmoli Bhattacharya4, Gurpreet Singh3. 1. Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India. 2. Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India. docaman5@hotmail.com. 3. Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India. 4. Department of Biophysics, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India.
Abstract
PURPOSE: The heterogeneity of triple-negative breast cancer (TNBC) confers variable response to chemotherapy that results in poor outcome and relapse. Due to lack of targeted therapy, there is a need to provide molecular classification of TNBC and identify probable therapeutic targets. METHODS: We classified TNBC into surrogate molecular subtypes by immunohistochemistry and evaluated hotspot mutations (N = 80) in PIK3CA (exon 4, 9, and 20) and AKT1 (exon 2) in TNBC subtypes by Sanger sequencing. RESULTS: TNBCs were classified into Basal-like 1(BL1) (n = 20, 25%), Mesenchymal (n = 19, 23.75%), Luminal Androgen (LAR) (n = 12, 15%), Basal+Mesenchymal (Mixed type) (n = 10, 12.5%), and unclassified subtype (n = 19, 23.75%). PIK3CA mutations were observed in 16.25% (13/80) TNBC cases. PIK3CA mutations were more frequent in exon 20 (8.7%) than in exon 9 (5%) and exon 4 (2.5%). PIK3CA mutations were frequent in LAR subtype (33.3%) followed by unclassified type (31.5%), Mesenchymal (10.5%), and BL1 (5%) subtypes. Two hotspot mutations were found in AKT1 (T21I, E17K) in mixed and unclassified subtype. CONCLUSIONS: This study highlights the heterogeneity within TNBCs. Higher frequencies of PIK3CA mutations were noted in LAR subtypes and unclassified type, comparable to their incidence reported in literature in ER-positive tumors. The mutation status can be used as potential biomarker for PI3K inhibitors in TNBC subgroups.
PURPOSE: The heterogeneity of triple-negative breast cancer (TNBC) confers variable response to chemotherapy that results in poor outcome and relapse. Due to lack of targeted therapy, there is a need to provide molecular classification of TNBC and identify probable therapeutic targets. METHODS: We classified TNBC into surrogate molecular subtypes by immunohistochemistry and evaluated hotspot mutations (N = 80) in PIK3CA (exon 4, 9, and 20) and AKT1 (exon 2) in TNBC subtypes by Sanger sequencing. RESULTS: TNBCs were classified into Basal-like 1(BL1) (n = 20, 25%), Mesenchymal (n = 19, 23.75%), Luminal Androgen (LAR) (n = 12, 15%), Basal+Mesenchymal (Mixed type) (n = 10, 12.5%), and unclassified subtype (n = 19, 23.75%). PIK3CA mutations were observed in 16.25% (13/80) TNBC cases. PIK3CA mutations were more frequent in exon 20 (8.7%) than in exon 9 (5%) and exon 4 (2.5%). PIK3CA mutations were frequent in LAR subtype (33.3%) followed by unclassified type (31.5%), Mesenchymal (10.5%), and BL1 (5%) subtypes. Two hotspot mutations were found in AKT1 (T21I, E17K) in mixed and unclassified subtype. CONCLUSIONS: This study highlights the heterogeneity within TNBCs. Higher frequencies of PIK3CA mutations were noted in LAR subtypes and unclassified type, comparable to their incidence reported in literature in ER-positive tumors. The mutation status can be used as potential biomarker for PI3K inhibitors in TNBC subgroups.
Entities:
Keywords:
Immunohistochemistry; Molecular heterogeneity; PI3K/AKT pathway; Triple-negative breast cancer
Authors: Bruce G Haffty; Qifeng Yang; Michael Reiss; Thomas Kearney; Susan A Higgins; Joanne Weidhaas; Lyndsay Harris; Willam Hait; Deborah Toppmeyer Journal: J Clin Oncol Date: 2006-11-20 Impact factor: 44.544
Authors: Sewha Kim; Byung-In Moon; Woosung Lim; Sanghui Park; Min Sun Cho; Sun Hee Sung Journal: Clin Breast Cancer Date: 2018-03-23 Impact factor: 3.225
Authors: Matthew D Burstein; Anna Tsimelzon; Graham M Poage; Kyle R Covington; Alejandro Contreras; Suzanne A W Fuqua; Michelle I Savage; C Kent Osborne; Susan G Hilsenbeck; Jenny C Chang; Gordon B Mills; Ching C Lau; Powel H Brown Journal: Clin Cancer Res Date: 2014-09-10 Impact factor: 12.531
Authors: Gloria J Morris; Sashi Naidu; Allan K Topham; Fran Guiles; Yihuan Xu; Peter McCue; Gordon F Schwartz; Pauline K Park; Anne L Rosenberg; Kristin Brill; Edith P Mitchell Journal: Cancer Date: 2007-08-15 Impact factor: 6.860
Authors: Mark Kriegsmann; Volker Endris; Thomas Wolf; Nicole Pfarr; Albrecht Stenzinger; Sibylle Loibl; Carsten Denkert; Andreas Schneeweiss; Jan Budczies; Peter Sinn; Wilko Weichert Journal: Oncotarget Date: 2014-10-30
Authors: John D Carpten; Andrew L Faber; Candice Horn; Gregory P Donoho; Stephen L Briggs; Christiane M Robbins; Galen Hostetter; Sophie Boguslawski; Tracy Y Moses; Stephanie Savage; Mark Uhlik; Aimin Lin; Jian Du; Yue-Wei Qian; Douglas J Zeckner; Greg Tucker-Kellogg; Jeffrey Touchman; Ketan Patel; Spyro Mousses; Michael Bittner; Richard Schevitz; Mei-Huei T Lai; Kerry L Blanchard; James E Thomas Journal: Nature Date: 2007-07-04 Impact factor: 69.504
Authors: Brian D Lehmann; Bojana Jovanović; Xi Chen; Monica V Estrada; Kimberly N Johnson; Yu Shyr; Harold L Moses; Melinda E Sanders; Jennifer A Pietenpol Journal: PLoS One Date: 2016-06-16 Impact factor: 3.240