Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations
Fabio Conforti,
Laura Pala,
Eleonora Pagan,
Elena Guerini Rocco,
Vincenzo Bagnardi,
Emilia Montagna,
Giulia Peruzzotti,
Tommaso De Pas,
Caterina Fumagalli,
Silvana Pileggi,
Chiara Pesenti,
Sergio Marchini,
Giovanni Corso,
Caterina Marchio’,
Anna Sapino,
Rossella Graffeo,
Laetitia Collet,
Philippe Aftimos,
Christos Sotiriou,
Martine Piccart,
Richard D. Gelber,
Giuseppe Viale,
Marco Colleoni,
Aron Goldhirsch
Affiliations
Fabio Conforti
Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy; Corresponding author. Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy.
Laura Pala
Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy
Eleonora Pagan
Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
Elena Guerini Rocco
Division of Pathology, IEO, European Institute of Oncology, IRCCS, Milano, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Vincenzo Bagnardi
Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
Emilia Montagna
Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy
Giulia Peruzzotti
Division of Data Management, IEO, European Institute of Oncology IRCCS, Milan, Italy
Tommaso De Pas
Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy
Caterina Fumagalli
Division of Pathology, IEO, European Institute of Oncology, IRCCS, Milano, Italy
Silvana Pileggi
Department of Oncology, Mario Negri Institute for Pharmacological Research, IRCCS, Italy
Chiara Pesenti
Department of Oncology, Mario Negri Institute for Pharmacological Research, IRCCS, Italy
Sergio Marchini
Department of Oncology, Mario Negri Institute for Pharmacological Research, IRCCS, Italy
Giovanni Corso
Division of Senology, European Institute of Oncology, IRCCS, Milan, Italy
Caterina Marchio’
Department of Medical Sciences, University of Torino, Turin, Italy; Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, TO, Italy
Anna Sapino
Department of Medical Sciences, University of Torino, Turin, Italy; Unit of Pathology, Candiolo Cancer Institute - FPO, IRCCS, Candiolo, TO, Italy
Rossella Graffeo
High Risk Clinic, Oncological Genetics Service, Oncology Institute of Southern Switzerland, Ospedale Italiano, Lugano, Switzerland
Laetitia Collet
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Philippe Aftimos
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Christos Sotiriou
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Martine Piccart
Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Richard D. Gelber
Department of Data Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, Frontier Science & Technology Research Foundation, Boston, USA
Giuseppe Viale
Department of Pathology, IEO, European Institute of Oncology IRCCS & State University of Milan, Milan, Italy
Marco Colleoni
Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy
Background: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) Methods: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012.Primary objective was to assess the invasive disease-free survival(iDFS).Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene.Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes. Results: Among 4152 ILCs, 74(1.8%) were TN and were analyzed.The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0–61.6) and 37.2%(95%CI,25.5–48.8), respectively.The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31).Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001).20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45).Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR<0.05), there were ErbB-signaling and DNA-damage-response pathways. Conclusions: TN-ILCs are rare tumors with poor prognosis. Their specific biological features require newly defined targeted therapeutic strategies
