Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations. (October 2021)

• Record Type: Journal Article
• Authors: Conforti, Fabio; Pala, Laura; Pagan, Eleonora; Rocco, Elena Guerini; Bagnardi, Vincenzo; Montagna, Emilia; Peruzzotti, Giulia; De Pas, Tommaso; Fumagalli, Caterina; Pileggi, Silvana; Pesenti, Chiara; Marchini, Sergio; Corso, Giovanni; Marchio', Caterina; Sapino, Anna; Graffeo, Rossella; Collet, Laetitia; Aftimos, Philippe; Sotiriou, Christos; Piccart, Martine; Gelber, Richard D.; Viale, Giuseppe; Colleoni, Marco; Goldhirsch, Aron
• Is Part Of: Breast. Volume 59(2021)
• Page Start: 94
• Page End: 101
• Publication Date: 2021-10
• Subjects: Triple negative invasive lobular carcinoma -- ERBB2 gene mutations -- HER2/PI3K/AKT pathway -- Androgen receptor -- Luminal androgen receptor subtype; Breast -- Diseases -- Periodicals; Breast -- Tumors -- Periodicals; Breast -- Periodicals; Electronic journals; Periodicals; 616
• DOI: 10.1016/j.breast.2021.06.011
• Languages: English
• ISSNs: 0960-9776

Abstract

Abstract: 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 Highlights: Triple-negative ILCs are distinct from both TN-IDCs and endocrine-responsive ILC. TN-ILCs are enriched for actionable mutations in ErbB2 gene and DNA Damage Response genes. The Luminal Androgen Receptor (LAR) is the most prevalent subtype in TN-ILCs.