Stefania Stella1,2, Silvia Rita Vitale3,2, Michele Massimino3,2, Gianmarco Motta2,4, Claudio Longhitano2,5, Katia Lanzafame2,6, Federica Martorana3,2, Carmine Fazzari6,7, Giada Maria Vecchio8, Elena Tirrò2,9, Nicola Inzerilli2,10, Rosaria Carciotto2,5, Livia Manzella3,2, Michele Caruso7, Paolo Vigneri3,2. 1. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; stefania.stel@gmail.com. 2. Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy. 3. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy. 4. Medical Oncology, Mediterranean Institute of Oncology, Viagrande, Italy. 5. Medical Oncology, ASL 7 Ragusa, Ragusa, Italy. 6. Pathology Unit, Ospedale Umberto I, Siracusa, Italy. 7. Pathology Unit, Humanitas Istituto Clinico Catanese, Catania, Italy. 8. Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Pathology Unit, University of Catania, Catania, Italy. 9. Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy. 10. Oncology and Hematology Department, Oncology Unit, Piacenza General Hospital, Piacenza, Italy.
Abstract
BACKGROUND/AIM: Triple-negative breast cancers represent 15% of all mammary malignancies and encompass several entities with different genomic characteristics. Among these, luminal androgen receptor (LAR) tumors express the androgen receptor (AR) and are characterized by a genomic profile which resembles luminal breast cancers. Moreover, LAR malignancies are usually enriched in PIK3CA, KMTC, CDH, NF1, and AKT1 alterations. Still, molecular features, clinical behavior and prognosis of this variant remain controversial, while identification of effective treatments represents an unmet medical need. Additionally, the predictive role of the AR is unclear. MATERIALS AND METHODS: We performed an extensive next generation sequencing analysis using a commercially available panel in a cohort of patients with LAR breast cancer followed at two local Institutions. We next employed bioinformatic tools to identify signaling pathways involved in LAR pathogenesis and looked for potentially targetable alterations. RESULTS: Eight patients were included in the study. In our cohort we found 26 known genetic alterations (KGAs) in 15 genes and 64 variants of unknown significance (VUS) in 59 genes. The most frequent KGAs were single nucleotide variants in PIK3CA, HER2, PTEN and TP53. Among VUS, CBFB, EP300, GRP124, MAP3K1, RANBP2 and TSC2 represented recurrently altered genes. We identified five signaling pathways (MAPK, PI3K/AKT, TP53, apoptosis and angiogenesis) involved in the pathogenesis of LAR breast cancer. Several alterations, including those in PIK3CA, ERBB2 and PI3K/AKT/mTOR signaling, were potentially targetable. CONCLUSION: Our findings confirm a role for PI3K/AKT/mTOR signaling in the pathogenesis of LAR breast cancers and indicate that targeting this pathway, along with ERBB2 mutations, may represent an additional therapeutic strategy which deserves further exploration in larger studies.
BACKGROUND/AIM: Triple-negative breast cancers represent 15% of all mammary malignancies and encompass several entities with different genomic characteristics. Among these, luminal androgen receptor (LAR) tumors express the androgen receptor (AR) and are characterized by a genomic profile which resembles luminal breast cancers. Moreover, LAR malignancies are usually enriched in PIK3CA, KMTC, CDH, NF1, and AKT1 alterations. Still, molecular features, clinical behavior and prognosis of this variant remain controversial, while identification of effective treatments represents an unmet medical need. Additionally, the predictive role of the AR is unclear. MATERIALS AND METHODS: We performed an extensive next generation sequencing analysis using a commercially available panel in a cohort of patients with LAR breast cancer followed at two local Institutions. We next employed bioinformatic tools to identify signaling pathways involved in LAR pathogenesis and looked for potentially targetable alterations. RESULTS: Eight patients were included in the study. In our cohort we found 26 known genetic alterations (KGAs) in 15 genes and 64 variants of unknown significance (VUS) in 59 genes. The most frequent KGAs were single nucleotide variants in PIK3CA, HER2, PTEN and TP53. Among VUS, CBFB, EP300, GRP124, MAP3K1, RANBP2 and TSC2 represented recurrently altered genes. We identified five signaling pathways (MAPK, PI3K/AKT, TP53, apoptosis and angiogenesis) involved in the pathogenesis of LAR breast cancer. Several alterations, including those in PIK3CA, ERBB2 and PI3K/AKT/mTOR signaling, were potentially targetable. CONCLUSION: Our findings confirm a role for PI3K/AKT/mTOR signaling in the pathogenesis of LAR breast cancers and indicate that targeting this pathway, along with ERBB2 mutations, may represent an additional therapeutic strategy which deserves further exploration in larger studies.
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