title: Molecular analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/everolimus.
abstract: The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER(+)/HER2(-) metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR(+))/HER2(-) stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patient's sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR(+) female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;
authors.forename: Melissa
authors.initials: M
authors.lastname: Frizziero
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA;
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Genoptix, Inc., Carlsbad, California 92008, USA;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hummel
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA;
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallo
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA;
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
authors.affiliation: Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA;
authors.forename: Wing
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Morrissey
authors.affiliation: Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, 37134 Verona, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Carbone
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Cottini
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, Italy;; Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, 37134 Verona, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
keywords: neoplasm of the breast