title: Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer.
abstract: Aromatase inhibition (AI) is the most effective endocrine treatment for breast cancer in post-menopausal patients, but a percentage of hormone receptor-positive cancers do not benefit from such therapy: for example, about 20% of patients treated with anastrozole do not respond and it is still impossible to accurately predict sensitivity. Our main goal was to identify a robust expression signature predictive of response to neoadjuvant treatment with anastrozole in patients with ER+ breast cancer. At the same time, we addressed the question of delineating treatment effects and possible mechanisms of intrinsic resistance occurring in non-responder patients. We analyzed the transcriptome of 17 tru-cut biopsies before treatment and 13 matched surgical samples after 3 months treatment with anastrozole taken from ER+ breast tumors. Molecular profiles were related to clinical response data. Treatment with anastrozole was associated with a decreased expression of genes relating to cell proliferation and an increased expression of genes relating to inflammatory processes. There was also an enrichment of induction of T-cell anergy, positive regulation of androgen signalling, synaptic transmission and vesicle trafficking in non-responders, and of cell cycle inhibition and induction of immune response in responders. We identified an expression signature of 77 probes (54 genes) that predicted response in 100% of our cases. Five of them were able to accurately predict response on an independent dataset (P = 0.0056) of 52 ER+ breast cancers treated with letrozole. Ten fixed independent samples from the anastrozole study were also used for RT-qPCR validations. This study suggests that a relative small number of genes analysed in a pre-treatment biopsy may identify patients likely to respond to AI neoadjuvant treatment. This may have practical utility translatable to the clinics. Furthermore, it delineates novel mechanisms of intrinsic resistance to AI therapy that could be further investigated in order to explore circumventing treatments.
authors.affiliation: Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Via Malta 3, 13900 Biella, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Mello-Grand
authors.forename: Vijay
authors.initials: V
authors.lastname: Singh
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghimenti
authors.forename: Maria
authors.initials: M
authors.lastname: Scatolini
authors.forename: Lea
authors.initials: L
authors.lastname: Regolo
authors.forename: Enrico
authors.initials: E
authors.lastname: Grosso
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.forename: Gian Antonio
authors.initials: GA
authors.lastname: Da Prada
authors.forename: Laura
authors.initials: L
authors.lastname: Villani
authors.forename: Vittorio
authors.initials: V
authors.lastname: Fregoni
authors.forename: Paola
authors.initials: P
authors.lastname: Baiardi
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: William R
authors.initials: WR
authors.lastname: Miller
authors.forename: Alberto
authors.initials: A
authors.lastname: Costa
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole