title: Tumour and cellular distribution of activated forms of PR in breast cancers: a novel immunohistochemical analysis of a large clinical cohort.
abstract: BACKGROUND
  The progesterone receptor (PR) is expressed by ∼70% of early breast tumours and is implicated in the progression of breast cancer. In cancerous tissues PR may be activated in the absence of a ligand, or when ligand concentrations are very low, resulting in aberrantly activated PR (APR). The presence of APR may indicate that patients with breast cancer are more likely to respond to antiprogestins. The aims of this study were to describe and classify the histological subnuclear morphology of active and inactive PR in archival breast cancer samples.
  
  
  METHODS
  Archived tumour specimens from 801 women with invasive breast cancer were collected. Tissue samples (n=789) were analysed for PR isoforms A and B (PRA and PRB), Ki67 and estrogen receptors (ERα) status, using immunohistochemistry. Medical records were used to determine human epidermal growth factor 2 (HER2) status, tumour stage and grade.
  
  
  RESULTS
  A total of 79% of tumours stained positive for either PRA or PRB, and of these 25% of PRA-positive and 23% of PRB-positive tumours had PR present in the activated form. APRA was associated with higher tumour grade (p=0.001). APRB was associated with a higher tumour grade (p=0.046) and a trend for a more advanced stage. Patients with PR-positive tumours treated with antiestrogens had better disease-free survival (DFS) than those with PR-negative tumours (p<0.0001). Cumulative progression rate and DFS were similar irrespective of APR status. Both APRA and APRB were independent of HER2, ERα and Ki67 expression.
  
  
  CONCLUSIONS
  APR had a binary mode of expression in the breast cancer specimens tested, allowing separation into two tumour subsets. APR is an independent target at the cellular and tumour level and may therefore be a suitable predictive marker for antiprogestins, such as onapristone. Using the described technique, a companion diagnostic is under development to identify APR in solid tumours.
authors.affiliation: Centre Oscar-Lambret, Université Lille Nord de France , Lille , France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonneterre
authors.affiliation: Institut Gustave Roussy , Villejuif , France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bosq
authors.affiliation: Centre Oscar-Lambret, Université Lille Nord de France , Lille , France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jamme
authors.affiliation: Institut Gustave Roussy , Villejuif , France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.affiliation: Invivis Pharmaceuticals Inc., Bridgewater, New Jersey, USA; Arno Therapeutics, Flemington, New Jersey, USA.
authors.forename: Erard M
authors.initials: EM
authors.lastname: Gilles
authors.affiliation: Arno Therapeutics , Flemington, New Jersey , USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Zukiwski
authors.affiliation: Baylor College of Medicine , Houston, Texas , USA.
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.affiliation: University of Minnesota Masonic Cancer Center , Minneapolis, Minnesota , USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Lange
authors.affiliation: Baylor-Sammons Cancer Center, Texas Oncology, US Oncology , Dallas, Texas , USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
keywords: activated; breast cancer; onapristone; progesterone receptor