title: High Ki-67 Expression and Low Progesterone Receptor Expression Could Independently Lead to a Worse Prognosis for Postmenopausal Patients With Estrogen Receptor-Positive and HER2-Negative Breast Cancer.
abstract: We examined the prognostic significance of progesterone receptor (PgR) expression in immunohistochemical-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration. The study included 327 surgically removed estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancers. High Ki-67 expression (> 15%) and low PgR expression (£ 20%) were significant independent factors resulting in worse distant relapse-free survival. This association was observed in postmenopausalwomen but not in premenopausal women.
  
  
  BACKGROUND
  Accurate classification of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered clinically important for determining effective adjuvant treatment. Although Ki-67 expression has been identified as an essential constituent for this classification, the role of progesterone receptor (PgR) expression has yet to be fully elucidated. Because PgR expression is influenced by the estrogen milieu, we examined the prognostic significance of PgR expression in immunohistochemical (IHC)-based luminal subtypes defined by Ki-67 expression, taking menopausal status into consideration.
  
  
  METHODS
  We examined 327 surgically removed ER(+) and HER2(-) breast cancer specimens. ER, PgR, and Ki67 expression was determined IHC for semiquantitative measurement. We used 1%, 20%, and 15% as the cutoff value for ER, PgR, and Ki-67, respectively.
  
  
  RESULTS
  Breast cancer with low PgR (≤ 20%) expression was significantly associated with postmenopausal status, a large tumor size, and low ER expression. The low PgR expression subset had significantly worse distant relapse-free survival (DRFS) than the high PgR expression subset (P = .0067). This association was observed consistently in postmenopausal women but not in the premenopausal women. Multivariate analysis demonstrated that high Ki-67 expression (hazard ratio [HR], 3.80; 95% confidence interval [CI], 1.57-10.58; P = .003) and low PgR expression (HR, 2.54; 95% CI, 1.08-6.40; P = .038) were significant independent factors affecting DRFS.
  
  
  CONCLUSIONS
  Low PgR expression was independently associated with a poorer prognosis for ER(+) and HER2(-) breast cancer. Determination of PgR expression combined with that of Ki-67 could thus improve the accuracy of IHC-based classification of luminal A and luminal B breast cancer, especially for postmenopausal women.
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Nishimukai
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yagi
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Yanai
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Miyagawa
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Enomoto
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Murase
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takatsuka
authors.affiliation: Sakita Clinic, Nishinomiya, Hyogo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Sakita
authors.affiliation: Uminosato Clinic, Minamiawaji, Hyogo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hatada
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Electronic address: ymiyoshi@hyo-med.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyoshi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008875:Middle Aged; D017698:Postmenopause; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human
keywords: Breast cancer; Ki-67; Postmenopausal; Progesterone receptor; Prognostic factor