title: Prognostic and predictive impact of central necrosis and fibrosis in early breast cancer: results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy.
abstract: A minority of early invasive breast cancers show a pattern of central necrosis and fibrosis (CNF). Previous studies have documented an adverse prognostic impact and association with other adverse pathological features, but its predictive importance for therapy selection is unknown. We examined the prognostic and predictive value of CNF in two randomized clinical trials comparing chemoendocrine therapy with endocrine therapy alone in patients with node-negative breast cancer. A total of 1,850 patients randomly assigned to treatment groups comparing endocrine with chemoendocrine therapy, and with centrally-assessed CNF, ER, PgR and HER2 were included in the analytic cohort. The median follow up was 10 years. CNF was present in 84 of 1,850 trial patients (4.5%). It was associated with tumor characteristics suggesting poor outcome, but was an independent adverse factor for disease-free survival. In the presence of CNF outcome was worse regardless of tumor grade, whereas in the absence of CNF, patients with grade 3 tumors had poorer outcome than those with grade 1-2 tumors. Among patients with estrogen receptor-absent tumors chemoendocrine therapy was superior to endocrine therapy alone only in the absence of CNF [HR (chemoendocrine:endocrine) = 0.46 in CNF-absent, 0.90 in CNF-present], while among those with receptor-positive disease chemoendocrine therapy was beneficial only in the presence of CNF [HR = 0.34 CNF-present, 0.96 CNF-absent]. The results suggest that the presence of CNF reflects a biological difference in early breast cancer that is important in modulating the efficacy of standard therapies. Accordingly we believe that its presence should be routinely reported.
authors.affiliation: Department of Pathological Anatomy, University of Bari, Bari, Italy. emaiorano@anatopat.uniba.it
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Mastropasqua
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
authors.forename: Monica
authors.initials: M
authors.lastname: Castiglione-Gertsch
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005355:Fibrosis / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage; D017273:Goserelin / Q000627:therapeutic use; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D009336:Necrosis / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003520:Cyclophosphamide; D005472:Fluorouracil; D017273:Goserelin; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C508053:ERBB2 protein, human