title: Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse.
abstract: The assessment of tumor molecular features in combination with the detection of occult malignant cells may provide important clinical information, beyond the standard staging of breast cancer. Using a nested RT-PCR technique, we assessed prospectively the presence of cytokeratin-19 (CK19) mRNA positive cells in the blood of 100 operated patients with breast cancer before the initiation of adjuvant chemotherapy and local radiotherapy. Tissue samples were prospectively collected and analyzed for estrogen (ER) and progesterone (PgR) receptor, c-erbB-2 overexpression, mutant-p53 and bcl-2 protein accumulation, proliferation index and microvessel density (MVD). CK-19 mRNA-positive cells were detected in the peripheral blood of 33% of patients. Simultaneous display of high intratumoral MVD and of CK-19 mRNA-positive cells, which characterized highly angiogenic and disseminated in the peripheral blood (HAD) disease was noted in 25% of patients. Detection of CK-19 positive cells was significantly associated with increased MVD (p = 0.002). In univariate analysis (median follow-up 30 months) CK19 mRNA detection and MVD were the most significant factors related to a short relapse-free survival (RFS), (p < 0.0001). In multivariate analysis, CK19 positivity, high MVD and c-erbB-2 overexpression were the only significant and independent variables associated with relapse (p = 0.0005, 0.03 and 0.04, respectively). Patients with HAD had an expected relapse rate close to 70% vs. <5% in the remaining patients irrespectively of the used chemotherapy regimen. The simultaneous presence of high MVD and CK19-positive cells in the blood of patients with early breast is linked with poor prognosis, which cannot be improved with standard chemotherapy regimens.
authors.affiliation: Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
authors.forename: Alexandra
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Stelios
authors.initials: S
authors.lastname: Kakolyris
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavroudis
authors.forename: Charalambos
authors.initials: C
authors.lastname: Kouroussis
authors.forename: Chrysa
authors.initials: C
authors.lastname: Mavroudi
authors.forename: Maria
authors.initials: M
authors.lastname: Perraki
authors.forename: Efthimios
authors.initials: E
authors.lastname: Sivridis
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000098:blood supply*; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007633:Keratins / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000097:blood*; D011379:Prognosis; D011446:Prospective Studies; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000097:blood; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics; D011960:Receptors, Estrogen / Q000097:blood / Q000235:genetics; D011980:Receptors, Progesterone / Q000097:blood / Q000235:genetics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D007633:Keratins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53