title: The neutrophil, not the tumor: serum CA 15-3 elevation as a result of granulocyte--colony-stimulating factor-induced neutrophil MU1C overexpression and neutrophilia in patients with breast carcinoma receiving adjuvant chemotherapy.
abstract: BACKGROUND
  Patients with resected breast carcinoma who received granulocyte-colony-stimulating factor (G-CSF)-supported adjuvant chemotherapy exhibited an increase in their serum CA 15-3 levels. The authors investigated the role of G-CSF-induced neutrophil MUC1 expression in this setting.
  
  
  METHODS
  Twenty-two patients with resected early breast carcinoma and 6 patients with high-grade lymphoma received chemotherapy cycles with or without G-CSF support. When given, G-CSF was administered for either 5 or 10 days per cycle. Immunocytochemical staining and flow cytometric analysis of peripheral blood neutrophils and bone marrow myeloid cells for MUC1 epitopes were performed during treatment.
  
  
  RESULTS
  At baseline, the median serum CA 15-3 was 16 U/mL, with weak MUC1 expression in peripheral neutrophils (median immunocytochemical score [ICCS] = 40, flow cytometric score [FCS] = 211 antibody molecules per neutrophil). For patients receiving chemotherapy cycles with 5-day G-CSF support, median CA 15-3 levels increased moderately (median = 28 U/mL; P = 0.016) and absolute neutrophil counts (ANC) did not increase, whereas ICC staining showed a moderate increase (median ICCS = 105; P = 0.015). For patients receiving chemotherapy cycles with 10-day G-CSF, serum CA 15-3 levels increased 2-4-fold from baseline levels and reached abnormal levels (median = 47; P < 0.0005) and the ANC increased (median = 21,400/mm(3); P = 0.007), whereas significant induction of MUC1 expression occurred in the cell membrane and mostly in the cytoplasm of neutrophils (median ICCS = 162; P = 0.001). Flow cytometry detected increased cytoplasmic, but not surface, neutrophil MUC1 expression in the 10-day G-CSF group only (baseline median FCS = 3975, 4th cycle median = 6327 molecules per cell; P = 0.028). In the bone marrow, induction of MUC1 expression was observed in the 10-day G-CSF group only in band forms and neutrophils, but not in more immature myeloid cells. Serum CA 15-3 levels and ICC score were found to demonstrate a linear relation. When ICCS and ANC were incorporated in a combined score, its relation with serum CA 15-3 levels demonstrated a parabolic (cubic) pattern. Serum CA 15-3 levels, ANC, and neutrophil MUC1 staining returned to baseline after the completion of therapy. No excess of malignant recurrences were observed.
  
  
  CONCLUSIONS
  Women with resected breast carcinoma who received G-CSF-primed chemotherapy showed serum CA 15-3 elevation due to an increase in peripheral blood neutrophil number and induced neutrophil cytoplasmic MUC1 expression, which was caused by G-CSF. Physicians should be aware of this interaction.
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. penther@ukonline.co.uk
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Malamou-Mitsi
authors.forename: Evangelos
authors.initials: E
authors.lastname: Briasoulis
authors.forename: Konstantina
authors.initials: K
authors.lastname: Damala
authors.forename: Amalia
authors.initials: A
authors.lastname: Vassou
authors.forename: George
authors.initials: G
authors.lastname: Vartholomatos
authors.forename: Nikos
authors.initials: N
authors.lastname: Kolaitis
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pavlidis
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001853:Bone Marrow / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D044584:Carcinoma, Ductal / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism*; D011446:Prospective Studies
chemical_list: D014408:Biomarkers, Tumor; D018396:Mucin-1; D016179:Granulocyte Colony-Stimulating Factor