title: Persistence of bone marrow micrometastases in patients receiving adjuvant therapy for breast cancer: results at 4 years.
abstract: We have previously developed a quantitative PCR (QPCR) technique for the detection of cytokeratin 19 (CK19) transcripts in blood and bone marrow and compared this to immunocytochemistry (ICC). Together, both have shown promise for monitoring therapeutic efficacy in patients with metastatic breast cancer. The aim of this study was to determine the feasibility and value of these assays for minimal residual disease (MRD) in monitoring efficacy of adjuvant therapy following surgery for primary breast cancer. Bone marrow aspirates and peripheral blood samples were taken at the time of surgery from patients with primary breast cancer and no evidence of metastases on conventional scans. These were tested for the presence of CK19 mRNA transcripts and cytokeratin positive cells. Follow-up bone marrow aspirates were taken at 3, 6, 12, 24, 36 and 48 months. Prior to surgery, 51% of patients displayed evidence of disseminated cancer cells in the bone marrow by either or both QPCR and ICC. Of 91 patients who had repeat samples assayed, 87% and 65% had positive results at some time using QPCR and ICC, respectively. All patients received adjuvant systemic therapy and in 44 cases where there was a positive result in either the pretreatment or 3-month aspirate, 32/44 (73%) showed a fall in CK19:ABL ratio (QPCR) and 15/24 (63%) showed a reduction in the number of cytokeratin-positive cells (ICC) during follow-up. These results indicate that MRD persists despite adjuvant therapy in a majority of patients with primary breast cancer up to 4 years following surgery.
authors.affiliation: Department of Cancer Cell Biology, Division of Medicine, Imperial College, London, United Kingdom. m.slade@imperial.ac.uk
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Slade
authors.forename: Anjana
authors.initials: A
authors.lastname: Singh
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Smith
authors.forename: Gopi
authors.initials: G
authors.lastname: Tripuraneni
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.forename: Samantha
authors.initials: S
authors.lastname: Fox
authors.forename: Helen
authors.initials: H
authors.lastname: Graham
authors.forename: Margreet
authors.initials: M
authors.lastname: Lüchtenborg
authors.forename: H Dudley
authors.initials: HD
authors.lastname: Sinnett
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D019046:Bone Marrow Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000175:diagnosis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D007633:Keratins