title: Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients.
abstract: The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4-22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5-25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4-10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0-100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6-16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.
authors.affiliation: Department of Oncology, Military Institute of Medicine, Szaserów St 128, 04-141, Warsaw, Poland, rdtt@wp.pl.
authors.forename: Renata
authors.initials: R
authors.lastname: Duchnowska
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Chirayu Pankaj
authors.initials: CP
authors.lastname: Goswami
authors.forename: Murat
authors.initials: M
authors.lastname: Dundar
authors.forename: Yesim
authors.initials: Y
authors.lastname: Gökmen-Polar
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.forename: Stephan
authors.initials: S
authors.lastname: Woditschka
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sosińska-Mielcarek
authors.forename: Bogumiła
authors.initials: B
authors.lastname: Czartoryska-Arłukowicz
authors.forename: Barbara
authors.initials: B
authors.lastname: Radecka
authors.forename: Zorica
authors.initials: Z
authors.lastname: Tomasevic
authors.forename: Piotr
authors.initials: P
authors.lastname: Stępniak
authors.forename: Konrad
authors.initials: K
authors.lastname: Wojdan
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D018275:Carcinoma, Lobular / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human