Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients

Renata Duchnowska, Jacek Jassem, Chirayu Pankaj Goswami, Murat Dundar, Yesim Polar, Lang Li, Stephan Woditschka, Wojciech Biernat, Katarzyna Sosińska-Mielcarek, Bogumiła Czartoryska-Arłukowicz, Barbara Radecka, Zorica Tomasevic, Piotr Stępniak, Konrad Wojdan, George W. Sledge, Patricia S. Steeg, Sunil Badve

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)205-216
Number of pages12
JournalJournal of Neuro-Oncology
Volume122
Issue number1
DOIs
StatePublished - 2015

Fingerprint

Breast Neoplasms
Neoplasm Metastasis
Gene Expression
Brain
Reverse Transcription
erbB-1 Genes
Polymerase Chain Reaction
Genes
Ligation
Multivariate Analysis
Recurrence
DNA
Neoplasms
Trastuzumab

Keywords

  • Brain metastasis
  • Breast cancer
  • HDGF
  • HER2
  • RAD51
  • TPR

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

Cite this

Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients. / Duchnowska, Renata; Jassem, Jacek; Goswami, Chirayu Pankaj; Dundar, Murat; Polar, Yesim; Li, Lang; Woditschka, Stephan; Biernat, Wojciech; Sosińska-Mielcarek, Katarzyna; Czartoryska-Arłukowicz, Bogumiła; Radecka, Barbara; Tomasevic, Zorica; Stępniak, Piotr; Wojdan, Konrad; Sledge, George W.; Steeg, Patricia S.; Badve, Sunil.

In: Journal of Neuro-Oncology, Vol. 122, No. 1, 2015, p. 205-216.

Research output: Contribution to journalArticle

Duchnowska, R, Jassem, J, Goswami, CP, Dundar, M, Polar, Y, Li, L, Woditschka, S, Biernat, W, Sosińska-Mielcarek, K, Czartoryska-Arłukowicz, B, Radecka, B, Tomasevic, Z, Stępniak, P, Wojdan, K, Sledge, GW, Steeg, PS & Badve, S 2015, 'Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients', Journal of Neuro-Oncology, vol. 122, no. 1, pp. 205-216. https://doi.org/10.1007/s11060-014-1704-y
Duchnowska, Renata ; Jassem, Jacek ; Goswami, Chirayu Pankaj ; Dundar, Murat ; Polar, Yesim ; Li, Lang ; Woditschka, Stephan ; Biernat, Wojciech ; Sosińska-Mielcarek, Katarzyna ; Czartoryska-Arłukowicz, Bogumiła ; Radecka, Barbara ; Tomasevic, Zorica ; Stępniak, Piotr ; Wojdan, Konrad ; Sledge, George W. ; Steeg, Patricia S. ; Badve, Sunil. / Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients. In: Journal of Neuro-Oncology. 2015 ; Vol. 122, No. 1. pp. 205-216.
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AU - Duchnowska, Renata

AU - Jassem, Jacek

AU - Goswami, Chirayu Pankaj

AU - Dundar, Murat

AU - Polar, Yesim

AU - Li, Lang

AU - Woditschka, Stephan

AU - Biernat, Wojciech

AU - Sosińska-Mielcarek, Katarzyna

AU - Czartoryska-Arłukowicz, Bogumiła

AU - Radecka, Barbara

AU - Tomasevic, Zorica

AU - Stępniak, Piotr

AU - Wojdan, Konrad

AU - Sledge, George W.

AU - Steeg, Patricia S.

AU - Badve, Sunil

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N2 - 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.

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