Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection

Brian D. Lehmann, Bojana Jovanović, Xi Chen, Monica V. Estrada, Kimberly N. Johnson, Yu Shyr, Harold L. Moses, Melinda E. Sanders, Jennifer A. Pietenpol

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.

Original languageEnglish (US)
Pages (from-to)e0157368
JournalPLoS One
Volume11
Issue number6
DOIs
StatePublished - Jan 1 2016

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Triple Negative Breast Neoplasms
Chemotherapy
breast neoplasms
drug therapy
Drug Therapy
Tumors
Gene expression
Microdissection
neoplasms
Lymphocytes
Biopsy
Biomarkers
Laser Capture Microdissection
Tumor-Infiltrating Lymphocytes
Ontology
Neoplasms
gene expression
Neoplasm Genes
Gene Expression Profiling
Standard of Care

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lehmann, B. D., Jovanović, B., Chen, X., Estrada, M. V., Johnson, K. N., Shyr, Y., ... Pietenpol, J. A. (2016). Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One, 11(6), e0157368. https://doi.org/10.1371/journal.pone.0157368

Refinement of Triple-Negative Breast Cancer Molecular Subtypes : Implications for Neoadjuvant Chemotherapy Selection. / Lehmann, Brian D.; Jovanović, Bojana; Chen, Xi; Estrada, Monica V.; Johnson, Kimberly N.; Shyr, Yu; Moses, Harold L.; Sanders, Melinda E.; Pietenpol, Jennifer A.

In: PLoS One, Vol. 11, No. 6, 01.01.2016, p. e0157368.

Research output: Contribution to journalArticle

Lehmann, BD, Jovanović, B, Chen, X, Estrada, MV, Johnson, KN, Shyr, Y, Moses, HL, Sanders, ME & Pietenpol, JA 2016, 'Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection', PLoS One, vol. 11, no. 6, pp. e0157368. https://doi.org/10.1371/journal.pone.0157368
Lehmann, Brian D. ; Jovanović, Bojana ; Chen, Xi ; Estrada, Monica V. ; Johnson, Kimberly N. ; Shyr, Yu ; Moses, Harold L. ; Sanders, Melinda E. ; Pietenpol, Jennifer A. / Refinement of Triple-Negative Breast Cancer Molecular Subtypes : Implications for Neoadjuvant Chemotherapy Selection. In: PLoS One. 2016 ; Vol. 11, No. 6. pp. e0157368.
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