Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
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.
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
Brian D
BD
Lehmann
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, United States of America.
Bojana
B
Jovanović
Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States of America.
Xi
X
Chen
Department of Medicine, Breast Cancer Research Program, Vanderbilt University, Nashville, Tennessee, United States of America.
Monica V
MV
Estrada
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
Kimberly N
KN
Johnson
Center for Quantitative Sciences, Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, United States of America.
Yu
Y
Shyr
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
Harold L
HL
Moses
Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
Melinda E
ME
Sanders
Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
Jennifer A
JA
Pietenpol
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D019295:Computational Biology; D066264:Datasets as Topic; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D046228:Microarray Analysis; D020360:Neoadjuvant Therapy / Q000379:methods*; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000145:classification* / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins