Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection
Top Cited Papers
Open Access
- 16 June 2016
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 11 (6), e0157368
- https://doi.org/10.1371/journal.pone.0157368
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.Keywords
This publication has 34 references indexed in Scilit:
- Association of BRCA1/2defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypesBreast Cancer Research, 2014
- The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014Annals of Oncology, 2014
- Molecular Regulation of Bone Marrow Metastasis in Prostate and Breast CancerBone Marrow Research, 2014
- Identification and use of biomarkers in treatment strategies for triple‐negative breast cancer subtypesThe Journal of Pathology, 2013
- Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular SubtypesClinical Cancer Research, 2013
- GSTP1 expression predicts poor pathological complete response to neoadjuvant chemotherapy in ER‐negative breast cancerCancer Science, 2012
- Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapiesJCI Insight, 2011
- TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumabBreast Cancer Research and Treatment, 2011
- Frozen robust multiarray analysis (fRMA)Biostatistics, 2010
- Pathologic Complete Response Rates in Young Women With BRCA1-Positive Breast Cancers After Neoadjuvant ChemotherapyJournal of Clinical Oncology, 2010