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Aleix Prat, MDPostdoctoral Research Associate at Perou Lab
Lineberger Comprehensive Cancer CenterUniversity of North Carolina, USA
Molecular Classification of Triple-Negative Breast Cancer (TNBC)
Emerging genomic and clinical data
Disclosures
• I have no relevant relationships to disclose.
Deconstructing the molecular portraits of breast cancer
Luminal A and BNormal-like
HER2-enrichedBasal-likeClaudin-low
Prat & Perou Mol Oncol 2011
Distribution of the intrinsic molecular subtypes (+/- Claudin-low) within TNBCs
Prat & Perou Mol Oncol 2011
N=87
Phase III TNBCs comprised of diverse molecular subtypes (CT +/- Iniparib, NCT00938652)
Affymetrix gene expression profiling of FFPE samples Intrinsic subtypes assigned using Sorlie et al, PNAS, 2003 data set and claudin-low classifier (Prat et al., BCR, 2010) [courtesy of J. Theilhaber and D. Bergstrom, Sanofi]
Rel
ativ
e fr
eque
ncy
in p
anel
Modified from O'Shaughnessy et al. ASCO 2011
Data Highlights1. 10-25% of all tumors.2. Highly proliferative (RB-
loss).3. TP53 mutations.4. BRCA1-associated.5. Highly aneuploid.
6. Distinct cell type of origin or developmental stage of arrest.
CRYABID4
c-KITKeratin 5
Keratin 17P-Cadherin
EGFR/HER1
HER2
Luminal
Proliferation
Basal-like subtype
Keratin 5/6EGFR
Data Highlights
1. 5-10% of tumors.2. Typically TNBCs.3. Low expression of
cell-cell junction proteins4. Stem cell + EMT (mesenchymal) features5. Lymphocyte infiltrates6. Distinct cell type of origin or developmental stage of arrest.
Immune infiltrate
HER2
Luminal
Proliferation
Claudin-low subtype
Basal
Claudin 7
Claudin 3Claudin 4
E-Cadherin
Gene Expression Characteristics of Claudin-low Tumors
Prat et al., Breast Cancer Res 2010
Differentiation/ Proliferation
Markers
MesenchymalMarkers
Stem CellMarkers
Basal-like
Claudin-low
HER2-enriched
Luminal A
Luminal BaCGH landscape
Weigman et al. submitted
Claudin-low tumors show low DNA copy number changes
52 cell lines from Neve et al. Cancer Cell 2006
SUM149-Basal-like
SUM159-Claudin-low
Identification of the Claudin-low subtype in a panel of breast cancer cell lines
Claudin-low Basal-like
TRIPLE-NEGATIVE
TRIPLE-NEGATIVE
Prat et al., Breast Cancer Res 2010
PhenotypeLum/HER2Basal B Basal A
Claudin-low/Basal B cell lines show low DNA copy number changes (CNA)
Kao et al., Plos One 2009
Intrinsic Subtyping of the histologically diverse sample set from Weigelt et al., Refinement of breast cancer classification by molecular
characterization of histological special types. J Pathol 216, 141-150 (2008).
Prat et al, Breast Cancer Res 2010
Association between metaplastics and medullary-likefeatures and Claudin-low tumors
Hennessy B. et al., Cancer Res, 2009
Association between Metaplastics and Claudin-low tumors
Clinical-pathological characteristics of the Claudin-low Intrinsic Subtype
Prat et al. Breast Cancer Res 2010
Cheang M & Prat A et al. unpublished dataNot for reproduction or citation
Pathological complete response (pCR) data after neoadjuvantanthracycline/taxane chemotherapy within TNBCs (n=188)
Basal-like vs. others, p<0.005Basal-like vs. Claudin-low, p<0.05
Array data obtained from: Hatzis et al. JAMA 2011
Basal-like Claudin-low
RCB III RCB III
Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features
Chad J. Creighton, Xiaoxian Li, Melissa Landis, J. Michael Dixon, Helen Wong, Anna Tsimelzon, Jason I. Herschkowitz, Cheng Fan, Xiaomei Zhang, Xiaping He, Anne Pavlick, Jian Huang,
M Carolina Gutierrez, William R Miller, Alexey A Larionov, Susan G. Hilsenbeck, Charles M. Perou, Michael T. Lewis, Jeffrey M. Rosen, and Jenny C. Chang.
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5. Epub 2009 Aug 3.
P53-null mouse model
Herschkowitz et al. PNAS 2011
Nat Med. 2009 Aug;15(8):907-13. Epub 2009 Aug 2.
Mammary Stem Cell (MaSC)
Luminal Progenitor
Mature Luminal
moresimilar
232 Human Breast Tumors analyzed for FAC sorted epithelial cell signatures
Prat & Perou, personal communication
Prat & Perou, Nat. Med 2009
Mammary development meets cancer genomics
Basal-like and Claudin-low tumors have epithelial tumor cells with mesenchymal characteristics (Intra-tumor heterogeneity )
Prat et al. Breast Cancer Res 2010
Prat et al. AACR 2011
Selected TNBC/Basal-like cell lines have cells with Claudin-low characteristics
Claudin-low more migratory
Claudin-low less proliferative
Basal-likeClaudin-low
Conclusions1. TNBCs are a heterogeneous group
primarily composed of Basal-like breast tumors.
2. Claudin-low tumors also constitute a significant proportion of TNBCs.
3. The molecular subtypes as of today haveno influence over treatment decisions for TNBC patients.
4. Chemotherapy benefit is typically high in Basal-like and Claudin-low tumors, although those with residual disease after treatment (claudin-low features??) have a high risk of relapse.
5. Basal-like and Claudin-low tumors are enriched with tumor cells with mesenchymal/stem cell features (intra-tumor heterogeneity) that may need specific targeted treatments.
The University of North Carolina at Chapel HillDepartments of Genetics and Pathology
Lineberger Comprehensive Cancer Center
Perou LabCharles M. PerouBarbara AdamoOlga KarginovaGrace SilvaJ. Chuck HarrellXiaping HeJerry UsaryJoel ParkerRJ YostKatie HoadleyDavid DarrMaggie CheangWei ZhaoGeorge ChaoLorraine Balletta
UNC CollaboratorsChris Fan, George Wu, Everett Zhou,Li Wen, Sara Cheek, Jianying Li, Dihui Lu, Feri Zsuppan,Jing Peng, John Berninger and Sai Balu (LCCC Bioinformatics) Steve Marron and Andrew Nobel (Statistics)Lisa Carey, Carey Anders, Neil Hayes, and Ned Sharpless (Oncology)Bob Millikan (Epidemiology) and Chad Livasy (Pathology)
Washington UniversityMatthew Ellis Lab
Elaine Mardis, Rick Wilsonand The Genome Center
University of British ColumbiaTorsten Nielsen Lab
University of UtahPhil Bernard Lab