molecular classification of triple-negative breast …e-syllabus.gotoper.com/_media/files/06 prat...

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