Breast Cancer Molecular Subtypes Patients and Tumors Between - - PowerPoint PPT Presentation

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Laura J. van ‘t Veer University of California, San Francisco Helen Diller Family Comprehensive Cancer Center

Breast Cancer Molecular Subtypes

How to use Molecular Diagnostic Tests in Breast Diseases

Between Patients: subtypes

Breast Cancer Heterogeneity Patients and Tumors

Within Tumors: subclones Nature Rev Cancer, 2012

The Opportunity of Today Tailoring Treatment

• Breast Cancer local and systemic

treatment is tailored

• Integrative Biospecimen Diagnostics

– breast cancer morphological type – breast cancer molecular subtype – prognosis, prediction, follow-up monitoring – activated pathways, individual targets

Kaplan-Meier Survival Curves Which Breast Cancers Return?

Breast Cancer - Survival

After surgery and Radiotherapy: 1) Who to treat, 2) How to treat

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Type of Breast Cancer

how to use understand: risk of recurrence tailor: choice of systemic-targeted treatment

• Invasive breast cancer is a clinically and histologically

heterogeneous disease

• ‘WHO Classification of Breast Tumors’ distinguishes

more than 30 morphologic types

• The classification is based on the growth pattern and

cellular features of the invasive tumor cells

Histology of breast cancer Histological types of breast cancer

Weigelt B et al, Nature Rev Cancer 2005

‘special types’

The phenotypic variation suggests differences in the etiology, genetics and behavior of breast cancers.

Prognosis of histological types

• est. 90%

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The Opportunity of Today Tailoring Treatment

• Breast Cancer local and systemic

treatment is tailored

• Integrative Biospecimen Diagnostics

– breast cancer morphological type – breast cancer molecular subtype – prognosis, prediction, follow-up monitoring – activated pathways, individual targets

Diagnostics of Cancer

from micro-scope to micro-array

Micro-scope Micro-array

Single gene, little information Comprehensive set shows the picture Gene Microarrays and Sequencers

TREATMENT DIAGNOSIS RNA Gene activity pattern

Microarray test of Breast Cancer

Tumor Detection

• f gene

activity

Red=active Green=inactive Yellow=neutral

Patient

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Multi Gene Expression Profiles in Clinical Practice

Perou & Sorlie et al, Nature 2000

Molecular Intrinsic Subtypes ‘Invasive Ductal Carcinoma’

MammaPrint: ‘07 FDA cleared IVDMIA for prognosis assessment Lymph node negative, adjuvantly untreated

70 Gene Prognosis Signature

70 significant prognosis genes Tumor samples Van’t Veer et al, Nature 2002

1. OncotypeDX Recurrence Score (Paik et al., NEJM, 2004) 2. MammaPrint (van de Vijver et al., NEJM, 2002) 3. The PAM50 Intrinsic Subtypes: LumA, LumB, Basal-like, HER2-enriched, Normal-like (Parker et al., JCO 2009) 4. The PAM50 Risk of Recurrence (ROR) (Parker et al., JCO 2009) 1. Genomic Grade Index (Sotiriou et al. JNCI 2006) 5. Breast Cancer Index: 2-gene ratio plus 5-gene proliferation (Ma et al., CCR 2008) 6. EndoPredict (Filipits et al., CCR 2011)

Breast Cancer Gene Expression Profiling Prognostic Tests

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International Treatment Recommendations

Quote: “IHC-based classification will be more widely applicable at lesser cost, notwithstanding its limited validation” => Multigene Assays more accurate

Goldhirsch et al. Ann Oncol 2013; NCCN 2014

Endocrine Therapy (chemo in selected cases) Endocrine + Chemo (most) Endocrine+ Chemo + anti-HER2 Chemo + anti-HER2 Chemo

Prat et al. Nature Rev Clin Oncol 2011

Reproducibility IHC, Grade and Molecular testing

Diagnostics of Cancer

from micro-scope to micro-array to nextgen sequencing

Micro-scope Micro-array

NextGen Sequencers

TCGA: comprehensive subtype analysis

Many authors and Christina Yau

• Nature. 2012;490:61-70

Consensus clustering over 4 platform technologies Highest hierarchy: 4 groups, roughly Luminal A, Luminal B, Basal, Her2 type The Cancer Genome Atlas

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Genomic and transcriptomic architecture -> 10 subtypes

Trans-acting copy number aberrations and subgroup-specific gene networks associated with outcome. Metabric dataset

(includes a TCellReceptor deletion-mediated adaptive immune response and a basal-specific chromosome 5 deletion- associated mitotic network)

• Nature. 2012;486:346-352

High risk for recurrence

Biology guides choice of (targeted) drugs

Hallmarks of Cancer

Evasion of immune system

TCGA Pan-Cancer Effort

Adapted from submitted position paper Figure 1

• TCGA network position paper in Nature Pan-Cancer focus
• Describes effort and highlight findings from ‘basket’ of

papers stemming from the Pan-Cancer effort

• Basket of 18 accepted Papers
• TCGA network acknowledged but not listed as author

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Tissue COCA

1 - LUAD-enriched 2 - Squamous-like 3 - BRCA/Luminal 4 - BRCA/Basal 5 - KIRC 6 - UCEC 7 - COAD/READ 8 - BLCA 9 - OV 10 - GBM 11 - small-various 12 - small-various 13 - AML COCA BLCA BRCA COAD GBM HNSC KIRC LAML LUAD LUSC OV READ UCEC Tissue Type

1 2 3 4 5 6 7 8 9 10 13

BLC A BR C A HNS C LUS C LUAD KIR C UC E C C OAD/R E AD OV GBM AML

Bronchioid Magnoid Squamoid

LUAD

Primitive Classical Secretory Basal

LUS C

Atypical Classical Mesenchymal Basal

HNS C

Luminal A Luminal B HER2-enriched Normal-like Basal-like

BR CA

m1 m2 m3 m4

KIR C UC E C

• cn

1 2 3 4

AML

1 2 3 4 5 6 7 I II III IV

BLC A

MSI/CIMP Invasive CIN

C OAD R E AD

Differentiated Immunoreactive Mesenchymal Proliferative

OV

G-CIMP Proneural Neural Classical Mesenchymal

GBM

Silhouette width

• Divergent

cancers:

Convergent subtypes:

C2-Squamous-like subtype combines head and neck and lung squamous cancers and a subset of bladder cancers. C1-LUAD-enriched combines lung adenocarcinoma and a subset of bladder cancers.

Though most subtype assignments were nearly identical to their pathological classification, several distinct cancer types were found to merge into a common subtype.

Pathway Characteristics of Integrative Subtypes

Pathway Implications (supported by both enrichment and sub-network) 1-LUAD enriched Activated Pathways : AP1, RAC1, Immune, p53, HIF1A, CDC42, p38 Repressed Pathways: E2F 2-Squamous Activated Pathways: p63, p53, MYC, FOXM1, RAC, RHO, XBP1, Immune, HIF1A, AP1, p38 Repressed Pathways: FOXA1/ER 3-BRCA Luminal Activated Pathways: FOXA1/ER, PI3K, p63, MYB, CDC42 Repressed Pathways: MYC, E2F, FOXM1, RAC, RHO, Immune, p53, p38 4-BRCA Basal Activated Pathways: p63, MYC, PLK1, Immune, XBP1, MYB, p73 Repressed Pathways: FOXA2, p53 5-KIRC Activated Pathways: HIF1A, Immune Repressed Pathways: Caspase, MYC, FOXM1, p63 6-UCEC Activated Pathways: E2F, XBP1, p53 Repressed Pathways: HIF1A, RAC, Immune, AP1, p38, MAP kinase 7-Colorectal Activated Pathways: MYC, E2F, p53, p38, (PKC) Repressed Pathways: IL12, IL27, AP-1, HIF1A, CDC42, PI3K 8-BLCA Activated Pathways: p63, p53 Repressed Pathways: HIF1A, il23 9-OV Activated Pathways: E2F, MYC, CDC42, XBP1 Repressed Pathways: p53, immune 10-GBM Activated: AKT, (PKC) Repressed Pathways: p53, immune, MYC, PI3K, ARF6 13-LAML Activated: MYC, p38, RHO, ERK/MAPK, caspase Repressed: PI3K, p53, RAC

TCGA Pan-Cancer-12 project

Based on this study, one in ten cancer patients would be classified differently by this new molecular taxonomy versus our current tissue-of-origin tumor classification system.

Therapeutic targeting of the hallmarks

• f cancer
• Cell. 2011;144:646-6

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"Here are my genes..."

The New Yorker