04-triple negative bc

7/27/2019 04-Triple Negative BC

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Triple-negativeBreast Cancer

Dr Rebecca DentSunnybrook OdetteCancer Center, Canada


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Basal-Like

The Triple Negative Breast Cancer

Estrogen Receptor (ER) negative

Progesterone receptor (PR) negative

Her2neu (HER2) negative

ER/PR/HER2 -

ER/PR/HER2 -


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Background

Increasing evidence that breast cancer is notone disease

Development of therapies targeting steroid hormonereceptors led to recognition of estrogen receptor-positive and negative

breast cancers

Trastuzumab (Herceptin) therapy highlighted the importance of reliably identifying tumors amplified

or over expressed HER2


4/35Baselga and Norton, 2002

Evolution in Breast Cancer Classification

Classical Diagnosis

Ductal infiltratingcarcinoma of breastwith high grade of

nuclear atypia

Protein Expression

ErbB2 over expressingbreast tumour

Gene ExpressionProfiling

Partial two dimensionalcluster analysis of

17 breast tumours

MorphologicalDiagnosis

Immunohistochemicalassessment

DNA microarrayanalysis


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Gene expression patterns of breast

carcinomas distinguish tumour subclasseswith clinical implications

Therese Srlie a,b,c, Charles M. Perou a,d, Robert Tibshirani e, Turid Aas f, Stephanie Geislerg, Hilde Johnsen b, Trevor

Hastie e, Michael B. Eisen h, Matt van de Rijn i, Stefanie S, Jeffrey j, Thor Thorsen k, Hanne Quist l, John C. Matese c,

Patrick O. Brown m, David Botstein c, Per Eystein Lnning g, and Anne-Lise Brresen-Dale b,n


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Basal-likeSubgroup

= E

HER2Subgroup

= D

Normalbreast

like

LuminalSubtype

C

LuminalSubtype

B

LuminalSubtype

A

ERGene

expression

E

D

C

B

A

O.S.

months

Adapted from Sorlie et al. PNAS, 2001

Gene Expression Patterns of Breast

Carcinomas Predict Survival

ER

Geneexpression


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Molecular classes are predictive of outcome

1

0.8

0.6

0.4

0.2

00 24 48 72 96

RFS

p


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Why is this group called

Basal-Like?


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Breast Cancers can be broadly divided

Expression of

luminal keratins

(ie. simple epithelial

type keratins)

CK 7, 8, 18 and 19

High levels of

expression of genes

that are characteristic

of basal epithelial

cells of the normalmammary gland

(ie. the stratified

epithelial cytokeratins)

CK 5, 6, 14, 15 and 17


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How do we identify Basal-Like Breast Cancers

in the clinical setting?


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Basal-Like Breast Cancers

Fadare O, and Yeh IT

Pathology Case Reviews

July/August 2007


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Immunohistochemical Characterization of the

Basal-Like Cancers Took 21 tumors defined as basal-like by microarray

and performed IHC analyses with six distinguishing

markers (ER, CK5/6, EGFR, HER2, cKIT)

Concluded that an IHC surrogate for gene arrayexperiments to identify basal-like breast cancers is:

ER

HER2

CK5/6 + and/or EGFR +

16 out of 21 tumors expressing the basal genesignature would have identified 76% of the BLC witha specificity of 100%

Nielsen et al. 2004


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Definition of Basal-Like Breast Cancers

Multiple immunohistochemical markers have beenused to identify Basal-Like differentiation

No universally agreed upon criteria or precise set ofbasal markers

Nielsen et al.

ER/PR/HER2 negativity in addition toeither EGFR + and/or CK5/6 +

Smith et al. high molecular weight cytokeratins CK5,14 and 17

Carey et al. ER/PR/HER2 negativity


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80 to 90% of these will beBasal-Like Breast Cancers

100 Patients withTriple Negative Breast Cancer

ER/PR/HER2 -ER/PR/HER2 -


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Triple Negative Breast Cancers

Comprise approximately 15% of all invasive cancers

More common in: Younger patients

African Americans

BRCA1 mutation carriers

Unique Morphologic Attributes

Pushing border

high grade

central scarring/acellular zone

Stromal/peritumoral lymphocytic infiltrate


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Ethnicity and the BLC

Carolina Breast Study (N=500, 1993-96)ALL women = 20%

Caucasians Pre and Postmenopausal = 16%

African American Women Premenopausal = 39% Postmenopausal = 14%

*Nigerian data up to 50-60% of women with invasive breast

cancer with the BLC (mean age of dx 44)

Olopade et al. AACR April 2005

Carey et al, JAMA 2006


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BRCA1 and BLC phenotype

BRCA1 is a tumor suppressor gene that functions inDNA repair

These tumors are often ER-, HER2- (up to 80% of BRCA1associated tumors have been shown to be basal-like)

Thoughmost basal-like tumors have normal BRCA1

Hereditary BRCA1 breast tumors and basal-likesporadic tumors have a similar phenotype and geneexpression signature

Suggesting involvement of BRCA1 in the pathogenesis ofsporadic basal-like cancer


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BRCA1/BLC

BRCA1 mutations are rarely found in sporadic breastcancer, but BRCA1 expression is often reduced,especially in basal-like breast cancers

Why?

BRCA1 promotor methylation has been demonstrated in

7 to 31% of sporadic cancers (Catteau et al) LOH of the BRCA1 locus which occurs in 15 to 45% of

sporadic breast cancers (Rio et al)

However, studies looking at the relationship between BRCA1methylation, BRCA1 LOH and clinical features of breasttumors have been inconsistent

ID4, a negative regulator of BRCA1, was found to be

expressed at a 9-10 times higher in BLC (Turner et al)


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Shared Features with BRCA-1 Cancers

BRCA1associated

breast cancer

Basal-LikeBreast Cancer

High grade

Cytogenic abnormalities

Estrogen receptor Negative

HER2 negative

Express Cytokeratin 5/6

EGFR overexpression and mutation

p53 mutation


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Turner et al. 2006

Typical Histological Features of Triple

Negative Breast CA

Grade 3, IDC,with central fibrosis

Positive Stainingfor EGFR

Positive Stainingfor CK 5/6


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Immunohistochemical Features:

Other Breast CA

n (%)

Basal-like

n (%)

p value

3/21 (14%)

< 0.001

C-KIT 67/605 (11%) 6/21(30%) < 0.001

< 0.001P53 protein 27/124 (22%) 32/63 (51%) < 0.006

0.0001

0/21 (0)

13/21 (62%)12/21(57%)

9/11 (82%)

17/18 (94%)

517/665 (78%)

23/87 (26%)

105/761 (14%)14/521 (8%)

13%

2/28 (7%)

ER expression

HER2

Cytokeratin 5/6EGFR

P53 mutation

Vimentin

Livasy et al, Sorlie et al, Foulkes et al, Nielsen et al


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Triple-Negative Breast Cancer: Clinical

Features and Patterns of Recurrence

HBBC database (1987-1997)

1601 (80%) of patients had details on hormonereceptors/HER2 and were eligible for the study

180 (12%) of the 1601 patients were defined astriple negative breast cancers

Mean follow up was 8.1 years

Dent, R. et al. Clin Cancer Res 2007


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Characteristics of Triple Negative vs. Other Breast Cancers

Characteristic

Other

(N=1421)number (percent)

Triple Negative

(N=180)number (percent)

Significance

p value *

Mean Age at Diagnosis (yrs) 57.7 53 p < 0.0001

Mean Tumor Size 2.1 cm 3.0 cm p < 0.0001

Tumor Size

(62.7) (36.5)

(55.6)

(7.9)

(54.4)

(44.6)

(9.8)

(24.2)

(66.0)

(32.8)

(4.6)

(45.6)

(54.4)

(19.9)

(51.8)

(28.3)

T1 ( 2 cm) 880 65 p < 0.0001

T2 (>2cm to 5cm) 461 99

T3 (>5cm) 64 14

Missing 16 2

Lymph Node Status

Positive 510 87 p = 0.02

Negative 609 70

Missing or Not Tested 302 23

III 336 101

Tumor GradeI 237 15 p < 0.0001

II 616 37

Missing

* p values were calculated wi th the use of the chi-square test

Dent, R. et al. Clin Cancer Res 2007


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Tumor Size by Nodal Status according to Basal-Like Group

Non Basal-like Group(N=1421)

Basal-like Group(N=180)

Tumour SizeLymph Node Positive

Number (percent)

Lymph Node Positive

Number (percent)


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Distant Recurrence

Dent, R. et al. Clin Cancer Res 2007;13:4429-4434

Prob

abilityofbeingrecurrence-free

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Years after diagnosis

p


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Overall Survival


Probabilityof

survival

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Years after diagnosis

p


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Hazard Rate of Distant Recurrence


HazardR

ate

0.35

0.00

0 1 2 3 4 5 6 7 8 9 10

Years after first surgery

Other (290 of 1421) Triple-negative (61 of 180)

0.30

0.25

0.20

0.15

0.10

0.05


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Median Time from Distant Relapse to Death

0 5 10 15 20 25

22 months

9 months Triple Negative

Breast CA

Other BreastCA

Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

H d R ti (HR) f l l d di t t & d th


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Hazard Ratios (HR) for local and distant recurrence & death

Basal-like vs.

Non-Basal aUnivariate Analysis

HR (95% CI)

Significance

p value

Multivariate Analysis

HR (95% CI)

Significance

p value

Recurrence Risk of Local

Whole FUP 1.12 (0.7 1.7) p = 0.6 0.82 (0.5 1.3) p = 0.38

Up to 5yrs 1.54 (0.9 2.5) p = 0.08 1.01 (0.6 1.7) p = 0.98

p = 0.12

p < 0.0001

p < 0.0001

p = 0.09

p < 0.0001

p < 0.0001

p = 0.84

(0.1 1.3) (0.1 1.2)

(0.8 1.5)

(1.1 2.0)

(0.1 0.8)

(1.0 1.6)

(1.3 2.4)

(0.5 1.2)

(1.4 2.5)

(2.0 3.5)

(0.2 1.1)

(1.3 2.2)

(1.9 3.6)

(0.6 1.5)

5 yrs to End 0.40 0.34 p = 0.08

1.9 1.2 p = 0.35

Risk of DistantRecurrence

2.6 1.5 p = 0.02

0.5 0.3 p = 0.02

1.71 1.25 p = 0.009

2.63 1.74 p = 0.0007

0.96 0.77 P = 0.22

Risk of Death

Adjusted by age at diagnoses, BR grade (1, 2, 3), tumor size, lymph node status, Tam. therapy (yes/no),

and chemo therapy (yes/no).


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Patterns of Metastatic Spread


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Patterns of Metastatic Spread

More likely to spread to brain, lung and possibly liverand less likely to spread to bone and soft tissues

Tsuda et al. 2000 Am J of Surgical Pathology Rodriguez-Pinilla et al. Clinical Cancer Research 2006

Fulford et al. Breast Cancer Research and Treatment 2007

Hicks et al. 2006 Am J of Surgical Pathology

More likely to present with visceral metastases

versus bone metastases as first site of metastases

70% vs 37%, p < 0.001 (Dent et al. SABCS 2007)

B l lik b t t d t b l


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Basal-like breast cancers tend to be largeand spread to lung, brain and liver

Why? Faster growing or not diagnosed

Faster growing tumors and more likely to be foundbetween annual mammograms

The mode of spread of these cancers may bedifferent and early hematogenous spread is favoured

possibly due to different protein expression profiles


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Angiogenic Switch and VEGF dependency

Adapted from Bergers G, et al. Nature 2002;3:40110

Small tumour (12mm)Avascular

Dormant

Larger tumour Vascular

Metastatic potential

Angiogenic

switch

Over-expression of pro-angiogenic signals, such as VEGF


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Triple Negative Breast Cancer Summary

Triple Negative breast cancers are a distinct category ofbreast cancer

Mean age of diagnosis is younger Tumors tend to be larger and higher grade

Most rapidly fatal breast cancer Rapid rise in risk of recurrence following diagnosis

Peak risk of recurrence at 1-3 y

Frequent vascular metastases to viscera

Likely early angiogenic switch and thus ideal group toevaluate the role of anti-VEGFR therapies such as

Bevacizumab early in the course of their treatment

04-triple negative bc

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