Epidemiology

DefinitionBiology

“Basal-Like”

The “Triple Negative” Breast Cancer

Estrogen Receptor (ER) negativeProgesterone receptor (PR) negative

Her2neu (HER2) negative

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

Clinical features

“Triple-Negative” Breast Cancer: Clinical Features and Patterns of

Recurrence• HBBC database (1987-1997)

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

• 180 (12%) of the 1601 patients were defined as “triple negative” breast cancers

• Mean follow up was 8.1 years

Dent, R. et al. Clin Cancer Res 2007

Characteristics of “Triple Negative” vs. Other Breast Cancers

CharacteristicOther

(N=1421)number (percent)

“Triple Negative”(N=180)

number (percent)

Significancep 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

T1 (≤ 2 cm) 880 (62.7) 65 (36.5) p < 0.0001

T2 (>2cm to ≤ 5cm) 461 (32.8) 99 (55.6)

T3 (>5cm) 64 (4.6) 14 (7.9)

Missing 16 2

Lymph Node Status

Positive 510 (45.6) 87 (54.4) p = 0.02

Negative 609 (54.4) 70 (44.6)

Missing or Not Tested 302 23

Tumor Grade

I 237 (19.9) 15 (9.8) p < 0.0001

II 616 (51.8) 37 (24.2)

III 336 (28.3) 101 (66.0)

Missing

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

Dent, R. et al. Clin Cancer Res 2007

Tumor Size by Nodal Status according to “Basal-Like” Group

Non “Basal-like” Group(N=1421)

“Basal-like” Group(N=180)

Tumour Size Lymph Node PositiveNumber (percent)

Lymph Node PositiveNumber (percent)

<1.0 cm 38 (19.3) 5 (55.6)

1 - 2 cm 180 (39.3) 25 (55.6)

2.1- 5 cm 238 (59.5) 43 (48.9)

>5.1 cm 53 (91.4) 12 (92.3)

p<0.0001 p=0.042

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

Dent, R. et al. Clin Cancer Res 2007

Distant Recurrence

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

Prob

abili

ty o

f bei

ng re

curr

ence

-fre

e

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<0.0001 (log-Rank test)

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

Overall Survival

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

Prob

abili

ty o

f sur

viva

l

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<0.0001 (log-Rank test)

Other (261 of 1420) “Triple-negative” (62 of 180)

Non-random distribution X² statistic 42.78p 0.0003

Subtype

Smid et al, Cancer Res, in press

Patterns of Metastatic Spread• More likely to spread to brain, lung and possibly liver

and 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)

Median Time from Distant Relapse to Death

0 5 10 15 20 25

22 months

9 months

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

“Triple Negative” Breast CA

Other Breast CA

Treatment

Days

0 20 40 60 80 100

Tum

or

Volu

me

(m

m3 )

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Control5mg Doxorubicin1.25mg Doxorubicin3mg Cisplatin1.25mg Cisplatin6mg Cisplatin (non-average)

Response of Brca1/p53 Mammary Tumors to Doxorubicin or Cisplatin/Carboplatin in vivo

Characteristics of retrieved studies Characteristics of retrieved studies - I- I

Study ComparisonHER2 status

determined (%)

NSABP B11 Paik S et al, JNCI 1998

PF vs PAF 638/682 (94%)

NSABP B15Paik S et al, JNCI 2000

CMF vs AC 2.034/2.295 (89%)

GUN 3 De Laurentiis M et al, ASCO 2001

CMF vs CMF/EV 123/220 (56%)

BelgianDi Leo A et al, Clin Cancer Res 2002

CMF vs HEC/EC 354/777 (46%)

Milan Moliterni A et al, J Clin Oncol 2003

CMF vs CMF→ A 506/552 (92%)

DanishKnoop AS et al, J Clin Oncol 2005

CMF vs FEC 805/980 (82%)

NCIC MA5 Pritchard KI et al, NEJM 2006

CMF vs CEF 628/710 (88%)

Gennari et al, JNCI 2008

Total (determined/randomised)Total (determined/randomised) 5.088/6.216 (82%)5.088/6.216 (82%)

Characteristics of studies - IICharacteristics of studies - II

Study MethodHER2

positive/screened

%

NSABP B11 IHC 239/638 37%

NSABP B15 IHC 599/2.034 29%

GUN 3 IHC 30/123 24%

Belgian FISH 73/354 21%

Milan IHC 95/506 19%

Danish IHC/FISH 246/805 33%

NCIC MA5 IHC/FISH/PCR 163/628 (FISH) 26%

Total (positive/screened)Total (positive/screened) 1.445/5.0881.445/5.088 28%28%

Gennari et al, JNCI 2008

Adjuvant Anthracyclines and HER2:Adjuvant Anthracyclines and HER2:Disease Free SurvivalDisease Free Survival

Anthra betterStudy HER2 status HR (95% CI)

+ 0.60 (0.44 to 0.82)- 0.96 (0.75 to 1.23)

+ 0.84 (0.65 to 1.08)- 1.02 (0.86 to 1.20)

+ 0.65 (0.34 to 1.26)- 1.35 (0.93 to 1.97)

+ 0.83 (0.46 to 1.49)- 1.22 (0.91 to 1.64)

+ 0.75 (0.53 to 1.06)- 0.79 (0.60 to 1.05)

+ 0.52 (0.34 to 0.80)- 0.91 (0.71 to 1.17)

Overall 0.90 (0.82 to 0.98)+ 0.71 (0.61 to 0.83)- 1.00 (0.90 to 1.11)

NSABP B11

NSABP B15

Belgian

Milan

DBCG 89D

NCIC MA5

HER2 specific

0.00 0.50 1.00 1.50 2.00

Test for interaction: 2 13.7, p< .001

Non anthra better

Gennari A. et al. JNCI 2008Gennari A. et al. JNCI 2008

Adjuvant Anthracyclines and HER2 :Adjuvant Anthracyclines and HER2 :Overall SurvivalOverall Survival

Study HER2 status HR (95% CI)

+ 0.66(0.42 to 1.01)- 0.90(0.69 to 1.18)+ 0.82(0.63 to 1.06)- 1.07(0.88 to 1.30)+ 0.85(0.27 to 2.69)- 1.64(0.85 to 3.15)+ 0.61(0.32 to1.16)- 1.26(0.89 to 1.79)+ 0.73(0.50 to 1.05)- 0.82(0.59 to 1.13)

+ 0.65(0.42 to 1.01)- 1.06(0.80 to1.40)+ 0.71(0.32 to 1.55)- 1.25(0.58 to 2.67)

Overall 0.91(0.79 to 1.04)+ 0.73(0.62 to 0.85)- 1.03(0.92 to 1.16)

NSABP B11

NSABP B15

GUN

Milan

DBCG 89D

NCIC MA5

HER2 specific

GOIRC

0.00 0.50 1.00 1.50 2.00 2.50 3.003.50

Test for interaction: 2 12.6, p< .001

Anthra betterNon anthra better

Gennari A. et al. JNCI 2008Gennari A. et al. JNCI 2008

Efficacy summaryEfficacy summary

•Risk of relapse

29%

HR 0.71 (0.61-0.83)

•Risk of death

27%

HR 0.73 (0.62-0.85)

HER2 positiveHER2 positive

Risk of relapse anthra ≈ non anthra HR 1.00 (0.90-1.11)

Risk of death anthra ≈ non anthra

HR 1.03 (0.92-1.16)

HER2 negativeHER2 negative

p <0.001p <0.001

p <0.001p <0.001

Gennari et al, JNCI 2008

Highly hormon-sensitive

Moderately hormon-sensitive

HER-2 amplified

Triple negative

Pathological Complete Response to Chemotherapy Differs by Subtipes

AC → TCarey CCR 07

T → FACRouzier CCR 05

Luminal A/B 4/62 (7%) 2/30 (7%)

Normal-like NA 0/10 (0)

HER2+ and ER- 4/11 (36%) 9/20 (45%)

Triple negative 9/34 (27%) 10/22 (45%)

Neoadjuvant Chemotherapy in Triple Negative Patients. MD Anderson Experience

• The largest date set available (1118 pts) 23% TNBC, pCR 15%

Regimens pts TNBC non-TNBC

FAC/FEC/AC 308 20% 5%

TFAC/TFEC 588 28% 17%

Taxanes 58 12% 2%

Other 164 14% 7%

Total 1118 22% 11%p 0.034

Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008

Neoadjuvant Chemotherapy in TNBCSurvival by Pathological Response

Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008

Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial

MetastaticMetastaticbreast cancerbreast cancer

N = 752N = 752

IxabepiloneIxabepilone++

CapecitabineCapecitabine

N = 375N = 375

CapecitabineCapecitabine

N = 377N = 377

Previous AnthraPrevious Anthra

Taxane ResistantTaxane Resistant

Vahdat LTVahdat LT et al: et al: ASCO2007ASCO2007

1.01.0

0.00.0

Prop

ortio

n Pr

ogre

ssio

n Fr

eePr

opor

tion

Prog

ress

ion

Free

MonthsMonths

0.60.6

0.80.8

0.40.4

0.20.2

00

MedianMedian

5.8 mo5.8 mo

4.2 mo4.2 mo

95 % Cl95 % Cl

(5.5 - 7.0)(5.5 - 7.0)

(3.8 - 4.5)(3.8 - 4.5)

HR: 0.75 (0.64-0.88)HR: 0.75 (0.64-0.88)p = 0.0003p = 0.0003

44 88 1212 1616 2020 2424 2828 3232 3636

IxabepiloneIxabepilone++ Capecitabine Capecitabine

CapecitabineCapecitabine

Vahdat LTVahdat LT et al: et al: ASCO2007ASCO2007

Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial

Ixabepilone+Capecitabine a Phase III TrialIxabepilone+Capecitabine a Phase III Trial

RugoRugo et al: et al: SABCS 2007SABCS 2007

Perspectives

Basal-like Breast Cancer and BRCA1

= BRCA1+

Sorlie T et al. PNAS 03