HER2 based expression subpopulations in TNBC: pathological aspects and

clinical significance
S.M.Ilie1,2, C.Desaw3,M.Hebbar3
1

Department of Oncology, Institute of Oncology Alexandru Trestioreanu,

Bucharest, Romania
2

University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Department of Medical Oncology, University Hospital, Lille, France

Background

Triple negative breast cancer (TNBC) phenotype, defined as less than 1%

cancer cells immunostaining for hormone receptors and either 0-1+ or 2+
score and in situ hybridization (ISH)-negativity for human epithelial growth
factor receptor 2 (HER2), tends to have the worst prognosis.

False negative HER2 assessments have been reported and HER2 negative
tumors can express an intracellular domain responsible for receptors tyrosine
kinase activity and displaying similar clinical characteristics as HER2 positive
phenotype.

Before Trastuzumab era, the prognostic was worse in HER2 over expressed
HR- early breast cancer than in triple negative counterpart.

Aim

To determine whether, different degree of tumor HER2 expression inside a

triple negative breast cancer population has a negative impact on survival.

Methods

Retrospective analysis of consecutive breast cancer patients primary

operable, addressed to the Department of Medical Oncology of University
Hospital of Lille France for adjuvant chemotherapy, between January 2010
and April 2013, with a minimum follow up of 24 months.

Primary outcome: median EFS according to HER2 expression and cumulative

5 year RFS probability in the specific population.

ER and PR were evaluated using standard immunohistochemistry (IHC)

techniques and HER2 positivity was defined according ASCO/CAP
recommendations by circumferential staining in >10% of tumor cells and, in

2+ equivocal score, using ISH test for HER2/CEP 17 ratio or average HER2
gene copy number.

Descriptive statistics, the global and the specific risk of recurrences, Kaplan
Maier five-year survival analyze, were performed using SPSS 22 and the level
of significance was p<0.05.

Results

We included 440 early stage breast cancer patients: 47 pts (10, 6%) triple
negative phenotype, 67pts (15,2%) HER2 positive, 326 pts (74,1%) luminal
type.
HR/HER2 status
Luminal HER2+
HER2 enriched
TNBC HER2 neg
TNBC HER2 pos

No.pts
47
20
29
18

%
10,6%
4,5%
6,5%
4,1%

Tabel 1.Patients distribution according HER inside all breast cancer population

The mean age of TNBC patients was 47 years old, the stage of disease mostly
IIA(48 %
, ,23pts), the histology principally invasive ductal carcinoma (74
%, 35pts), the surgery was conservatory in 28 pts(59,5%)and the majority,
44pts (93%), was anthracycline exposed. Deleterious BRCA1 or BRCA2
mutations were found in 10 pts (21%).

The distribution of HER2 score among TNBC patients were as follows: 62%
(29pts) negative,
27,6 %( 13pts) one plus, 10,4 %( 5pts) two plus and
negative for in situ hybridization.

In HER 2 negative subgroup we noticed more cases of cancer family history

(59%) and more deleterious BRCA mutations(24,13%) and in HER2 ++ more
cases with personal history of cancer(100%) and more frequently high KI67
score (60%).

HER 2 positivity has been correlated with pT (p=0, 05), Ki67 (p=0, 06) and
tumor grade (p=0, 08); pathologic stage pT, Ki67, and HER2 score were
associated with relapse (p<0, 05)

Variable
Age
Menopausal status
Premenopausal
Perimenopausal

HER2 neg,
N=29(62%)
47,812,8

HER2 one plus,

N=13 (27,6%)
47,311,9

HER2 two
plus,N=5(10,4%)
49,414,1

15(51,7%)
5(10,6%)

8(61%)
0(0%)

2(40%)
1(20%)

0,5

0,45

Postmenopausal
Personal history
Cancer
Other
No
Cancer Family history
Yes breast/ovarian
Yes other
No
cTNM
I
IIA
IIB
IIIA
Tumor extent
T1(<2cm)
T2(2,1-5cm)
T3(>5cm)
BRCA mutation
Deletrious
Nondeleterious
Type of surgery
Conservatory
Mastectomy
Histologic type
Ductal invasiv
Ductal invasiv +in situ
Other good prognostic
(tubular, medullary)
Other bad
prognostic(metaplastic)
pT
pT1b
pT1c
pT2
pT3
Tumor grade
G2
G3
pN
pN0
pN1a
pN2a
Ki67
<60%
60%
Adjuvant chemotherapy
3FEC100+3Txt
4FEC100+4Txt
4TC
Adjuvant RT
No
Yes
Relapse

9(3,1%)

5(38%)

2(40%)

13(44,8%)
1(3,4%)
15(51,7%)

7(53,8%)
2(15,1%)
4(30,1%)

5(100%)
0(0%)
0(0%)

0,5

9(31%)
8(27,5%)
12(41,5%)

3(23,07%)
2(15,4%)
8(61,6%)

4(80%)
1(20%)
0(0%)

0,61

5(17,24%)
15(51,72%)
6(20,68%)
3(10,34%)

4(30,8%)
6(46,15%)
1(7,6%)
2(15,45%)

1(20%)
2(40%)
1(20%)
1(20%)

10(34,5%)
17(58,6%)
2(7%)

8(61,5%)
2(15,4%)
3(23,1%)

1(20%)
2(40%)
2(40%)

0,09

7(24,13%)
1(3,44%)

1(7,7%)
1(7,7%)

0(0%)
0(0%)

0,45

19(65,5%)
10(34,5%)

7(53,9%)
6(46,1%)

2(40%)
3(60%)

0,49

20(68,7%)
7(24,13%)
1(3,5%)

11(84,6%)
2(15,4%)
0(0%)

4(80%)
0(0%)
1(20%)

0,44

1(3,5%)

0(0%)

0(0%)

4(13,8%)
6(20,7%)
13(44,8%)
6(20,7%)

4(30,8%)
1(7,7%)
5(38,5%)
3(23,1%)

0(0%)
2(40%)
1(20%)
2(40%)

0,047

3(10,3%)
26(89,7%)

3(23,1%)
10(76,9%)

1(20%)
4(80%)

0,082

17(58,5%)
10(34,5%)
2 ( 7%)

9(70%)
3(23%)
1(7%)

2(40%)
2(40%)
1(20%)

0,45

17(58,6%)
12(41,4%)

11(84,6%)
2(15,4%)

2(40%)
3(60%)

0,074

20(69%)
7(24,1%)
2(6,9%)

7(54%)
6(46%)
0(0%)

3(60%)
1(20%)
1(20%)

0,371

3(10,4%)
26(89,6%)

2(15%)
11(85%)

2(40%)
3(60%)

0,227

0,89

Yes
No

5(17,3%)
24(82,7%)

2(15,4%)
11(84,6%)

1(20%)
4(80%)

0,043

Tabel 2 TNBC Subgroups demographic, clinical, histological and treatment

characteristics according to HER2 score

For a median follow up of 38 months (range 24 to 52mo), 8pts (17%)

experienced recurrence: 3 pts loco regional and 5pts distant metastasis,
representing 20% of HER2++ patients.

The median event free survival (EFS) was 29, 8 months (range 7 to 76 mo),
shorter in HER2+ score (29,8 mo) respectively in HER2 positive (29,2mo)
population than in triple negative HER2 negative (31,8mo), without reaching
the significance (P=0, 9); in patients experienced recurrence, the median PFS
was 11,3months,

EFS (months)
95% Confidence Interval
HER2

Estimate

Std. Error

Lower Bound

Upper Bound

NEG

55,730

7,954

40,140

71,319

POZ

43,476

2,900

37,792

49,159

Log Rank Test value >0.05

EFS (months)

HER2cumullative event free survival probability acording to HER2 value

Fig.1 Cumulative survival probability according to HER2 value

Fig2. Cumulative survival probability according to presence or absence of HER2

expression

Conclusions and Implications

Proportion of HER2 score positivity inside TNBC population is valuable

HER2 two plus score correlates with negative prognostic tumor features and
is associated with a poor outcome in our small sample analysis

Anti-HER2 directed therapies consideration in HER2 expressing TNBC

population needs a larger retrospective analysis with a longer follow-up
period

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