Risk Predictors of Brain Metastases Development in Patients with HER2- Positive Breast Cancer

Table of Content

Introduction

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15%–25% of all breast cancers (BCs).  In the absence of treatment, it is associated with a high recurrence rate, a short disease-free survival, a disposition for brain metastases (BM) and reduced overall survival (OS). Young age, pulmonary metastases, negative hormone receptor status and HER2 amplification are some risk factors reports reported for development of BM but this has been documented in unselected patients with BC. Limited evidence exists that report risk factors for BM for cohorts of only HER2+ BC.

Aim

To define risk factors for the development of BM for early and advanced (metastatic) HER2+BC as well as to describe the local treatment approaches and outcomes of patients with BM

Patient Profile

  • Patients diagnose with HER2+ BC
Table 1: Baseline characteristics

Clinical values

Patients without a diagnosis of BM (n=431) No. (%)

Patients with a diagnosis of BM (n=52) No. (%)

P values

Age at dx, median (IQR), years

53.9 (44.4–62.0)

49.7 (38.0–60.2)

0.03

Age at diagnosis

 

 

0.0022

≤40 years

78 (18.05)

20 (38.4)

 

41–64 years

282 65.4)

24 (46.2)

 

≥65 years

71 (16.55)

8 (15.4)

 

Menopausal status at diagnosis

 

 

0.47

Premenopausal

183 (43.9)

27 (52.9)

 

Postmenopausal

225 (53.95)

23 (45.1)

 

Peri-menopausal

9 (2.15)

1 (2.0)

 

Missing

14

1

 

Type of surgery

 

 

<0.0001

   Breast-conserving surgery

135 (31.3)

5 (9.6)

 

Radical surgery

271 (62.9)

33(63.5)

 

No surgery

25 (5.8)

14 (26.9)

 

Histology

 

 

0.06

   Invasive carcinoma NST

387 (91.3)

43 (89.6)

 

Lobular carcinoma

18 (4.2)

3 (6.25)

 

Mixt

19 (4.5)

2 (4.15)

 

Others/missing

7

4

 

Tumour size

 

 

<0.0001

pT1

194 (45.5)

5 (10.0)

 

pT2

143 (33.6)

19 (38.0)

 

pT3–4

89 (20.9)

26 (52.0)

 

Missing

5

2

 

Nodal status

 

 

0.0002

pN0

243 (56.6)

14 (27.5)

 

pN1

162 (37.8)

32 (62.7)

 

pN2

14 (3.3)

1(2.0)

 

pN3

10 (2.3)

4 (7.8)

 

Missing

2

1

 

Tumour grade

 

 

0.46

G1

10 (2.4)

0 (0)

 

G2

138 (32.5)

15 (29.4)

 

G3

276 (65.1)

36 (70.6)

 

Missing

7

1

 

Hormone receptor status

 

 

0.53

   ER and/or PR positive

308 (71.5)

35 (67.3)

 

   ER and PR negative

123 (28.5)

17 (32.7)

 

HER2-to-CP17 ratio

 

 

0.18

<5

241 (55.9)

24 (46.2)

 

≥5

190 (44.1)

28 (53.8)

 

Type of chemotherapy

 

 

0.0085

 

Anthracyclines

82 (19.0)

18 (34.6)

 

 

Taxanes

37 (8.6)

6 (11.5)

 

 

Anthracyclines+taxanes

261 (60.6)

20 (38.5)

 

 

Other

7 (1.6)

3 (5.8)

 

 

None

44 (10.2)

5 (9.6)

 

 

Type of anti-HER2 treatment

 

 

0.14

 

Trastuzumab

277 (64.3)

27 (51.9)

 

 

Trastuzumab+lapatinib

10 (2.3)

1 (1.95)

 

 

Trastuzumab+pertuzumab

19 (4.4)

1 (1.95)

 

 

Lapatinib

6 (1.4)

0 (0)

 

 

None

119 (27.6)

23 (44.2)

 

 

Adjuvant endocrine therapy in patients with HR+BC

 

 

0.003

 

Administered

275 (89.3)

25 (71.4)

 

 

Not administered

33 (10.7)

10 (28.6)

 

 

Adjuvant radiotherapy

 

 

0.65

 

Yes

146 (33.9)

16 (30.8)

 

 

No

285 (66.1)

36 (69.2)

 

 

             

BM, brain metastases; ER, estrogen receptor; G, tumor grade; HR+BC, hormone receptor-positive breast cancer; N, nodal status; NST, no special type; PR, progesterone receptor; T, tumor size; dx, diagnosis; p, stage given by histopathological examination

Methods

  • Retrospective, single-institutional analysis
  • Institute Jules Bordet (IJB), Brussels, Belgium between January 2000 and December 2014
  • N= 483 patients
  • Patients diagnose with HER2+ BC
  • Follow-up data or electronic charts were reviewed for patient and disease characteristics, treatment regimens for primary, metastatic and CNS disease and clinical outcomes

Study Endpoints

  • The primary objective was to define risk factors for the development of BM both at the time of initial BC diagnosis and at the time of metastatic disease diagnosis
  • Secondary objectives included epidemiological aspects of BM and outcome of patients with BM

Results

  • Development of metastases was reported in 108/483 (22.4%) and 52 (10.8%) developed BM
    • Among the 52 BM, 7 patients (13.5%) had BM as the first site of metastatic disease and 5 patients (9.6%) developed BM as the only site of distant relapse
  • Among 96 metastatic patients without BM at diagnosis
    • 40 (41.7%) developed BM in the course of their disease

Risk Factors for the Development of BM

  • Median follow-up was 64.1 months for the cohort including 52 patients with BM
  • In multivariate analysis, the risk factors for the development of BM were
    • Age ≤40 years (HR 2.10)
    • Tumour size >2 cm (HR 4.94)
    • Nodal involvement (HR 3.48)
    • Absence or late start (≥6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79 or HR 2.65)
    • Development of lung metastases as the first site of relapse (HR 6.97)
  • There was no effect of biological factors such as hormone receptor status, the degree of HER2 amplification and tumour grade on the development of BM both
Table 2: Risk factors for the development of BM

Variable

 

HR

P values

Time of initial BC diagnosis (excluding de-novo metastatic patients)

Univariate analysis

 

 

 

Age at BC diagnosis

>40 years

1

 

≤40 years

2.61

0.0078

Tumour size

T1

1

 

T2–4

6.68

0.0004

Nodal status

N0

1

 

N1–3

5.00

0.0002

Type of surgery

BCS

1

 

Mastectomy

7.86

0.0054

No breast surgery

3.70

0.29

Multivariate analysis

 

 

 

Age at BC diagnosis

>40 years

1

 

≤40 years

2.10

0.045

Tumour size

T1

1

 

T2–T4

4.94

0.0036

Nodal status

N0

1

 

N1–3

3.48

0.0045

Adjuvant anti-HER2 treatment

Early anti-HER2 treatment*

1

 

Late anti-HER2 treatment†

2.65

0.043

No anti-HER2 treatment

3.79

0.0042

Time of metastatic disease diagnosis (including de-novo metastatic patients)

Variable                   

 

HR     

P values

Univariate analysis

 

 

 

 Age at MBC diagnosis

>40 years

1

 

≤40 years

2.11

0.028

Time from initial diagnosis to metastatic disease

<1 year

1

 

≥1 year

2.18

0.017

Type of metastatic disease

De-novo

1

 

Recurrent

1.97

0.0040

First metastatic site

Other than lung

1

 

Lung de-novo

0.84

0.75

Lung (not de-novo)

6.97

<0.0001

Multivariate analysis

 

 

 

First metastatic site

Other than lung

1

 

Lung de-novo

0.84

0.84

Lung (not de-novo)

6.97

<0.0001

*Start within the first 6 months after BC diagnosis. †Start ≥6 months after BC diagnosis. BC, breast cancer; BCS, breast-conserving surgery; BM, brain metastases; MBC, metastatic breast cancer; N, nodal status; T, tumor size.

The outcome of patients with HER2+ BC and BM

  • Compared with asymptomatic patients, symptomatic patients were treated more often with whole brain radiotherapy. alone (63.65% vs 36.7%, p=0.023).
  • Median  overall survival (OS)for metastatic patients without CNS events was 46.7 months  and for patients with BM 20.8 months
  • Asymptomatic patients at the time of BM diagnosis showed better overall survival than symptomatic patients (HR 0.49)
  • Anti-HER2 treatment after diagnosis of BM had no impact on the development of a second CNS event or on OS
 Table 3: Local treatment approaches for the first BM

Treatment modality

Asymptomatic patients

(n=30)

No. (%)

Symptomatic patients

(n=44)

No. (%)

P values

Radiotherapy (RT)-based

 

 

 

WBRT only

11 (36.7)

28 (63.65)

0.023

SRS only

12 (40)

7 (15.9)

0.02

WBRT+SRS

4 (13.3)

3 (6.8)

0.35

No RT

3 (10)

6 (13.65)

0.8

Surgery-based

 

 

 

Surgery alone

0

1 (2.3)

1

Surgery+RT

2 (6.7)

8 (18.2)

0.19

BM, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole brain radiotherapy.

Conclusion

  • The study demonstrated that a considerable number of patients with metastatic HER2+ BC will develop BM
  • Five risk factors were identified associated with the development of BM in HER2+ BC patients (age ≤40 years, tumour size >2 cm, nodal involvement, absence or late start of adjuvant anti-HER2 treatment and the development of lung metastases as the first site of relapse)
  • Compared to asymptomatic patients, symptomatic patients at the time of BM diagnosis showed a better overall survival
  • Screening patients with risk factors for BM may lead to early detection of BM in patients with HER2+ BC might be associated with improved outcome
  • Use of MRI as a screening method for BM in patients with metastatic BC needs further research before an approach is recommended

ESMO Open 2018;3: e000440. doi10.1136/esmoopen-2018-000440