1. Beyond breast specific—Graded Prognostic Assessment in patients with brain metastases from breast cancer: treatment impact on outcome
Gaia Griguolo
DiSCOG-University of Padova
IOV – Istituto Oncologico Veneto I.R.C.C.S.

2. Brain metastases – a common issue in breast cancer
Breast cancer is one of the commonest causes of brain metastases
10–15% of patients diagnosed with metastatic breast cancer will eventually develop brain metastases
Rates are higher in HER2-positive (≈30%) and triple negative breast cancer (≈50%)
Breast cancer brain metastases have been traditionally linked to poor prognosis
Median OS from CNS metastasis
6.8 mos
Lin NU et al. JCO 2004; Altundag K et al. Cancer 2007

3. Brain metastases – dissecting the abyss
Prognostic scores proposed up to 2008 were created from databases containing patients with brain metastases from many different types of primary tumors
Score PS
Age
Extracranial metastases
Primary tumor control
Interval
Number of brain met.
Volume of brain met.
RPA 3 classes
included
BSBM 4 classes
SIR 3 classes
GPA 4 classes
Rades et al. 4 classes
Only a minority of these patients had primary breast cancer
Nieder C et al, BMC Cancer 2009

4. It’s not just cancer, it’s BREAST cancer
Breast Specific – Graded Prognostic Assessment
A retrospective database of patients treated for brain metastases at 11 istitutions radiation oncology departments between June 1993 and January 2010
Total: 3,940 patients
Breast Cancer: 400 patients
Breast Specific – Graded Prognostic Assessment Score
0.5
1.0
1.5
2.0
Karnofsky PS
≤50 60
70-80
90-100
BC subtype TN -
ER+/HER2-
ER-/HER2+
ER+/HER2+
Age (years)
≥60
<60
Prognostic categories: 0-1.0; ; ;
Sperduto PW et al. Int J Radiat Oncol Biol Phys 2010
Sperduto PW et al. Int J Radiat Oncol Biol Phys 2011

5. Breast Specific – Graded Prognostic Assessment
Breast Specific-GPA N %
Median OS from BM (95% CI)
133
33%
25.30 mos ( )
140
35%
15.07 mos ( )
104
26%
7.70 mos ( ) 23 6%
3.35 mos ( )
Sperduto PW et al JCO 2012

6. Is this really applicable to our every-day clinics?

7. Population
Breast cancer patients diagnosed with brain metastases between 1st December 1999 and March 2016 and referred to the Istituto Oncologico Veneto
Inclusion Criteria:
Histologically proven invasive breast carcinoma
age >18 years at the time of breast cancer diagnosis
intradural brain metastasis radiologically confirmed using cerebral CE/CT scan and/or brain MRI
Exclusion Criteria:
Breast cancer bone metastasis extending into the cranium in the absence of intradural brain metastasis
Diagnosis of leptomeningeal carcinomatosis concomitant to brain metastasis diagnosis and patients with diagnosis of leptomeningeal carcinomatosis alone

8. intra-cranial lesions
Population flowchart
219 patients with
breast cancer related
intra-cranial lesions
1 patient without
available data
218 patients
5 patients with breast cancer bone metastasis extending into the cranium
213 patients
14 patients with leptomeningeal disease alone
199 patients
18 patients with concomitant leptomeningeal disease
181 patients
Last follow-up May 20, 2016

9. Patient characteristics at time of BC diagnosis
 Clinicopathological features
N. of patients %
AJCC stage at diagnosis
I-II 92
50.8%
III 53
29.3 % IV 36
19.9%
Tumor histology
Ductal
Lobular
Other histology NA
158
87.3% 18
9.9% 2
1.1% 3
1.7%
Grade
G1-G2 G3 54
29.8%
122
67.4% 5
2.8%
HR status
Negative
Positive 64
35.4%
115
63.5%
HER2 status 90
49.7% 72
39.8% 19
10.5%
Molecular subtype TN
ER-/HER2+
ER+/HER2+
ER+/HER2- 34
18.8% 30
16.6% 42
23.2% 56
30.9%
Median age at BC diagnosis: 51 (24-80)

10. Patient characteristics at time of BM diagnosis
Clinicopathological features N. %
Age at brain metastasis diagnosis (years)
<60
≥60
133 73 48 26
Number of brain metastases 1 2 3 ≥4 40 22 20 12 7 4
113 62
Control of extra-cranial disease
Yes No 68 38
Performance status (KPS)
>70
≤70 77 43 92 51
Breast Specific-GPA
3.5-4
2.5-3
1.5-2
0-1 NA 11 69 45 25 18 10 29 16
Systemic treatment received 59 33
120 66
Local treatment received 53
127 70
Sperduto 2012
33%
35%
26% 6% 13 45 30 12
30 patients (16.6%) did not receive neither local nor systemic treatment after the diagnosis of brain metastases. A total of 127 patients (70.2%) underwent local treatment for brain metastases. A minority of patients (n 21, 11.6%), were treated with neurosurgery. Most patients (n 124, 68.5%) received radiotherapy, in the form of either stereotactic radiotherapy or extensive radiotherapy fields such as whole brain radiation therapy, as primary treatment or after localized treatment. Most patients (n 104, 57.5%) received whole brain radiotherapy, while 16 (8.8%) patients received stereotactic radiotherapy and 13 (7.2%) patients received other kinds of radiotherapy, such as semi-localized boosts to the site of previous neurosurgery. A total of 120 patients (66.3%) received at least a systemic treatment, namely chemotherapy, endocrine therapy or target therapy for 101 (55.8%), 36 (19.9%) and 50 (27.6%) patients, respectively. The median number of lines of systemic treatment received by patients after the diagnosis of brain metastases was one line per patient (range 0–9).
100

11. Prognostic factors for OS after BM diagnosis
Median OS from brain metastasis diagnosis was 7.7 mos (95% CI 5.4–10.0)
vs 13.8 mos (Sperduto 2012)
 Clinicopathological features
Median OS mos (95% CI)
HR (95%CI) p
Molecular subtype
ER+/HER2-
8.6 ( )
ref
0.082 TN
5.1 ( )
1.59 ( )
ER-/HER2+
7.7 ( )
1.35 ( )
ER+/HER2+
11.0 ( )
0.90 ( )
Age at BM diagnosis
<60 yrs
9.2 ( )
0.070
≥60 yrs
4.6 ( )
1.40 ( )
KPS
>70
16.2 ( )
<0.001
≤70
4.2 ( )
2.03 ( )
Number of BM
<4
8.2 ( )
0.312 ≥4
7.4 ( )
1.18 ( )
Control of extra-cranial disease
Yes
11.4 ( ) No
6.0 ( )
1.35 ( )
BS-GPA index
3.5-4
18.8 ( )
0.014
2.5-3
8.8 ( )
1.58 ( )
1.5-2
6.2 ( )
1.86 ( )
0-1
3.6 ( )
2.97 ( )
Number of local treatments
3.0 ( ) 1
8.8 ( )
0.50 ( ) 2
21.0 ( )
0.34 ( ) 3
35.1 ( )
0.19 ( )
Systemic treatment received
3.1 ( )
13.8 ( )
0.41 ( )

12. Prognostic factors for OS after BM diagnosis
from Sperduto 2012
25.30 mos ( )
15.07 mos ( )
7.70 mos ( )
3.35 mos ( )

13. Interaction and multivariate analysis
Patients in the less favorable BS-GPA category (BS-GPA index ≤1) were less likely to receive systemic treatment after brain metastasis diagnosis compared to other BS-GPA categories (44% vs. 71%, p = 0.021)
No significant association was observed between BS-GPA category and local treatment (p = 0.264)
Patients undergoing increased lines of local treatments where more likely to receive systemic therapy (p < 0.001)
Prognostic impact on OS
HR (95%CI)
HR (95%CI) corrected
by BS-GPA
Systemic
treatment No
ref
ref*
Yes
0.41 ( )
0.47 ( )*
Number local treatments 1
0.50 ( )
0.52 ( ) 2
0.34 ( )
0.48 ( ) 3
0.19 ( )
0.14 ( )
* patients with BS-GPA index <1 excluded
No significant association was observed between BS-GPA category and local treatment (80, 74, 71 and 61% of patients received at least 1 local treatment in BS-GPA categories 3.5–4, 2.5–3, 1.5–2, 0.5–1, respectively, p = 0.264).
Patients undergoing increased lines of local treatments where more likely to receive systemic therapy (43, 77 and 77% of patients treated respectively with 0, 1, and 2 or more local treatments also received systemic therapy, p < 0.001).
Therefore, to correct the prognostic role of treatments for patient-related features (resumed in the BS-GPA) avoiding potential bias, we performed two separate analyses: (a) Overall survival from brain metastasis diagnosis according to number of local treatments, corrected for BS-GPA category; (b) Overall survival from brain metastasis diagnosis according to systemic treatments corrected for BS-GPA category (patients with BS-GPA index ≤1 excluded). Both local and systemic treatment added independent prognostication beyond BS-GPA (Table 3).

14. Conclusions
BC brain metastasis patients represent an extremely heterogeneous group
Increasing evidence supports individualization of treatment for selected good-prognosis patients
Several prognostic tools have been proposed to aid clinicians in these decisions
We should be cautious when applying these prognostic tools in every-day clinics, as substantial differences in patient characteristics may be present
BS-GPA confirmed its prognostic significance in a real-life cohort of BC patients
Both local and systemic treatment added independent prognostication beyond BS-GPA

15. The next step…Collaboration
Department of Gynaecology,
Martin-Luther-Universitaet
Halle-Wittenberg, Germany
Prof. Christoph Thomssen
Dr. Eva Kantelhardt
Department of Medical Oncology,
Montpellier, France
Nice Cedex, France
Dr. William Jacot
Dr. Amélie Darlix
Thank you for your attention

17. Time to brain metastases
Median time to brain metastasis was 41.4 months (CI 95% 32.5–50.3 months).
As expected, breast cancer subtype significantly influenced time from BC diagnosis to brain metastasis occurrence.

18. It’s not just cancer, it’s BREAST cancer
And in breast cancer, tumor biology counts
Nieder C et al, BMC Cancer 2009