Download Why brain surveillance?

Indivisualized approach
for brain surveillance
in high-risk breast cancer patients
Soohyeon Lee
Yonsei Cancer Center
Severance Hospital
Division of Medical Oncology
Department of Internal Medicine
Yonsei University College of Medicine
[email protected] [email protected]
http://bravomybreast.com
Surveillance program
• Hypothesis
– “Early detection and aggressive treatment of tumor
recurrence provides the best change for long-term
survival even in patients with effective adjuvant
treatments were performed.”
– “Earliest intervention in the presence of minimal
disease burden and good performance status may
also possess a greater likelihood of response and
therefore the most favorable outcomes.”
– “Surveillance program can change the natural course
of breast cancer patients.”
Why brain surveillance?
• High incidence rate in specific group
• More dismal course and decreased QoL
after brain metastasis (than other site
metastasis)
• No guideline, no evidence and no clinical
trial for brain surveillance until now
• Development of effective drug (HER2) and
treatment modality (Surgical and
Radiological intervention)
Autopsy study
Solitary metastasis : 81/193 (42% of cases with brain metastasis or 7.8% of all
breast cancer cases)
Tsukada Y et al, Cancer 1983;52:2349-2354
Autopsy study
Symptoms : motor weakness (23), convulsion (22), headache (15),
confusion (13), Nausea/vomitting (11), Cranial nerve sign (10), aphasia
(2), ataxia (2), miscellaneous (8)
Tsukada Y et al, Cancer 1983;52:2349-2354
Incidence of CNS metastasis
in BC based in autopsy
Miller KD et al, Ann Oncol 2003;14:1072-1077
Occult CNS involvement in mBC
Miller KD et al, Ann Oncol 2003;14:1072-1077
Survival comparison :
No CNS mets vs occult CNS mets
Uing clinical trial setting : brain screening protocol
Limitation of this data
Heavily treated patients (more than 3 regimen in metastating setting)
Disease sites : 2 more
Not available trastuzumab therapy in HER2 positive patients
Miller KD et al, Ann Oncol 2003;14:1072-1077
Different biology in Brain metastasis
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BM incidence rate among breast cancer subtype
Onset time according to subtype
Systemic therapy for extracranial disease control
HER2 vs TNBC
Organ-specific metastatic extravasation
Genes that mediate breast cancer metastasis to the brain
- COX2, EGFR ligand : previously linked to breast cancer infiltration of
the lungs (not bones or liver)
- ST6GALNAC5 : specifically mediates brain metastasis and enhances
their adhesion to brain endothelial cells and their passage through the
brain-brain barrier
Bos PD et al, Nature 2009;459(18):1005-1009
Reason for a higher propensity for
brain metastasis – HER2
• Upregulation of CXCR4 receptor expression – SDF-1a
(stromal cell-derived factor-1a) of CXCR4 ligand : BC
cells that express CXCR4 are attracted by tissues
expressing high levels of SDF-1a, which causes BC cells
to leave the circulation and to proliferate and induce
angiogenesis and metastasis.
• Trastuzumab, unable to penetrate the intact blood-brain
barrier
Li YM et al, Cancer Cell 2004;6(5):459-469
Arya M et al, Tumour Biol 2007;28(3);123-31
Reason for a higher propensity for
brain metastasis – TNBC
• No evidence of the CXCR4-SDF1a axis in basal-like BC
• Related with EMT feature
– Loss of epithelial characteristics : E-cadherin,
occludins, luminal cytokeratin
– Gain of mesenchymal characteristics : vimentin, Ncadherin, b-catenin
– EMT inducer : Snail, Slug, Twist, ZEB
• Earilier disrupt the blood-brain barrier in TN
Sarrio D et al, Cancer Res 2008;68(4):989-997
Risk factors of brain metastasis
in breast cancer
HR
95% CI
P-value
Triple-negative
4.2
2.3-7.6
<0.0001
HER2 positive
3.4
3.1-10.9
0.005
Age<50
2.0
1.2-3.5
0.012
T
1.9
1.2-3.6
0.02
N+
2.4
1.1-5.1
0.028
TNBC (N=284)
HER2+ (N=245)
HR+ (N=1912)
Age≤50
3.8 (1.3-11.2)
1.0 (0.4-2.8)
2.0 (1.2-3.5)
T
2.2 (1.1-9.7)
1.5 (0.9-6.7)
2.1 (1.2-5.1)
N+
4.1 (0.8-19.7)
2.2 (0.6-8.8)
2.4 (1.1-5.1)
Heitz et al. E Jur Cancer 2009;45:2792-2798
Onset of BM and clinical outcome
Time course and frequency of
cerebral metastasis
Survival after the first diagnosis of
cerebral invovlement
From primary diagnosis to occurrence of brain metastasis
: TN 22 months vs HER2 30 months vs 63.5 months
Heitz et al. E Jur Cancer 2009;45:2792-2798
Metastatic behavior of BC subtypes
All BC
Excluding EBC
Kennecke H et al, J Clin Oncol 2010;28(20):3271-3277
Brain metastasis by BC subtype
independent of clinicopathologic variables
Kennecke H et al, J Clin Oncol 2010;28(20):3271-3277
CNS metastasis in HER2+
Brufsky AM et al, CCR 2011;17::4834-4843
HER2 positivity in BM
Case matching analysis :
HER2 overexpression was a significant
determinant for the development of brain
metastasis with an adds ratio of 4.00
(95% CI, 1.34-11.96; p=.005)
Gabos Z et al, J Clin Oncol 2006;24:5658-5663
CNS metastasis in TNBC
Lin NU et al, Cancer 2008;113(10):2638-2645
Characteristics of
CNS metastasis in
TNBC
• Parenchymal mets main
• Nuerologic symptoms 77%
• Uncontrolled systemic
disease status 83%
• Tx
WBRT +- surgical resection,
SRS, IT Chemo etc
Lin NU et al, Cancer 2008;113(10):2638-2645
Breast- Graded Prognostic Assessment
(GPA)
Sperduto PW et al, Int J Radiation Oncology Biol Phys, 2012;82(5):2111-2117
Ahn and Lee et al, NeuroOncol 2012;14(8):1105-1113
Extracranial disease control
Sperduto’s GPA score
New BC-GPA score
Ahn and Lee et al, NeuroOncol 2012;14(8):1105-1113
Rationale for brain surveillance
• The high frequency of brain metastases among
patients with HER2-enriched (28.7%), basal-like
(25.2%), and TN nonbasal (22%) disease may
support a more aggressive approach to imaging
for patients with newly diagnosed distant
disease.
• Studies of specific CNS preventive agents may
be of benefit in basal-like and HER2-positive
early breast cancer.
– Radiosensitizer combination with radiation therapy
– Prophylactic PCI
Need to prospective cohort group in
high risk patients
• Currently, there is no evidence for a benefit of early
detection of brain metastasis in BC patients.
• This may be due to the lack of adequate selection
criteria for cohorts at high risk.
• CNS screening would not have to be extended over a
long period of time.
• The expected number of patients who would have to be
screened is small.
Issues in Brain surveillance
• Who? / How?/ When? / How often?
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Time to brain metastasis
Primary tumor characteristics (subtypes)
Disease extent
Treatment factors
• Survival after identification of occult CNS metastasis
• The importance of CNS therapy
– Prophylactic PCI
– Aggressive brain control : combination therapy
– Neurocognition, QoL, Survival benefit (OS, NS, RS)
• Effective systemic therapy : TN vs HER2
Brain surveillance cohort
• Population :
– TN or HER2,
– Young age (<45 yrs)
– Stage lll
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Imaging modality : Brain MRI
Enrollment : 2 years
Screening interval : 6 month
Duration : 3 years
Follow up : 2 years
If asymptomatic brain metastasis, consider RCT
– 1-3 metastasis  SRS/Surgery vs SRS/Surgery followed by
WBRT
– Oligometastasis  SRS vs SRS followed by WBRT
– Multiple metastasis  WBRT vs WBRT + RT sensitizer