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

• 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, N cadherin, 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

Triple-negative HER2 positive Age<50 T N+

Age≤50 T N+

HR

4.2

3.4

2.0

1.9

2.4

TNBC (N=284) 3.8 (1.3-11.2) 2.2 (1.1-9.7) 4.1 (0.8-19.7)

95% CI

2.3-7.6

3.1-10.9

1.2-3.5

1.2-3.6

1.1-5.1

HER2+ (N=245) 1.0 (0.4-2.8) 1.5 (0.9-6.7) 2.2 (0.6-8.8)

P-value

<0.0001

0.005

0.012

0.02

0.028

HR+ (N=1912) 2.0 (1.2-3.5) 2.1 (1.2-5.1) 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?

– 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 • 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