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brain metastasis from breast cancer

Thursday 12 April 2012

BMBC

Definition: With the improvement of therapeutic options for the treatment of breast cancer, the development of brain metastases has become a major limitation to life expectancy in many patients. Brain metastatic breast cancer (BMBC) is uniformly fatal and increasing in frequency.

The overwhelming majority of cancer deaths are due to metastasis. Brain metastatic breast cancer (BMBC) occurs in approximately 20% of all breast cancer cases, is uniformly fatal, and may be increasing in frequency in patients with a particular subtype. Occult brain metastasis are exceedingly common at autopsy.

Images

- 50yow, h/o breast cancer, single ring-enhancing cerebellar lesion

EpCAM- CTCs

Circulating tumor cells (CTCs) represent the primary cause of intractable metastatic disease and are considered essential for metastasis formation. However, characterization of CTCs that induce metastasis remains elusive because platforms that capture CTCs are not comprehensive, owing to the phenotypic heterogeneity of CTCs.

For example, the Veridex CellSearch platform—the only test approved by the U.S. Food and Drug Administration (FDA)—relies on the use of antibodies targeting the epithelial cell adhesion molecule (EpCAM); thus, it is only capable of capturing EpCAM-positive CTCs, but not CTCs that are EpCAM-undetectable or EpCAM-negative (both termed “EpCAM-” here).

CellSearch is also unable to capture CTCs in 30 to 35% of metastatic breast cancer patients, and over 60% of patients with BMBC who have undetectable CTCs by CellSearch analyses. Therefore, new approaches to identify and characterize EpCAM− CTCs in breast cancer patients are needed.

EpCAM− CTCs are crucial to understanding cancer metastasis, with the ultimate goal of developing treatments to prolong patient survival.

CTCs derived from breast cancer patients with clinically detectable BMBC rarely express EpCAM, and EpCAM− CTCs have been shown to positively correlate with the presence of brain metastases in a large cohort of patients. (23576814)

CTCs detection

Previously described methods for CTC detection, isolation, and enrichment are based on procedures involving density, immunomagnetic, size-exclusion and/or flow manipulation in microfluidic devices.

However, similar to CellSearch, most of these approaches are limited by the heterogeneous nature of CTCs, often “missing” the EpCAM− CTCs.

Furthermore, the fraction of CTCs that extravasate and are able to generate distant metastases may have lost EpCAM expression and are believed to have undergone the epithelial-mesenchymal transition (EMT), which results in the downregulation of epithelial cell markers, such as E-cadherin, claudins, cytokeratins, and EpCAM.

Several groups have also reported that CTCs express stem cell and/or EMT-associated markers; however, it is unclear whether CTCs that no longer express EpCAM are metastasis-competent.

CTCs long-term culture

Although tumors can be formed in animals by cells from the peripheral blood of patients, and murine CTCs have been successfully cultured, long-term culture of isolated human CTCs has not been reported until 2013. (23576814)

In a study, zuthors isolated EpCAM− CTCs from patients with metastatic breast cancer, developed CTC lines from 3 of these patients, and then characterized these EpCAM− CTCs for metastatic competence by selecting for the protein signature HER2+/EGFR+/HPSE+/Notch1+ (the “brain metastasis selected markers (BMSM) signature”). (23576814)

They show that CTCs selected for this signature possess high propensities to metastasize to the brain and lungs once injected in immunodeficient animals, whereas parental CTCs metastasize to lung. (23576814)

Physiopathology

Despite its devastating outcome, mechanisms causing BMBC remain largely unknown. The mechanisms that implicate circulating tumor cells (CTCs) in metastatic disease, notably in BMBC, remain elusive.

A study characterized CTCs isolated from peripheral blood mononuclear cells (PBMCs) of patients with breast cancer, and also develop CTC lines from three of these patients. (23576814)

In epithelial cell adhesion molecule (EpCAM)–negative CTCs, it identified a potential signature of brain metastasis comprising “brain metastasis selected markers (BMSM)” HER2+/EGFR+/HPSE+/Notch1+. (23576814)

These CTCs—which are not captured by the CellSearch platform because of their EpCAM negativity—were analyzed for cell invasiveness and metastatic competency in vivo.

CTC lines expressing the BMSM signature were highly invasive and capable of generating brain and lung metastases when xenografted in nude mice. (23576814)

Notably, increased brain metastatic capabilities, frequency, and quantitation were detected in EpCAM− CTCs overexpressing the BMSM signature. (23576814)

The presence of proteins of the BMSM CTC signature was also detected in the metastatic lesions of animals. The isolation, characterization, and long-term culture of human breast cancer CTCs, led to the description of a BMSM protein signature that is suggestive of CTC metastatic competency to the brain. (23576814)

Open references

- The identification and characterization of breast cancer CTCs competent for brain metastasis. Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D. Sci Transl Med. 2013 Apr 10;5(180):180ra48. doi : 10.1126/scitranslmed.3005109 PMID: 23576814 [Free]

CGH

- Brain metastases, in general, display similar chromosomal aberrations as primary tumors, but with a notably higher frequency.

- Statistically significant differences are found at nine different chromosomal loci, with a gain and amplification of EGFR (7p11.2) and a loss of 10q22.3-qter being among the most significant aberrations in brain metastases (p@<@0.01, fdr@<@0.04).

- Allelic imbalance (AI) patterns at 10q PTEN loci is found significantly more often in brain metastases (52%) and primary tumors with a brain relapse (59%) compared to primary tumors from patients without relapse (18%; p=0.003) or relapse other than brain tumors (12%, p=0.006).

- Loss of PTEN is especially frequent in HER2-negative brain metastases (64%).

- Furthermore, PTEN mRNA expression is significantly down-regulated in brain metastases compared to primary tumors and PTEN mutations were frequently found in brain metastases.

- Brain metastases often show very complex genomic aberration patterns, suggesting a potential role of PTEN and EGFR in brain metastasis formation.

References

- Relevance of PTEN loss in brain metastasis formation of breast cancer patients. Wikman H, Lamszus K, Detels N, Uslar L, Wrage M, Benner C, Hohensee I, Ylstra B, Eylmann K, Zapatka M, Sauter G, Kemming D, Glatzel M, Muller V, Westphal M, Pantel K. Breast Cancer Res. 2012 Mar 19;14(2):R49. PMID: 22429330