What is cancer metastasis?

Cancer cells spread from the primary tumor site to form new tumors in distant organs or tissues.
It is not random: cancer cells often spread to specific organs (e.g breast cancer commonly spreads to bone, brain, lung, liver) — called organotropism
Cancer cells after metastasis are still the same tyoe. (e.g breast cancer cells in the brain are not brain cancer)
Metastasis is responsible for the vast majority of deaths (>90%)

Key steps in metastasis

Local invasion
- EMT
- Breakdown of basement membrane
Intravasation
- Entry into blood or lymph vessels
- Role of tumor-associated macrophages (TAMs)
Circulation (CTCs)
- Circulating tumor cells face immune attack and shear stress
- Often travel in clusters
Extravasation
Colonization

Idea of the existence of CTCs was proposed a long time ago
1990s-2000s: CTC detection re-emerged, especially with the development of enrichment and detection platforms using nanotechnology.
In 2004, the CellSearch system (Veridex) became the first FDA-cleared teset for enumerating CTCs in metastatic breast, prostate, and colorectal cancers.

Red blood cells (RBCs) are by far the most numerous (~4.5-6 million per mL).
- Has no nucleus
White blood cells (WBCs) are far fewer (~4,000-11,000 per mL).
- Has nucleus, diverse types, larger than RBC
Platelets are intermediate (~150,000-450,000 per mL).
- No nucleus, cell fragments
CTCs (if present in cancer patients) occur at <10 cells per mL of blood - extremely rare).
- Has nucleus, cell origins, often epithelial, larger than RBC

In 2004, the CellSearch system (Veridex) became the first FDA-cleared test for enumerating CTCs in metastatic breast, prostate, and colorectal cacners.
It is the first and only clinically validated, FDA-cleared blood test for enumerating circulating tumor cells.
As of late 2016, when Menarini Silicon Biosystems acquired the CellSearch CTC business from Janssen Diagnostics (previously Veridex), it was reported that approximately 300 laboratories worldwide were actively using CellSearch.

Enrolled 177 mBC patients.
Kaplan-Meyer plot for overall survival for enrolled patients./
- Patients with <5 CTCs overall survival is 21.9 months.
- Patients with >5 CTCs have an overall survival of 10.9 months.
Number of CTCs impact the overall survival

A statistiacl method to estimate the probability of an event occurring at different points in time
Frequently used for clinical trials to observe treatments effectiveness
Survival curve is generated (non-parametric) by observing “events (i.e deaths) at time intervals
Tou need to follow up patients and know their survival time

A liquid biopsy is a test done on a sample of blood (or sometimes other fluids like uring or cerebrospinal fluid) to detech diseases (for example cancer metastasis)
CellSearch system is one kind of liquid biopsy technology
There are other technology platforms developed

Metastatic tumors are often hard to reach
Metastatic burden is dynamic, and liquid biopsy allows repeated sampling over time.
It provides a non-invasive snapshot of the tumor evolution, heterogeneity, and treatment resistance.

CellSearch capture CTCs via anti-EpCAM. This is a major limitation. Some cancer types do not have EpCAM expression.
Parsortix use microfluidic and cell deformability.
- Tumor cells are larver and less deformable than blood cells

Circulating tumor DNA: fragments from DNA released by tumor into blookd stream
The company focused on developing detection of ctDNA Guardant Health
Guardant Health was co-founded by Helmy Eltoukhy and AmirAli Talasaz during 2012-2013; both got Ph.D from Stanford

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