Blood tests called liquid biopsies can be used to collect circulating tumor cells (CTCs) from the bloodstream of cancer patients with solid tumors like breast cancer. These non-invasive tests are becoming an important tool for monitoring response to therapy and for providing prognostic information. But, could CTCs themselves be targeted to stop the most lethal aspect of cancer, cancer metastasis?
Upwards of 90% of all cancer-related deaths are caused by metastasis, the process whereby cancer cells leave the primary or original tumor, enter the blood or lymph system, spread throughout the body, and seed new tumors in a secondary site. For example, a breast cancer cell can leave the breast and seed new tumors in the bone, lung, liver, or brain. These secondary tumors are called metastatic tumors or metastases, and they are infinitely more difficult to treat than localized primary tumors.
Importantly, CTCs shed from the primary tumor that survive therapy and remain in the body as minimal residual disease can become activated to form metastatic tumors months or even years after a breast cancer patient has been told they are cured. This concept is discussed further here.
Unfortunately, the overwhelming majority of current clinical trials are not designed to test therapies that specifically benefit metastatic cancer patients. The characterization of CTCs could guide therapy choice. Treatments designed to target the CTC population of cells could prevent them from colonizing new metastatic tumors at secondary sites.
The ongoing European Organisation for Research and Treatment of Cancer (EORTC) Treat CTC phase 2 trial (clinicaltrials.gov NCT01548677) is testing this concept in breast cancer patients at 72 hospitals across 5 European countries (Austria, Belgium, Germany, France, and the United Kingdom). The trial is for patients whose primary breast tumors do not display abnormal expression the HER2 protein and who have already been through chemotherapy, yet still have residual disease in the breast or residual metastatic disease in their lymph nodes.
The Treat CTC trial is the first clinical study examining whether treating CTCs with Herceptin can prevent the formation of new breast cancer metastases. Herceptin targets the HER2 protein and has been shown to effectively kill breast cancer CTCs after 6 cycles of treatment even when the primary breast tumor does not abnormally express HER2.
Preliminary results from 350 patients within the Treat CTC trial were published this year in the European Journal of Cancer. The cutoff date for this initial analysis was May of 2015. After completing chemotherapy, 12% of breast cancer patients had ≥1 CTC per 15 mL blood sample that was detectable using FDA approved CELLSEARCH® technology. At least one HER2 positive CTC was found in 24% of these 26 patients whose primary tumor did not abnormally express HER2, supporting the concept that not all cancer cells within one tumor express the same proteins. This is known as tumor heterogeneity and it is a major contributor to therapy failure.
Among patients who tested positive for CTCs, 26 were randomized to receive either 6 cycles of Herceptin or to observation alone. The important analyses correlating the number of CTCs identified and Herceptin treatment with clinical outcome will only be available after 3 years of follow up.
Currently, many treatment decisions are based solely on the characteristics of the primary tumor. Hopefully in time, the Treat CTC study will demonstrate the clinical potential of CTCs as a blood-borne, real-time accessible sign of breast cancer progression, and show the that Herceptin is effective for targeting CTCs and improving survival in HER2‑negative breast cancer patients. For now, study leaders have at least been able to demonstrate that CELLSEARCH® technology can be used to detect a single CTC from the blood of breast cancer patients in a variety of clinical settings.