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‘Molecular clock’ blood test could track spread of breast cancer in multiple organs and help monitor treatment

A blood test to watch breast cancer’s ‘molecular clock’ could help track the growth of multiple tumours around the body and monitor how they are responding to treatment, new research suggests.

26 November 2020

Peter Barry, Surgical Oncology lead for the Breast Cancer Now LEGACY Study, and Consultant Breast Surgeon at The Royal Marsden

The test, developed by scientists at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, could help identify the most actively growing tumours as breast cancer spreads around the body, helping to guide the best treatment for individual patients.

The new study found that the spread of breast cancer to multiple sites follows a traceable, orderly sequence, with the majority of new tumours in distant organs being formed by cancer cells all derived from one cell in the original breast tumour.

While further development is required, scientists believe the test would be highly sensitive and relatively cheap, as it doesn’t require prior knowledge of the genetic make-up of a patient’s cancer.

The approach has been developed following new results from an innovative rapid autopsy study, the LEGACY Study.

Secondary (or metastatic) breast cancer is the term given to breast cancer that has spread to another part of the body, such as the bones, liver, lungs, or brain. Accessing metastatic tissue through biopsies can be difficult and sometimes painful due to the tumour's location and does not allow for the entirety of the tissue to be analysed. Post-mortem studies such as LEGACY provide researchers with the best opportunity to understand secondary breast cancer, how it works, and how to stop it.

Led by Mr Peter Barry, consultant breast surgeon at The Royal Marsden, two women living with secondary breast cancer in London volunteered to donate their cancer tissue for research shortly after their deaths as part of this pilot rapid autopsy programme.

Sponsored by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, and largely funded by Breast Cancer Now, the LEGACY study enabled surgeons, pathologists, oncologists, and researchers to remove and study secondary tumours rapidly after death, maintaining the integrity of key molecules within tumours (such as DNA, RNA and proteins).

As well as taking blood samples and biopsies from all the secondary tumours, whole lymph nodes were also removed, with all tissue being rapidly frozen at -80°C. Researchers led by Professor Andrea Sottoriva at The ICR then studied the DNA from these secondary breast cancer cells, to try to gain a better understanding of how these cancer cells had changed over time.

Researchers found evidence of tumours being established by monoclonal seeding, meaning that tumours originated from a single cell from the primary tumour in the breast, leading them to believe that if this is the dominant way for breast cancer to spread, it could mean that tracking secondary breast cancer is more achievable than previously thought.

The team then went on to develop a new kind of blood test for cancer DNA to track how secondary breast cancer has spread. Over time cells that actively grow and multiply accumulate molecular marks on their DNA, which appear in distinct patterns. The scientists found that by analysing cancer DNA fragments in the blood, it was possible to establish the ‘molecular clock’ of cancer cells that the DNA had come from, which identifies how many times they had multiplied.

By analysing these traceable ‘molecular clocks’ and comparing the blood test with the tumours collected during autopsy, the test built a family tree of the cancer cells, and the level of cancer cell DNA in the blood then provided information on which secondary tumours were the most active.

The researchers did however find defects in the way cancer cells were adding molecular marks to their DNA in one of the patients, and so further research is needed to understand how common this challenge might be before a test for clinical use could be developed.

In addition, looking at data from an earlier study of eleven primary breast cancer patients whose disease had spread to the lymph nodes and for whom tissue and blood samples were available, the team confirmed that the ‘molecular clock’ blood test mirrored the genetic make-up of the tumour samples.

The authors propose that the blood test could be used to track how secondary tumours evolve over time, and to monitor their response to a range of treatments, including chemotherapy, immunotherapy or targeted therapies, as well as radiotherapy. With further development, it is hoped that the ‘molecular clock’ blood test could also be used in the early detection of recurrence or spread following treatment, and may also be relevant for other forms of cancer.

Peter Barry, Surgical Oncology lead for the Breast Cancer Now LEGACY Study, and Consultant Breast Surgeon at The Royal Marsden, London, said:

“This was a wonderful result of innovative collaboration and points the way to potentially sample one active metastatic site in a patient and then using the molecular clock signature with regular blood tests, test and monitor new treatments in real-time. Rather than requiring more complex sequencing, this is more economical and can be carried out by most labs using relatively simple sequencing methods.

“Clearly we need to expand this testing to a larger cohort of patients to see how widely applicable it might just be – in breast cancer patients as well as potentially in patients with other cancer types. I am wholeheartedly grateful to the patients and their families who so generously made this study possible.”