Vacutainer_blood_bottles

Image credit: public domain 2014 (Author:Tom Mallinson)

40, 000 new cases of prostate cancer are diagnosed every year and it is the most common cancer in UK men, according to the NHS [1].  One of the major challenges for oncologists is stratifying patients so they receive medication that will be effective at treating their specific cancer. Researchers from the Institute of Cancer Research UK (ICRUK) and The Royal Marsden Hospital, London have demonstrated that tumor DNA present in the blood stream can be used to stratify patients and monitor disease progression and drug resistance.

Cancer is caused by a series of genetic mutations which ultimately leads to the uncontrolled growth of cells and generation of a tumor. Resistance to drugs which stop this cell growth is a common problem in oncology, as cancers that were responding to treatment suddenly start to grow. This can happen through several mechanisms such as cancer cell mutation or repair of drug-induced DNA damage. Regardless of the mechanism, drug resistance can leave patients with limited therapy options and a poor prognosis.  Sequencing tumor DNA can help identify the aberrant genes responsible for tumor growth and resistance, and help clinicians prescribe specific, targeted therapy, thus avoiding unnecessary chemotherapy side effects [3].

A tissue biopsy involves a doctor or surgeon taking a piece of tumor tissue and sending it to a laboratory for processing (such as DNA sequencing). While this is currently the gold standard method for obtaining tumor information, it has several limitations; This procedure is not only distressing for the patient but it also can be inconsistente in identifying mutations, as one tumor piece may have different mutations compared to another tumor piece. Additionally, not all tumors are easily accessible and the increased risk of clinical complications associated with this invasive procedure is a significant consideration.

A new method of sampling tumor DNA, the “liquid biopsy”, may offer a more complete genetic picture of the cancer. Circulating free DNA (cfDNA), are pieces of cell free tumor DNA found in the blood stream. Cancer patients have significantly higher concentrations of cfDNA in their blood and this DNA harbors information about genetic mutations which are specific to certain cancers. When first discovered, these sequences of cfDNA were too small to analyze, however with the emergence of new technologies such as next-generation sequencing, this is now possible and soon may become the norm in routine cancer care. [3].

Prostate cancer study may have the answer

20% to 30% of lethal prostate cancers have alterations in genes which are involved in DNA repair, such as BRCA1,2 and ATM. A phase 2 clinical trial called TOPARP-A demonstrated that olaparib, a drug that targets BRCA, was effective at treating BRCA2 and ATM mutation positive metastatic prostate cancer [2]. Olaparib is part of a drug group called PARP inhibitors (short for Poly (ADP-ribose) polymerase), which block tumor growth, and is normally prescribed for ovarian cancer.

Dr de Bono, one of the lead authors of this work, found that a decline in cfDNA concentrations correlated with patient outcomes, indicating that this method may have significant prognostic value. Concentrations of cfDNA fell by 50% after 8 weeks of olaparib therapy and it was associated with longer overall patient survival [2].

The authors found that cfDNA analysis was comparable to the gold standard tissue biopsy for detecting mutations in genes such as ATM and BRCA2, 1. This technique could therefore help clinicians avoid invasive procedures when investigating tumor DNA and help select specific patients that they know would respond to olaparib treatment [2].

By taking blood samples before and at the time of disease resistance, the investigators identified when patients stopped responding to treatment and switched them alternative drugs. Importantly, mutations caused specifically by olaparib treatment were identified. Information about resistance to olaparib will provide valuable insight and may have future implications for other PARP inhibitor treatment strategies [2].

This study is not the first to explore the use of tumor DNA in the blood, as liquid biopsies have also been compared to the gold standard tumor biopsy for other cancer types. For example, a study published in the journal Nature Medicine found that cfDNA analysis was comparable to tumor biopsy at detecting mutations in the genes BRAF and KRAS in colorectal cancer patients [3].

This study by ICRUK and others, demonstrates that cfDNA analysis is revolutionizing oncology research and treatment, by providing information for diagnosis, prognosis and drug resistance. In the near future, this technique will hopefully provide vital information to clinicians so they can make rapid early treatment decisions and discourage ineffective strategies. A simple, routine blood sample taken in a GP surgery could replace the often uncomfortable and painful tumor biopsy. In addition, this innovative new procedure could help avoid the toxicities that are associated with chemotherapy over-treatment.  The obvious economic benefits are another facet to this breakthrough, as the health care costs related to over-treatment must not be overlooked; particularly in an increasingly overstretched NHS.

 

 

References:

[1] http://www.nhs.uk/Conditions/Cancer-of-the prostate/Pages/Introduction.aspx

[2] Goodall J and Mateo J et al, 2017, Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Discovery. 10.1158/2159-8290.CD-17-0261

http://cancerdiscovery.aacrjournals.org/content/early/2017/06/16/2159-8290.CD-17-0261

[3] Thierry et al, 2014, Clinical Validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nature Medicine.

https://www.ncbi.nlm.nih.gov/pubmed/24658074