Liquid biopsy furthers cancer research

Submitted on Mon, 02/26/2018 - 15:11
Matti Annala/ Kuva: Jonne Renvall
“New and more targeted cancer medicines are constantly becoming available. Since they target genetic defects unique to cancer cells, they have less negative side effects,” says Matti Annala.

Prostate cancer treatment can be tailored more precisely by using liquid biopsies

Text: Jaakko Kinnunen
Photo: Jonne Renvall

A new study lays the groundwork for more personalised treatment of men with metastatic prostate cancer. In the study, liquid biopsies were used to compare the effects of two prostate cancer drugs.

Researchers from the University of Tampere collaborated closely with the Canadian Vancouver Prostate Centre in the study. Patients were treated in Vancouver and its surrounding areas, and data collected from blood samples was analysed in Tampere.

According to Doctoral Researcher Matti Annala, the term “liquid biopsy” refers to taking a blood sample from patients in order to isolate circulating extracellular DNA fragments.

“Even healthy people carry billions of these DNA fragments in their bloodstream. They are released into the bloodstream when cells die. If a person has metastatic cancer, a significant share of the circulating DNA can come from cancer cells, which allows us to map the mutations they carry,” Annala says.

New information on patients’ response to medication

The study compared the efficacy of abiraterone and enzalutamide, two potent hormonal therapies that are widely used in the treatment of metastatic prostate cancer.

“The practice of using these drugs varies between hospitals. One of our aims was to establish which medication should be administered to the patients first,” Annala says.

The study included 202 patients randomly divided into two groups who received different drugs. Prior to starting the treatment, 10-millilitre blood samples were collected from the patients, and circulating DNA was isolated for analysis.

“Our aim was to use liquid biopsies to enable more effective use of these drugs. Our results suggest that the drugs have a similar patient response, but that mutations carried by cancer cells can be used to predict the efficacy of both drugs. The similar efficacy of the two drugs suggests that hospitals can choose between the drugs based on price and other factors,” Annala explains.

Annala is currently conducting a new study on how cancer becomes resistant to abiraterone and enzalutamide, and how patients respond when they are switched over to the other drug.

“We are now using liquid biopsies to experiment with personalised combination therapies for patients in whom abiraterone and enzalutamide do not function well as monotherapies,” Annala says.

Testosterone plays a key role in the treatment of prostate cancer

If a man is diagnosed with aggressive prostate cancer, the first treatment is usually surgical removal of the prostate. The operation is called radical prostatectomy.

After the operation, the patient is monitored for metastatic progression. If metastases are found, the patient starts receiving hormonal therapy. Hormonal treatments in prostate cancer can be divided into two main categories. One class of drug inhibits testosterone production in the patient's body. Abiraterone belongs to this class. The other class of drug prevents testosterone from binding to a protein called the androgen receptor. Enzalutamide is based on this mechanism.

“Prostate cells need testosterone to survive. Already in the 1940s, it was shown that if a man's testosterone level is reduced to zero, prostate cancer cells begin to die,” Annala says.

Hormonal treatments are highly effective against metastatic prostate cancer, but they are not curative. After a few years, cancer cells become resistant to the hormonal treatment and start forming new metastases.

If prostate cancer forms metastases, they usually first appear in bones. In the past, a tissue sample of metastatic disease was needed to diagnose DNA mutations in cancer cells, but they are difficult to acquire and uncomfortable for the patient.  With liquid biopsies, mutations in cancer cells can be detected from a standard blood sample.

Finding personalised medication is important

The study also revealed a great deal of new information on the effect of various genetic defects on drug efficacy.

Annala mentions one example: In about 20 percent of patients with metastatic prostate cancer, the BRCA2, ATM or PALB2 genes are broken. These genes play an important role in DNA repair. The study showed that abiraterone and enzalutamide are less effective against cancers in which these genes do not function properly.

These patients are now undergoing experimental treatment with PARP inhibitors because that type of drug is particularly effective against cancers that carry this genetic defect.

“Preliminary studies show that these patients can live over six months longer when treated with PARP inhibitors. However, PARP inhibitors are not effective against cancers that do not carry this genetic mutation,” Annala points out.

Cancer drugs are potent and come with side effects, which is why they should only be administered to patients that benefit from them. If PARP inhibitors were administered to all patients with metastatic prostate cancer, only one in five patients would benefit from the treatment. The rest of the patients would merely suffer the side effects.

Ineffective medication is also costly, and useful treatments may be delayed if many ineffective therapies need to be tried first. Liquid biopsies allow drugs to be targeted to the correct patient populations.

“New and more targeted cancer medicines are constantly becoming available. Since they target genetic defects unique to cancer cells, they have less negative side effects,” Annala says.