Liquid Biopsy Predicts Prostate Cancer Docetaxel Resistance

Liam Davenport

November 12, 2021

Performing regular liquid biopsies to detect circulating tumour cells (CTCs) could help detect, or even predict, resistance to docetaxel in patients with prostate cancer and allow them to switch them to alternative therapies, suggests a UK study.

Researchers took blood samples before, during and after chemotherapy in 56 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC).

Analysis showed that higher numbers of CTCs pre-treatment was associated with disease progression and poor overall survival in both patient groups, according to Caitlin Davies, a PhD research student at Barts Cancer Institute, Queen Mary University of London, UK, and colleagues.

There were also associations between individual types of CTCs and disease progression and survival, and between increases in CTCs towards the end of treatment and disease progression.

The research, presented at the 2021 NRCI Festival on November 10, also revealed that high expression of the KLK2 gene, which encodes for a prostate-associated protein, was seen in patients who did not respond to docetaxel.

Ms Davies said in a press release that the patterns of CTC dynamics they identified in the study could be applied “to future patients, with the goal to predict whether they would respond to therapy, and pre-emptively decide on the best course of action that will have maximal benefit”.

She continued: “By monitoring the appearance of potentially drug-resistant CTCs, we can change treatment tactics early on and in a patient-personalised and timely manner.” This “may significantly improve patients’ chances of long-term survival”.

In addition, liquid biopsies are “minimally invasive, painless and easily repeatable, so patients can avoid undergoing painful tissue biopsies”, she said.

“It takes a matter of minutes for the patient, and we can get results within two to three days, whereas a tissue biopsy can take up to 10 days.” Liquid biopsies are also very cost effective compared with tissue biopsies or imaging.

Ms Davies told Medscape News UK that, currently, CTC liquid biopsies are “confined to preclinical studies”, although a “new liquid biopsy test for cell-free DNA is being trialled by the NHS”.

She added that their laboratory “may conduct follow-up studies to conform our significant findings in independent, larger patient cohorts”.

Dr Matthew Hobbs, Director of Research at Prostate Cancer UK, told Medscape News UK that “finding new ways to predict and monitor men’s response to treatment is an important area of research that could improve outcomes for men with advanced prostate cancer”.

“Although this research is still at an early stage, it helps us understand how and when liquid biopsies might be used to personalise treatment for men, and give them the best chance of a good outcome.”

Dr Hobbs added that the charity is “proud to be funding several studies, including a large-scale clinical trial, to explore the potential of different types of liquid biopsy and the difference they could make to men’s lives”.

Hashim Ahmed, chair of the NCRI prostate group and professor of urology at Imperial College London, UK, who was not involved in the research, said in the press release that the current results are “promising” and “have the potential to change clinical practice, if they are confirmed by further research”.

“Assessing the responsiveness of an individual patient’s tumour to docetaxel treatment by means of blood tests will enable clinicians to personalise cancer treatment more easily and effectively, without the patient having to undergo invasive procedures such as tissue biopsies.

“It could also help to avoid patients undergoing unpleasant systemic treatments that are going to be unsuccessful,” he said.

The researchers note that, although docetaxel significantly improves overall survival in mCRPC, and has recently been used as chemo-hormonal therapy in mHSPC, some patients have inherent or acquired resistance.

To examine the utility of measuring CTCs in liquid biopsies in the prediction and/or monitoring of treatment response, they recruited prostate cancer patients undergoing six cycles of docetaxel chemotherapy.

Peripheral blood samples for liquid biopsy were collected less than two months before starting treatment, between the first and second cycles, between the fourth and fifth cycles, and less than four months after the sixth cycle.

They used the Parsortix (Angle plc) blood filtration system to identify CTCs, and then analysed the samples for changes in CTC number, phenotype and mRNA expression.

They included 44 patients with mHPSC and 12 with mCRPC, and 205 peripheral blood samples were available for analysis.

CTCs were detected in 34 patients. Among patients with progressive disease while on treatment, 75% were CTC-positive before starting docetaxel, compared with 44% who had a partial response.

There was a significant inverse correlation on Spearman’s analysis between CTC parameters and both overall and progression-free survival.

Overall survival was significantly correlated with CTC score (p=0.0095) and a high total CTC number (p=0.0311) in mCPRC, and with the number of cytokeratin-positive (CK+) CTCs in the overall cohort (p=0.0013) and in mCRPC (p=0.0024).

In mHSPC patients, the presence of ≥6 CTC pre-treatment was associated with a shorter time to progression than in those with fewer CTCs, with a hazard ratio of 2.1 (p=0.1944), and with a significantly shorter median overall survival, at hazard ratio of 7.452 (p=0.0124).

Moreover, mHSCPC patients who experienced an increase in mesenchymal CTCs between the pre-treatment and pre-fifth cycle blood draws had a shorter time to disease progression, 3 months versus 23 months in patients who did not have such an increase.

Kaplan-Meier analysis revealed that poor overall survival was correlated with both a positive CTC score and the presence of ≥1 CK+ CTC before starting docetaxel across the whole cohort (p=0.0117). This also predicted overall survival (p=0.0018) and progression-free survival (p=0.0240) in mCRPC.

Poor overall survival was predicted best in mHSPC by the presence of ≥6 CTCs (p=0.0194).

Polymerase chain reaction using a custom-designed 32-gene panel of CTC mRNA showed that high expression of KLK2 at each blood collection point was seen in patients with progressive disease and in those with poor overall and progression-free survival.

Moreover, it was significantly more predictive than expression of KLK3, which encodes for prostate-specific antigen.

“These are important findings as they highlight KLK2 as a possible alternative and better biomarker for prostate cancer prognosis,” said Ms Davies.

“Analysis of CTC gene expression and detection of genes associated with resistance to docetaxel may aid the development of a new generation of therapies.”

 

The study was funded by the Medical Research Council.

No relevant financial relationships declared.

NCRI Festival: Abstract 3599. Presented November 10.

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