A new study has identified a way to predict resistance to a type of chemotherapy commonly used to treat advanced prostate cancer.
Using samples from more than 200 men with advanced prostate cancer, researchers found a significant association between chromosomal instability in circulating tumor cells (CTCs) (cells released into the bloodstream from the primary tumor) and worse treatment outcomes with cabazitaxel.
In this study, researchers showed that assessment of chromosomal instability in CTCs is feasible and can predict clinical outcomes such as survival and tumor response.
This simple marker can help doctors identify patients with advanced prostate cancer who are less likely to respond to cabazitaxel, thereby avoiding unnecessary toxicity and guiding patients to more effective options.
Genomic information is key to decision-making
For men living with metastatic castration-resistant prostate cancer (mCRPC), treatment decisions become increasingly complex as the disease progresses.
Most of these patients will have already received hormone-targeted therapy as well as chemotherapy.
If these options fail, oncologists face the difficult question of what to do next.
A common choice is cabazitaxel, a chemotherapy drug that has been shown to prolong survival better than switching to another hormone-targeted drug.
A landmark study called the CARD trial, which recruited participants from more than 60 centers in 13 European countries, confirmed that cabazitaxel generally works better than a second-line androgen receptor pathway inhibitor (ARPI) in this setting. This established it as the standard of care for patients progressing on docetaxel and ARPI.
But some men endure the harsh side effects of chemotherapy, such as fatigue, infections, and neurological damage, without gaining any extra time. Until now, there has been no reliable way to predict who will benefit and who will not.
Analyzing blood samples from patients with advanced prostate cancer
The research team behind the current study analyzed blood samples from participants in the CARD trial who had already received docetaxel and progressed within 12 months of starting treatment with ARPI.
Because CTCs are rare in whole blood, the researchers used an innovative technique to isolate these cells without using traditional enrichment methods such as immunomagnetic capture.
They processed four blood slides to remove red blood cells, stained them with fluorescent antibodies, and used semi-automated analysis to count CTCs in the white blood cells.
They then used a proprietary algorithm that classifies cells as chromosomally unstable or “normal” based solely on cell morphology.
Chromosomal instability is a problem
Advanced prostate cancer patients with high CTC chromosomal instability had significantly worse outcomes. Median overall survival decreased from approximately 15 months in the low instability group to just under 9 months in the high instability group.
However, the most clinically relevant insights were predictive. When chromosomal instability was high, cabazitaxel did not perform better than switching to another hormone-targeted drug. In other words, for these patients, chemotherapy brought no benefit, only side effects.
This suggests that chromosomal instability in CTCs may serve as a biomarker to guide treatment decisions, helping physicians avoid ineffective chemotherapy and consider alternative strategies for specific patients.
Aiming for precision oncology for advanced prostate cancer
“Clinicians rely on clinical trial results from large studies such as CARD to guide decision-making for the vast majority of patients, but predicting an individual’s response to treatment is the holy grail in oncology,” said Osian Longoria, lead author of the study and clinical research fellow at ICR.
“Molecular markers are now increasingly involved, allowing us to look deeper into the causes of each patient’s cancer.”
“Our findings build on decades of research at the ICR and elsewhere and represent a major advance in the field of liquid biopsies and circulating tumor cells,” explained Professor Johan de Bono, Senior Research Fellow at the ICR and Regius Professor in Cancer Research.
“This is the first prospective confirmation that chromosomal instability predicts cabazitaxel resistance in patients with advanced prostate cancer.”
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