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New research has identified a way to predict resistance to a cancer drug commonly used to treat advanced prostate cancer. Using samples from more than 200 men, researchers found a significant association between chromosomal instability in circulating tumour cells (CTCs) – those shed from the primary tumour into the bloodstream – and worse outcomes from treatment with cabazitaxel.
Chromosomal instability, defined as the structural or numerical alteration of chromosomes or chromosomal segments due to abnormal cell divisions, can already be assessed using existing techniques. However, these are impractical for routine clinical use.
In this study, the researchers show that assessing chromosomal instability in CTCs is feasible and can predict clinical outcomes such as survival and tumour response. This simple marker could help doctors identify patients unlikely to respond to cabazitaxel, sparing them from unnecessary toxicity and guiding them towards more effective options.
The study was led by scientists at The Institute of Cancer Research, London, and funded by Sanofi. The findings were published in the journal JCI Insight.
Genomic information is key to treatment 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 already have gone through hormone-targeting therapies – drugs such as abiraterone or enzalutamide that block the androgen receptor pathway – as well as chemotherapy. When those options fail, oncologists face a difficult question: what next?
A common choice is cabazitaxel, a chemotherapy drug that has been proven to extend survival more than switching to another hormone-targeting agent. A landmark study called the CARD trial, which recruited participants from more than 60 sites across 13 European countries, confirmed that cabazitaxel generally outperforms a second androgen receptor pathway inhibitor (ARPI) in this setting. This established it as the standard of care for patients progressing on docetaxel and ARPIs.
But “generally” is not the same as “always”. Some men endure the harsh side effects of chemotherapy – which can include fatigue, infections and neuropathy – without gaining extra time. Until now, there has been no reliable way to predict who will benefit and who will not.
The study behind the discovery
The research team behind the current study analysed blood samples from the participants of the CARD trial, all of whom had mCRPC, had already received docetaxel and had then progressed within 12 months of starting treatment with an ARPI.
CTCs are rare in whole blood, so the researchers used an innovative technique to isolate these cells without traditional enrichment methods such as immunomagnetic capture. They treated four blood slides to remove red blood cells, stained them with fluorescent antibodies and used semi-automated analyses to count the CTCs among white blood cells – somewhat akin to finding a needle in a haystack. They then used a proprietary algorithm that uses cell morphology alone to categorise cells as chromosomally unstable or ‘normal’.
The researchers isolated CTCs at three points: before treatment began, after two cycles of therapy and at the end of treatment. They then assessed chromosomal instability in these cells, noting how disordered the cancer’s genetic material had become.
The scientists’ goal was twofold. Firstly, they wanted to see whether chromosomal instability in CTCs predicts overall survival and progression-free survival. Secondly, they were keen to determine whether it could be used to identify patients who do not benefit more from cabazitaxel than from an ARPI switch.
What the results showed
The findings were striking. Men with high chromosomal instability in their CTCs had significantly worse outcomes. Median overall survival dropped from about 15 months in the low-instability group to just under nine months in the high-instability group.
However, the most clinically relevant insight was predictive: when chromosomal instability was high, cabazitaxel did not outperform switching to another hormone-targeting drug. In other words, for these patients, chemotherapy offered no advantage – only side effects. This suggests that chromosomal instability in CTCs could serve as a biomarker to guide treatment decisions, helping doctors avoid ineffective chemotherapy and consider alternative strategies for certain patients.
Why chromosomal instability matters
Chromosomal instability is not a new concept in cancer biology. It has long been associated with aggressive disease and poor outcomes. Tumours with chaotic genomes evolve rapidly, developing resistance to therapies that once worked. What is new here is the potential translation of that concept into a practical, clinically usable test.
By measuring chromosomal instability in CTCs, which can be collected through a simple blood draw, the test avoids invasive biopsies and provides real-time insight into tumour biology. The researchers collected samples at baseline and early during treatment, aligning with real-world decision points. If validated in larger studies, this approach could become part of routine care, allowing oncologists to personalise therapy rather than being forced to adopt a trial-and-error process.
For patients, the implications are profound. Chemotherapy is not just another pill; it’s a treatment that can sap strength, cause infections and diminish quality of life. If a blood test can show that chemotherapy is unlikely to help, doctors can spare patients that ordeal and pivot to other options sooner.
An additional benefit is that this approach allows oncologists to identify patients with an unmet clinical need. This subpopulation of patients with aggressive cancer can then be targeted for inclusion in clinical trials to test alternative therapeutic strategies.
A step towards precision oncology
First author Ossian Longoria, Clinical Research Fellow at the ICR, said:
“This study fits into a broader trend in cancer care: moving from one-size-fits-all treatment to precision oncology. Clinicians rely on clinical trial outcomes from large studies such as CARD to guide decision-making for the majority of patients. However, being able to predict individual response to treatment is a holy grail in oncology. Now, molecular markers are increasingly entering the picture, offering a deeper look at what drives each patient’s cancer.
“Chromosomal instability in circulating tumour cells is part of that evolution. This assay doesn’t just count tumour cells; it provides insight on tumour biology with direct clinical consequence. This insight turns out to be a powerful signal – not only of prognosis but of likely resistance to a key drug. For men with mCRPC, that knowledge could mean fewer wasted months on ineffective therapy and more time on treatments that can work.”
Senior author Professor Johann de Bono, Regius Professor of Cancer Research at the ICR and Consultant Medical Oncologist at The Royal Marsden Hospital, said:
“Our findings build on decades of research at the ICR and elsewhere, and they represent a big breakthrough in the liquid biopsy and circulating tumour cell fields. This is the first prospective confirmation that chromosomal instability predicts cabazitaxel resistance in patients.
“Further work is needed to validate the results, but for patients and families, our discovery offers hope that we will soon be able to make treatment decisions that are smarter, kinder and more effective.”
Image credit: Gerd Altmann from Pixabay
