Researchers identify new indicator for response to therapy in paediatric cancers

A study by researchers at the University of Birmingham has identified a new biomarker for response to a specific cancer therapy, treating children with Ewing Sarcoma and other tumour types.

The study published in Clinical Cancer Research, which is a Phase I/II treatment arm within the eSMART Trial, carried out at the Cancer Research UK Clinical Trials Unit (CRCTU) with Gustave Roussy as international sponsor, recruited 70 patients, and of those 66 were treated across four countries (the UK, France, the Netherlands and Spain). All these patients had solid tumours, 36 had Ewing Sarcoma and 34 had various other tumour types, mainly types of sarcoma and central nervous system tumours.

Patients’ tumours included Ewing Sarcoma and other cancers such as:

• osteosarcoma, a type of bone cancer,
• neuroblastoma, a tumour arising from the adrenal gland or sympathetic chain,
• rhabdomyosarcoma, a tumour arising from the soft tissue mimicking skeletal muscle,
• nephroblastoma, a tumour of the kidney,
• medulloblastoma, a tumour of the brain, and
• choroid plexus carcinoma, a much rarer brain tumour affecting 4 patients per year in the UK.

The chances of a cure for these types of tumours significantly decreases to less than 30% if the cancer has spread or recurs - when patients were enrolled in eSMART they had relapsed several times and although the trial may induce some response, a cure was not expected.

Researchers wanted to understand if the combination of a low dose or irinotecan (a chemotherapy drug commonly used in paediatric cancers) and a PARP inhibitor (a DNA repair inhibitor used in treatment of various cancer in adults) would be tolerated and effective in treating paediatric cancers. The researchers also wanted to investigate if there was a particular sensitivity in tumours with alterations in genes, which may cause faulty DNA repair in Ewing sarcoma, a cancer shown to have similar faulty DNA repair in the lab as adult cancers which respond to PARP inhibitors.

The study found that 12 patients benefitted from this therapy across the different tumour types, either responding with partial or complete tumour shrinkage or showing stable disease for more than six months. Importantly, gene alterations which predicted faulty DNA repair or Ewing sarcoma itself did not predict benefit from therapy.

Crucially, however, retrospective analysis of the patients’ tumours who benefitted and the remaining 49 patients’ tumours without benefit revealed that a certain change of the tumour genome called aneuploidy was distributed differently between all patients, with those patients whose cancers had a high aneuploidy score significantly more likely to benefit from therapy.

Dr Louise Hopkins, Trial Management Team Leader for the Children’s Cancer Trial Team at the Cancer Research UK Clinical Trials Unit, said: This study is a major breakthrough in paediatric oncology because it provides a potential roadmap for personalising treatment in some of the most difficult-to-treat childhood cancers.

“The impact of this study lies in its potential to change how clinicians approach treatment for children with high-risk, relapsed cancers; clinicians may now be able to determine in advance whether advanced therapies—specifically PARP inhibitors—will be effective for a specific child.”

Dr Susanne Gatz, Associate Clinical Professor in Paediatric Oncology in the Department of Cancer and Genomic sciences at the University of Birmingham, said: “These are really exciting data, and we are grateful to all the patients and families who enrolled into this study.

“Having identified high aneuploidy score as a potential biomarker for benefit to DNA repair inhibitor trials in paediatric cancers could identify such a specific cancer group. More research is needed to see if this finding can be translated to other DNA repair inhibitor trials, and to better understand the link between high aneuploidy score and treatment benefit.”

This is the first time that aneuploidy score has been associated with response to therapy in a paediatric cancer trial. The high score did not correlate with specific tumour types, but with benefit from this specific therapy, which suggests that a high aneuploidy score could potentially emerge as a biomarker for benefit for other DNA repair inhibitor trials in paediatric cancer. The team hope that this high aneuploidy score could be a wider applicable biomarker, not only for paediatric cancer but also for trials for adult cancers.