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Two Studies Analyze Genomic Signatures and Blood-Based Biomarkers in Pediatric and Young Adult Cancer

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Two Studies Shed Light on Chemotherapy Monitoring in Young Cancer Patients

Two separate studies published in leading scientific journals have examined the use of genomic analysis and blood tests to monitor the effects of chemotherapy and predict treatment outcomes in children and young adults with cancer. The research, conducted by international teams, focuses on identifying DNA changes caused by treatment and biomarkers that may inform future clinical decision-making.

Study 1: Chemotherapy-Induced Genomic Signatures in Childhood Tumors

Methodology and Participants

Researchers from The Hospital for Sick Children (SickKids), Memorial Sloan Kettering Cancer Center, and the Children's Cancer Institute at Sydney Children's Hospital analyzed over 600 tumors from 544 pediatric patients in Canada, Australia, and the United States. The team used whole genome sequencing, medical records, and computational methods to identify distinct genomic signatures—specific patterns of DNA changes—associated with different types of chemotherapy.

Key Findings

  • Within 18 months of treatment, 48% of tumors showed a detectable genomic signature linked to platinum-based chemotherapy, a drug class administered to nearly half of all treated pediatric cancer patients.
  • Some of these signatures appeared as early as 91 days after the start of treatment.

Significance and Potential Applications

The study, published in Nature, is described by the authors as the largest exploration of therapy-related genomic signatures in childhood cancer using whole genome sequencing.

The researchers propose that genomic signatures could act as biomarkers for an early warning system, potentially allowing clinicians to detect treatment resistance or tumor evolution before a cancer returns or spreads.

The findings suggest the possibility of earlier intervention, such as adjusting therapy based on genomic changes observed as early as three months post-treatment. Lead author Dr. Adam Shlien, Senior Scientist in Genetics & Genome Biology at SickKids, stated that the number of mutations linked to chemotherapy was unexpected. First author Dr. Mehdi Layeghifard, Senior Research Associate in the Shlien Lab, noted that these signatures could potentially help identify patients where chemotherapy could be de-escalated if concerning signatures appear.

Background

Childhood cancer survival rates have exceeded 85% over the past 50 years, according to the study's authors. However, chemotherapy is known to cause long-term side effects, including heart damage and secondary cancers. The research was supported by the Garron Family Cancer Centre, SickKids Foundation, Canadian Institutes of Health Research (CIHR), National Institutes of Health, and the Australian Federal Government Department of Health.

Study 2: Blood Test Analysis to Predict Chemotherapy Efficacy in Germ Cell Tumors

Methodology and Participants

Researchers from the Princess Máxima Center in the Netherlands, in collaboration with experts from Italy and Slovakia, investigated whether fragments of tumor DNA in the blood can predict the effectiveness of chemotherapy for young adults with germ cell tumors where standard treatment is insufficient. Blood samples were analyzed from 69 patients receiving high-dose chemotherapy and 26 patients receiving standard chemotherapy in Italy and Slovakia.

The researchers used shallow whole-genome sequencing to assess circulating tumor DNA (cfDNA) for tumor fraction (TF) and copy number alterations (CNAs). These findings were compared with progression-free survival and overall survival, as well as with an existing biomarker, miR-371a-3p.

Key Findings

  • Tumor fraction was detected in 75% of patients treated with high-dose chemotherapy. A high tumor fraction correlated with poorer survival in both high-dose and standard-dose chemotherapy groups.
  • The biomarker miR-371a-3p was effective in detecting the presence of disease but did not predict survival.
  • Specific genetic alterations, including 3p gain, 9q and 11q gains, and 6q loss, were more prevalent in high-dose chemotherapy patients with a poor prognosis.
  • Histological subtypes with abnormalities consistent with extra-embryonic histology (yolk sac tumor and choriocarcinoma) were associated with worse survival outcomes.
  • High-dose chemotherapy appeared more effective than standard chemotherapy in patients exhibiting a high tumor fraction.

Implications and Next Steps

The authors state that analysis of cfDNA provides prognostic information for germ cell tumors that do not respond to or recur after standard chemotherapy.

These minimally invasive biomarkers may enhance risk stratification and assist in treatment decisions, particularly concerning the initiation of intensive chemotherapy in relapsed cases.

The insights could also aid in identifying new targets for the development of treatments with fewer side effects. Further research is required before clinical implementation. The team plans to validate these findings in a larger, international cohort that includes adolescents and children with germ cell tumors.

Background on Germ Cell Tumors

Germ cells are precursors to sperm and eggs. Cancer can develop from these cells, primarily affecting boys and young men in the testis and other body sites. According to the study, approximately 30 children and 850 young men are diagnosed with germ cell tumors annually in the Netherlands. For one in ten young adults, standard chemotherapy is ineffective, and half of this group dies despite high-dose chemotherapy.

This research was supported by Stichting Kinderen Kankervrij (KiKa) and the Italian Ministry of Health and was published in the Journal of Clinical Oncology.