Genomic Sequencing in Pediatric Cancer: For Every Patient at Every Relapse

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Results of a new study support genomic sequencing at relapse for pediatric patients with persistent cancers, according to researchers.1

The investigators sequenced tumors from patients with a range of cancers and found that more than one-third of tumors carried a high mutation burden.

The researchers also identified mutational signatures that could leave those tumors susceptible to currently available therapies.


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“We think of pediatric cancers as having a lower tumor mutation burden than adult cancers,” said study author Giselle Saulnier Sholler, MD, of Levine Children’s Hospital in Charlotte, North Carolina.

“But this really shows that, in one-third of the relapsed patients, their tumors do accumulate more mutations over time.”

Dr Sholler and colleagues sequenced more than 200 tumors across 46 different cancer types, including neuroblastoma, glioblastoma, osteosarcoma, hepatoblastoma, and malignant peripheral nerve sheath tumor, among others.

Given the amount of genomic data collected, clinical outcomes were not reported, Dr Sholler said, but they will be published in a forthcoming paper. 

The researchers performed tumor-normal whole-exome sequencing (WES) and mRNA sequencing of 250 tumors from 202 patients. The patients were enrolled in consortium clinical trials (ClinicalTrials.gov Identifier: NCT01355679, NCT01802567, and NCT02162732) between May 2011 and June 2018.

There were 121 male and 81 female participants, and their median age at diagnosis was 6 years (range, less than 1 year-20 years).

Key Findings

WES revealed a median somatic tumor mutational burden (TMB) of 1.4 mutations per megabase. The median TMB was highest in neuroblastoma (3.4) and lowest in ependymoma (0.5).

In all, 33.9% of tumors had a pediatric high TMB, defined as at least 2 mutations per megabase.

The researchers said they identified recurrent genomic features that have not been reported in prior studies, including gains involving RECQL4, CARD11, CCND1, MAPK1, and DGCR8 and losses involving CASP3, FAT1, SDHA, ROBO2, FHIT, FES, BLM, CHD2, POLG, and PML

The investigators also found chemotherapy-related mutational signatures in 43.2% of sequenced tumors, primarily associated with platinum chemotherapy, while 8.7% of patients had a germline variant that was pathogenic or likely pathogenic.

Another discovery was that 35.6% of tumors showed evidence of homologous recombination repair deficiency, which suggests they might be susceptible to treatment with a PARP inhibitor.

In addition, a subset of tumors were found to be microsatellite instability-positive, which suggests they might be targeted with immune checkpoint inhibitors.

Taken together, these findings highlight the importance of performing genomic sequencing at diagnosis and after each progression, according to Dr Sholler.  

She cited as an example a 2017 case study2 of a 4-month-old girl with choroid plexus carcinoma who relapsed after tumor resection and chemotherapy. Genomic profiling revealed altered mTOR, PDGFRB, FGF2, and HDAC pathways, which were successfully targeted with a combination of sirolimus, thalidomide, sunitinib, and vorinostat, for a 92% reduction in tumor size.

“Every oncologist should be doing this for every patient,” Dr Sholler said. “At every relapse, patients should have the option, and clinicians should be able to order sequencing to show what is changing over time.”

Disclosures: This research was supported by private organizations, foundations, and federal funding. One study author declared funding from Exelixis and QED Therapeutics. Dr Sholler and the remaining authors declared no potential conflicts of interest. Please see the original reference for a full list of disclosures.

References

  1. Byron SA, Hendricks WPD, Nagulapally, AB, et al. Genomic and transcriptomic analysis of relapsed and refractory childhood solid tumors reveals a diverse molecular landscape and mechanisms of immune evasion. Cancer Res. Published online October 2, 2021. doi:10.1158/0008-5472.CAN-21-1033
  2. Cornelius A, Foley J, Bond J et al. Molecular guided therapy provides sustained clinical response in refractory choroid plexus carcinoma. Front Pharmacol. 2017;8:652. doi:10.3389/fphar.2017.00652



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