Neuroendocrine carcinoid under microscope

Biomarker Uncovered by Roswell Park Team Identifies NET Patients Likely to Have Blood Side Effects from PRRT

Researchers propose screening and monitoring to guide treatment for patients with neuroendocrine tumors

  • PRRT is a relatively new treatment shown to benefit patients with NETs
  • Hard to predict which patients receiving PRRT will experience blood toxicities
  • Mutations in DNA-damage response genes can be tracked to guide patient care

BUFFALO, N.Y. — New work from a team at Roswell Park Comprehensive Cancer Center will help guide the care of patients with neuroendocrine tumors, or NETs. In a poster presentation at the American Society of Clinical Oncology (ASCO) virtual Annual Meeting 2021, Abhay Singh, MD, MPH, and colleagues outline their discovery of a potential biomarker to predict which patients are likely to experience blood toxicity side effects from a new targeted radiation treatment, peptide receptor radionuclide therapy (PRRT).

While PRRT has been shown to be beneficial for patients with neuroendocrine tumors, it sometimes causes hematologic side effects that can be permanent. The study, Mutant PPM1D and TP53 populate the hematopoietic compartment after peptide receptor radionuclide therapy (PRRT) exposure (abstract 10605), demonstrates that clonal expansion of cells harboring certain genetic mutations contributes to blood toxicities following this treatment.

Abhay Singh, MBBS
Dr. Abhay Singh

“With the application of highly sensitive and state-of-the-art sequencing technologies, our group has identified — for the first time — a high incidence of premalignant hematopoiesis or clonal hematopoiesis in neuroendocrine tumor patients,” reports Dr. Singh, a Hematology-Oncology Fellow at Roswell Park.

The researchers analyzed patients’ blood samples before and after PRRT, looking for clonal mutations that may help characterize the selective pressures this therapy puts on stem cells. They used a targeted 100-gene molecular panel, and set a variant allele frequency cutoff of 1 percent to classify clonal hematopoiesis.

“Fifty-four percent of patients were noted to have clonal hematopoiesis in our study,” he continues. “We have reported the presence of putative therapy-related myeloid neoplasm driver mutations such as those involving DNA-damage response genes, for example, TP53 and PPM1D, prior to peptide receptor radionuclide therapy exposure.”

Using genomic sequencing to track these mutations, the team uncovered the presence of expanding allelic fractions of DDR clones following PRRT.

Eunice Wang, MD
Dr. Eunice Wang

“These large shifts in allelic frequencies are highly significant, as they were associated with emergence and persistence of clinically significant cytopenias or PRRT-associated hematological toxicity,” notes study co-author Eunice Wang, MD, Chief of Leukemia at Roswell Park.

“We believe that the detection of clonal hematopoiesis mutations in DDR genes offers the first potential predictive biomarker to assess risk of subsequent hematological toxicity to peptide receptor radionuclide therapy in patients receiving this novel therapy,” says Dr. Wang, who is also Professor of Oncology and Medical Director of Infusion Services. “Screening and longitudinal monitoring of clonal hematopoiesis may serve as a key risk-mitigation strategy for patients with neuroendocrine tumors receiving peptide receptor radionuclide therapy.”

Another important consideration before prescribing this novel therapy is that PRRT’s selective pressures have varying effects on different mutations. The researchers note that a larger study with longer patient follow-up is needed to better understand the biology of therapy related-myeloid neoplasms and the link between therapy related-clonal hematopoiesis and cytopenias.


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