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Acquired multiple secondary BRCA2 mutations upon PARPi resistance in a metastatic pancreatic cancer patient harboring

Haitao Tao1, Sisi Liu2, Di Huang1

  • 1The First Medical Center of Chinese PLA General Hospital Beijing, China.

American Journal of Translational Research
|March 21, 2020
PubMed

Insights

Pancreatic cancer patients with BRCA2 mutations initially respond to PARP inhibitors (PARPi). However, tumors can acquire new BRCA2 mutations, leading to resistance and poor overall survival.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Biology

Background:

  • PARP inhibitors (PARPi) show efficacy in advanced cancers with germline BRCA mutations (gBRCAm), including pancreatic cancer.
  • Despite improved progression-free survival, overall survival remains unchanged in gBRCAm pancreatic cancer patients treated with PARPi.
  • Understanding PARPi resistance mechanisms is crucial for improving patient outcomes.

Observation:

  • A patient with advanced pancreatic cancer and a germline BRCA2 mutation (V1804Kfs) plus somatic KRAS, TP53, and PTEN mutations was treated with cisplatin and olaparib.
  • The patient achieved stable disease initially, but experienced rapid progression after 18 weeks of treatment.
  • Genomic profiling of liver metastasis and liquid biopsy revealed acquired BRCA2 mutations, including reversion mutations potentially restoring BRCA2 function.

Findings:

  • Acquired secondary BRCA2 mutations, including reversion mutations, can emerge in tumors during PARPi therapy.
  • These secondary mutations may restore DNA repair integrity, conferring resistance to PARPi.
  • The rapid evolution of drug resistance through secondary mutations contributes to limited overall survival benefits.

Implications:

  • This case highlights the rapid evolution of drug resistance in gBRCAm pancreatic cancer under PARPi treatment.
  • Acquired BRCA2 mutations are a key mechanism of resistance, potentially explaining the lack of overall survival improvement.
  • Further research into overcoming acquired resistance mechanisms is essential for enhancing therapeutic strategies in pancreatic cancer.
Keywords:
PARP inhibitorPancreatic cancergermline BRCA2 mutationreversion mutation

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