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Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a

Maysa Abu-Khalaf1, Chun Wang1, Zhenchao Zhang1

  • 1Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Cancers
|June 24, 2022
PubMed

Insights

Genomic alterations in circulating tumor DNA (ctDNA) can predict resistance to palbociclib in metastatic breast cancer (MBC). New mutations emerge during treatment, impacting prognosis and offering targets for overcoming resistance.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Cyclin-dependent kinase 4/6 inhibitors (e.g., palbociclib) are crucial for treating estrogen receptor-positive metastatic breast cancer (ER+ MBC).
  • Emergence of resistance mechanisms necessitates identification of predictive biomarkers.
  • Genomic profiling of circulating tumor DNA (ctDNA) offers a non-invasive approach to track resistance evolution.

Purpose of the Study:

  • To identify genomic aberrations in ctDNA associated with palbociclib resistance in ER+ MBC patients.
  • To compare genomic alterations between inflammatory breast cancer (IBC) and non-IBC subtypes.
  • To investigate the prognostic significance of acquired mutations during treatment.

Main Methods:

  • Collection of 35 pre- and post-treatment blood samples from 16 ER+ MBC patients (9 with IBC).
  • Isolation of circulating cell-free DNAs (cfDNAs) for targeted sequencing of 91 genes.
  • Comparative analysis of genomic profiles between baseline and follow-up samples, and between IBC and non-IBC cohorts.

Main Results:

  • Specific genes (FBXW7, CDK6) were altered more in IBC, while PIK3CA was more frequent in non-IBC.
  • Follow-up cfDNA samples showed a higher mutation burden than baseline samples.
  • Acquired mutations in RB1, CCNE1, FBXW7, EZH2, ARID1A, and loss of TSC2 mutations were observed post-treatment, with CCNE1 mutations or TSC2 loss correlating with unfavorable prognosis.

Conclusions:

  • Genomic aberrations in ctDNA provide insights into palbociclib resistance mechanisms in MBC.
  • Specific mutations (e.g., CCNE1, TSC2) acquired during treatment are associated with poor outcomes.
  • Further large-scale studies are needed to validate these ctDNA-based biomarkers for guiding therapy.
Keywords:
circulating tumor DNAmetastatic breast cancerpalbociclibsomatic mutationtreatment resistance

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