Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): comprehensive circulating tumor DNA (ctDNA) analysis

Lorenzo Gerratana, Andrew A. Davis, Marko Velimirovic, Katherine Clifton, Whitney L. Hensing, Ami N. Shah, Charles S. Dai, Carolina Reduzzi, Paolo D’Amico, Firas Wehbe, Arielle Medford, Seth A. Wander, William J. Gradishar, Amir Behdad, Fabio Puglisi, Cynthia X. Ma, Aditya Bardia, Massimo Cristofanilli

Research output: Contribution to journalArticlepeer-review

Abstract

Background: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice. Methods: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored. Results: The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases. Conclusions: The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making.

Original languageEnglish
Article number112
JournalBreast Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Dec 2023

Keywords

  • Circulating biomarker
  • Endocrine therapy
  • Next generation sequencing

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