Related Experiment Video
Updated: Jul 15, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with
Lorenzo Gerratana1, Andrew A Davis2, Marko Velimirovic3,4
1Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
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.
Insights
Specific ESR1 and PIK3CA mutations in metastatic breast cancer (MBC) impact metastasis patterns and prognosis. Circulating tumor DNA (ctDNA) next-generation sequencing (NGS) reveals these associations, guiding personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Hormone-receptor positive, HER2-negative metastatic breast cancer (MBC) is often characterized by ESR1 and PIK3CA mutations.
- Current clinical practice simplifies these mutations into dichotomous categories (mutated or wild type).
- This simplification overlooks the nuanced biological and clinical implications of specific mutation variants.
Purpose of the Study:
- To investigate the differential associations of specific ESR1 and PIK3CA codon variants with clinical characteristics, oncogenic pathway alterations, and metastatic patterns in luminal-like MBC.
- To explore the prognostic impact of these variants in conjunction with pathway alterations.
- To highlight the utility of circulating tumor DNA (ctDNA) next-generation sequencing (NGS) for understanding tumor evolution and guiding treatment decisions.
Main Methods:
- Analysis of a multi-institutional cohort of 703 patients with luminal-like MBC.
- Characterization of circulating tumor DNA (ctDNA) using next-generation sequencing (NGS).
- Pathway classification based on established oncogenic pathways (e.g., ER, PI3K, MYC).
- Annotation of single nucleotide variations (SNVs) for oncogenicity using OncoKB, including only pathogenic variants.
- Exploration of associations between clinical characteristics, pathway classifications, and ESR1/PIK3CA codon variants.
Main Results:
- Differential associations were observed for ESR1 and PIK3CA codon variants regarding co-occurring pathway alterations, metastatic dissemination patterns, and prognosis.
- ESR1 537 variants correlated with ER/RAF pathway SNVs, MYC pathway CNVs, and bone metastases.
- ESR1 538 variants were linked to cell cycle pathway SNVs and liver metastases.
- PIK3CA 1047 and 542 variants were associated with PI3K pathway CNVs and bone metastases.
Conclusions:
- Specific ESR1 and PIK3CA codon variants, alongside alterations in oncogenic pathways, differentially influence the biology and clinical phenotype of luminal-like MBC.
- These findings underscore the importance of detailed ctDNA analysis via NGS for characterizing tumor evolution.
- The results support the optimization of clinical decision-making, particularly with the development of novel targeted therapies like selective estrogen receptor degraders (SERDS) and PI3K inhibitors.
