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Updated: Aug 12, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer:
Matteo Allegretti1, Vittoria Barberi2, Cristiana Ercolani3
1Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, Rome, Italy.
Abstract:
Under therapeutic pressure aggressive tumors evolve rapidly. Herein, a luminal B/HER2-low breast cancer was tracked for >3 years during a total of 6 largely unsuccessful therapy lines, from adjuvant to advanced settings. Targeted next generation sequencing (NGS) of the primary lesion, two metastases and 14 blood drawings suggested a striking, unprecedented coexistence of three evolution modes: punctuated, branched and convergent. Punctuated evolution of the trunk was supported by en bloc inheritance of a large set (19 distinct genes) of copy number alterations. Branched evolution was supported by the distribution of site-specific SNVs. Convergent evolution was characterized by a unique asynchronous expansion of three actionable (OncoKB level 3A) mutations at two consecutive ESR1 codons. Low or undetectable in all the sampled tumor tissues, ESR1 mutations expanded rapidly in blood during HER2/hormone double-blockade, and predicted life-threatening local progression at lung and liver metastatic foci. Dramatic clinical response to Fulvestrant (assigned off-label exclusively based on liquid biopsy) was associated with clearance of all 3 subclones and was in stark contrast to the poor therapeutic efficacy reported in large liquid biopsy-informed interventional trials. Altogether, deconvolution of the tumor phylogenetic tree, as shown herein, may help to customize treatment in breast cancers that rapidly develop refractoriness to multiple drugs.
Insights
Aggressive breast cancer exhibits rapid evolution under treatment, displaying punctuated, branched, and convergent tumor evolution. Liquid biopsies revealed actionable ESR1 mutations predicting progression and guiding effective Fulvestrant therapy.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Aggressive breast cancers, particularly luminal B/HER2-low subtypes, rapidly develop therapeutic resistance.
- Understanding tumor evolution dynamics is crucial for optimizing treatment strategies in advanced breast cancer.
Observation:
- A >3-year longitudinal study tracked a luminal B/HER2-low breast cancer through six therapy lines.
- Targeted next-generation sequencing (NGS) of primary tumor, metastases, and serial liquid biopsies revealed complex evolutionary patterns.
- Three distinct evolutionary modes—punctuated, branched, and convergent—coexisted within the tumor over time.
Findings:
- Punctuated evolution was evidenced by bulk inheritance of copy number alterations, while branched evolution was supported by site-specific single nucleotide variants (SNVs).
- Convergent evolution manifested as asynchronous expansion of actionable ESR1 mutations at adjacent codons, detected primarily in liquid biopsies.
- ESR1 mutations, initially undetectable in tissue, rapidly expanded in blood during HER2/hormone blockade, predicting metastatic progression and clinical resistance.
Implications:
- Liquid biopsy-guided therapy demonstrated significant clinical response to Fulvestrant, achieving subclone clearance, contrasting with outcomes in large interventional trials.
- Deconvoluting tumor phylogenetic trees through serial liquid biopsies can enable personalized treatment selection for refractory breast cancers.
- This approach may improve therapeutic customization for patients with rapidly evolving, multi-drug resistant breast cancer.
