Patient: 73-year-old female with hormone receptor–positive, HER2-negative metastatic invasive ductal carcinoma of the breast (luminal B–like), with liver, bone, lung metastases and residual breast mass.
Clinical Testing:
Alterations:
- ESR1 (p.D538G) – pathogenic (plasma cfDNA, VAF 6.41%)
- PIK3CA (p.H1047L) – pathogenic (plasma cfDNA, VAF 11.25%)
- DPYD, TYMS, UGT1A1 – wild type (supports standard fluoropyrimidine dosing)
Genes / Pathways Affected:
- PI3K/AKT/mTOR pathway
- MAPK signaling
- Estrogen receptor (ER) signaling
- Endocrine resistance pathways
Treatment Options:
- Selective estrogen receptor degrader (SERD): Elacestrant for ESR1-mutated endocrine-resistant disease
- PI3K/AKT pathway inhibitors: Alpelisib, Inavolisib, Capivasertib in combination with Fulvestrant
- Targeted endocrine combinations guided by liquid biopsy findings
- Clinical-trial–based targeted therapies addressing dual ESR1–PIK3CA resistance
Indication:
Hormone receptor–positive, HER2-negative metastatic breast carcinoma with progression on CDK4/6 inhibitor plus endocrine therapy and chemotherapy intolerance.
Research Findings:
Comprehensive liquid biopsy profiling identified dual oncogenic drivers (ESR1 D538G and PIK3CA H1047L) explaining resistance to prior SERD and CDK4/6 inhibitor therapy. ESR1 mutation drives ligand-independent estrogen signaling, while PIK3CA activation sustains tumor proliferation via PI3K/AKT and MAPK pathways. Low HRD, MSI, and TMB indicate a genomically stable, low-immunogenic tumor, supporting a targeted endocrine and PI3K-pathway–focused treatment strategy over immunotherapy or PARP inhibition. Serial cfDNA monitoring enables dynamic assessment of resistance evolution and treatment optimization.