Genomic profiling and treatment of HER2+, ER+, PgR+ “triple positive” breast cancer: A case report and literature review

BackgroundBreast cancer expressing all three diagnostic markers (estrogen receptor, ER+; progesterone receptor, PgR+; human epidermal growth factor receptor 2, HER2+) is insufficiently characterized even though it is a sizable patient population. An invasive ductal carcinoma (IDC) triple-positive breast cancer (TPBC) case is genomically profiled and the literature reviewed to illustrate the molecular heterogeneity and interconnectivity of the disease biology.Presentation of caseA premenopausal, 48-year-old female with no family history of breast cancer presented with IDC (1.5 cm primary tumor, 5 nodal metastases of 23 axillary nodes examined, pT1cN2a AJCC/UICC stage). Immunohistochemical analysis showed strong staining of all three diagnostic markers (ER 4+, PgR 4+, HER2 3+). HER2 amplification was confirmed by FISH (HER2/cen17 ratio=5.7). Ki-67 nuclear staining was detected in 30% of tumor cells.Genomic findingsERRB2 was amplified (9 copies) and activated by mutation (S310F). The PI3K pathway was activated through a catalytic subunit activating mutation (PIK3CA-E545K), a regulatory subunit amplification (PIK3R2, 8 copies) and an AKT1 activating mutation (E17K). Additional alterations were identified (IGF1R, SMO, DOT1L, ERG, CEBPA). BRCA1/2 germline abnormalities were not identified. Surgery followed by adjuvant therapy APHINITY trial (Taxotere, carboplatin, Herceptin, 50% chance of pertuzumab) and anti-estrogen therapy. These therapies either directly (ER, HER2) or indirectly (PI3K) target the patient-specific tumor biology. The patient is free of disease 40 months post-surgery.ConclusionGenomic profiling detected multiple alterations impinging on the PI3K signaling pathway and gene regulation suggesting important contributions of these processes to this TPBC, despite two dominant pathway engagements (ER, HER2).