We aimed to systematically evaluate the characteristics of HER2 expression/amplification in gynecologic carcinosarcomas using standardized staining methods and scoring criteria.
Whole-exome sequencing studies have recently demonstrated mutations or aberrant activation of multiple genes/pathways in CSs including HER2, PI3K/AKT/mTOR, EGFR, MAPK, genes related to histones and chromatin structure, and genes related to cell-cycle regulation.
Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy.
<i>In vivo</i> studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX.<b>Conclusions:</b> SYD985 may represent a novel and highly effective ADC against HER2-expressing CS.
Of 24 patients with actionable mutations, five were given genotype-matched drugs corresponding to actionable mutations: everolimus to PIK3CA mutation in parotid carcinosarcoma (partial response) and tracheal squamous cell carcinoma (stable disease; 21% reduction), sorafenib to PDGFRA mutation in auditory canal adenocarcinoma (partial response), sorafenib to BRAF mutation in microcytic adnexal carcinoma (progressive disease), and afatinib to ERBB2 mutation in esophageal adenocarcinoma (progressive disease).
HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014μM±0.004vs.0.164μM±0.019 p=0.0003).
EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one carcinosarcoma (CS).
It still needs to be clarified whether HER-2/neu overexpression increases the aggressiveness of carcinosarcoma, or whether HER-2/neu has a direct role in its pathogenesis, as described in breast cancers.
Amplification of the ERBB-2 gene as determined by FISH was observed in 3/7 (43%) carcinosarcomas with 2+ or 3+ overexpression, resulting in an overall 3/22 (14%) amplification rate.