The molecular landscape of breast mucoepidermoid carcinoma

Abstract

Mucoepidermoid carcinoma (MEC) of the breast is an extremely rare salivary gland‐type tumor characterized by epidermoid, basaloid, intermediate, and/or mucinous cells arranged in solid and cystic patterns. Despite their triple‐negative phenotype, breast MECs are generally considered low‐risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor‐infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death‐ligand 1 (PD‐L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements in MAML2 and EWSR1 were investigated by fluorescent in situ hybridization. Targeted next‐generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (n = 10, 77%), with the presence of TILs (n = 9/12; 75%) and PD‐L1 combined positive score ranging from 10 to 20 (n = 4/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K/AKT/mTOR and cell cycle regulation pathways, while only one case harbored TP53 mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lack TP53 mutations found in high‐grade forms of triple‐negative breast cancers and MAML2 or EWSR1 rearrangements pathognomonic of salivary MECs. Triple‐negativity and PD‐L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low‐risk neoplasms.

Mucoepidermoid carcinoma—a rare salivary gland-type tumor of the breast: are we dealing with primary or secondary?—a case report and literature review

“…To better understand the pathogenesis of MEC in salivary versus extra-salivary origins, researchers have compared the molecular profile of primary breast MECs with salivary and extra-salivary MECs ( 33 ). Primary MEC in the salivary gland and lung have been found to be associated with MAML2 fusion ( 34 , 35 ), however, the pathogenesis of primary thyroid MEC seems to be MAML2-independent ( 36 ).…”

Immune Biomarkers in Triple-Negative Breast Cancer: Improving the Predictivity of Current Testing Methods

“…For this reason, various types of PD-L1 tests are available, accompanied by different scoring systems, each having distinct threshold values that determine patient eligibility for specific drugs [7,[18][19][20]. In particular, a combined positive score (CPS) cut-off value of 10 is used to identify patients who are suitable for pembrolizumab treatment, while a 1% immune-cell (IC) cut-off value guides the selection for atezolizumab treatment [2,10,21,22]. There are currently four FDA-registered PD-L1 IHC assays that employ four distinct PD-L1 antibodies (22C3, 28-8, SP263, SP142) and are implemented on two different IHC platforms (i.e., Dako and Ventana).…”