Defining triple-negative breast cancer with neuroendocrine differentiation (TNBC-NED)

Abstract

Primary breast neuroendocrine (NE) neoplasms are uncommon, and definitions harbor controversy. We retrospectively collected 73 triple-negative breast cancers (TNBC) and evaluated NE biomarker expression along with p53 aberrant staining (which correlates with TP53 gene mutation) and Rb protein loss by immunohistochemistry. In the study cohort, we found 11 (15%) cases of TNBC with neuroendocrine differentiation (TNBC-NED) showing positivity for one or more NE markers (synaptophysin/chromogranin/insulinoma-associated protein 1 [INSM1]). We also identified one separate small cell neuroendocrine carcinoma. Histologic types for these 11 TNBC-NED cases were as follows: 8 invasive ductal carcinoma (IDC) not otherwise specified (NOS), 2 IDC with apocrine features, 1 IDC with solid papillary features. INSM1 had the highest positivity and was seen in all 11 carcinomas. Seven (64%) cases showed p53 aberrant staining, 6 (55%) had Rb protein loss, while 6 (55%) had p53/Rb co-aberrant staining/protein loss. TNBC-NED was associated with Rb protein loss (p < 0.001), as well as p53/Rb co-aberrant staining/protein loss (p < 0.001). In 61 cases negative for NE markers, 37 (61%) showed p53 aberrant staining, while 5 (8%) had Rb protein loss. We also analyzed genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) PanCancer Atlas of 171 basal/TNBC patients. Transcriptomic analysis revealed mRNA expression of RB1 to be correlated negatively with SYN1 mRNA expression (p = 0.0400) and INSM1 mRNA expression (p = 0.0106) in this cohort. We would like to highlight the importance of these findings. TNBC-NED is currently diagnosed as TNBC, and although it overlaps morphologically with TNBC without NED, the unique p53/Rb signature highlights a genetic overlap with NE carcinomas of the breast.

Keywords: RB1; TNBC-NED; TP53; breast; carcinoma; neuroendocrine.

Figure 1

Histological and immunohistochemistry findings in breast cancers showing neuroendocrine differentiation. (A) 51‐year‐old patient with a poorly differentiated TNBC with small cell morphology and positive synaptophysin expression, showing Rb protein loss and p53 aberrant staining (MM type) by IHC with a high Ki‐67 proliferative index. The terminology for this tumor is NEC, but more specifically SCNEC. (B) 37‐year‐old with a poorly differentiated TNBC with positive INSM1 expression and a high Ki‐67 proliferative index found to have Rb protein loss and p53 aberrant staining (NM type) by IHC. We propose the terminology for this tumor as TNBC‐NED.

Figure 2

TCGA analysis for breast basal/TNBC. (A) t‐Test demonstrating lower RB1 mRNA expression in tumors with altered SYN1. (B) Spearman and Pearson correlation coefficients between SYN1 and RB1 expression. (C) t‐Test demonstrating lower RB1 mRNA expression in tumors with altered INSM1. (D) Mutational co‐alteration frequency for RB1 mutated TNBC‐NED cases.