INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer

Insulinoma associated protein 1 (INSM1) is a relatively new marker of neuroendocrine differentiation. It has been shown to have a high sensitivity for neuroendocrine tumours arising from different organs. This study evaluated INSM1 as a marker for neuroendocrine differentiation in infiltrating breast cancers (IBC). The expression of INSM1, together with other neuroendocrine markers (synaptophysin, chromogranin and CD56) was assessed in a large IBC cohort using tissue microarray by immunohistochemistry. Overall, 13.1%, 4.6%, 7.0% and 6.5% of the cases were positive for synaptophysin, chromogranin, INSM1 and CD56, respectively. INSM1 expression showed similar clinicopathological and biomarker profiles as chromogranin and synaptophysin. They were associated positively with luminal profile (p<0.001) and hormone receptors expression (p≤0.015), but negatively with HER2 (p≤0.044) and high molecular weight cytokeratins (p≤0.047). Using synaptophysin and/or chromogranin to define neuroendocrine differentiation, INSM1 showed a sensitivity of 37.3%, and was more sensitive than chromogranin (33.5%) and CD56 (16.4%) but less than synaptophysin (94.6%). Interestingly, INSM1 expression segregated IBC with neuroendocrine differentiation into different prognostic subgroups, particularly within luminal B subtype. Among the synaptophysin/chromogranin+ luminal B cancers, INSM1 expression was associated with significantly better survival (DFS: χ²=8.009, p=0.004; BCSS: χ²=3.873, p=0.049). Multivariate analysis showed that synaptophysin/chromogranin+ INSM1- status was an independent adverse factor for DFS (HR=2.282, 95%CI=1.196-4.356, p=0.012) in the luminal B subtype. Our data supported the usefulness of INSM1 in detecting neuroendocrine differentiation in IBC. Furthermore, INSM1 expression suggested a favourable prognostic impact; thus, it could be useful for stratifying neuroendocrine tumours with different prognosis.