Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor

Aims Recent evidence indicates that weakly positive immunohistochemical staining of oestrogen receptor (ER) is not associated reliably with a luminal subtype, with the majority reclassified as basal‐like by gene expression profile. In this study we assessed the capacity of recently identified immunohistochemical markers of basal‐like subtype not dependent upon ER status – positive expression of nestin or loss of inositol polyphosphate‐4‐phosphatase (INPP4b) – to discriminate intrinsic subtypes, focusing on clinically problematic cases with weak ER positivity. Methods and results Formalin‐fixed paraffin‐embedded blocks, enriched for large proportions of ER‐negative and ER weakly positive breast cancers, were selected from two previous studies conducted in the period 2008–13 and used for (i) RNA extraction for 50‐gene subtype predictor (PAM50) intrinsic subtyping and (ii) tissue microarray construction for immunohistochemical assessment of nestin and INPP4b. Fifty‐eight cases were weakly positive for ER (Allred 3–5), among which 28 (48%) were assigned as basal‐like by PAM50 gene expression. In these 58 cases, the nestin/INPP4b panel identified 23 basal‐like cases with a positive predictive value of 87% [95% confidence interval (CI) 78–95%] and excluded luminal subtype with a negative predictive value of 95% (95% CI 88–100%). Weakly positive ER patients assigned as basal‐like by nestin/INPP4b definition demonstrated a median survival time of 45.8 months, significantly lower than 65 months among other ER weakly positive cases (P = 0.012). Conclusions Immunohistochemical assessment of nestin and INPP4b provides an accurate, accessible and inexpensive tool to identify basal‐like breast cancer subtype in the clinically problematic setting of weak ER positivity. This panel identifies poor prognosis patients who might need strong considerations for non‐endocrine‐based therapies.