A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard

Abstract

Gene expression profiling of breast cancer delineates a particularly aggressive subtype referred to as 'basallike', which comprises B15% of all breast cancers, afflicts younger women and is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) and/or EGFR are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature. A parallel comparison of 46 proposed immunohistochemical biomarkers of basal-like breast cancer was performed against a gene expression profile gold standard on a tissue microarray containing 42 basal-like and 80 non-basal-like breast cancer cases. Ki67 and PPH3 were the most sensitive biomarkers (both 92%) positively expressed in the basal-like subtype, whereas CK14, IMP3 and NGFR were the most specific (100%). Among biomarkers surveyed, loss of INPP4B (a negative regulator of phosphatidylinositol signaling) was 61% sensitive and 99% specific with the highest odds ratio (OR) at 108, indicating the strongest association with basal-like breast cancer. Expression of nestin, a common marker of neural progenitor cells that is also associated with the triple-negative/basal-like phenotype and poor breast cancer prognosis, possessed the second highest OR at 29 among the 46 biomarkers surveyed, as well as 54% sensitivity and 96% specificity. As a positively expressed biomarker, nestin possesses technical advantages over INPP4B that make it a more ideal biomarker for identification of basal-like breast cancer. The comprehensive immunohistochemical biomarker survey presented in this study is a necessary step for determining an optimized surrogate immunopanel that best defines basal-like breast cancer in a practical and clinically accessible way.

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…It has been widely postulated that enhanced PIP3 signaling is the critical factor impacting cancer development; however evidence is accumulating that PI(3,4)P2 dysregulation may also contribute. Loss of INPP4B is associated with metastatic potential or poor prognosis in multiple cancer types, including breast [22,[39][40][41], prostate [42] and ovarian [22,43] cancers, melanoma [44] and leukemia [45,46]. In fewer cases, there are also evidences of altered INPP4A expression in prostate cancer [47] and leukemia [48].…”

Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer

“…For practical reasons, surrogate markers studied on tissue specimens are often used to define the basal-like subtype, instead of the more time-consuming and costly gene expression profiling 4 . However, there is currently no consensus on the preferred definition of basal-like tumours, although several individual biomarkers and combinations have been suggested 5–7 .…”

Frequency and Distribution of Cytoplasmic and Nuclear P63 in Recognizing the Basal-Like and Non-Basal-Like Types of Breast Cancer Based on Age.

“…In the next step, a block with a sniper blocking solution and 10 min incubation was performed. The subsequent process of basal-like determination was carried out by adding 100 μl of CK 5/6 solution on each preparation with a positive (basal-like absorbing the dye solution) and negative (non-basal-like absorbing no dye solution) [14].…”