Assessment of Predictive Biomarkers in Breast Cancer: Challenges and Updates

Abstract

The management of patients with breast cancer (BC) relies on the assessment of a defined set of well-established prognostic and predictive markers. Despite overlap, prognostic markers are used to assess the risk of recurrence and the likely benefit of systemic therapy, whereas predictive markers are used to determine the type of systemic therapy to be offered to an individual patient. In this review, we provide an update and present some challenges in the assessment of the main BC-specific molecular predictive markers, namely hormone receptors (oestrogen receptor [ER] and progesterone receptor [PR]), human epidermal growth factor receptor 2 (HER2), and KI67. As the main platform for assessing these markers in BC is immunohistochemistry (IHC), we address the cut-off values used to define positivity, the ER-low subgroup, the existence and significance of the ER−/PR+ phenotype, the use of PR in routine practice, and the role of hormone receptors in ductal carcinoma in situ. We discuss the newly introduced HER2-low class of BC and the clinical/biological difference between different HER2 groups (e.g., HER2 IHC score 3+ BCs vs. those with a HER2 IHC score 2+ with <i>HER2</i> gene amplification). The review concludes with an update on the applications of KI67 assessment in BC and observations on the role of immune checkpoint identification in BC.

Expression, assessment and significance of Ki67 expression in breast cancer: an update

“…Furthermore, 20% of Ki67 expression was accepted by the FDA (Food and Drug Administration) as the best cut-off for adding CDK4/6 inhibitor with endocrine therapy to high-risk luminal BC patients 67. In addition, it could be considered to predict the response of CDK4/6 inhibitor 68…”

“…Stromal expression of Ki67 could be helpful in the assessment of some cases, including multinucleated giant stromal cells in benign fibroepithelial lesions, which show low Ki67 expression; however, in malignant giant cells, it shows high Ki67 expression 68. In addition, expression of Ki67 in stromal cells could be helpful in grading phyllodes tumours rather than mitotic figures that are affected by fixation issues 88…”

“…Stromal expression of Ki67 could be helpful in the assessment of some cases including multinucleated giant stromal cells in benign fibroepithelial lesions, which show low Ki67 expression; however, in malignant giant cells, it showed high Ki67 expression 72 .…”

An update on the pathological classification of breast cancer

“…Of the individual molecular markers, ER and HER2 have proven of predictive and prognostic value. ER and HER2 status, which are an essential part of the diagnostic workup of all BC patients, are determined using standardized techniques according to well‐defined published guidelines 12,37–39 . Clinically, all invasive BCs are grouped into following biomarker‐defined subtypes/groups for treatment purposes: (1) ER‐positive, HER2‐negative, (2) ER‐positive, HER2‐positive, (3) ER‐negative, HER2‐positive, and (4) ER‐negative, HER2‐negative cancers 20 .…”

Immunohistochemistry in Breast Cancer: Practice Points and Pitfalls

“…These are the mainstay markers that determine management of breast cancer patients and their assessment relies on IHC. Challenges and updates on determining predictive biomarkers in breast cancer are addressed by Dr. Emad Rakha and colleagues [3]. These included the definition of receptor positivity, the value of PR evaluation in breast cancer, the ER-low positive category, assessment of hormone receptor status in DCIS, and HER2 expression encompassing the differential response of HER2-positive breast cancer based on protein expression.…”