Rb expression in metastatic ER-positive breast cancer: implications for precision oncology

The retinoblastoma protein (Rb) is a critical cell-cycle regulator, and its loss of function can lead to resistance to CDK4/6 inhibitors (CDK4/6i), which are the standard first-line treatment for estrogen receptor (ER)-positive metastatic breast carcinoma (mBC). Thus, identifying Rb-deficient mBC is crucial for optimal personalized breast cancer management. This study aimed to determine the prevalence of Rb loss by immunohistochemistry (IHC) in a cohort of ER + mBC and to assess its correlation with RB1 genetic inactivation.

We analyzed Rb IHC in 50 consecutive ER-positive mBC. Histopathologic and clinical features were analyzed. p16 IHC was performed in a subset of Rb-deficient cases. Targeted next-generation tumor-normal sequencing (NGS) data using MSK-IMPACT were retrospectively analyzed in 38 mBCs.

Rb loss was identified in 20% (10/50) of mBC, and was either partial (8%, 4/50) or complete (12%, 6/50). In all evaluable cases (100%, 9/9), Rb loss was associated with p16 positivity. Neuroendocrine (NE) features were observed in 40% (4/10) of mBCs with Rb loss. MSK-IMPACT data were available for six Rb-deficient cases and revealed pathogenic RB1 alterations in two (33%). None of the tumors with preserved Rb expression (80%, 40/50) showed RB1 genetic alterations or NE features. Notably, one mBC case demonstrated disease progression on CDK4/6 inhibitor therapy, accompanied by acquired Rb loss and acquisition of an NE phenotype.

Rb loss in mBC can be reliably detected by Rb IHC, especially when interpreted alongside p16, offering a rapid and cost-effective means of assessing Rb status. This approach may identify Rb-deficient tumors that are missed by conventional methods, such as next-generation sequencing, and help guide personalized therapeutic strategies in patients with mBC.