The Effects of HER2 on CDK4/6 Activity in Breast Cancer

We studied the effects of HER2 on CDK4/6 activity by assessing the phosphorylated retinoblastoma protein (pRb) levels in HER2-positive breast cancer (HER2 positivity is defined by immunohistochemical study or FISH, regardless of ER status). There are significantly higher levels of pRb in HER2-positive breast cancer compared to HER2-negative breast cancer. The pRb level seems to be positively correlated with the HER2 gene copy number when the HER2 gene is amplified. Our study suggests HER2-positive breast cancer may potentially be responsive to CDK4/6 inhibitors, and pRb may be considered as a biomarker to predict the responsiveness. Background: CDK4/6 inhibitors have been used to treat hormone receptor-positive HER2-negative advanced breast cancer. Their benefit in HER2-positive breast cancer has not been determined yet. In this study, we investigated the effects of HER2 on CDK4/6 activity by assessing the level of downstream phosphorylated retinoblastoma protein (pRb) in HER2-positive breast cancer (HER2 positivity is defined by immunohistochemical study or FISH, regardless of ER status) to determine if these cases may be responsive to CDK4/6 inhibitors. Materials and Methods: One hundred and thirty cases of breast biopsies with invasive carcinoma were collected, including 77 cases of HER2+ (39 cases of ER +PR +/- HER2+ and 38 cases of ER-PR-HER2+) and 53 cases of HER2- (ER-PR-HER2-) breast cancer. immunohistochemical study of pRb was performed and the pRb level was assessed by H-score (intensity x percentage of positive cells). Results: The pRb H-score ranges from 3 to 270. The average H-scores for the ER-PR-HER2+, ER+PR +/- HER2+ and ER-PR-HER2- groups are 115.8 +/- 75.8, 93.1 +/- 68.6 and 63.1 +/- 65.6, respectively. By comparison, HER2+ cases have significantly higher pRb levels than HER2- cases (P = .001). Among HER2+ cases, there was a trend of positive correlation between the HER2 gene copy number, and the pRb level although not statistically significant (r = 0.192, 95% CI, [-0.033, 0.399], P = .09). Conclusion: In breast cancer, HER2 positivity leads to significantly higher levels of CDK4/6 activity as reflexed by pRb. Breast cancer that is positive for HER2 may respond to CDK4/6 inhibitors and pRb may potentially be used as a biomarker to predict the responsiveness. (C) 2021 Elsevier Inc. All rights reserved.