Understanding the Efficacy of CDK4/6 Inhibitors in Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer, Based on HER2-Low Expression

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In cases of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, there are few markers to determine cyclin-dependent kinase (CDK)4/6 inhibitor efficacy. The ER and HER2 pathways appear to be related, and their co-occurrence impacts endocrine resistance. In patients treated with CDK4/6 inhibitors, Bao and colleagues explored the relationship between HER2-low expression and the clinical outcome of patients with ER-positive, HER2-negative metastatic breast cancer (MBC). They analyzed institutional cancer registry patients who were identified with ER-positive, HER2-negative MBC who had been treated with a CDK4/6 inhibitor combined with either letrozole or fulvestrant between March 2017 and June 2020. The time from the initiation of CDK4/6 inhibitor therapy to the date of radiologic or clinical progression or death was how progression-free survival (PFS) was defined.

For the analysis, a total of 106 women with MBC were considered eligible. At time of treatment, the median patient age was 58 years (range, 23.0-91.4 years). Eighty-four percent of patients had been treated with palbociclib while the remainder were treated with ribociclib.

In 50.9% of cases, a CDK4/6 inhibitor was used as first-line therapy. Overall, 22.6% of the patients had bone-only disease; most tumors were of ductal histology (83%) and progesterone receptor–positive (84.9%). The majority (77.3%) of instances were HER2-low expressing.

Compared with HER2 immunohistochemistry score 0 counterpart, HER2-low expression was associated with a significantly shorter PFS measured at a median of 8.9 months compared with 18.8 months (P = .014). After adjusting for the specific line of treatment, progesterone receptor status, and disease extent, HER2-low expression was significantly associated with an inferior PFS (hazard ratio, 1.96; P = .041). An inferior PFS was associated with low expression of HER2, potentially serving as a marker for CDK4/6 inhibitor efficacy in patients with ER-positive, HER2-negative MBC treated with CDK4/6 inhibitors.

In future clinical trials, the HER2-low expression subgroup warrants prospective evaluations, based on promising findings regarding CDK4/6 inhibitors combined with anti-HER2 agents, in HER2-low expressing MBC.


Bao KKH, Sutanto L, Tse SSW, et al. The association of HER2 low expression with the efficacy of CDK4/6 inhibitor in hormone receptor positive HER2 negative metastatic breast cancer. Presented at: American Society of Clinical Oncology 2021 Annual Meeting, June 4-8. Abstract 1052.

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