Differences in Treatment Outcomes Between Patients with HER2-Low versus HER2-Zero, Hormone Receptor-Positive Advanced-Stage Breast Cancer Treated with Ribociclib

Abstract

Background Metastatic breast cancers (MBC) with no expression of human epidermal growth factor receptor-2 (HER2) are recently classified into two groups; HER2-zero [HER2-immunohistochemistry (IHC) score of 0 (IHC-0)] and HER2-low, defined as those with IHC score of 1+ or 2+ with negative in situ hybridization (ISH) assay. We investigate differences in treatment outcomes between both groups treated with endocrine therapy (ET) and the CDK4/6 inhibitor ribociclib. Methods Data were retrospectively collected for patients with HR-positive+/HER2−negative MBC who received ribociclib with an aromatase inhibitor (AI) or fulvestrant and were divided into two groups: HER2-zero and HER2-low. Results A total of 257 patients, median age 48 (22–87) years, all with MBC who were treated with ET and ribociclib were enrolled. One hundred and thirty-seven (53.3%) patients had de novo MBC, and majority (n = 162, 63.0%) received ribociclib as a first-line therapy. In total, 114 (44.4%) patients had HER2-zero (IHC-0), while 143 (55.6%) others had HER2-low disease. The overall response rate (ORR) was 52.0% for the HER2-zero group compared to 39.4% for the HER2-low group, p = 0.005. The median PFS was 22.2 (95% confidence interval [CI], 19.4-NR) months for HER2-zero versus 17.3 (95% CI, 14.1–20.6) months for HER2-low, P = 0.0039. In multivariable analysis, HER2-low expression remained significant determinant of inferior PFS after adjusting for other factors, including the site of metastasis, prior chemotherapy, and the line of treatment. Conclusion In patients with MBC treated with ET and ribociclib, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better response rate and PFS compared to those with HER2-low disease. These findings, if confirmed in larger studies, may help oncologists select patients with HER2-low for better treatment options.

Comprehensive Clinical Characterization of Decade-Long Survivors of Metastatic Breast Cancer

“…While the predictive role of HER2-low status on ET response is not firmly established, our data suggest that HR+/HER2−low MBC may derive less benefit from ET than HR+/HER2−zero MBC. Recent retrospective studies also reported consistent results suggesting bidirectional crosstalk between the HR and HER2 pathways as a potential mechanism of hormonal resistance and poor outcomes [36,37].…”

The association between HER2-low status and survival in patients with metastatic breast cancer treated with Cyclin-dependent kinases 4 and 6 inhibitors: a systematic review and meta-analysis

“…Nine studies encompassing a total of 2705 patients were included in the analyses. The four studies were conducted in the first line [ 18 , 23 – 25 ], while mixed cohorts were present in five studies [ 17 , 19 , 26 – 28 ]. Five studies were multicenter, and single-center data were reported in four studies.…”

“…However, the effects of low-level HER2 expression on the survival are yet to be defined [ 15 , 16 ]. While some studies reported inferior survival in patients with HR+HER2-low tumors, several studies stated similar survival in HER2-low and HER2-zero tumors [ 17 – 19 ]. In addition to the prognosis, the low levels of HER2 expression could affect the efficacy of anti-endocrine agents, including the CDK 4/6 inhibitors, due to the pivotal role of the ErbB2 receptor on endocrine resistance [ 20 ].…”

Serum HER2 Level Predicts Therapeutic Efficacy and Prognosis in Advanced Breast Cancer Patients [Letter]

“…1 However, HER2 negative levels can affect the treatment results of patients with HER2-zero who have low response rates and the better progression-free survival (PFS) compared with patients with HER2-low disease; therefore, studies with larger samples are recommended that can help oncologists select HER2-low patients for better treatment options. 5 …”