Among patients with HR+/ERBB2− MBC treated with CDK4/6 inhibitors, we observed that ERBB2-low expression was associated with an inferior PFS. This may serve as a potential marker candidate associated with CDK4/6 inhibitor efficacy. An intrinsic subtypes genomic analysis of the MONALEESA studies 3 found that, overall, the ERBB2-enriched (formerly HER2-enriched) subtype was associated with 2.3-fold increased risk of disease progression compared with the luminal A subtype. Our results provide phenotypical evidence suggesting the inferior efficacy of CDK4/6 inhibitors in the ERBB2-low expression subgroup. Some limitations of this study include its retrospective nature with limited sample size, the lack of patients receiving abemaciclib, and the lack of data on PIK3CA mutation status. Given novel anti-ERBB2 antibody-drug conjugates, such as trastuzumab deruxtecan, demonstrated clinical efficacy in ERBB2-low-expressing MBC, 4 coupled with emerging evidence supporting the combination use of CDK4/6 inhibitors with anti-ERBB2 agents, 5 this subgroup may be of high clinical relevance and warrant prospective evaluations in future trials.
1052 Background: Markers for the efficacy of CDK4/6 inhibitor in estrogen receptor (ER) positive, HER2 negative advanced breast cancer are limited. The bidirectional crosstalks that exist between ER and HER2 pathways contribute to endocrine resistance. We investigated the association between low levels of HER2 expression and the clinical outcome of patients with ER+ HER2- metastatic breast cancer (MBC) treated with CDK4/6 inhibitors. Methods: We identified consecutive patients with ER+ HER2- MBC who received CDK4/6 inhibitor plus either letrozole or fulvestrant between Mar 2017 - Jun 2020 from an institutional cancer registry. HER2-low expression was defined as IHC score 1+, or 2+ with a negative ISH. Progression-free survival (PFS) was defined as the time from the initiation of CDK4/6 inhibitor to the date of radiological or clinical progression, or death. The relationship between HER2 expression levels and PFS was evaluated using log-rank test and multivariable Cox regression modelling. Results: 106 women with MBC were eligible for analysis. Median age at treatment was 58 (23.0-91.4). The majority received palbociclib (84%) while the rest received ribociclib. CDK4/6 inhibitor was used as first-line treatment in 50.9% of cases. Most tumors were of ductal histology (83%) and progesterone receptor (PgR) positive (84.9%), and 22.6% of the patients had bone-only disease. 77.3% of cases were considered HER2-low expressing. HER2-low expression was associated with a significantly shorter PFS compared with HER2 IHC 0 counterpart (median, 8.9 vs 18.8 months, p= 0.014). In multivariate analysis, HER-2 low expression remained significantly associated with an inferior PFS (HR 1.96, 95%CI 1.03-3.75, p= 0.041) after adjusting for the line of treatment, PgR status and disease extent (bone only vs extra-osseous disease). Conclusions: In patients with ER+ HER2- MBC treated with CDK4/6 inhibitors, HER2-low expression was associated with an inferior PFS, and may serve as a potential marker candidate for CDK4/6 inhibitor efficacy. As novel anti-HER2 antibody-drug conjugates demonstrated efficacy in HER2-low expressing MBC, coupled with the emerging evidence for the combination of CDK4/6 inhibitors with anti-HER2 agents, this HER2-low expression subgroup warrants prospective evaluations in future trials.
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