Analysis of circulating tumor DNA (ctDNA) in HER2-low metastatic breast cancer (MBC) has revealed distinct genomic profiles and potential therapeutic strategies, according to research published in Nature. The study, involving over 1000 MBC patients, compared the ctDNA landscapes of HER2-low, HER2-0, and HER2-positive subtypes, identifying actionable mutations and differential responses to targeted therapies. These findings could refine treatment approaches for this significant subset of breast cancer patients.
Mutation Landscape of HER2-Low MBC
The study found that the most frequently mutated genes in HER2-low MBC were TP53 (47.8%), PIK3CA (37.1%), and ESR1 (12.1%). Notably, 37.1% of patients could potentially benefit from PI3K inhibitors like alpelisib, 18.0% from PARP inhibitors like olaparib, and 12.3% from AKT inhibitors like capivasertib. Overall, 67.0% of patients exhibited actionable events, ranging from 1 to 8. When comparing the HER2-low group to HER2-0, lower mutation frequencies were observed for TP53, EGFR, and HGF, while IDH1, MLH3, and ROS1 showed higher frequencies. Compared to HER2-positive, HER2-low had lower ERBB2, MSH2, and TP53 mutations but higher ESR1, AKT1, PTEN, and FAT1 mutations.
Impact of HR Status and Molecular Subtypes
The study also investigated the impact of hormone receptor (HR) status on the genomic landscape of HER2-low MBC. HR-positive HER2-low tumors exhibited higher mutation frequencies of ESR1, MAP3K1, GATA3, and PIK3CA compared to HR-negative tumors, while TP53, STK11, FGFR3, and IGF1R were less frequent. Mutations in HR-positive tumors were enriched in PI3K, ERBB2, and metabolic pathways, whereas HR-negative tumors showed more mutations in the DNA-damage response (DDR) pathway.
In luminal breast cancer, PIK3CB, ACVR1B, HGF, and ERG were key genes with varying mutation frequencies between luminal HER2-low and luminal HER2-0 subgroups. In triple-negative breast cancer (TNBC), FGFR3, ATRX, and IGF1R showed distinct mutation frequencies between TNBC HER2-low and HER2-0 subtypes. All ERBB2 mutations observed in TNBC occurred exclusively within the TNBC HER2-low subgroup.
Efficacy of HER2-TKIs in ERBB2-Mutated MBC
An exploratory analysis of HER2-negative patients with ERBB2 mutations treated with pyrotinib, a HER2-TKI, showed that HER2-low MBC patients had a higher disease control rate (DCR) and objective response rate (ORR) compared to HER2-0 MBC patients. HER2-low patients also exhibited significantly prolonged progression-free survival (PFS) following pyrotinib treatment compared to HER2-0 (median PFS: 6.9 months vs 2.3 months, P=0.011). These findings suggest that TKI treatment may be beneficial for HER2-low MBC patients with ERBB2 mutations, while HER2-0 MBC patients are less likely to benefit.
Treatment Outcomes Based on Metabolic Gene Mutations
The efficacy of chemotherapy (docetaxel plus capecitabine) was assessed in HER2-0 and HER2-low MBC patients. While the DCR was higher in HER2-low MBC compared to HER2-0 MBC (96.8% vs 84.9%, P=0.045), there was no statistically significant difference in PFS and OS between the two groups. However, in patients with metabolic pathway-related gene (MRG) mutations, the HER2-low group showed a longer PFS than the HER2-0 group (median PFS: 12.6 months vs 7.0 months, P=0.035). Furthermore, HER2-low MBC patients with MRG mutations exhibited superior PFS compared to HER2-0 when treated with adjuvant endocrine therapy (median PFS: 53.0 months vs 37.0 months, P=0.017) and CDK4/6 inhibitors (median PFS: 4.0 months vs 2.0 months, P=0.011).
Molecular Clusters in HER2-Low MBC
Analysis of mutation signatures identified three distinct molecular clusters within HER2-low MBC. These clusters exhibited varying mutation frequencies in RTK–RAS, PI3K, ERBB2, and metabolic pathways. Cluster 1 had a higher blood tumor mutation burden (bTMB) compared to clusters 2 and 3. The mutation frequencies of PIK3CA, ERBB2, ERBB3, and EGFR genes also varied across the clusters. The study found that Cluster 1, 2, and 3 were more similar to those of treatment-sensitive samples receiving AET, TX regimens chemotherapy, and CDK4/6 inhibitor therapy, respectively. These findings highlight the heterogeneity within the HER2-low MBC population and offer potential strategies for targeted therapies.
