Topic:
 
Issue Section:
 Biomarkers, translational research and precision medicine
Background: Preclinical studies suggest that HER2 mutations lead to constitutive HER2 activation, but knowledge about effective treatment options and clinical resistance mechanisms remain uncharacterized.
Methods: We performed dynamic monitoring of > 300 serial plasma samples collected from 49 metastatic breast cancer patients used targeted sequencing of 425 clinically relevant genes, to detect HER2 mutations and track resistance to HER2-targeted treatments in HER2-mutant breast cancer.
Results: We identified activating HER2 mutations (S310F, D769Y, V777L, 778insGSP) in ctDNA and paired tissue samples from four patients with ER positive/HER2-amplification negative metastatic breast cancer, who had developed resistance to multi-line (>3) endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. Intriguingly however, analysis of ctDNA revealed that the NF2 mutation was acquired from a patient with HER2S310F/V777L who had developed resistance to HER2-targeted treatments. We showed that HER2S310F/D769Y/V777L/778insGSP mutations were constitutively active, and T47D and MCF7 overexpressing HER2S310F/V777L/778insGSP were sensitive to HER2 targeted therapies combined with everolimus. Consistent with our clinical findings, NF2 knockdown in HER2 S310F/V777L/778insGSP overexpressing T47D and MCF7 contributed to HER2-targeted therapy resistance. Furthermore, MEK inhibitor remarkably sensitized NF2 knockdown and HER2 mutations co-expressing T47D and MCF7 cells to trastuzumab.
Conclusions: Dynamic monitoring of ctDNA could provide the candidate resistance genes for metastatic HER2-mutant breast cancer. Our findings validated NF2 mutations as a potential mechanism of resistance to HER2-targeted therapy, and the combined use of HER2 and ERK inhibitors may overcome resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Legal entity responsible for the study: Dalian Medical University.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
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