Clinical Molecular Characteristics Of HER2-Low Breast Cancer Patients And Its Correlation With The Efficacy Of Neoadjuvant Therapy

Background:In the era of precision medicine,human epidermal growth factor receptor 2(HER2)is an important therapeutic target and prognostic biomarker for breast cancer,and a novel anti-HER2 antibody drug conjugate has shown its efficacy in previously treated HER2-low metastatic breast cancer.The study found that it can show activity in HER2-low breast cancer through its effective transmembrane action resulting in "bystander effect",which makes HER2-low breast cancer gradually gain widespread clinical attention and HER2-low may become a new type of breast cancer.This has led to the emergence of HER2-low breast cancer as a new type of breast cancer,which will be treated with more precise treatment.However,HER-low are still few studies on the treatment of HER2-low breast cancer patients,and the clinicopathological characteristics of HER2-low breast cancer are not well understood,and the results of related studies in the literature are controversial.Methods: A total of 409 patients with early-stage HER2-negative breast cancer who received neoadjuvant therapy at Anhui Provincial Hospital of Anhui Medical University and the First Affiliated Hospital of Anhui Medical University from September 2015 to September 2021 were retrospectively included in this study,and the study endpoint was pathological complete remission(p CR).Clinical characteristics of the patients,including age,hormone receptor(HR)expression,HER2 expression,Ki-67 index,and both neoadjuvant regimens,were collected,and chi-square tests were used to investigate the correlation between clinical parameters and HER2 expression status.And blood specimens and fresh cancer tissue specimens before neoadjuvant chemotherapy were collected for ct DNA sequencing,whole exon sequencing(WES)and RNA sequencing(RNA-seq),and patients were divided into HER2-low group and HER2-0group according to their HER2 expression status,by bioinformatics analysis and statistical methods,so as to further analyze the molecular characteristics of HER2-low breast cancer.Results: A total of 409 HER2-negative breast cancer patients were included in the analysis,with a median age of 49 years(24-79 years)in all populations,and HER2 status(HER2-0 vs HER2-low)was significant between HR status(P=0.000),Ki67 index(P=0.025),and p CR rate(P= 0.008),In the HER2-low subgroup,most(85.8%)tumors of patients were luminal tumors,and Ki67 in the HER2-low subgroup was higher than that in the HER2-low subgroup.Compared with HER2-low patients,HER-0 patients has more high p CR rate;baseline tumor serum samples from 42 enrolled patients were tested for ct DNA,and PIK3 CA,BRIP1,DDR2 and PTEN mutations were enriched in HER2-low,while BRCA2 mutations were enriched in the HER2-0 group;a total of 18 patients who had WES and RNA testing were included,and the WES results suggested that the HER2-low group had The HER2-low group had a hig HER rate of PIK3 CA mutations and a hig HER frequency of PI3 K pathway variants,and the HER2-low group had a hig HER number of concomitant mutations and reached statistical significance(P=0.03);in terms of expression profiles,HER2-low and HER2-0 patients had different expression profiles,and the top50 genes were ranked differently to distinguish the two groups.Three genes with highly significant expression differences between the two groups were uncovered,namely IP6K3,SHC4 and MUC19;higher expression of chemoresistance pathwayrelated genes was observed in the HER2-low group as a whole,with nine of them having more significant expression differences,suggesting that the reason for the low p CR rate in the HER2-low group may also be related to chemoresistance.Conclusion:.Our study shows a significant difference in p CR rates between the HER2-low group and the HER2-0 group,and further analysis after stratification according to different HR status shows a non-significant difference in efficacy between the two groups.In addition,this study shows that there are differences in clinical and molecular characteristics between the HER2-low group and the HER2-0 group in breast cancer patients.