In current study, lncRNA-AL390243.1, POTEH-AS1, and lncRNA-AC009975.1 expression level were statistically increased in core biopsies tissues from non-apCR group compared to those from apCR group, possessing rather high diagnostic efficiency, the AUC of three-lncRNA set was 0.789 with a sensitivity of 80.6%, and a specificity of 61.0%. More importantly, according to the multivariate analysis, lncRNA-AL390243.1 expression level, nodal stage and tumor type from HER2 + patients were independent predictors of apCR after NAT, which also possessed a higher diagnostic efficiency with 0.859 (95%CI: 0.790–0.929). The nomogram might be especially helpful in predicting which patients might gain a benefit from NAT with regard to nodal response, allowing a more individualized assessment of nodal conversion probability. The lncRNA-AL390243.1 was significantly expressed higher in nodal positive breast cancer than in nodal negative cancer, suggesting lncRNA-AL390243.1 expression level might be a novel biomarker for nodal metastasis diagnostics. In addition, the high level of lncRNA-AL390243.1 was associated with poor DFS, indicating that lncRNA-AL390243.1 might take part in the tumor progression after NAT.
The benefits of NAT for early breast cancers have been well described by others [16–17]. Furthermore, the achievement of pathological complete response (pCR) after NAT is a surrogate marker of improved oncologic outcomes, especially in HER2 + breast cancer [18–20]. The use of effective chemotherapy as well as targeted therapies such as trastuzumab and (or) pertuzumab for HER2 + disease in the neoadjuvant setting have led to an increase in the rate of pCR after NAT ranging from 30 to 63%. However, the bpCR was not completely consistent with apCR. There was difference of therapeutic effect between breast primary tumor and ALN. And this difference was most significant in HER2 + subgroup. So, we want to explore whether there were differentially lncRNAs in primary tumors that could predict apCR of HER2 + breast cancer.
Previous studies demonstrated the potential value of lncRNAs as efficacy prediction biomarkers for breast cancer [11–13]. LncRNA H19 could promote drug resistance in HR + breast cancer cells through inhibiting BIK and NOXA expression [21]. Liang et al. [22] found that lncRNA PRLB could act as an oncogene through affecting the miR-4766-5p/SIRT pathway, and significantly increase breast cancer proliferation and chemoresistance. Zhang et al. [23] found that lncRNA ITGA9-AS1 had a high predictive value for pCR after NAT with an AUC value was 0.800, and the expression level was higher in non-pCR. Yuan et al. [24] observed that lncRNA ATB could promote trastuzumab resistance and invasion-metastasis cascade in breast cancer by competitively biding miR-200c, upregulating E-box-binding protein 1 and zinc finger protein 217, and then induced epithelial-mesenchymal transition and invasion. In addition, Shi et al. [25] also found that lncRNA ATB was much higher in trastuzumab resistance patients. Li et al. [26] screened a microarray of lncRNA involved in trastuzumab-resistant SKBR-3/Tr cells. The result showed that the expression of lncRNA GAS5 was decreased in SKBR-3/Tr cells. Further research showed that GAS5 suppresses cancer proliferation by acting as a molecular sponge for miRNA-21, leading to the de-repression of phosphatase and tension homologs, the endogenous target of miRNA-21. Moreover, mTOR activation associated with reduced GAS5 expression.
However, most studies focused on the lncRNA efficacy prediction value of breast primary tumor. The strength of our study was that our study might be first research to explore whether lncRNA had nodal efficacy prediction value. In the current study, we demonstrated lncRNA-AL390243.1, POTEH-AS1, and lncRNA-AC009975.1 were increased in non-apCR group significantly and stably. We believe these three lncRNAs play a crucial role in the tumorigenesis and nodal efficacy prediction of breast cancer, but the underlying molecular mechanisms needs further studies to illuminate.
For patients with initial cN+ and ycN0 disease after NAT, the feasibility of SLNB after NAT has been confirmed in NCCN guideline and St. Gallen international expert consensus [5–6, 8]. However, the overall FNR of SLNB after NAT was still high. Optimizing candidate’s selection could improve the sensitivity of selection. If patients have better therapy response and higher apCR rate, they might have more chance to avoid ALND after NAT [27]. In other word, individualized surgical treatment could be chosen according to the therapy response after NAT. So, our nomogram could help to make clinical decision.
There were also several limitations. The most important was the retrospective design. And we involved a limited number of patients at a single institution, which increased the probability of selection bias. Second, we could not take some factors associated with apCR into account. The clinical application of genomics still needs to be validated using a large, independent, prospective cohort.
In conclusion, our study identified that lncRNA-AL390243.1, POTEH-AS1, and lncRNA-AC009975.1 were upregulated in non-apCR breast cancer tissues and acted as a new potential biomarker for the nodal efficacy prediction of breast cancer. At the same time, lncRNA-AL390243.1 might act as a potential biomarker for nodal metastasis prediction of breast cancer.