scholarly journals Identification of A 10-Gene Signature To Predict Efficacy of Neoadjuvant Therapy in Patients With HER2 Positive Breast Cancer.

2021 ◽  
Author(s):  
Yusong Wang ◽  
Mozhi Wang ◽  
Xiangyu Sun ◽  
Litong Yao ◽  
Mengshen Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Neoadjuvant Therapy ◽  
Spline Regression ◽  
Her2 Positive ◽  
Immune Infiltration ◽  
Her2 Positive Breast Cancer ◽  
Non Linear ◽  
Er Status ◽  
Positive Breast Cancer

Abstract Background:Patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer represent a poor prognosis, which are recommended to be treated with neoadjuvant therapy (NAT). Tumor immune microenvironment, especially tumor infiltrating cells (TILs), are proved to predict the efficacy of NAT. However, validated immune-related multi-gene signatures for HER2-positive BC are still lacking.Methods:We collected gene expression arrays of pre-NAT samples from the National Center for Biotechnology Information Gene Expression Omnibus. Totally 4 studies are included in our study (n=295, no. of train=207, no. of validation=95) to construct the signature. Single Sample Gene Set Enrichment Analysis (ssGSEA)and weighted gene co-expression network analysis (WGCNA)were used to quantify immune-infiltrating components in tumor environment and to identify immune related modules. We used spline regression to evaluate non-linear effect of genes and to construct the signature.Results:Immune infiltration status was significantly related to pathological complete response (pCR) (p=0.02). We filtered 80 differential expression genes according to immune infiltration status, and identified two gene modules correlated to pCR and immune infiltration status. CCL5, CD72, PTGDS, CYTIP, PAX5, and estrogen receptor (ER)status were significantly related to pCR in linear multivariate analysis. In spline regression, non-linear aspects of MAP7, IL2RB, CD3G, PTPRC, TRAC were relevant to pCR. We constructed a signature concerning both linear and non-linear effects of genes, which was validated in 5-fold cross validation (AUC=0.81) and an external validation cohort (n=88) (AUC=0.797).Conclusions:In HER2 positive BC, immune infiltration status should be involved into consideration to make optimal regimens. A ten-gene generalized non-linear signature including ER status could predict the efficacy of NAT.

scholarly journals Identification of a 10-Gene Signature Model to Predict Efficacy of Neoadjuvant Therapy in Patients With HER2 Positive Breast Cancer.

2021 ◽  
Author(s):  
Yusong Wang ◽  
Mozhi Wang ◽  
Xiangyu Sun ◽  
Litong Yao ◽  
Mengshen Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Neoadjuvant Therapy ◽  
Spline Regression ◽  
Her2 Positive ◽  
Linear Effect ◽  
Immune Infiltration ◽  
Non Linear ◽  
Er Status ◽  
Positive Breast Cancer

Abstract BackgroundPatients with human epidermal growth factor receptor 2 (HER2) positive breast cancer represent a poor prognosis, which are recommended to be treated with neoadjuvant therapy (NAT). Tumor immune microenvironment, especially tumor infiltrating cells (TILs), are proved to predict the efficacy of NAT. However, validated immune-related multi-gene signatures for HER2-positive BC are still lacking.MethodsWe collected gene expression arrays of pre-NAT samples from the National Center for Biotechnology Information Gene Expression Omnibus. Totally 4 studies are included in our study (n=295, no. of train =207, no. of validation=95) to construct the signature. Single Sample Gene Set Enrichment Analysis (ssGSEA)and weighted gene co-expression network analysis (WGCNA)were used to quantify immune-infiltrating components in tumor environment and to identify immune related modules. We used spline regression to evaluate non-linear effect of genes and to construct the signature.ResultsImmune infiltration status was significantly related to pathological complete response (pCR) (p=0.02). We filtered 80 differential expression genes according to immune infiltration status, and identified two gene modules correlated to pCR and immune infiltration status. CCL5, CD72, PTGDS, CYTIP, PAX5, and estrogen receptor (ER)status were significantly related with pCR in linear multivariate analysis. In spline regression, non-linear aspects of MAP7, IL2RB, CD3G, PTPRC, TRAC were relevant to pCR. We constructed a signature concerning both linear and non-linear effect of genes, which was validated in 5-fold cross validation (AUC=0.81) and an external validation cohort (n=88) (AUC=0.797).ConclusionsIn HER2 positive BC, immune infiltration status should be involved into consideration to make optimal regimens. A ten-gene generalized non-linear signature including ER status could predict the efficacy of NAT.

scholarly journals UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

2021 ◽  
Author(s):  
Jun Hua ◽  
Zhe Zhang ◽  
Lili Zhang ◽  
Yan Sun ◽  
Yuan Yuan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Neoadjuvant Therapy ◽  
Needle Biopsy ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Trastuzumab Treatment ◽  
Her2 Positive Breast Cancer ◽  
Trastuzumab Therapy ◽  
Positive Breast Cancer

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

scholarly journals Role of Post-Neoadjuvant therapy with trastuzumab emtansine in HER2-positive breast cancer

2021 ◽  
pp. 68-74
Author(s):  
E. V. Lubennikova ◽  
Ya. V. Vishnevskaya
Keyword(s):  
Breast Cancer ◽  
Adjuvant Therapy ◽  
Neoadjuvant Therapy ◽  
Locally Advanced ◽  
Residual Tumor ◽  
Long Term Results ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The widespread introduction of anti-HER2 agents has changed the natural course of Her2-positive breast cancer. The use of trastuzumab, and later dual anti-HER2 blockade with pertuzumab, in neoadjuvant regimens significantly increased the chances of complete cure. However, among patients with early and locally advanced forms of Her2-positive cancer, there is a cohort with an extremely unfavorable prognosis – tumors that have not achieved complete pathomorphological regression after neoadjuvant chemotherapy.The presence of a residual tumor in Her2-positive breast cancer has long been only a prognostically unfavorable factor without the potential to influence disease outcome. The results of the international phase III study KATHERINE, which demonstrated the high efficacy of post-adjuvant therapy with trastuzumab emtansine (T-DM1) in this patient cohort, have established a new standard of care. Due to T-DM1 adjuvant therapy, the possibility to significantly improve long-term results determined the predictive characteristics of the morphological response to the choice of treatment tactics, which became an important argument in favor of neoadjuvant therapy in patients with not only locally advanced but also primarily resectable Her2-positive breast cancer, followed by personalization of therapy.This article presents our own experience with post-neoadjuvant therapy with trastuzumab emtansine in a young patient with a residual tumor. The data of the main studies in early Her2-positive breast cancer are summarized.

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