Prognostic value of tumor mutation burden and the relationship between tumor mutation burden and immune infiltration in HER2+ breast cancer: a gene expression-based study.

BACKGROUND: Whether tumor mutation burden (TMB) correlated with improved survival outcomes or promotion of immunotherapies remained controversy in various malignancies. We aimed to explore the prognostic value of TMB and the relationship between TMB and immune infiltration in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: We downloaded somatic mutation data and clinical information for 216 HER2+ BC patients from the The Cancer Genome Atlas (TCGA) and cBioPortal databases. Patients were divided into high- and low-TMB groups through TMB calculation. Cox regression analysis was used to establish an immune- and mutant-related risk model based on 5-hub genes. The relationship between 5-hub genes mutants and the level of immune infiltration, as well as the relationship between the risk model and the immune microenvironment were analyzed by "TIMER" database. RESULTS: TMB was negatively correlated with overall survival (OS) and disease-free survival (DFS), and high TMB may inhibit immune infiltration in HER2+ BC. Furthermore, risk score classified effectively patients into low- and high-risk groups in training and validation cohorts. The infiltration of CD4+ T cells and NK cells and the levels of immune checkpoint pathway genes were lower in the high-risk group, which indicated a poor prognosis. CONCLUSIONS: Higher TMB correlated with poor survival outcomes and might inhibit the immune infiltrates in HER2+ BC. The 5-hub TMB-related signature conferred lower immune cells infiltration which deserved further validation.

Construction and validation of a risk prediction model for clinical axillary lymph node metastasis in T1-2 breast cancer.

The current diagnostic technologies for assessing the axillary lymph node metastasis (ALNM) status accurately in breast cancer (BC) remain unsatisfactory. Here, we developed a diagnostic model for evaluating the ALNM status using a combination of mRNAs and the T stage of the primary tumor as a novel biomarker. We collected relevant information on T1-2 BC from public databases. An ALNM prediction model was developed by logistic regression based on the screened signatures and then internally and externally validated. Calibration curves and the area under the curve (AUC) were employed as performance metrics. The prognostic value and tumor immune infiltration of the model were also determined. An optimal diagnostic model was created using a combination of 11 mRNAs and T stage of the primary tumor and showed high discrimination, with AUCs of 0.828 and 0.746 in the training sets. AUCs of 0.671 and 0.783 were achieved in the internal validation cohorts. The mean external AUC value was 0.686 and ranged between 0.644 and 0.742. Moreover, the new model has good specificity in T1 and hormone receptor-negative/human epidermal growth factor receptor 2- negative (HR-/HER2-) BC and good sensitivity in T2 BC. In addition, the risk of ALNM and 11 mRNAs were correlated with the infiltration of M2 macrophages, as well as the prognosis of BC. This novel prediction model is a useful tool to identify the risk of ALNM in T1-2 BC patients, particularly given that it can be used to adjust surgical options in the future.

A literature review of the promising future of TROP2: a potential drug therapy target.

Background and Objective: Previous studies have demonstrated that the oncogene trophoblast cell surface antigen 2 (TROP2) has great application prospects as a therapeutic target. However, few literature reviews have systematically summarized and evaluated its role in cancer therapy. This study aims to summarize the molecular structure, functions, signal transduction pathways, and prognostic value of TROP2, and explore therapeutic agents that target TROP2. Methods: A total of 1,376 published literatures from PubMed and 614 published literatures from EMBASE were retrieved by searching "TROP2" or "Trophoblast cell surface antigen 2". The search was conducted on December 12, 2020, and updated on November 20, 2022. The cBioportal and GEPIA (Gene Expression Profiling Interactive Analysis) databases were used to analyze the expression, mutation, and prognostic value of TROP2 in different types of cancer. Key Content and Findings: TROP2 is overexpressed in different tumor tissues and plays roles in cell proliferation, invasion, migration, apoptosis, and treatment resistance by binding to or interacting with several molecules. As a therapeutic target, TROP2 is particularly suitable for antibody-based therapies. Monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), virus-like particles, and antibody drugs in combination with traditional chemotherapy, immunotherapy, radioimmunotherapy, photoimmunotherapy, and nanoparticles that target TROP2 have thus far been rapidly developed. For example, sacituzumab govitecan (IMMU-132), a TROP2-targeting ADC, was granted accelerated approval for the treatment of metastatic triple-negative breast cancer (TNBC). Anti-TROP2 antibody-conjugated nanoparticles (ST-NPs) are a promising vehicle for delivering doxorubicin in targeted TNBC therapy. Conclusions: The availability of TROP2-targeting ADCs makes TROP2 an accessible and promising therapeutic target for advanced metastatic cancers. The present review describes the important role of TROP2 in tumorigenesis and its potential applications as a promising biomarker and therapeutic target that is capable of reversing resistance.

Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data.

PURPOSE: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. EXPERIMENTAL DESIGN: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. RESULTS: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). CONCLUSIONS: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

Corrigendum: Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis.

[This corrects the article DOI: 10.3389/fonc.2020.00811.].

Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity. Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed. Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3-4 AEs. Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.