A Review and Meta-analysis on Trastuzumab Resistance in Patients with HER2+Breast Cancer

Background Trastuzumab is a monoclonal antibody that revolutionized the treatment of HER2+ breast cancer. However, about 30% of patients demonstrate resistance to this drug Objective The purpose of this study is to identify the mechanisms involved in resistance to treatment with trastuzumab in women undergoing HER2+ breast cancer treatment. Methods A wide review and meta-analysis were performed in the PubMed and Scielo databases up to January 2022. All articles that analyzed the efficacy of the drug in HER2+ human patients treated with trastuzumab were selected, except reviews, meta-analyses, and reports. Egger's test was applied to verify publication bias. Forest plot and PRISMA flowchart were employed. Results 60 articles were selected for the review and 15 included in the meta-analysis. A total of 102 resistance mechanisms were identified, 73 of which are different from each other. The mechanisms have been classified into 5 different categories. The main resistance mechanisms found are in the PI3K/Akt/mTOR pathway or related to low HER2, often resulting from failure to assess HER2 status. Both groups presented statistical significance. The two groups were not significantly different from each other. Conclusion Drug resistance is the main challenge of trastuzumab-based treatment. To overcome this challenge, it is important to continue efforts to understand the mechanisms of cancer drug resistance, identify therapies that can treat refractory cancer to current therapies, and possibly create a panel of genes that predict resistance, avoiding symptomatic and economic costs. The main limitation of this study was the selection and population bias. PROSPERO Registration Number This study is registered in PROSPERO (CRD42020169304).

Automated summary

This study aims to identify the mechanisms of resistance to trastuzumab treatment in HER2+ breast cancer patients. Through comprehensive literature review and meta-analysis, a total of 102 resistance mechanisms were identified, mainly focused on the PI3K/Akt/mTOR pathway and low HER2 expression. Drug resistance poses a major challenge to trastuzumab-based treatment, and it is crucial to understand the mechanisms of cancer drug resistance, identify new therapeutic approaches, and develop predictive gene panels.