A Review and Meta-analysis on Trastuzumab Resistance in Patients with HER2+ Breast Cancer
Alexandre Holzbach Júnior1, Bernardo Perin Cima2, Mari Dalva Staffen2
1Centro de Ciências da Saúde, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brasil.
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.
Insights
Drug resistance to trastuzumab remains a challenge in HER2+ breast cancer treatment. This study identified 102 resistance mechanisms, primarily involving the PI3K/Akt/mTOR pathway or low HER2 status, to guide future therapies.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Trastuzumab, a monoclonal antibody, has transformed HER2+ breast cancer therapy.
- Approximately 30% of patients exhibit resistance to trastuzumab treatment.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Approach:
- A comprehensive literature review and meta-analysis of PubMed and Scielo databases up to January 2022.
- Inclusion of 60 articles for review and 15 for meta-analysis, excluding reviews and reports.
- Statistical analysis using Egger's test, forest plots, and PRISMA flowchart to ensure methodological rigor.
Key Points:
- Identified 102 distinct mechanisms of trastuzumab resistance, categorized into 5 groups.
- Primary resistance mechanisms involve the PI3K/Akt/mTOR pathway or low HER2 expression.
- Failure to accurately assess HER2 status contributes significantly to resistance.
Conclusions:
- Trastuzumab resistance is a significant hurdle in HER2+ breast cancer management.
- Further research into resistance mechanisms and development of novel therapies are essential.
- Predictive gene panels could personalize treatment and reduce costs.
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