Targeting DNA repair in breast cancer
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Shani Paluch-Shimon1, Ella Evron2
1Department of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel.
Abstract:
Targeting of DNA repair is an important therapeutic approach in breast cancer, particularly for BRCA1/2 associated breast cancers and those characterized by a "BRCAness" phenotype including those with "triple negative" subtype. Various assays and scores have been developed to evaluate degree of homologous recombination deficiency in the hope that this would aid in predicting for susceptibility to DNA repair targeting agents, and yet, presence of a germline mutation in BRCA1/2 remains the strongest predictor for therapeutic efficacy of such agents. Pre-clinical studies suggested increased sensitivity to agents that damage DNA in a way that interferes with DNA replication forks and which subsequently require DNA repair by homologous recombination, such as platinum salts, and this data was further confirmed clinically. Recently published phase III data favor the use of PARP inhibitors amongst patients with BRCA1/2 associated advanced breast cancer. Novel chemotherapeutic agents targeting DNA damage repair are under evaluation as well as further combinations of PARP inhibitors with immuno-therapeutics and other biological agents.
Insights
Targeting DNA repair is crucial for treating breast cancer, especially BRCA1/2-mutated or BRCAness subtypes. Germline BRCA1/2 mutations are the best predictor of response to DNA repair targeting agents like PARP inhibitors.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- DNA repair targeting is a key therapeutic strategy in breast cancer.
- This is particularly relevant for BRCA1/2-mutated cancers and those with a "BRCAness" phenotype, including triple-negative breast cancer.
- Homologous recombination deficiency (HRD) assays aim to predict response to DNA repair targeting agents.
Purpose of the Study:
- To review the role of DNA repair targeting in breast cancer therapy.
- To highlight the predictive value of germline BRCA1/2 mutations for therapeutic efficacy.
- To discuss current and emerging therapeutic agents and combinations.
Main Methods:
- Review of pre-clinical and clinical studies on DNA repair targeting agents.
- Analysis of phase III trial data for PARP inhibitors in BRCA1/2-mutated advanced breast cancer.
- Evaluation of novel chemotherapeutic agents and combination therapies.
Main Results:
- Germline BRCA1/2 mutations are the strongest predictor of response to DNA repair targeting agents.
- Clinical data confirm pre-clinical findings of sensitivity to DNA damaging agents like platinum salts.
- Phase III data support the use of PARP inhibitors in BRCA1/2-mutated advanced breast cancer.
Conclusions:
- Targeting DNA repair pathways, particularly homologous recombination, is effective in specific breast cancer subtypes.
- PARP inhibitors represent a significant advancement, with ongoing research into novel agents and combinations with immunotherapy and other biological agents.
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