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BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial
Rebecca Byler Dann1, Julie A DeLoia, Kirsten M Timms
1Magee Womens Hospital of UPMC, Pittsburgh, PA 15213, USA.
Objective:
Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect patients with advanced epithelial ovarian cancer (EOH).
Methods:
BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24 patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers when normal tissue was available. BRCA expression was ascertained by quantitative rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed.
Results:
Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3% of the mutations were found to be somatic. Three mutations were novel. The majority of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total, 38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend toward platinum-sensitive disease was seen in BRCA mutation carriers (p=0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors (OR=0.29; p value=0.048).
Conclusions:
BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting the DNA repair pathway are being investigated.
Insights
BRCA1/2 mutations are more common in platinum-sensitive ovarian cancer, indicating a need for tumor profiling to guide DNA repair targeted therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Advanced epithelial ovarian cancer (EOC) often develops resistance to platinum-based chemotherapy.
- BRCA1 and BRCA2 mutations are implicated in DNA repair pathways and can influence treatment response.
Purpose of the Study:
- To determine the frequency of BRCA1/2 deficiency in platinum-sensitive versus platinum-resistant EOC.
- To explore the association between BRCA deficiency and platinum response in EOC patients.
Main Methods:
- BRCA1/2 mutation analysis was conducted on 53 patients with advanced EOC (29 platinum-sensitive, 24 platinum-resistant).
- Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assessed BRCA expression.
- Statistical analyses examined correlations between BRCA status, expression, and platinum response.
Main Results:
- BRCA1/2 mutations were identified in 28.3% of EOC tumors (15/53).
- Mutations were more prevalent in platinum-sensitive tumors (38%) compared to platinum-resistant tumors (17%).
- BRCA deficiency was associated with a lower likelihood of platinum-resistant disease (OR=0.29, p=0.048).
Conclusions:
- BRCA mutations are significantly more frequent in platinum-sensitive EOC.
- The substantial rate of BRCA deficiency in EOC highlights the importance of tumor genetic profiling for targeted therapy selection.
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