BRCA1 and BRCA2 mutation status predicts progression-free survival (PFS) in carboplatin-treated women with recurrent or metastatic triple-negative breast cancer (TNBC), according to findings from the randomized phase 3 TNT clinical trial (Triple Negative Breast Cancer Trial; ClinicalTrials.gov Identifier: NCT00532727) presented at the 2016 San Antonio Breast Cancer Symposium.1

“TNT supports rapid testing for germline mutation in BRCA1 and BRCA2 but not for BRCA1 methylation or BRCA1 mRNA silencing to guide treatment in metastatic TNBC,” said lead study author Andrew Tutt, MBChB, PhD, of the Institute of Cancer Research in London, England, on behalf of the TNT Trial Management Group and Investigators.

BRCA1 and BRCA2 germline mutation is associated with a significant interaction with response and PFS following carboplatin in metastatic breast cancer,” Dr. Tutt said.

Up to 40% of TNBCs harbor methylated BRCA1 genes, and CpG methylation is associated with transcriptional silencing of BRCA1 mRNA.

The authors tested the hypothesis that BRCA1 methylation is associated with carboplatin treatment outcomes in patients with TNBC.

They were able to analyze primary tumors for 191 patients, of which mRNA and methylation status data were available for 184. Sixty-six percent of methylated tumor samples were gene-silenced, Dr Tutt noted.

Objective response in mRNA-silenced BRCA1 was similar between carboplatin and docetaxel (P = 0.073 with a trend favoring docetaxel, not significant).

Epigenetic methylation silencing of BRCA1 was not associated with PFS for patients with advanced triple-negative breast cancer who received carboplatin, he added. “This is despite BRCA1 methylation association with high HRD [homologous recombination deficiency] in the primary tumor.”

“It is likely that epigenetic silencing is both heterogenous and reversible under the selective pressure of standard of care DNA-damaging adjuvant chemotherapy,” Dr Tutt said.

In subgroup analyses of BRCA mutation-status and average PFS, survival was longer in patients with BRCA mutations who were treated with carboplatin than BRCA-wildtype patients or BRCA-mutant status patients treated with docetaxel.

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The researchers hypothesized that DNA-damaging adjuvant chemotherapy causes loss of methylation via selection favoring non-methylated clones in methylation-heterogenous primary tumors, whereas BRCA gene mutations are usually retained, resulting in subsequent evolution of micrometastases into unmethylated macrometastatic tumor clones that are nonresponsive to platinum therapy and genetically-mutated clones that are responsive but are quickly outcompeted by resistant clones under platinum-therapy selection pressures.

Reference

  1. Tutt A, Cheang MCU, Kilburn L, et al. BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.