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11-05-2018 | Breast cancer | News | Article

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Germline BRCA status may influence advanced TNBC chemotherapy choice

medwireNews: Testing for BRCA1 and BRCA2 mutations could inform the choice of chemotherapeutic agent in women with advanced triple-negative breast cancer (TNBC), suggest the results of the TNT trial.

In the phase III trial – conducted in 74 centers in the UK – 376 participants with TNBC were randomly assigned to receive up to eight cycles of carboplatin given to an area under the curve dose of 6 or docetaxel 100 mg/m2, both administered on the first day of each 3-weekly cycle.

Andrew Tutt, from The Institute of Cancer Research in London, UK, and team observed no significant difference in the objective response rate (ORR) between the carboplatin and docetaxel groups in the overall study population, at 31% versus 34%.

But among the 43 patients harboring germline BRCA1/2 mutations, carboplatin treatment was associated with a significantly higher ORR than docetaxel, with corresponding rates of 68% and 33%.

Progression-free survival was similarly significantly improved with carboplatin versus docetaxel in these patients, at a median of 6.8 and 4.4 months, respectively, but overall survival was comparable, albeit “with interpretation confounded by the preplanned crossover at progression,” say the authors.

They write in Nature Medicine that these findings “support BRCA1/2 germline testing to select patients for platinum chemotherapy for advanced disease.”

The TNT investigators also assessed the efficacy of the drugs in subgroups of patients with “features of aberrant BRCA1/2-associated function,” comprising those with BRCA1 methylation, BRCA1 messenger RNA-low tumors, or a high score on homologous recombination deficiency assays.

They postulated that carboplatin, which is a DNA-crosslinking agent, would have greater activity than the microtubule-disrupting drug docetaxel in patients who were deficient in DNA damage response. But this hypothesis was not supported by the results, which showed comparable outcomes with carboplatin and docetaxel in all of these subgroups.

Tutt et al therefore say that patients with advanced TNBC do not benefit from the characterization of BRCA1 methylation or homologous recombination deficiency “to inform choices on platinum-based chemotherapy.”

And they conclude: “[T]he TNT Trial provides evidence that a widely available, affordable off-patent biomarker […] has utility in selecting a population that could benefit during this period from the biologically targeted use of a highly active and inexpensive platinum chemotherapy agent rather than the current licensed standard-of-care chemotherapies for breast cancer.”

By Shreeya Nanda

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