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Study Links BRCA1/2 Germline Mutations to Platinum Drug Response in TNBC

NEW YORK (GenomeWeb) – Results from a study funded by Myriad Genetics, Breast Cancer Now, and Cancer Research UK suggest that the platinum-based, DNA crosslinking chemotherapy drug carboplatin is more apt to benefit triple-negative breast cancer (TNBC) patients who carry cancer-related germline mutations in BRCA1/2 genes.

The findings from the so-called TNT Trial support the notion that "many women with triple-negative breast cancer should be considered for testing for faults in the BRCA genes so those who test positive can benefit from carboplatin," corresponding and first author Andrew Tutt, a researcher affiliated with the Institute of Cancer Research Breast Cancer Now Research Centre and King's College London, said in a statement, noting that "this simple test enables us to guide treatment for women within this type of breast cancer." 

For their Phase III randomized trial, reported online today in Nature Medicine, Tutt and colleagues from the UK and US compared objective response rates in advanced TNBC cases treated with six to eight cycles of carboplatin or docetaxel, a taxane chemotherapy drug with a distinct mechanism of action. In the unselected arm of the study, where half of the 376 advanced TNBC patients received each drug, they saw overall survival rates of 31.4 percent in the carboplatin-treated group and 34 percent in the docetaxel-treated group.

When the team considered cases marked by germline BRCA1/2 mutations or tumor "BRCAness" — shared mutational signatures stemming from muted BRCA1 expression or other homologous recombination deficiency (HRD) — it found that the objective response rate rose to 68 percent in carboplatin-treated tumors from the 43 individuals with germline BRCA1/2 mutations compared to 33 percent in the other advanced TNBC cases.

"A pre-specified protocol enabled biomarker-treated interaction analyses in the [germline-mutated BRCA1/2 breast cancer] and BRCAness subgroups," the authors explained.

They noted that the carboplatin drug did not show the same enhanced effect in individuals with tumors from the broader BRCAness subgroups, including tumors with BRCA1 methylation, low BRCA1 expression, or a high score on Myriad's HRD assay.

Based on these results, Tutt and co-authors wrote that "patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy."

Beyond that, the team detected ties between docetaxel drug response in non-basal breast cancer tumors, which it attributed to poor platinum carboplatin response in the non-basal breast tumors without "targetable BRCAness." On the other hand, the authors noted that platinum treatment may be a "reasonable option in basal-like TBNC, particularly in those who fail to tolerate or have previously received taxane." 

"Women with triple-negative breast cancer often only survive for one to two years after the cancer has relapsed and spread to other parts of the body, so there is an urgent need to find alternative treatments for this group of patients," senior author Judith Bliss, a researcher with the ICR Clinical Trials and Statistics Unit, said in a statement. "Our study has shown that this doesn't have to mean developing new drugs. We can use existing — and often cheaper, generic — drugs more effectively by targeting treatment based on weaknesses in individual patients' tumors."