TNT Trial Supports Platinums in BRCA-Mutated Breast Cancer


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Andrew Tutt, MB, ChB, PhD, MRCP, FRCR

TNT Trial

Although the TNT trial gave no evidence to support superior activity of carboplatin over docetaxel in unselected triple-negative breast cancer patients, the results for germline BRCA-positive patients supported their greater sensitivity to carboplatin.

—Andrew Tutt, MB, ChB, PhD, MRCP, FRCR

The TNT trial, presented at the 2014 San Antonio Breast Cancer Symposium, provided no evidence that unselected advanced triple-negative breast cancer patients are more likely to respond to carboplatin than to docetaxel.1 However, patients with BRCA1/2 mutations do have a greater response and a longer progression-free survival with carboplatin, according to Andrew Tutt, MB, ChB, PhD, MRCP, FRCR, of Kings College and Institute of Cancer Research London.

“The TNT trial supports BRCA1/2 genotyping to inform therapy choice in metastatic triple-negative breast cancer and familial breast cancer,” Dr. Tutt said.

TNT Details

Subgroups within triple-negative breast cancers appear to share impaired DNA repair mechanisms—in particular, homologous recombination repair deficiency (HRD)—with BRCA1/2 germline mutation–positive patients. This impairment is thought to confer sensitivity to platinum agents. The TNT trial tested this hypothesis in women with recurrent locally advanced or metastatic BRCA-positive tumors or triple-negative breast cancer.

According to Dr. Tutt, TNT is the first study to directly compare single-agent platinum chemotherapy with the mechanistically distinct taxanes in these populations. The study included 376 patients (91% with metastatic disease) from 74 centers in the United Kingdom. A total of 43 mutations were identified. A BRCA1/2 germline mutation was noted for 9% of the carboplatin arm and 6.4% of the docetaxel arm.

Patients were randomly assigned to receive carboplatin (area under the curve of 6 every 3 weeks) or docetaxel (100 mg/m2 every 3 weeks) for 6 to 8 cycles or until disease progression, with crossover possible on disease progression. The primary endpoint was intent-to-treat objective response rate to cycle 6. TNT aimed to detect a 15% improvement in response with carboplatin compared with docetaxel.

Unselected Population

After a median follow-up of 11 months, objective responses were observed in 59 of 188 patients (31.4%) in the carboplatin arm and 67 of 188 patients (35.6%) in the docetaxel arm, for an absolute difference of –4.2% (carboplatin response rate minus docetaxel response rate; 95% confidence interval [CI] = –13.7% to 5.3%), which was not statistically significant (P = .44). Similarly, after crossover (n = 182), the response rates were 2.8% higher for the docetaxel cohort crossing over to receive carboplatin (95% CI = –9.6% to 15.2%), but again, this was not statistically significant (P = .73).

The median progression-free survival was 3.1 months (95% CI = 2.5 to 4.2) in the carboplatin arm and 4.5 months (95% CI = 4.1 to 5.2) in the docetaxel arm (P = .29). The median overall survival was 12.4 months (95% CI = 10.4 to 15.3) and 12.3 months (95% CI = 10.5 to 13.6) respectively (P = .31), Dr. Tutt reported.

BRCA1/2-Positive Population

Among the 43 BRCA-positive patients, however, a difference emerged between the regimens. The objective response rate was 68% with carboplatin and 33% with docetaxel, a 34.7% absolute difference (95% CI = 6.3% to 63.1%), which was statistically significant (P = .03). In contrast, for the 273 BRCA-negative patients, response rates were not significantly different at 28.1% and 36.6% (absolute difference = –8.5%, 95% CI = –19.6% to 2.6%), respectively (P = 0.16).

“Carboplatin demonstrated significantly increased activity vs docetaxel in BRCA carriers, and there was a positive test for the interaction between the randomization arm and BRCA1/2 status (P = .01),” Dr. Tutt noted.

This finding was obvious by the difference observed in the carboplatin arm according to BRCA status: BRCA-positive patients had a median progression-free survival of 6.8 months (95% CI = 4.4 to 8.1), compared with 3.1 months (95% CI = 2.4 to 4.2) in patients with nonmutated BRCA receiving carboplatin. The differences were not seen with docetaxel.

“In the metastatic setting, it’s important to know the BRCA status of patients and for a platinum to be considered among their treatment options,” Dr. Tutt said.

HRD Score Findings

The HRD score was available for 195 patients, with 81 patients classified as HRD “high” (≥ 42) and 114 as HRD “low” (< 42). (For 25 patients, the test failed.) Dr. Tutt explained that this score was the mean of three analyses by Myriad Genetics and is now the company’s published cut-point.

“The dichotomized HRD score did not select for sensitivity to carboplatin over docetaxel when conducted on the primary tumor DNA,” Dr. Tutt indicated. “BRCA1/2-mutant tumors, as expected, had high HRD scores.”

Response rates were 38.2% in HRD-high patients receiving carboplatin and 42.6% for those receiving docetaxel (absolute difference = –4.4%, 95% CI = –26.0% to 17.2%, P = .82). Among the HRD-low patients, response rates were 29.2% to carboplatin and 34.7% to docetaxel (absolute difference = –5.4%, 95% CI = –22.7% to 11.9%, P = .55).

The investigators proposed that nonmutated HRD-high cancers may more frequently reverse the homologous repair defect in metastases than mutated tumors.

“We feel that further development of homologous recombination defect assays for BRCA status in non-BRCA1/2 tumors is required, especially in the metastatic setting,” Dr. Tutt suggested.

The investigators also observed similar performance between carboplatin and docetaxel in both core basal-like (by central immunohistochemistry) and PAM50-based Prosigna assay basal-like subgroups. However, in the nonbasal subtype by the PAM50-based Prosigna assay, response to docetaxel was much greater than to carboplatin: 73.7% vs 16.7% with carboplatin (absolute difference = –55.5%, 95% CI = –82.4% to –28.6%, P = .01) The test for interaction was significant (P = .01).

“Although the TNT trial gave no evidence to support superior activity of carboplatin over docetaxel in unselected triple-negative breast cancer patients, the results for germline BRCA-positive patients supported their greater sensitivity to carboplatin,” Dr. Tutt concluded. ■

Disclosure:  Dr. Tutt reported no potential conflicts of interest.

Reference

1. Tutt A, et al: The TNT trial. 2014 San Antonio Breast Cancer Symposium. Abstract S3-01. Presented December 11, 2014.

 

 


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