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Metastatic TNBC

No Improvement with Carboplatin Compared with Docetaxel—Study Did, However, Show Importance of Molecular Testing to Identify Responsive Subsets

Susman, Ed

doi: 10.1097/01.COT.0000461866.15246.07
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SAN ANTONIO—For patients with triple-negative breast cancer, treatment with carboplatin produced no advantage over use of docetaxel, according to a study reported at the San Antonio Breast Cancer Symposium. Still, there were hints that certain subgroups of patients, especially those with BRCA1 or BRCA2 mutations, could be identified and would be helped by one drug or the other.

“The TNT trial provides no evidence of superior response to carboplatin compared with docetaxel in unselected triple-negative breast cancer patients,” Andrew Tutt, MD, PhD, Clinical Consultant in Oncology and Professor of Oncology at King's College, London, said in his plenary presentation.

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However, pre-specified subset analyses appear to show that in certain groups of patients, distinguished by molecular and genetic testing, some women do better than others with carboplatin, and some women do better with docetaxel than with carboplatin, he said.

“Patients with BRCA1 or BRCA2 mutations experienced significantly greater responses and greater progression-free survival with carboplatin than with docetaxel. The TNT trial supports BRCA1 and BRCA2 genotyping to inform therapy choice in metastatic triple-negative breast cancer and familial breast cancer.”

On the other hand, other molecular tests showed mixed results in helping patients and clinicians in determining what treatments might be beneficial.

For example, Tutt said the researchers determined that “a dichotomized homologous recombination repair deficiency test (Myriad HRD) score did not select for sensitivity to carboplatin over docetaxel when conducted on primary tumor DNA in this metastatic context.

“Further development of homologous repair defect assays for BRCAness in non-BRCA1/2 tumors is required, especially in the metastatic treatment setting,” he said.

TNT (the Triple Negative Breast Cancer Trial) was funded by Cancer Research UK and Breakthrough Breast Cancer. The use of the Prosigna PAM 50 assay did not show differences between treatment with carboplatin or docetaxel in tumors expressing basal-like characteristics, Tutt continued.

“The apparent greater sensitivity of docetaxel over carboplatin in the Prosigna non-basal-like subgroup of locally defined triple-negative breast cancers needs further investigation. We intend to further analyze this group of non-basal-like tumors.”

In answer to a question from the audience, Tutt said he considered it now important to know the BRCA mutation status of patients with advanced breast cancer, particularly those with metastatic disease, and that platinum should be considered among the options available.

“I think it would be a strong step to say this study defines this as standard of care against which new interventions should be compared. But certainly this could be an option if the mutation status of the patient is known.”

Tutt said the research was aimed at determining if distinct subsets among women with BRCA1 and BRCA2 mutations and some triple-negative breast cancers are sensitive to platinum-based therapy as suggested by pre-clinical and some previous clinical data sets. “But no study has directly compared single-agent platinum chemotherapy with standard-of-care, mechanistically distinct taxanes in these populations of metastatic breast cancer patients.”

Tutt reported that at a median follow-up of 11 months, the results of the randomized, Phase III study determined that for the primary endpoint of objective response in the intention-to-treat analysis, there was no significant difference between the arms. A total of 31.4 percent of the patients on carboplatin achieved an objective response compared with 35.6 percent of patients on docetaxel.

About 50 percent of the patients in each group crossed over to the other drug as was permitted in the protocol; and in that group of 182 patients who did switch drugs, about 22 percent of those on carboplatin had an objective response compared with about 23 percent of those on docetaxel.

“There was no difference in progression-free survival, with the median progression-free survival of 4.5 months in the docetaxel patients and 3.1 months among those on carboplatin,” he said. “Overall survival was also not different between the groups—12.4 months for patients on carboplatin and 12.3 months for those on docetaxel.”

In the pre-specified BRCA1 and BRCA2 mutation carrier population of 43 individuals, the objective response to carboplatin was significantly greater than docetaxel—a 68 percent objective response with carboplatin compared with 33.3 percent with docetaxel. In the 273 patients with wild-type BRCA 1 or BRCA 2, 28.1 percent responded to carboplatin and 36.6 percent responded to docetaxel.

“The interaction between randomized treatment and BRCA mutation status was significant, indicating that in the BRCA mutation carriers, carboplatin has significantly greater activity when compared with docetaxel at its greatest licensed dose,” he said.

“In the carboplatin arm, the median progression-free survival was 6.8 months in the patients with BRCA mutations and 3.1 months in the patients with wild-type BRCA—those without mutations. The progression-free survival on docetaxel was not affected by BRCA mutation status.”

The progression-free survival of those with mutation in the genes was 4.8 months and 4.6 months in those with non-mutated BRCA.

In the pre-specified homologous recombination repair deficiency (HRD) analysis that included 195 of the 376 patients in the study, there was no significant difference between the performance of these two agents, with carboplatin patients with high scores showing an approximately 38 percent response and patients on docetaxel had an approximately 43 percent. In patients with low HRD scores who were on carboplatin, the rates were 29 percent and 35 percent, respectively. There was no significant interaction between treatment and HRD scores, Tutt said.

Tissue collected from 211 patients was tested using the Prosigna PAM50 analysis. The results showed basal-like features in 174 patients; non-basal like features in 36 patients; and undetermined features in one patient. “In the basal-like subset analysis the performance of the two agents was similar,” he said, and among the carboplatin patients with this subtype, about 33 percent had a response compared with about 35 percent of the docetaxel patients.

In the small group of 36 patients with non-basal-like tumor characteristics, about 17 percent responded to treatment with carboplatin and about 74 percent (13 of 18 patients) responded to treatment with docetaxel. “We need to exercise caution in interpreting these results in this subgroup,” Tutt said in response to a question from the audience after his presentation.

“This is a very small group of patients. I think we need to look at the detail behind that. I guess one might speculate that there are populations in the non-basal-like triple-negative group that in previous studies have shown high levels of chemotherapy sensitivity. We need to understand if this finding is real before we conclude too much.”

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Side Effects

Tutt reported that the toxicities were as anticipated. Febrile neutropenia and neuropathy were significantly greater among the docetaxel patients. About 26 percent of the patients on docetaxel developed febrile neutropenia compared with about two percent of those on carboplatin. Neuropathy was experienced by about seven percent of patients on docetaxel and about one percent of patients on carboplatin.

The incidence of febrile neutropenia was reduced markedly when the protocol was amended to include primary prophylaxis with granulocyte-colony stimulating factor in May 2011. Overall, carboplatin was better tolerated than docetaxel, he noted.

Asked for her opinion, Stephanie Bernik, MD, Chief of Surgical Oncology at Lenox Hill Hospital in New York, said: “The standard of care for metastatic triple-negative breast cancer is chemotherapy. Some clinicians advocate monotherapy and others advocate giving more than one agent at a time. The toxicity is higher when chemotherapeutic agents are combined.

“There has been some suggestion that platinum-based regimens may be of benefit, especially in BRCA1-positive women with triple-negative disease, but this study showed there was no benefit over at least one other chemotherapeutic agent.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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