San Antonio Breast Cancer Symposium 2014
TNT: A Randomized Phase III Trial of Carboplatin compared with Docetaxel for Patients with Metastatic or Recurrent Locally Advanced Triple Negative or BRCA 1/2 Breast Cancer.
A Tutt, et al.
It is clear that triple negative breast cancer (TNBC) is a heterogeneous classification to which various subtypes, including BRCA 1 or 2 mutated breast cancers, are included. At present, TNBC lacks a standard defined targeted therapeutic strategy, other than conventional cytotoxic agents. This phase III trial, TNT, was the 1st phase III RCT to compare single agent platinum chemotherapy to a single agent taxane therapy in TNBC, with a priori planned subgroup analyses in BRCA 1/2 mutated breast cancer and the basal like subtype.
376 patients (across 74 UK centres) were randomized to either carboplatin (AUC 6) q3 weekly for 6 cycles or docetaxel 100 mg/m2 q 3 weekly for 6 cycles. Upon progression, cross-over to the other arm was encouraged. The primary end-point was overall response rate (ORR) at cycle 3 or 6. Overall, the two treatment arms were relatively well balanced with 8% of the population having a known BRCA 1/2 mutation, 33% having received an adjuvant taxane and 53% having visceral disease. Median follow up on study was 11 months.
* Prior to implementation of mandatory primary GCSF prophylaxis in docetaxel arm
CARE Faculty Canadian Perspective:
· In an unselected triple negative MBC population, the use of either docetaxel at 100 mg/m2 or carboplatin (AUC 6) demonstrated similar efficacy in terms of response rate, time to progression and overall survival.
· However docetaxel at 100 mg/m2 is not deliverable with palliative intent, for the rate of febrile neutropenia was significantly higher (25%) at this dose such that the study subsequently mandated the use of primary prophylaxis with growth factors.
· In BRCA 1 or 2 mutated breast cancer, the platinum was superior in terms of response rate and time to progression. This finding supports the biology of inherent DNA repair deficiency in BRCA 1/2 mutated breast cancers and leveraging this ‘Achilles Heel’ with a platinum salt. Future studies should incorporate PARP inhibitors and platinum salts in BRCA 1/2 mutated tumours.
· In unselected triple negative MBC, the prognosis with conventional chemotherapy is still poor with a median PFS of 3-4 months and median OS of 12 months only. We desperately need to identify actionable targets, based on biology, and study novel therapeutics in this cohort of patients.
· The role of immunotherapy (e.g. PDL1 and PD1 antibodies) in TNBC brings significant interest and excitement. While early data suggests a possible role (Abstract S1-09 2), randomized trials with clinically relevant end-points are needed.
- CARE Breast Cancer Faculty
1. TNT: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 breast cancer. Tutt A, Ellis P, Kilbum L, et al. San Antonio Breast Cancer Symposium 2014.
2. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Nanda R, Chow LQ, Dees EC, et al. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract S1-09.