Do you add a platinum agent to neoadjuvant chemotherapy for triple negative breast cancer in BRCA 1/2 mutation carriers?

Several studies in the metastatic setting (e.g. the TNT trial) have suggested an improved response and progression free survival with platinums in BRCA –mutant breast cancer. In the neoadjuvant setting, a study of 107 women with breast cancer and BRCA1 mutation, treated with 4 cycles of cisplatin, had a pCR of 61% (Byrski T et al, 2014). Another study reported a pCR rate of 36% in 80 patients with TNBC treated with the carboplatin-gemcitabine combination, including 47% in patients with germline BRCA mutations (Telli, ML et al, 2015).

Interest in platinum agents emerged in BRCA mutants and sporadic TNBC breast cancer based on a high frequency of DNA repair defects in TNBC that may render TNBCs particularly susceptible to cross-linking agents. The GeparSixto and CALGB/Alliance 40603 trials prospectively examined the addition of platinum to neoadjuvant chemotherapy regimens in TNBC. Both trials demonstrated improved rates of pCR in breast/axilla with the addition of carboplatin in sporadic breast cancer not selected by mutation status. In GeparSixto, BRCA carriers had an increase in pCR by 25% (P=.005). The 2 studies included different chemo regimens and platinum dosing and had divergent results in terms of improved event- free survival. Also, both studies were considered underpowered for long-term outcome end points. There were added toxicities with the addition of carboplatin, such as increased grade 3-4 neutropenia and thrombocytopenia, requiring dosing adjustments of paclitaxel in the CALGB/Alliance trial.

The data for the addition of platinum to standard chemotherapy in the neoadjuvant setting are encouraging. However, given the complicating factors of toxicity and dosing, as well as unclear long-term benefit, platinum is not ready to be included in current standard neoadjuvant or adjuvant chemotherapy regimens for all patients with TNBC. It remains unclear how to incorporate platinum, and it is not known whether platinum could be used to substitute for anthracycline, taxane, or an alkylating agent rather than added to the current regimens.

Sequential anthracycline-taxane chemotherapy continues to represent a commonly used standard of care in TNBC, including BRCA mutant breast cancer. Several ongoing phase III studies may provide additional insight regarding platinum in the adjuvant and neoadjuvant setting and will hopefully provide additional insight on long-term outcomes (the ADAPT trial evaluating nab-paclitaxel in combination with either carboplatin or gemcitabine for patients with TNBC; the NRG BR003 study of adjuvant doxorubicin plus cyclophosphamide followed by weekly paclitaxel with or without carboplatin for node-positive or high-risk TNBC ).

Despite data suggesting that platinums are likely beneficial in patients with BRCA-mutant breast cancer, I believe that results from ongoing randomized trials in BRCA carriers through the Translational Breast Cancer Research Consortium (TCBRC) TBCRC trial 030 and TBCRC 031, should be awaited prior to including platinum agents in standard neoadjuvant regimens. Eventual results of these trials will examine pCR, long-term clinical response rate, toxicities and may provide more insight into how to incorporate platinum in this special subgroup.

Although the data right now are somewhat mixed for adding platinum to neoadjuvant chemotherapy for TNBC, I am impressed by the TNT trial comparing carboplatin to docetaxel in the subgroup of metastatic BRCA associated cancers. I usually use AC x 4 (q3w) followed by paclitaxel weekly x 12, and add carboplatin (AUC 1.5-2 qw) if the patient is BRCA positive.