Lancet Oncol. 2014-06-01
Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.
Abstract
Background
Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.
Methods
Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880.
Findings
296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5.
Interpretation
The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.
Funding
GlaxoSmithKline, Roche, and Teva.
Related Questions
Would you consider omitting platinum from neoadjuvant chemotherapy in women > 50 years of age with localized triple negative breast cancer?
I would not use the results cited above from the >50 subgroup (which was just 30% of their study population) of the study from the Tata Memorial Centre to justify omission of carboplatin from the neoadjuvant regimen for TNBC in otherwise healthy patients over 50 with TNBC. There is compelling data f...
Would you consider avoidance of AC and proceeding to surgery in a cT2N0 TNBC patient who achieves a significant clinical response to carboplatin, paclitaxel, and pembrolizumab as part of the KEYNOTE-522 regimen?
Full disclosure -- I trained in breast cancer at UCLA, where we generally avoid anthracyclines. The main downside of adding an anthracycline to a taxane-based regimen is the elevated risk of leukemia, myelodysplasia, and congestive heart failure or weakening of the heart long-term. I use neoadjuvant...
Would you treat a premenopausal woman with T2N0 ER-, PR+ (15-20%), HER2- breast cancer with neoadjuvant chemotherapy like a triple negative breast cancer?
Yes, I would treat this patient with neoadjuvant chemotherapy as I would for a "triple-negative" breast cancer as certainly the biopsy of an ER 0%, weakly PR positive tumor is similar. I would not send an OncoType on this tumor - if it was low or intermediate, I still would not trust this patient wo...
Which neoadjuvant chemotherapy regimen would you use in a young, premenopausal woman with a rapidly growing clinical node positive poorly differentiated TNBC with a germline PALB2 mutation?
My preference is 2) weekly paclitaxel/carboplatin followed by AC, with adjuvant capecitabine if residual disease. There is no doubt that the addition of carboplatin increases the pCR rate in TNBC, and data from GeparSixto and patients on CALGB 40603 in whom doses of paclitaxel/carboplatin were not o...
In what scenarios would you incorporate platinum for patients with localized TNBC?
In the neoadjuvant setting, I include a platinum - specifically carboplatin - in the chemo regimen in essentially all patients with TNBC. Not only have 3 randomized studies (CALGB 40603, BrighTNess and GeparSixto) demonstrated significantly higher pCR rates with addition of carboplatin, if you look ...
How would you manage a patient with synchronous breast and ovarian cancer, s/p neoadjuvant chemotherapy and surgery for ER+/HER2- breast cancer and found to have an ER+ ovarian cancer nodal metastases at TAH/BSO?
I usually treat my triple negative breast cancer patients (whether or not there's a deleterious mutation in the homologous recombination repair pathway, e.g. BRCA1 or BRCA2) with neoadjuvant docetaxel + carboplatin. The addition of carboplatin to taxane-based neoadjuvant chemotherapy regimens was ev...
Would you consider using an anthracycline-based regimen again for a breast cancer patient who previously received doxorubicin 10 years prior?
I would not re-treat with an anthracycline for several reasons. She is at higher risk of heart failure (HF) by virtue of the prior exposure to anthracyclines, and you couldn't get in standard course of anthracyclines because of quickly exceeding the 450 mg/m2 limit where the risks HF increase dramat...
How do you choose a neoadjuvant therapy regimen for a patient with a triple negative breast cancer and a synchronous ER-/Her2+ breast cancer?
Assuming there is no contraindication to administration of an anthracycline, I would favor weekly paclitaxel and weekly carboplatin with every 3 week trastuzumab and pertuzumab x 12 weeks followed by ddAC x 4. This gives the TNBC the benefit of the higher pCR rate seen with the addition of carboplat...
Do you incorporate carboplatin into the treatment for triple negative breast cancer?
In the neoadjuvant setting, I recommend the addition of carboplatin in all patients (unless medically contraindicated) with stage IIA or higher TNBC. There are now 3 randomized studies - CALGB 40603, GeparSixto and BrighTNess - that have demonstrated significantly higher pCR rates with carboplatin t...
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, h...