Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015-01-01
Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance).
Abstract
Purpose
One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab.
Patients and methods
Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed.
Results
Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated.
Conclusion
In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.
Related Questions
Would you proceed to anthracycline based neoadjuvant regimen for locally advanced triple negative breast cancer without clinical response to neoadjuvant paclitaxel or proceed to surgery?
While a lack of response to paclitaxel (don't you now wish that you had added carboplatin?) is concerning and could indicate that the patient has a type of TNBC that responds poorly to chemotherapy, such as AR+, the patient may respond to a different chemo regimen and thus you should proceed to trea...
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...
How do you manage therapy in an elderly, >80 years of age, patient with triple-negative breast cancer that is not a surgical candidate?
Treatment decisions for these patients can best be made based on geriatric assessment, estimated life expectancy, whether the treatment goal is prolonged survival or palliation, the potential benefits and toxicities of a specific treatment, and the patient’s personal goals for treatment. The number ...
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...