Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal-encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice
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Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II–III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR.
Patients received six cycles of TLC-D99 (50 mg/m2 every 3 weeks), paclitaxel (80 mg/m2 weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla.
Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5 % of patients and 14.5 % had inflammatory BC. Conservative surgery was performed in 46.8 % of the patients and pCR was achieved in 63 % (95 % CI 50.5–75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5 %; P = 0.028). Forty-five patients (72.6 %) completed study treatment and 80.6 % received at least five treatment cycles. No patients developed congestive heart failure and 14.5 % of patients showed a ≥10 % decrease in the left ventricular ejection fraction.
The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.
KeywordsAntibodies Breast neoplasm Drug therapy Prospective study Treatment outcome
The authors thank HealthCo (Madrid, Spain) for assistance in the preparation of this manuscript. The financial support of this project was provided by Teva Pharma. Editorial assistance was provided by Mary Hines of inScience Communications, Springer Healthcare; this assistance was also funded by Teva Pharma.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Bear HD, Anderson S, Smith RE et al (2006) Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol 24(13):2019–2027PubMedCrossRefGoogle Scholar
- 9.Fernandez-Morales LA, Segui MA, Andreu X et al (2007) Analysis of the pathologic response to primary chemotherapy in patients with locally advanced breast cancer grouped according to estrogen receptor, progesterone receptor, and HER2 status. Clin Breast Cancer 7(7):559–564PubMedCrossRefGoogle Scholar
- 14.Coudert BP, Largillier R, Arnould L et al (2007) Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. J Clin Oncol 25(19):2678–2684PubMedCrossRefGoogle Scholar
- 17.Buzdar AU, Ibrahim NK, Francis D et al (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23(16):3676–3685PubMedCrossRefGoogle Scholar
- 18.Buzdar AU, Valero V, Ibrahim NK et al (2007) Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 13(1):228–233PubMedCrossRefGoogle Scholar
- 19.Gianni L, Eiermann W, Semiglazov V et al (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375(9712):377–384PubMedCrossRefGoogle Scholar
- 20.Batist G, Ramakrishnan G, Rao CS et al (2001) Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19(5):1444–1454PubMedGoogle Scholar
- 22.O’Brien ME, Wigler N, Inbar M et al (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15(3):440–449PubMedCrossRefGoogle Scholar
- 25.Chang JCN, Mayer IA, Forero-Torres A et al (2011) TBCRC 006: A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer [abstract]. J Clin Oncol 29(15 suppl):505Google Scholar
- 29.Untch M, Fasching PA, Konecny GE et al (2011) Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 29(25):3351–3357PubMedCrossRefGoogle Scholar
- 30.Antón A, Ruiz A, Plazaola A, Calvo L et al (2011) Phase II clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neoadjuvant treatment in stages II and IIIA HER2-overexpressing breast cancer patients. GEICAM 2003-03 study. Ann Oncol 22(1):74–79PubMedCrossRefGoogle Scholar
- 32.Gianni L, Pienkowski T, Im YH et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32PubMedCrossRefGoogle Scholar
- 36.Hyams D, Leichman G, Klein P (2009) Phase II trial of neoadjuvant pegylated liposomal doxorubicin with paclitaxel and trastuzumab in patients with operable Her-2-positive breast cancer. Cancer Res. 69 (suppl 24) Abstract 1098Google Scholar
- 40.Kanter PM, Bullard GA, Ginsberg RA et al (1993) Comparison of the cardiotoxic effects of liposomal doxorubicin (TLC D-99) versus free doxorubicin in beagle dogs. Vivo 7(1):17–26Google Scholar
- 41.Kanter PM, Klaich G, Bullard GA et al (1994) Preclinical toxicology study of liposome encapsulated doxorubicin (TLC D-99) given intraperitoneally to dogs. Vivo 8(6):975–982Google Scholar
- 43.Burris HA 3rd, Hurwitz HI, Dees EC et al (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23(23):5305–5313PubMedCrossRefGoogle Scholar
- 45.Spector NL, Blackwell K, Hurley J, et al. (2006) EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response. J Clin Oncol. 24 (suppl 18): Abstract 502Google Scholar
- 46.Storniolo AM, Burris H, Pegram M, et al. (2005) A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen. J Clin Oncol. 23 (suppl 16): Abstract 559Google Scholar
- 51.Allison DE, Malik M, Qureshi F (2003) Pharmacokinetics of HER2-targeted rhuMAb 2C4 (pertuzumab) in patients with advanced solid malignancies: phase Ia results. Proc Am Soc Clin Oncol 22:197 Abstract 790Google Scholar
- 56.Buzdar A, Suman VJ, Meric-Bernstam FA, et al. (2013) ACOSOG Z1041 (Alliance): definitive analysis of randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P + T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P + T → FEC + T) in HER2 + operable breast cancer [abstract 502]. J Clin Oncol. 31(Suppl)Google Scholar
- 57.Ewer M, Suman VJ, Buzdar A, et al. (2013) ACOSOG Z1041 (Alliance): cardiac events (CE) among those receiving neoadjuvant anthracyclines (A) and taxanes with trastuzumab (T) for HER2 + breast cancer [abstract 526]. J Clin Oncol. 31(Suppl)Google Scholar
- 58.Schneeweiss A, Chia S, Hickish T (2011) Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II Study (TRYPHAENA). Cancer Res 71(suppl 24):112s Abstract nr S5–6Google Scholar