Summary
We conducted a phase I trial to determine the feasible dose for lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor, with paclitaxel and gemcitabine as a neoadjuvant treatment in HER2 positive patients. In this phase I dose-escalation study, cohorts of 3–6 HER2-positive operable breast cancer patients received lapatinib (1,000 mg/day or 1,250 mg/day PO) with paclitaxel (80 mg/m2) and gemcitabine (1,000 or 1,200 mg/m2) on days 1 and 8 every 21 days to determine the tolerable dosages. Among 13 patients enrolled, 12 (stage III; n = 11: stage II; n = 1) completed treatment and one withdrew consent. The recommended doses were 1000-mg/day lapatinib, 80-mg/m2 paclitaxel, and 1,000-mg/m2 gemcitabine. One patient developed dose-limiting grade 3 hepatotoxicity; 3 experienced dose-limiting grade 4 neutropenia. No notable decline in left ventricle ejection fraction occurred. Eight patients achieved clinical partial response and four achieved clinical complete response (CR). Three patients (25%) achieved both tumor and nodal pathologic CR, 5 (42%) achieved tumor pathologic CR, and 6 (50%) underwent breast-conserving surgery. No relationship between lapatinib dose intensity and tumor response was apparent. Median follow-up was 16.2 (range, 6.5–20.7) months. Lapatinib plus paclitaxel and gemcitabine was tolerable with no overlapping toxicity.
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Buchholz TA, Hunt KK, Whitman GJ, Sahin AA, Hortobagyi GN (2003) Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks. Cancer 98:1150–1160
Faneyte IF, Schrama JG, Peterse JL, Remijnse PL, Rodenhuis S, van de Vijver MJ (2003) Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome. Br J Cancer 88:406–412
Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, Smith TL, Asmar L, Frye D, Manuel N, Kau SW et al (1999) Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412–3417
Marchetti P, Urien S, Cappellini GA, Ronzio G, Ficorellar C (2002) Weekly administration of paclitaxel: theoretical and clinical basis. Crit Rev Oncol Hematol 44:3–13
Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992
Yardley DA (2004) Gemcitabine and taxanes as a new standard of care in breast cancer. Clin Breast Cancer 4(Suppl 3):S107–112
Colomer R (2004) Gemcitabine and paclitaxel in metastatic breast cancer: a review. Oncology (Williston Park) 18:8–12
Colomer R, Llombart-Cussac A, Lluch A, Barnadas A, Ojeda B, Caranana V, Fernandez Y, Garcia-Conde J, Alonso S, Montero S, Hornedo J et al (2004) Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER2 extracellular domain. Ann Oncol 15:201–206
Delfino C, Caccia G, Gonzales LR, Mickiewicz E, Rodger J, Balbiani L, Morales DF, Comba AZ, Brosio C (2004) Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced breast cancer. Oncology 66:18–23
Lee KS, Ro J, Lee ES, Kang HS, Kim SW, Nam BH, Kwon Y, Kim EA, Shin KH (2010) Primary systemic therapy with intermittent weekly paclitaxel plus gemcitabine in patients with stage II and III breast cancer: a phase II trial. Invest New Drugs 28:83–90
Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M 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 23:3676–3685
Ro. J, Im. S, Lee. KS, Lee E, Kwon Y, Noh D, Park I, Ahn J, Kim J (2010) Phase II prospective multicenter study of preoperative paclitaxel, gemcitabine, and trastuzumab combination therapy in HER2-positive stage II/III breast cancer: KCSG BR07-01. Breast Cancer Symposium 2010
Nahta R, Yuan LX, Du Y, Esteva FJ (2007) Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther 6:667–674
Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitset M, Climent MA 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 375:377–84
Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C et al (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28:2024–31
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, Aura C, De Azambuja E, Gomez H, Dinh P, Fauria K, Van Dooren V, Paoletti P et al (2010) First Results of the NeoALTTO Trial (BIG 01-06/EGF106903): A Phase III, Randomized, Open Label, Neoadjuvant Study of Lapatinib, Trastuzumab, and Their Combination Plus Paclitaxel in Women with HER2-Positive Primary Breast Cancer [abstract]. San Antonio Breast Cancer Symposium Abstract 2010:S3–3
Untch M, Loibl S, Bischoff J, Eidtmann H, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Freienberg R, Tesch H, Hanusch C et al (2010) Lapatinib vs Trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based Chemotherapy: Primary Efficacy Endpoint Analysis of the GEPARQUINTO STUDY (GBG44) [abstract]. San Antonio Breast Cancer Symposium 2010:S3–1
Mackey J, Clemons M, Cote M, Delgado D, Dent S, Paterson A, Provencher L, Sawyer MB, Verma S (2008) Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol 15:24–35
Ewer SM, Ewer MS (2008) Cardiotoxicity profile of trastuzumab. Drug Safety 31:459–67
Jung SY, Kim SK, Nam BH, Min SY, Lee SJ, Park C, Kwon Y, Kim EA, Ko KL, Park IH, Lee KS et al (2010) Prognostic Impact of [18F] FDG-PET in operable breast cancer treated with neoadjuvant chemotherapy. Ann Surg Oncol 17:247–253
Dunnwald LK, Doot RK, Specht JM, Gralow JR, Ellis GK, Livingston RB, Linden HM, Gadi VK, Kurland BF, Schubert EK (2011) PET Tumor Metabolism in Locally Advanced Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy: Value of Static versus Kinetic Measures of Fluorodeoxyglucose Uptake. Clin Cancer Res 17:2400–09
Park J, Moon W, Lyou C, Cho N, Kang KW, Shung JK (2011) The assessment of breast cancer response to neoadjuvant chemotherapy: comparison of magnetic resonance imaging and 18 F-fluorodeoxyglucose positron emission tomograpy. Acta Radiol 52:21–8
Acknowledgements
We are grateful to the National Cancer Center for supporting this study under grant number 0910320. We would also like to acknowledge all participating patients, research coordinators, and the GSK for providing lapatinib.
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The authors declared that they have no conflicting interests.
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Park, I.H., Lee, K.S., Kang, HS. et al. A phase Ib study of preoperative lapatinib, paclitaxel, and gemcitabine combination therapy in women with HER2 positive early breast cancer. Invest New Drugs 30, 1972–1977 (2012). https://doi.org/10.1007/s10637-011-9759-5
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DOI: https://doi.org/10.1007/s10637-011-9759-5