Abstract P5-20-18: Comparison of paclitaxel plus T-DM1 and pertuzumab versus paclitaxel plus trastuzumab and pertuzumab with carboplatin for HER2 overexpressed breast cancer models
Authors: Sun Y , Lin X , Jepperson T , Williams C , De P , Leyland-Jones B 
Published: February 2018

Background: Remarkable progressions have been made in the breast cancer treatments over the past years, however, patients getting relief from the toxicity of cancer treatments are still unmet needs. The neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab is standard choice for patients with HER2 positive breast cancer (Phase III results of the KRISTINE trial, SA Hurvitz et al., 2016). Trastuzumab emtansine (T-DM1) plus pertuzumab (P) has shown superior anti-tumor effect comparing with trastuzumab/Herceptin (H) plus P in preclinical HER2 positive breast cancer models (Y Sun et al., 2013). In this study we aimed to evaluate the preclinical efficacy of paclitaxel (T) plus T-DM1 and P versus paclitaxel plus H and P with carboplatin (C) (TCHP) in HER2 positive breast cancer models. Methodology: 1) HER2 amplified/overexpressed with ER+ BT474 (H- sensitive) and BT474HerR, an H-resistant derivative from BT474, were used. 2) 6-7 week-old female NCr (nu/nu, 20-25g) athymic mice (Taconic) were used for in vivo tumor growth inhibition studies. 3) Mice were injected s.c. on the flank with 5 x 106 BT474 or BT474HerR cells. All mice were also received s.c. injection of 1 mg/kg estradiol valerate (JHP Pharmaceuticals) once weekly to promote tumor cell growth. 4) Mice bearing BT474 or BT474HerR tumors were treated with different combinations of T (20 mg/kg, i.v., every 4 days, total 7 doses), C (40 mg/kg, i.v., one dose), H (10 mg/kg, i.p., twice weekly for 4 weeks), T-DM1 (10 mg/kg, i.v., every 3 weeks, total 3 doses) and P (15 mg/kg, i.p., once weekly for 8 weeks) versus vehicle control. 5) In vivo data were analyzed by Student's t-test. A p-value of 0.05 was considered statistically significant. Results: We observed that 1) both regimens of TCHP and paclitaxel plus T-DM1 and P inhibited tumor growth in BT474 (TCHP p&lt;0.0043 vs. T+T-DM1+P p&lt;0.0025) and BT474HerR (TCHP p&lt;0.00044 vs. T+T-DM1+P p&lt;0.000037) xenograft models; 2) T+T-DM1+P caused almost complete regression in both models (comparing to 1 day before treatment started, the mean tumor volume at the end of study was decreased ˜ 91.13% in BT474 model and ˜ 100% in BT474HerR model) whereas TCHP caused significant tumor growth inhibition in both models (comparing to 1 day before treatment started, the mean tumor volume at the end of study was decreased ˜ 74.6% in BT474 model and ˜ 73.31% in BT474HerR model). Conclusion: Our in vivo data suggest that 1) T+T-DM1+P shows equivalent excellent antitumor activity to TCHP in HER2 overexpressed BT474 model; 2) T+T-DM1+P shows superior antitumor activity to TCHP (p&lt;0.0045) in HER2 overexpressed BT474HerR model; 3) comparing to TCHP, the combination of T+T-DM1+P may have better safety profile in patients.

Citation Format: Sun Y, Lin X, Jepperson T, Williams C, De P, Leyland-Jones B. Comparison of paclitaxel plus T-DM1 and pertuzumab versus paclitaxel plus trastuzumab and pertuzumab with carboplatin for HER2 overexpressed breast cancer models [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-18.