Lapatinib or placebo plus letrozole as preoperative treatment of hormone receptor-positive HER2-negative operable breast cancer. Preliminary report of safety and activity of the double-blind randomized phase IIb LET-LOB study

Background: Crosstalk between hormone- and EGFR-family pathways is a possible cause of resistance to aromatase inhibitors (AI), as suggested by the increased expression of HER2, EGFR and MAPK in long-term estrogen-deprived breast cancer (BC) cells. Lapatinib (Lap) is an orally active small molecule inhibitor of EGFR and HER2 tyrosine-kinases. Combination of an AI and Lap in ER+/HER2- tumors could avoid the onset of resistance due to early stimulation of EGFR and HER2 pathways. To evaluate these effects, we designed an international multicenter phase IIb double-blind randomized trial in ER+/HER2- BC pts candidates for hormone neoadjuvant therapy. Methods: Postmenopausal pts with stage II-IIIa, HR+/HER2- BC are randomized to letrozole (Let; 2.5 mg/d) plus lapatinib (Lap; 1,500 mg/d) or placebo (P), given continuously for 24 weeks before surgery. Activity (with ultrasonographyc, US) and cardiac safety (with echocardiogram) assessment are performed after 12 and 24 weeks. Tissue biomarkers of hormone and EGFR-family related pathways are analyzed before and after treatment. An initial sample size of 42 pts will be enrolled assuming a 50% chance of cOR with Let+P and a 40% increase in cOR with the Let+Lap (equal to 70% absolute cOR). Additional 48 pts will be treated in case we observe 20 cOR in the first cohort (Simon's design). Results: 19 Italian and European centers are participating in the study. From April 2007, 28 pts have been randomized, and 15 pts were treated for at least 3 months (mo). Six pts completed the six mo treatment, and 4 underwent surgery. At diagnosis, mean US tumor size was 2.87 cm (range 2-6 cm). All pts were ER+ (73% ER+/PR+) and HER2-. No significant decrease in mean LVEF was observed at the 3-mo evaluation (60.9%-61.5%). No grade 3-4 toxicities were reported. A 34% absolute reduction in median longest US tumor diameter has been observed after 3 mo (15 pts) and 65% reduction has been obtained at 6 mo (6 pts). Updated blinded safety and activity results will be presented. Conclusions: The combination of Lap or P with Let in ER+/HER2-operable breast cancer was safe, without any early cardiac toxicity, and induced clear tumor shrinkage.