Immunohistochemical (IHC) prediction of lapatinib efficacy in HER2-positive advanced breast cancer patients.

Konference: 2014 50th ASCO Annual Meeting - účast ČR

Kategorie: Zhoubné nádory prsu

Téma: Postery

Číslo abstraktu: 639

Autoři: M.D. Renata Duchnowska, Ph.D.; Piotr Jan Wysocki; Konstanty Korski; Bogumila Czartoryska-Arlukowicz; M.D. Anna Niwińska, Ph.D.; Marlena Orlikowska; Barbara Radecka; M.D. Maciej Studzinski; Doc. MUDr. Regina Demlová, Ph.D.; Barbara Ziolkowska; Monika Merdalska; Lukasz Hajac; Paulina Mysliwiec; Dorota Zuziak; Sylwia Debska; Prof. Dr. István Lang; Malgorzata Foszczynska-Kloda ; Anna Kowalczyk; Wojciech Biernat; prof. dr hab. n. med. Jacek Jassem


Background: Molecular mechanisms of resistance to lapatinib are not well understood. We analyzed retrospectively expression of six potentially useful biomarkers and correlated their status with clinical efficacy of lapatinib. 

Methods: Study group included 199 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine after progression of trastuzumab-based therapy. Expression of MAP-K, pAMPK alpha2, HIF-2 alpha, p-P70S6K alpha, cyclin E and PTEN in tumor samples of primary tumor was investigated by IHC using tissue microarray technology and industrial kits. Staining H-score was calculated for all markers as percent of stained tumor cells x average staining intensity graded from 0 to 3, resulting in a score value between 0 and 300. The most discriminative cut-off values (Cox regression) were subjected to multivariate analysis considering other predictive variables. 

Results: Median duration of lapatinib therapy was 6 months (range 0-52). In 82% of patients lapatinib therapy was discontinued due to disease progression. Using best discriminative values, expression of p-P70S6K alpha (P=0.014) and cyclin E (P=0.05) was predictive for progression free survival (PFS), the primary endpoint, and their predictive value was confirmed in the multivariate analysis (HR 0.44; 95%CI 0.24-0.80;P=0.007 and HR 1.87; 95% CI 1.09-3.21; P=0.024, respectively). PFS was also associated with the presence of brain metastasis (HR 1.79; 95% CI 1.28=2.49; P=0.001). Overall survival (OS) was associated with expression of cyclin E (p=0.015), p-P70S6K alpha (P=0.021), PTEN (P=0.034) and pAMPK alpha2 (P=0.020), of which cyclin E and MAP-K were confirmed in multivariate analysis (HR 3.66; 95%CI 1-55-8.81; P=0.003 and HR 1.59; 95%CI 1.12-2.27; P=0.010, respectively). Another independent determinant of OS was the presence of brain metastasis (HR 1.69; 95% CI 1.17-2.40;P=0.005). 

Conclusions: Clinical efficacy of lapatinib is associated with activity of downstream signaling pathways – PI3K/AKT/mTOR and MAPK, that seem to play opposite roles. Further investigation may indicate potential role of combining lapatinib with MAP pathway inhibitors.

J Clin Oncol 32:5s, 2014 (suppl; abstr 639)

Datum přednesení příspěvku: 2. 6. 2014