Toxicities Can Be a Surrogate Predictive Marker for Lapatinib Efficacy in Patients with HER2 Positive Breast Cancer

Abstract

Background: Lapatinib (LAP), a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) 1/2, is active in HER2-positive metastatic breast cancer (MBC) that has progressed after trastuzumab (Tmab)-based therapy. Besides HER2, an optimal surrogate predictive biological marker has not been established for LAP efficacy. In this retrospective study, we searched for other clinical predicative makers except HER2 for LAP based treatment. Patients and Methods: Between June 2009 and November 2012, 66 HER2-MBC patients were treated with LAP and capecitabine (CAP) at our single institution. At a median follow-up of 13 months, mean age was 56.8 ( +/- 9.8) years and 40 of 66 patients had received prior adjuvant chemotherapy including 17 Tmab containing regimen. Visceral metastases were identified in 44, bone metastases in 32, and brain metastases in 15. The median number of chemotherapeutic lines for metastatic disease before LAP treatment was 2 (range: 0-8), and 57 of 66 patients had received prior Tmab containing regimen with 33 vinorelbine, 32 taxanes, 29 CAP, and 12 endocrine therapies.We evaluated a correlation between the incidence of any adverse events (AEs) or basal characteristics factors and clinical outcome of 66 patients after Tmab progression. Result(s): The median time to progression free survival (PFS) was 259 days in the LAP-CAP combination in Tmab-refractory 66 patients.We compared 18 patients with longer PFS (LPFS) who had more than 12-month to 22 shorter PFS (SPFS) who had less than 6-month. LPFS had more frequent incidence of diarrhea (p < 0.035), hand-foot skin reaction (HFSR) (p < 0.016), and skin rash (p < 0.024) than SPFS.We reevaluated the correlation of these 3 AEs and outcome in all 66 patients, HFSR and Diarrhea were statistically significant favorable factors (p = 0.0004 and 0.0275) in Log rank analysis. Skin rash had tendency of predictive value of efficacy (p = 0.007 in generalizedWilcoxon). Furthermore, median PFS of patients who had all 3 AEs (n = 19) were 365 days, while 84 days (n = 6) who had not (p= 0. 18 x 10-3).We did not find any other clinical predictive factors except 3 AEs. Conclusion(s): EGFR inhibitor related toxicities might be alternative predicative markers for LAP in HER2-MBC patients.