Multi-institutional retrospective analysis of clinical and pathological factors predicting resistance to lapatinib-based therapy in HER2 positive metastatic breast cancer (HER2+ MBC)

P5-19-25Background The combination of the dual HER1/HER2 inhibitor lapatinib (L) and capecitabine (C) is a therapeutic option for patients (pts) with HER2+MBC whose disease progresses after treatment with the monoclonal antibody trastuzumab. At present time, no clinical or pathological factors except HER2 status are clearly recognized as predictors of the activity of LC. We conducted a retrospective analysis of pts with HER2-positive metastatic breast cancer receiving LC after trastuzumab failure to identify factors associated with resistance to LC. Materials and methods We collected clinical and pathological data from 151 pts with HER2+ MBC receiving LC after failing a prior trastuzumab-based treatment (either adjuvant or for metastatic disease) treated at 13 Italian Institutions between March 2007 and December 2013. Time to progression (TTP) and overall survival (OS), calculated by the Kaplan Meier (KM) method, were from LC treatment beginning to disease progression or to death in the absence of progression (TTP), and to the date of death or to the date of last follow-up (OS), respectively. LC resistance was defined as TTP from treatment initiation lower or equal to the median TTP for the overall population. KM curves were compared by the Log-rank test. Logistic regression analysis was used to study predictors of TTP below the median value for patients receiving LC. Analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL). Results At a median follow-up of 41 months (IQR 23-62), median TTP to LC therapy was 7 months (IQR 5.5-8.5) and median OS was 18 months (IQR 10-28). Fifteen pts were excluded because of short follow-up (i.e. on LC treatment and <7 months of fu). Of the remaining 136, a total of 74 pts with a PFS≤7 months were defined LC-resistant (LC-R) and a total of 62 pts were defined LC-sensitive (LC-S). All clinical and pathological variables analyzed resulted evenly distributed between the two groups, except best tumor response (CR+PR) to LC, which was higher in patients with LC-S disease (72% vs 29%, p<0.001). Conversely, best tumor response in LC-R patients showed higher rates of PD (43% vs 2%, p<0.001). Median OS was 14 months (IC 95% 11.4-22.6) and 26 months (IC 95% 22.5-29.5) in LC-R and LC-S pts, respectively (p<0.001). Although we could not find independent predictors of LC-R, factors indicating failure of the first-line trastuzumab based therapy, as PD as best tumor response and short duration of first-line trastuzumab, were associated to LC-R. Conclusions A short time to progression during capecitabine and lapatinib (LC-R) is associated with reduced OS in patients failing prior trastuzumab based therapy for HER2+ MBC. Patients who had modest clinical benefit from previous trastuzumab-based therapy could experience LC-R indicating the possibility of primary resistance to anti HER2-treatment. For these patients, alternative targeting strategies are urgently needed.