Serum-transforming growth factor-α (TGF-α) and response to lapatinib plus capecitabine in HER2-positive (HER2+) metastatic breast cancer (MBC).

Abstract

1102 Background: Although lapatinib plus capecitabine is effective in trastuzumab-resistant HER2+ MBC, predictive biomarker of the treatment has not been identified. We investigated biomarkers from serum of patients receiving lapatinib and capecitabine. Methods: Patients received lapatinib 1,250 mg once daily and capecitabine 2,000 mg/m2/day, day 1 to 14, every 3 weeks. Serum samples were obtained prior to treatment initiation. Levels of TGF-α, EGF, EGFR-extracellular domain (ECD) and HER2-ECD were measured by ELISA. We analyzed the association between the serum levels and response to the treatment. Besides, the effect of TGF-α on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated. Results: A total of 64 women were enrolled. All patients had HER2+ MBC and had progressed after trastuzumab containing regimen. The overall response rate was 31.3% and median TTP was 4.5 months in the study population. Among the serum markers, serum TGF-α level was significantly lower in responders (PR) compared to nonresponders (SD or PD) (median, 3.5 vs. 8.2 pg/mL; p=0.005). The EGFR-ECD level tended to be lower in responders than nonresponders (median, 21.9 vs. 24.9 ng/mL; p=0.190). The response rate was significantly higher in patients with low (≤3.75 pg/mL) than high TGF-α [61.1% (11/18) vs. 19.6% (9/46), respectively; p=0.001]. The response rate was also significantly higher in patients with low (≤22.2 ng/mL) than high EGFR-ECD [50.0% (11/22) vs. 21.4% (9/42), respectively; p=0.019]. In multivariate analysis adjusting for baseline characteristics, low serum TGF-α (adjusted OR, 17.1; 95% CI, 3.19 - 91.7) and low EGFR-ECD (adjusted OR, 10.7; 95% CI, 2.07 - 55.1) were independent predictive factors for response. Patients with low TGF-α tended to have longer TTP than those with high TGF-α [median, 6.5 (95% CI, 6.1-6.8) vs. 3.8 months (95% CI, 2.3-5.4); p=.067]. We confirmed that TGF-α diminished the sensitivity of SK-BR-3 cell to lapatinib in vitro, which was restored by cetuximab. Conclusions: These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine in HER2+ MBC. No significant financial relationships to disclose.