Our study provided evidence that if patients were resistant to trastuzumab, switching to the combination of lapatinib and capecitabine had longer PFS than those patients continued use of trastuzumab. Findings from our analysis suggest that the effect of lapatinib on PFS may be explained by excellent effect in primary resistant patients.
The results of the current study accord with two small randomized trials comparing capecitabine plus lapatinib with trastuzumab plus lapatinib as treatment for patients progressed on trastuzumab-containing therapy. An analysis of 86 women who were HER-2 positive, locally advanced breast cancer or metastatic breast cancer (MBC) and developed resistance to trastuzumab demonstrated that the trastuzumab combined with capecitabine led to a not significant inferior PFS compared with lapatinib , median PFS (7.1 months（LX）VS 6.1 months（HX）,HR 0.81 90% CI 0.55-1.21, P =0.39). These data were supported by study results from Bian, et al，who randomly assigned 120 HER-2 positive MBC patients with resistance to trastuzumab in a 1:1 ratio to receive capecitabine with either trastuzumab or lapatinib, median PFS (4.5 months VS 6 months, HR=0.61，95%CI：0.42-0.88，P=0.006). 30% of patients in trastuzumab group and 55% in the lapatinib group experienced a PFS longer than 6 months. In consistence with those reports, our study suggests that patients can respond to further HER2-directed regimens after development of resistance to HER2- directed therapy. The optimal anti-HER2 treatment for patients who failed trastuzumab treatment in clinical practice would be lapatinib when pertuzumab / T-DM1 are not available.
Our findings differ in part from two studies that compare tyrosine kinase inhibitors with trastuzumab for HER2-overexpressing metastatic breast cancer. In the LUX-Breast 1 trial, an oral irreversible ErbB family blocker afatinib plus vinorelbine resulted in similar PFS compared with trastuzumab plus vinorelbine in HER2-positive metastatic breast cancer who had progressed on trastuzumab. Median PFS was 5.5 months in the afatinib group and 5.6 months in the trastuzumab group (hazard ratio 1.10 95% CI 0.86–1.41; P =0.43). For patients receiving first-line therapy, PFS was also insignificantly different between the afatinib and trastuzumab-based therapy (hazard ratio 1.102 95% CI 0.759–1.600; P =0.61). In the MA.31 trial, PFS was shorter for lapatinib plus taxane compared with trastuzumab plus taxane administrated as first-line therapy of metastatic breast cancer (9.0 months VS 11.3 months; HR 1.37 [95% CI 1.13–1.65]; P=0.001). The trial was terminated earlier. However, although afatinib is a second-generation, broader inhibitor of the ErbB family of proteins, no randomized trials to compare the efficacy of afatinib with lapatinib in women progressed during trastuzumab treatment. Furthermore, a major difference between MA.31 trial and our study was that a large part of patients were newly diagnosed advanced breast cancer and were trastuzumab-naïve. This might affect the survival outcome.
Lapatinib has a different mechanism of inhibition on HER2 and EGFR signaling compared with trastuzumab. Preclinical evidence suggests non–cross resistance of trastuzumab and lapatinib. PTEN abrogates phosphatidyl inositol-3-kinase (PI3K), which results in inhibition of Akt signaling. Non-existent or limited expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10), might be a marker of resistance to trastuzumab. Previous studies have confirmed PTEN expression has no correlation with response to lapatinib. IGF-1R (insulin-like growth factor receptor) is important for cell proliferation and survival. It has been reported that overexpression of IGF-1R predicted resistance to trastuzumab in breast cancer cells[31-33]. IGF-1R belongs to the tyrosine kinase receptor family and breast cancer cells that express IGF-1R may still be sensitive to lapatinib.
We try to identify subsets of patients who would derive the greatest benefit from further HER2-directed therapy. To this end, we examined whether the prognosis in the primary resistant patients paralleled those of the secondary resistant to HER2-directed therapy. Indeed, in multiple lines, the data showed that those primary resistant patients who received LX tended to have longer PFS with statistical significance, while the PFS of secondary resistant patients receiving the TBP regimen was similar with the patients receiving the LX regimen. p95 HER2 (a truncated version lacking the extracellular domain) would preventtrastuzumab binding and are associated with poor prognosis in patients. Lapatinib inhibits p95HER2 phosphorylation while trastuzumab doesn’t. That may explain why switching to lapatinib predicts for extended PFS in the primary resistant group.
Unlike primary resistant patients, a clinical benefit was observed for treatment with trastuzumab-containing regimen in patients acquired resistance to anti-HER-2 therapy. Trastuzumab might have additional anti-tumour efficacy via antibody-dependent cellular-cytotoxicity (ADCC), by which induces immune effector cells to kill cancer cells[36, 37].
We also found patients in the second line treatment had a higher proportion of trastuzumab beyond progression therapy than those in the third-line setting. The predominant HER-2 targeted therapy in the second line setting was trastuzumab instead of lapatinib. A plausible reason for the disparities concerns the assumption that patient refractory to prior chemotherapy agent but not to trastuzumab itself. Secondly, anti-HER2 therapy is expensive and time consuming, and varying medical insurance policies may contribute to the continued use of trastuzumab.
Breast cancer patients with HER2 overexpression have greater risk for developing brain metastasis, and trastuzumab treatment has emerged as a factor contributing to this risk. Previous studies support the hypothesis that brain is a ‘sanctuary’ site for the development of metastases due to the limited ability of trastuzumab in penetrating the Blood Brain Barrier (BBB). Lapatinib is a small dual tyrosine-kinase inhibitor of HER1 and HER2 with a hypothetical ability to cross the BBB. The combination of lapatinib with capecitabine has central nervous system (CNS) activity for the treatment of patients with HER2-positive brain metastatic breast cancer. Clinical evidence supports that patients with HER2-positive brain metastasis achieved a significant clinical benefit from lapatinib and capecitabine both as single agents and in combination in patients with brain metastases[41-43]. In the present study, the percentage of patients with central nervous system progression was higher in the TBP group. In addition, the comparison of CNS progression rate indicates that lapatinib is more effective in brain metastases than trastuzumab. These findings are consistent with the result of a randomized clinical trial which evaluate the effect of neratinib compared with trastuzumab in previously untreated metastatic ERBB2-Positive Breast Cancer. Neratinib, another kind of oral irreversible ERBB family blocker, was associated with fewer central nervous system recurrences (relative risk, 0.48; 95%CI, 0.29-0.79; P =0 .002) and also delayed the time to CNS relapses compared with trastuzumab (HR, 0.45; 95%CI, 0.26-0.78; P = 0.004). In EMILIA trial, modest activity of lapatinib plus capecitabine upon CNS recurrences, 2.0% (9/450) in the T-DM1 group and 0.7% (3/446) in the LX group developed new brain metastases[22, 45]. It appears that switching patients with treated brain metastases to lapatinib-containing treatment more effectively prevent brain progression.
It should be noted that there were a few limitations in our study. First, it’s retrospectively, potential imbalance in contributing factors of patient prognosis and patient heterogeneity in terms of treatment does exist. For example, women who switching to lapatinib were younger and more likely to achieve antitumor activity of new anti-HER2 regimen. Second, patients who received chemotherapy and trastuzumab sequentially or concomitantly may affect the prognosis. Third, some data could not be abstracted from medical records and missing.