Lapatinib in combination with capecitabine versus continued use of trastuzumab in breast cancer patients with trastuzumab-resistance: a retrospective study of a Chinese population

Breast cancer is one of the most common invasive cancers and is expected to account for 14% of all cancer deaths in women worldwide [1]. Activation and overexpression of epidermal growth factor receptor (EGFR, also known as ErbB) family members, including EGFR (ErbB1 or HER1), HER3 (ErbB3), HER4 (ErbB4), and HER2 (ErbB2), govern multiple important cellular processes in breast cancer. Activation of HER2, a tyrosine kinase receptor, induces homo- and heterodimerization, which leads to the activation of downstream effectors and pathways such as PI3K/AKT and RAS/MAP K[2].

Amplification of the HER2 gene and/or overexpression of its protein product occurs in approximately 20–25% of breast cancer s[3]. Clinically, HER2-positive tumors are characterized by an aggressive clinical course and a poor overall prognosi s[4]. The introduction of the anti-HER2 monoclonal antibody trastuzumab into clinical practice has dramatically improved the poor prognosis of this population of patient s[5‐7]. Trastuzumab binds to the extracellular domain of the HER2 receptor and prevents receptor homo- and heterodimerization, thereby inhibiting the activation of downstream oncogenic signalin g[8]. Adding trastuzumab to the treatment regimen is the standard approach for treating HER-2 positive metastatic breast cancer. However, despite its overall clinical efficacy, de novo and acquired resistance to trastuzumab administration have been observe d[9]. The development of distant metastases to liver, bone, lung and brain has become a major challenge in the management of patients with HER-2 positive breast cancer, probably due to their longer life expectancy and acquired trastuzumab resistanc e[10]. Therefore, there is an urgent need to develop a new strategy for salvage therapy of patients who have developed resistance to trastuzumab.

However, consensus guidelines on targeted treatment for resistance in HER2-positive breast cancer are not availabl e[11, 12]. Combinations of anti-HER2 agents with chemotherapy, anti-HER2/HER3 dimerization agents, or inhibitors of its downstream signaling pathways might improve patient prognosi s[13]. Fujimoto-Ouchi demonstrated that trastuzumab in combination with taxanes or capecitabine showed antitumor activity in a trastuzumab-resistant mode l[14].

The GBG 26/BIG 3–05 enrolled patients with HER2-positive metastatic breast cancer (stage IV) that progressed during treatment with trastuzumab. Among these patients, 78 patients were randomly assigned to receive capecitabine, and 78 patients were assigned to capecitabine plus trastuzumab. The results showed that the median TTPs were 5.6 months vs 8.2 months, P = 0.033 8[15]. In a similar study, patients who received trastuzumab treatment beyond progression (TBP) had a longer median OS than those who terminated trastuzumab (21.3 months vs 4.6 months (P<0.0001 )[16]. Taken together, the findings of these studies suggest that a clinical benefit has been observed for treatment with trastuzumab beyond progression.

Lapatinib, an orally active small-molecule tyrosine kinase inhibitor, has shown non-cross-resistance with trastuzumab. It binds reversibly to the cytoplasmic domains of both EGFR and HER2, which then blocks the activating signaling cascades in the MAPK and PI3K pathway s[17]. Given its unique mechanistic function, lapatinib might be a suitable treatment option for HER2-positive MBCs that have become resistant to suppression by trastuzumab.

Some studies have also shown that the phosphorylation of p95 HER2 (a truncated version lacking the extracellular domain) and the formation of heterodimers between HER2 and other members of the HER family might be inhibited by lapatinib but not trastuzuma b[18, 19]. In the EGF100151 trial, lapatinib plus capecitabine reduced the hazard for time-to-disease progression (hazard ratio 0.49; 95% CI 0.34–0.71; P < 0.001) in cases of HER2-positive breast cancer that progressed on anthracycline, a taxane and trastuzuma b[11, 20].

In 2010, the US FDA approved the use of lapatinib in combination with capecitabine for the treatment of patients with HER2-positive MBC. In addition, lapatinib in combination with capecitabine shows excellent activity against central nervous system (CNS) metastases. The results of one study suggested that patients with brain metastases achieved significantly longer overall survival in the lapatinib group compared with those on the trastuzumab-based therapy (19.1 vs 12 months, P = 0.039 )[21].

Clinical trials have demonstrated that other HER-2 targeted agents, such as T-DM1 and pertuzumab, have shown efficacy in patients pretreated with trastuzuma b[22, 23]. However, these regimens remain unavailable in China. Therefore, trastuzumab plus chemotherapy or switching to the lapatinib plus capecitabine regimen are common options for Chinese patients who have developed resistance to trastuzumab. No compelling evidence indicates if certain patients benefit more from the continuation of trastuzumab compared with switching to lapatinib. In the present analysis, we compare the clinical outcome of continuing trastuzumab treatment or replacing trastuzumab with lapatinib for metastatic breast cancer (MBC) patients who are resistant to trastuzumab.

Our study provides evidence that if patients are resistant to trastuzumab, switching to the combination of lapatinib and capecitabine resulted in a longer PFS than continuing the use of trastuzumab. Findings from our analyses suggest that the effect of lapatinib on PFS may be explained by its excellent effect in primary resistant patients.

The results of the current study are in accordance with two small randomized trials comparing capecitabine plus lapatinib with trastuzumab plus lapatinib as treatment for patients progressing on trastuzumab-containing therapy. An analysis of 86 women who were HER-2 positive, had 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 significantly inferior PFS compared with lapatinib, with a median PFS (7.1 months on LX vs 6.1 months on HX, HR 0.81, 90% CI 0.55–1.21, P = 0.39 )[24]. These data are 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, and reported a median PFS (4.5 months vs 6 months, HR = 0.61, 95% CI: 0.42–0.88, P = 0.006 )[25]. They found that 30% of patients in the trastuzumab group and 55% in the lapatinib group experienced a PFS longer than 6 months. Consistent with those reports, our study suggests that patients can respond to further HER2-directed regimens after the development of resistance to HER2-directed therapy. The optimal anti-HER2 treatment for patients who do not respond to trastuzumab treatment in clinical practice is lapatinib when pertuzumab /T-DM1 is not available.

Our findings differ in part from two studies that compared tyrosine kinase inhibitors with trastuzumab for treating HER2-overexpressing metastatic breast cancer. In the LUX-Breast 1 tria l[26], an oral irreversible ErbB family blocker, afatinib, combined with vinorelbine, resulted in a similar PFS as trastuzumab plus vinorelbine in women with HER2-positive metastatic breast cancer who had progressed on trastuzumab. The 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 did not differ significantly among 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 administered 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 )[27]. The trial was terminated early. However, although afatinib is a second-generation, broader inhibitor of the ErbB family of protein s[28], no randomized trials have been conducted to compare the efficacy of afatinib with lapatinib for women who progressed during trastuzumab treatment. Furthermore, a major difference between the MA.31 trial and our study was that in the MA.31 trial, a large proportion of patients were newly diagnosed with advanced breast cancer and were trastuzumab-naïve. This might affect their survival outcomes.

Lapatinib has a different mechanism of inhibition on HER2 and EGFR signaling compared with trastuzumab. Preclinical evidence suggests non-cross-resistance to trastuzumab and lapatinib. PTEN abrogates phosphatidyl inositol-3-kinase (PI3K), which results in inhibition of Akt signaling. Nonexistent or limited expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10) might be a marker of resistance to trastuzuma b[29]. Previous studies have confirmed PTEN expression has no correlation with response to lapatini b[30]. IGF-1R (insulin-like growth factor receptor) is important for cell proliferation and surviva l[31]. It has been reported that overexpression of IGF-1R predicted resistance to trastuzumab in breast cancer cell s[31‐33]. IGF-1R belongs to the tyrosine kinase receptor family, and breast cancer cells that express IGF-1R may still be sensitive to lapatini b[34].

We tried 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 that were secondary resistant to HER2-directed therapy. Indeed, in multiple lines, the data showed that the primary resistant patients who received LX tended to have a longer PFS with statistical significance, while the PFS of secondary resistant patients receiving the TBP regimen was similar to that of the patients receiving the LX regimen. p95 HER2 (a truncated version lacking the extracellular domain) prevents trastuzumab binding and is associated with a poor prognosis. Lapatinib inhibits p95HER2 phosphorylation, while trastuzumab doesn’ t[35]. That may explain why switching to lapatinib was associated with an extended PFS in the primary resistant group.

Unlike primary resistant patients, a clinical benefit has been observed for treatment with trastuzumab-containing regimens among patients with acquired resistance to anti-HER-2 therapy. Trastuzumab might have additional anti-tumor efficacy via an antibody-dependent cellular-cytotoxicity (ADCC) mechanism, by which it induces immune effector cells to kill cancer cell s[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 these disparities concerns the assumption that the patients were refractory to a prior chemotherapy agent but not to trastuzumab itself. Second, 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 a greater risk for developing brain metastases, and trastuzumab treatment has emerged as a factor contributing to this ris k[38]. Previous studies have supported the hypothesis that the brain is a ‘sanctuary’ site for the development of metastases due to the limited ability of trastuzumab to penetrate the blood-brain barrier (BBB )[39]. Lapatinib is a small dual tyrosine-kinase inhibitor of HER1 and HER2 with a hypothetical ability to cross the BB B[40]. 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 indicates that patients with HER2-positive brain metastases achieve a significant clinical benefit from lapatinib and capecitabine both as single agents and as a combinatio n[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 the CNS progression rates indicates that lapatinib is more effective against brain metastases than trastuzumab. These findings are consistent with the results of a randomized clinical trial that evaluated the effect of neratinib compared with trastuzumab in previously untreated metastatic ERBB2-positive breast cancer. Neratinib, another 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 delayed the time to CNS relapses compared with trastuzumab (HR, 0.45; 95% CI, 0.26–0.78; P = 0.004 )[44]. In the EMILIA trial, there was modest activity of lapatinib plus capecitabine against CNS recurrences, where 2.0% (9/450) in the T-DM1 group and 0.7% (3/446) in the LX group developed new brain metastase s[22, 45]. It appears that switching patients with brain metastases to lapatinib-containing treatment regimens more effectively prevents brain lesion progression.

It should be noted that there were a few limitations to our study. First, it is a retrospective study, and there may be potential imbalances in factors contributing to patient prognosis and patient heterogeneity in terms of treatment. For example, women who switched to lapatinib were younger and more likely to achieve antitumor activity with the new anti-HER2 regimen. Second, the inclusion of patients who received chemotherapy and trastuzumab sequentially or concomitantly may affect the outcomes. Third, some data could not be extracted from the medical records or were missing.

In conclusion, these data confirm that after developing resistance to trastuzumab, patients can still derive benefit from HER-2 targeted therapy. The combination of lapatinib and capecitabine results in prolonged survival compared with TBP in patients with prior trastuzumab exposure.