Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
We sought to describe patterns of treatment and clinical outcome in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy . One hundred eighty-four consecutive HER2-positive advanced breast cancer patients received trastuzumab-based therapy between September 1999 and September 2004 . Patients were followed up until death or May 2005 . For patients progressing on trastuzumab-based therapy , we calculated the response rate ( RR ) to the first post-progression treatment , overall survival ( OS ) from the first administration of trastuzumab , time to second progression ( TT-SP ) , and post-progression survival ( PPS ) , according to treatment . At the time of this analysis , 132 patients had progressed on trastuzumab-based therapy  , and 89 had died . Of the progressing patients , 21 experienced rapid progression and could not receive additional anticancer treatments;40 patients continued trastuzumab either alone ( 12 patients with isolated central nervous system progression ) , with chemotherapy ( 23 patients ) , or with endocrine therapy ( 5 patients ) ; and 71 stopped trastuzumab and received chemotherapy ( 61 patients ) or endocrine therapy ( 10 patients ) as the first post-progression treatment . Excluding patients with rapid progression , clinical outcomes were similar whether trastuzumab was continued or not , in terms of RR ( 18 % and 27 % , respectively ) , OS ( 31 and 30 months , respectively ) , TT-SP ( 6 and 7 months , respectively ) , and PPS ( 21 and 19 months , respectively ) . The clinical outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy might not be influenced by continuing trastuzumab . The optimal therapeutic strategy in this setting of patients needs evaluation in r and omized trials Purpose Lapatinib is a small molecule , dual tyrosine kinase inhibitor of epidermal growth factor receptor ( EGFR ) and human epidermal growth factor receptor type 2 ( HER2 ) . Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab . Up date d efficacy and initial biomarker results from this trial are reported . Methods Women with HER2-positive , locally advanced or metastatic breast cancer previously treated with anthracycline- , taxane- , and trastuzumab-containing regimens were r and omized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m2 days 1–14 of a 21-day cycle or capecitabine 2,500 mg/m2 on the same schedule . The primary endpoint was time to progression ( TTP ) as determined by an independent review panel . Relationship between progression-free survival ( PFS ) and tumor HER2 expression and serum levels of HER2 extracellular domain ( ECD ) were assessed . Results 399 women were r and omized . The addition of lapatinib prolonged TTP with a hazard ratio ( HR ) of 0.57 ( 95 % CI , 0.43–0.77 ; P < 0.001 ) and provided a trend toward improved overall survival ( HR : 0.78 , 95 % CI : 0.55–1.12 , P = 0.177 ) , and fewer cases with CNS involvement at first progression ( 4 vs. 13 , P = 0.045 ) . Baseline serum HER2 ECD did not predict for benefit from lapatinib . Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive , advanced breast cancer progressing after treatment with anthracycline- ,  taxane- , and trastuzumab-based therapy . Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine BACKGROUND Lapatinib , a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 ( HER2 , also referred to as HER2/neu ) and epidermal growth factor receptor ( EGFR ) , is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy . In this trial , we compared lapatinib plus capecitabine with capecitabine alone in such patients . METHODS Women with HER2-positive , locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab  were r and omly assigned to receive either combination therapy ( lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle ) or monotherapy ( capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle ) . The primary end point was time to progression , based on an evaluation by independent review ers under blinded conditions . RESULTS The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group . The hazard ratio for the independently assessed time to progression was 0.49 ( 95 % confidence interval , 0.34 to 0.71 ; P<0.001 ) , with 49 events in the combination-therapy group and 72 events in the monotherapy group . The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group . This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events . CONCLUSIONS Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab . ( Clinical Trials.gov number , NCT00078572 [ Clinical Trials.gov ] . )
CONTEXT AND OBJECTIVE Around 16 % to 20 % of women with breast cancer have advanced , metastasized breast cancer .
At this stage , the disease is treatable , but not curable .
The objective here was to assess the effectiveness of lapatinib for treating patients with advanced or metastasized breast cancer .