the human epidermal growth factor receptor 2 gene ( her2 ) encodes a 185-kd transmembrane glycoprotein receptor ( p185her2 ) and is amplified in 25%-30% of human breast .
patients with her2 overexpression exhibit shorter disease - free survival ( dfs ) and overall survival ( os ) .
trastuzumab ( herceptin ; f. hoffmann - la roche ltd , basel , switzerland ) is a humanized murine monoclonal antibody that binds specifically to the extracellular domain of the her2 protein .
the survival benefit from trastuzumab has beenwell established in numerous clinical trials of patients with early and metastatic breast cancer who had overexpression of her2 .
the use of trastuzumab either in monotherapy or combination with chemotherapy   and endocrine therapy all resulted in survival benefit .
trastuzumab is most frequently combined with chemotherapy agents including paclitaxel , docetaxel , vinorelbine , gemcitabine and carboplatin , and also provides a survival advantage to women who have been previously treated with chemotherapy for metastatic disease .
furthermore , efficacy has been observed following continuation of trastuzumab after trastuzumab progression according to data from a phase  randomized study [ german breast group ( gbg)-26 ] . in china ,
the first clinical trial using trastuzumab in metastatic breast cancer was a phase  trial published in 2003 .
however , while the trastuzumab in combination with chemotherapy has been a standard regimen for over ten years , and its usage was limited by its high cost .
however , more widespread use resulted from a public welfare project for trastuzumab was managed by the china cancer foundation in august 2011 .
thus , in the past 2 or 3 years there has been no large - scale study of trastuzumab in advanced breast cancer in china . in this observational study ,
the majority of data were collected over the past two years ( 72/90 patients ; 80.0% ) . since pertuzumab and t - dm1
have not been approved in china , trastuzumab and lapatinib remain the only available anti - her2 targeted therapies for chinese patients . in this article , we evaluated the outcome of patients with advanced breast cancer who received trastuzumab treatment in routine clinical practice .
this observational study focused on the efficacy and safety of trastuzumab combined with chemotherapy for first - line treatment and beyond progression upon trastuzumab treatment of her2-overexpressing advanced breast cancer .
women with advanced ( either metastatic or locally advanced ) measurable disease and her2-overexpressing breast cancer who had at least one dose of trastuzumab were eligible for this study .
her2-positivity was defined as 3(+ ) staining in immunohistochemistry ( ihc ) or amplification of fluorescence in situ hybridization ( fish , ratio 2.0 ) if the ihc staining score was 2(+ ) , a life expectancy 3 months and performance status [ on the eastern cooperative oncology group ( ecog ) scale ] 2 .
in addition , a cardiac evaluation with echocardiography had to show an ejection fraction value 50% at baseline .
patients were excluded if they had clinically significant cardiac disease , infection , bleeding disorder , abnormal pulmonary function , or other significant medical conditions .
the study was approved by the ethics committee of beijing cancer hospital ( beijing , china ) and informed consent was obtained from all patients before starting treatment .
the study observed 90 patients with her2-overexpressing advanced breast cancer from january 2006 to september 2014 , and there were 72/90 ( 80.0% ) cases from september 2012 to september 2014 .
nine of 90 ( 10.0% ) patients were initially diagnosed with advanced breast cancer , and the rest 81 ( 90.0% ) experienced metastatic diseases after breast cancer surgery , wherein 23/81 ( 28.4% ) patients underwent re - biopsy at a metastatic tumor site .
patients were aged between 31 - 73 years ( median , 51 years ) at diagnosis .
patients who had received either first - line trastuzumab combined with chemotherapy or trastuzumab treatment beyond progression were enrolled .
trastuzumab was given 4 mg / kg ( in 82 patients ) or 8 mg / kg ( in 8 patients ) loading dose , followed by 2 mg / kg weekly or by 6 mg / kg per 3 weeks respectively .
the chemotherapy regimen was administered according to normal clinical practice and advanced breast cancer guidelines , and trastuzumab was continued after first - line trastuzumab progression unless the patients refuse treatment for cost , side effects or other factors , in which case chemotherapy agents were changed from first - line chemotherapy agents .
history , physical examination , ecog status , blood cell count and serum chemistry were assessed at baseline and repeated before each cycle .
a left ventricular ejection fraction ( lvef ) measurement was performed at baseline by echocardiography and reassessed every three months .
tumor measurement was performed by computed tomography ( ct ) scan or magnetic resonance imaging ( mri ) , and was repeated every two cycles of treatment ( by 2 months ) , upon which pathology was reviewed , especially for patients who were not initially treated in the department of breast oncology , peking university cancer hospital .  
the secondary end points included os , objective response rate ( orr ) , and adverse events ( aes ) .
the tumor response rate was evaluated using the response evaluation criteria in solid tumors criteria version 1.1 .
pfs and os were calculated as the time from the first trastuzumab administration to progression and death at the last valid observation point .
aes were graded according to the national cancer institute common terminology criteria for adverse events version 3.0 ( ctcae 3.0 ) .
the pfs and os at specific time points were estimated using spss software ( version 19.1 ; spss inc . ,
the pfs was calculated as time from the date of treatment to the first recurrence of disease at local , regional , or distant site or death .
the kaplan - meier method and the log - rank test were used to analyze potential prognostic factors .
the cox proportional hazards regression model was used for the analyses taking into account all variables simultaneously .
women with advanced ( either metastatic or locally advanced ) measurable disease and her2-overexpressing breast cancer who had at least one dose of trastuzumab were eligible for this study .
her2-positivity was defined as 3(+ ) staining in immunohistochemistry ( ihc ) or amplification of fluorescence in situ hybridization ( fish , ratio 2.0 ) if the ihc staining score was 2(+ ) , a life expectancy 3 months and performance status [ on the eastern cooperative oncology group ( ecog ) scale ] 2 .
in addition , a cardiac evaluation with echocardiography had to show an ejection fraction value 50% at baseline .
patients were excluded if they had clinically significant cardiac disease , infection , bleeding disorder , abnormal pulmonary function , or other significant medical conditions .
the study was approved by the ethics committee of beijing cancer hospital ( beijing , china ) and informed consent was obtained from all patients before starting treatment .
the study observed 90 patients with her2-overexpressing advanced breast cancer from january 2006 to september 2014 , and there were 72/90 ( 80.0% ) cases from september 2012 to september 2014 .
nine of 90 ( 10.0% ) patients were initially diagnosed with advanced breast cancer , and the rest 81 ( 90.0% ) experienced metastatic diseases after breast cancer surgery , wherein 23/81 ( 28.4% ) patients underwent re - biopsy at a metastatic tumor site .
patients were aged between 31 - 73 years ( median , 51 years ) at diagnosis .
patients who had received either first - line trastuzumab combined with chemotherapy or trastuzumab treatment beyond progression were enrolled .
trastuzumab was given 4 mg / kg ( in 82 patients ) or 8 mg / kg ( in 8 patients ) loading dose , followed by 2 mg / kg weekly or by 6 mg / kg per 3 weeks respectively .
the chemotherapy regimen was administered according to normal clinical practice and advanced breast cancer guidelines , and trastuzumab was continued after first - line trastuzumab progression unless the patients refuse treatment for cost , side effects or other factors , in which case chemotherapy agents were changed from first - line chemotherapy agents .
history , physical examination , ecog status , blood cell count and serum chemistry were assessed at baseline and repeated before each cycle .
a left ventricular ejection fraction ( lvef ) measurement was performed at baseline by echocardiography and reassessed every three months .
tumor measurement was performed by computed tomography ( ct ) scan or magnetic resonance imaging ( mri ) , and was repeated every two cycles of treatment ( by 2 months ) , upon which pathology was reviewed , especially for patients who were not initially treated in the department of breast oncology , peking university cancer hospital .  
the secondary end points included os , objective response rate ( orr ) , and adverse events ( aes ) .
the tumor response rate was evaluated using the response evaluation criteria in solid tumors criteria version 1.1 .
pfs and os were calculated as the time from the first trastuzumab administration to progression and death at the last valid observation point .
aes were graded according to the national cancer institute common terminology criteria for adverse events version 3.0 ( ctcae 3.0 ) .
the pfs and os at specific time points were estimated using spss software ( version 19.1 ; spss inc . ,
the pfs was calculated as time from the date of treatment to the first recurrence of disease at local , regional , or distant site or death .
the kaplan - meier method and the log - rank test were used to analyze potential prognostic factors .
the cox proportional hazards regression model was used for the analyses taking into account all variables simultaneously .
all 90 patients received at least one dose of trastuzumab , but 5 patients only received one dose of trastuzumab for observing safety profile only .
the duration of follow - up was from january 2006 to september 2014 , and the median followup duration was 50 months ( range , 8 - 352 months ) .
this cohort had more aggressive disease and only 9 patients received trastuzumab in an adjuvant setting . in total , 37.78% of cases were hormone receptor negative , 59.26% had lymph node metastasis at initial diagnosis after surgery , and 9 patients had initial advanced disease with multiple site metastasis .
twenty - nine ( 32.22% ) patients were diagnosed with lung metastasis and 56 ( 62.22% ) with liver metastasis , while 80.00% had invasive metastasis ( both lung and liver involvement ) , and 3 or more metastatic sites were evident in 35.56% of patients . furthermore , 65.43% ( 53/81 ) of patients experienced a relapse within 3 years , and 77 ( 85.56% ) patients had already undergone adjuvant chemotherapy with anthracycline and/or taxane . at the time of trastuzumab treatment , 43 ( 47.78% )
patients had progressed after one or more extensive prior palliative chemotherapy regimens for a metastatic setting , 4 had initial advanced disease ; 20 as second - line , 15 as third - line , and 8 for beyond third - line treatment .
the first - line or subsequent lines of trastuzumab was used as the initial anti - her2 therapeutic agent in different patient settings .
there were 47 patients received trastuzumab as first - line therapy , after progression from first - line trastuzumab treatment , the number of patients who continued trastuzumab treatment as second - line , thirdline and beyond therapy were 34,14 , and 6 , respectively . in total
, there were 920 treatment cycles in this group of patients , the median number was 8 cycles ( range , 2 - 70 cycles ) , and 49 ( 54.4% ) patients received trastuzumab for more than 8 cycles . for second - line treatment ,
only 3 patients were treated longer for more than 1 year , with 15,18 , and 18 cycles , respectively . for third - line treatment ,
only 3 of 14 patients were treated with more than 5 cycles ( 2 patients underwent 5 cycles and 1 patient underwent 8 cycles ) , while for fourth - line treatment and beyond the median number of cycles , it was very low at 3 cycles ( range , 2 - 5 cycles ) . for chemotherapy agents , at first - line treatment , 56 patients received paclitaxel / docetaxel , paclitaxel was given 175 mg / m in the first day ( d 1 ) , or 175 mg / m divided in d 1 and the eighth day ( d 8) , every 3 weeks ( q3w ) , and docetaxel was given 75 mg/ m , d 1 , q3w ; 19 patients received vinorelbine ( 30 mg / m , d 1and d 8 , q3w ) ; 11 received gemcitabine ( 1,000 mg / m , d 1 and d 8 , q3w ) ; and 27 patients received capecitabine [ 1,000 mg/ m , d 1-d 14 , twice per day ( bid ) ] . the most frequently used combination regimens were taxane plus platinum in 12 patients , paclitaxel / docetaxel plus capecitabine ( tx ) in 9 patients , paclitaxel / docetaxel plus gemcitabine ( tg ) in 5 patients , and vinorelbine plus capecitabine ( nx ) in 7 patients . in the secondline and third - line setting , chemotherapy agents were different from first - line agents .
we also analyzed 44 patients treated with single agent chemotherapy and compared with 41 patients treated with combination chemotherapy .
a total of 85 patients could be evaluated for efficacy of first - line trastuzumab in advanced disease , resulting in a median pfs of 10 months ( range , 2 - 59 months ) , a median os from the date of trastuzumab treatment to the date of death from any cause of 16 months ( range , 2 - 70 months ) , and a median os after metastasis or initially local advanced disease of 22 months ( range , 2 - 116 months ) .
the median os from initially diagnoses was 50 months ( range , 8 - 352 months ) ( table 2 ) .
pfs and os of first - line trastuzumab treatment ( n=85 ) complete response ( cr ) in first - line trastuzumab treatment was achieved in 5/85 ( 5.9% ) patients , and partial response ( pr ) in 37/85 ( 43.5% ) , while 28/85 ( 32.9% ) experienced stable disease ( sd ) .
response of trastuzumab in different lines ( n=85 )  
 the impact of several prognostic characteristics on orr and pfs was analyzed , focusing on the subgroups of patients continuing trastuzumab treatment after first - line trastuzumab therapy , or those who received trastuzumab in different disease conditions , and/or those who were administered trastuzumab in parallel with a single or combination chemotherapy agent .
the efficacy for continuing trastuzumab treatment after disease progression and trastuzumab in different disease statuses really influenced the results .
patients who progressed after their initial trastuzumab treatment continued to receive trastuzumab , and their response rates are shown in table 3 . among 34,14 and 6 patients who continued using trastuzumab in the second - line , third - line and beyond fourth - line settings , respectively , 1 achieved cr , 10 achieved pr in the second - line , and 2 achieved pr in the third - line .
while no orr was obtained after this point , longer therapeutic cycles were employed in the early lines of trastuzumab treatment ( table 3 ) , with concomitant longer pfs .
patients with different therapeutic cycles ( > 6 cycles vs. 6 cycles ) showed statistically different pfs ( p = 0.007 ; figure 1 ) .
progression - free survival ( pfs ) of different cycles of first - line trastuzumab treatment ( p=0.007 ) .
there were 47/85 ( 55.3% ) patients treated with trastuzumab in the first relapse disease .
the orr ( cr+pr ) for disease was 57.4% , with a cr of 10.6% ( 5/47 ) and a pr of 46.8% ( 22/47 ) .
the trastuzumab treatment achieved high responses in patients without previous chemotherapy for advanced disease , and better pfs was obtained compared with later disease treatment ( p=0.004 ; figure 2 ) .
progression - free survival ( pfs ) of first - line trastuzumab treatment initiated at different disease lines ( p=0.004 ) .
no major prognostic impact was detected for hormone receptor status or age , or for other factors that may influence efficacy such as the site of metastasis or the number of metastatic sites .
because in this cohort , 80.00% of patients had liver and lung metastasis , and 64.44% had more than two sitesof metastasis .
different chemotherapy agents were not analyzed in this study , because 62.22% of patients underwent taxanebased chemotherapy , and thus , this population subgroup was imbalanced .
regarding the chemotherapy regimen , the pfs of patients undergoing single agent chemotherapy was not statistically different compared with those receiving combination chemotherapy treatment ( p=0.305 ; figure 3 ) .
progression - free survival ( pfs ) of first - line trastuzumab treatment , single / sequential single agent vs. multiple agents ( p=0.305 ) .
a safety analysis was performed in all 90 patients who received at least one dose of trastuzumab , however , most patients were treated with chemotherapy simultaneously so chemotherapyrelated side effects such as hemotological effects are not presented here .
nine patients ceased treatment because of the following side effects : angina pectoris in 3 patients ( 1 of whom stopped treatment immediately ) , liver failure ( multiple liver metastasis ) in 1 , lung injury in 2 , serum creatinine increase in 1 , thrombus in 1 , and finger necrosis in 1 .
furthermore , 8 patients refused further treatment because of high costs , and 15 were diagnosed with brain metastases during the treatment period .
the other most common treatment - related adverse events were chill in 11 ( 12.2% ) patients , and fever in 15 ( 16.6% ) .
most treatment - related adverse events were mild to moderate , except in 5 patients who stopped treatment immediately , and most occurred during the first drug infusion .
all 90 patients received at least one dose of trastuzumab , but 5 patients only received one dose of trastuzumab for observing safety profile only .
the duration of follow - up was from january 2006 to september 2014 , and the median followup duration was 50 months ( range , 8 - 352 months ) .
this cohort had more aggressive disease and only 9 patients received trastuzumab in an adjuvant setting . in total , 37.78% of cases were hormone receptor negative , 59.26% had lymph node metastasis at initial diagnosis after surgery , and 9 patients had initial advanced disease with multiple site metastasis .
twenty - nine ( 32.22% ) patients were diagnosed with lung metastasis and 56 ( 62.22% ) with liver metastasis , while 80.00% had invasive metastasis ( both lung and liver involvement ) , and 3 or more metastatic sites were evident in 35.56% of patients . furthermore , 65.43% ( 53/81 ) of patients experienced a relapse within 3 years , and 77 ( 85.56% ) patients had already undergone adjuvant chemotherapy with anthracycline and/or taxane . at the time of trastuzumab treatment , 43 ( 47.78% )
patients had progressed after one or more extensive prior palliative chemotherapy regimens for a metastatic setting , 4 had initial advanced disease ; 20 as second - line , 15 as third - line , and 8 for beyond third - line treatment .
the first - line or subsequent lines of trastuzumab was used as the initial anti - her2 therapeutic agent in different patient settings .
there were 47 patients received trastuzumab as first - line therapy , after progression from first - line trastuzumab treatment , the number of patients who continued trastuzumab treatment as second - line , thirdline and beyond therapy were 34,14 , and 6 , respectively . in total
, there were 920 treatment cycles in this group of patients , the median number was 8 cycles ( range , 2 - 70 cycles ) , and 49 ( 54.4% ) patients received trastuzumab for more than 8 cycles . for second - line treatment , only 3 patients were treated longer for more than 1 year , with 15,18 , and 18 cycles , respectively . for third - line treatment , only 3 of 14 patients were treated with more than 5 cycles ( 2 patients underwent 5 cycles and 1 patient underwent 8 cycles ) , while for fourth - line treatment and beyond the median number of cycles , it was very low at 3 cycles ( range , 2 - 5 cycles ) . for chemotherapy agents , at first - line treatment , 56 patients received paclitaxel / docetaxel , paclitaxel was given 175 mg / m in the first day ( d 1 ) , or 175 mg / m divided in d 1 and the eighth day ( d 8) , every 3 weeks ( q3w ) , and docetaxel was given 75 mg/ m , d 1 , q3w ; 19 patients received vinorelbine ( 30 mg / m , d 1and d 8 , q3w ) ; 11 received gemcitabine ( 1,000 mg / m , d 1 and d 8 , q3w ) ; and 27 patients received capecitabine [ 1,000 mg/ m , d 1-d 14 , twice per day ( bid ) ] .
the most frequently used combination regimens were taxane plus platinum in 12 patients , paclitaxel / docetaxel plus capecitabine ( tx ) in 9 patients , paclitaxel / docetaxel plus gemcitabine ( tg ) in 5 patients , and vinorelbine plus capecitabine ( nx ) in 7 patients . in the secondline and third - line
we also analyzed 44 patients treated with single agent chemotherapy and compared with 41 patients treated with combination chemotherapy .
a total of 85 patients could be evaluated for efficacy of first - line trastuzumab in advanced disease , resulting in a median pfs of 10 months ( range , 2 - 59 months ) , a median os from the date of trastuzumab treatment to the date of death from any cause of 16 months ( range , 2 - 70 months ) , and a median os after metastasis or initially local advanced disease of 22 months ( range , 2 - 116 months ) .
the median os from initially diagnoses was 50 months ( range , 8 - 352 months ) ( table 2 ) .
pfs and os of first - line trastuzumab treatment ( n=85 ) complete response ( cr ) in first - line trastuzumab treatment was achieved in 5/85 ( 5.9% ) patients , and partial response ( pr ) in 37/85 ( 43.5% ) , while 28/85 ( 32.9% ) experienced stable disease ( sd ) .
 
 the impact of several prognostic characteristics on orr and pfs was analyzed , focusing on the subgroups of patients continuing trastuzumab treatment after first - line trastuzumab therapy , or those who received trastuzumab in different disease conditions , and/or those who were administered trastuzumab in parallel with a single or combination chemotherapy agent .
the efficacy for continuing trastuzumab treatment after disease progression and trastuzumab in different disease statuses really influenced the results .
patients who progressed after their initial trastuzumab treatment continued to receive trastuzumab , and their response rates are shown in table 3 . among 34,14 and 6 patients who continued using trastuzumab in the second - line , third - line and beyond fourth - line settings , respectively , 1 achieved cr , 10 achieved pr in the second - line , and 2 achieved pr in the third - line .
while no orr was obtained after this point , longer therapeutic cycles were employed in the early lines of trastuzumab treatment ( table 3 ) , with concomitant longer pfs .
patients with different therapeutic cycles ( > 6 cycles vs. 6 cycles ) showed statistically different pfs ( p = 0.007 ; figure 1 ) .
progression - free survival ( pfs ) of different cycles of first - line trastuzumab treatment ( p=0.007 ) .
there were 47/85 ( 55.3% ) patients treated with trastuzumab in the first relapse disease .
the orr ( cr+pr ) for disease was 57.4% , with a cr of 10.6% ( 5/47 ) and a pr of 46.8% ( 22/47 ) .
the trastuzumab treatment achieved high responses in patients without previous chemotherapy for advanced disease , and better pfs was obtained compared with later disease treatment ( p=0.004 ; figure 2 ) .
progression - free survival ( pfs ) of first - line trastuzumab treatment initiated at different disease lines ( p=0.004 ) .
no major prognostic impact was detected for hormone receptor status or age , or for other factors that may influence efficacy such as the site of metastasis or the number of metastatic sites .
because in this cohort , 80.00% of patients had liver and lung metastasis , and 64.44% had more than two sitesof metastasis .
different chemotherapy agents were not analyzed in this study , because 62.22% of patients underwent taxanebased chemotherapy , and thus , this population subgroup was imbalanced .
regarding the chemotherapy regimen , the pfs of patients undergoing single agent chemotherapy was not statistically different compared with those receiving combination chemotherapy treatment ( p=0.305 ; figure 3 ) .
progression - free survival ( pfs ) of first - line trastuzumab treatment , single / sequential single agent vs. multiple agents ( p=0.305 ) .
a safety analysis was performed in all 90 patients who received at least one dose of trastuzumab , however , most patients were treated with chemotherapy simultaneously so chemotherapyrelated side effects such as hemotological effects are not presented here .
nine patients ceased treatment because of the following side effects : angina pectoris in 3 patients ( 1 of whom stopped treatment immediately ) , liver failure ( multiple liver metastasis ) in 1 , lung injury in 2 , serum creatinine increase in 1 , thrombus in 1 , and finger necrosis in 1 .
furthermore , 8 patients refused further treatment because of high costs , and 15 were diagnosed with brain metastases during the treatment period .
the other most common treatment - related adverse events were chill in 11 ( 12.2% ) patients , and fever in 15 ( 16.6% ) .
most treatment - related adverse events were mild to moderate , except in 5 patients who stopped treatment immediately , and most occurred during the first drug infusion .
however , the most widely - used treatment for advanced breast cancer in china is trastuzumab as a result of a public welfare project in 2011 .
thus , there remains the need to find new combinations or new schedules to prolong clinical benefit and survival of this subset of patients . in this observational study ,
we evaluated the use of trastuzumab in advanced her2-positive breast cancer , and our data represent important information on the application , efficacy , and safety of trastuzumab in clinical practice .
our study found that high response rate was more frequently attained in earlier therapy , like disease in the firstline cr achieved in 5/85 ( 5.8% ) patients , but only one cr in the second - line setting .
besides , in this cohort , there was a high proportion of patients with aggressive diseases coupled with liver and lung metastasis , more multiple sites of metastasis and more previous rounds of chemotherapy for advanced disease , but we still can see the response and prolonged patients survival .
therefore , patients can be treated in some aggressive situations . in a report from france , of 1,234 patients with metastatic breast cancer treated with chemotherapy between 2001 and 2010,217
, 38% had liver metastases at first occurrence of advanced breast cancer , and the median os was 45.2 months .
another phase  trial ( m77001 )   of first - line trastuzumab with docetaxel demonstrated an orr of 61% [ 95% confidence interval ( 95% ci),50%-71%],6 crs ( 7% ) and 50 prs ( 54% ) , with stable disease observed in 27% .
this result also indicated that trastuzumab had a high response as a first - line treatment .
the patients who continued trastuzumab beyond disease progression achieved modest responses , as observed in an original pivotal trial ( also an extension study ) , in which 247 patients were enrolled and the orr was 11% .
additionally , our data also showed that patients receiving two or more trastuzumab - containing regimens survived significantly longer than those who discontinued trastuzumab in disease progression .
here we presented a pfs that was significantly longer following more than six cycles of trastuzumab treatment ( 9 months vs. 16 months ; p=0.007 ) .  

this is especially inspiring under the current circumstances since pertuzumab and t - dm1 are not available in china for metastatic breast cancer patients as alternative options foranti - her2 treatment .
therefore , trastuzumab could be a maintenance therapy for these patients , especially in first to third lines .
an italian retrospective analysis identified a trend for better survival from the start of trastuzumab treatment in patients continuing beyond disease progression compared with those who halted the drug [ hazard ratio ( hr)=0.78 ; 95% ci : 0.58- 1.32 ] , although the response rate tended to be lower with each subsequent line . in this trial ,
orr in the first - line , secondline , third - line and fourth - line setting was 35%,16%,15% , and 0% , respectively , which is similar to our data .
however , in the gbg 26/big 3 - 05 phase  study , a significant survival benefit for treatment beyond progression with trastuzumab was not demonstrated .
nevertheless , another retrospective study reported no clinical benefit from continuing trastuzumab beyond progression in metastatic breast cancer . in this study
, vinorelbine - based salvage therapies were retrospectively investigated in 60 patients progressing during initial treatment with a trastuzumab - based regimen .
twentynine patients receiving vinorelbine - based salvage treatment and continuing trastuzumab had an orr of 21% . in the 31 patients who stopped trastuzumab ,
these data imply that the efficacy of trastuzumab would continue across multiple lines of therapy , and it also had limitations
. however , our results also showed that there is a difference between early trastuzumab treatments compared with later usage .
these findings revealed that the orr became sequentially worse though disease progression from the first- , second- , thirdline setting and beyond at 31.8%,10.6%,7.1% , and 0% , respectively .
a similar study reported that women with her2- overexpressing metastatic breast cancer had progressed after one or two chemotherapy regimens , 8 achieved cr and 26 achieved pr , with an orr of 15% in the intent - to - treat population .
the median duration of response was 9.1 months , and the median duration of survival was 13 months .
this also suggested that anti - her2 therapy should be used as early as possible .
the most frequently used chemotherapy agents were paclitaxel , docetaxel or vinorelbine , gemcitabine and even carboplatin .
there is no evidence to indicate a preferred chemotherapy regimen in the first - line setting for advanced breast cancer treatment . in the above
mentioned german study , the orr was the highest in the subgroup receiving trastuzumab together with chemotherapy ( 60% ) .
our study found that in her2-positive patients , a taxane - based regimen presented a better pfs but not os benefit compared with nontaxane- based regimens when combined with trastuzumab .
however , a relatively high proportion of patients who received taxane were included in our study , which could bias the results .
this implies that all of the described drugs should be considered as alternative firstline options .
another interesting result found in our study was that there was no difference in pfs between patients treated with either single / sequential - single chemotherapy or combined chemotherapy .
this observation was also showed in the bcirg 007 study , which presented a response rate of 72% for both docetaxel plus trastuzumab ( th ) and docetaxel plus carboplatin and trastuzumab ( tch ) groups treatment regimens , and median os of 37.1 and 37.4 months , respectively .
this differed from another study , which showed that docetaxel plus capecitabine and trastuzumab ( txh ) treatment demonstrated significantly longer pfs , with a median of 17.9 months compared with 12.8 months with th , which translates to a gain of around 5 months .
these findings suggested that for metastatic breast cancer , single / sequential - single chemotherapy rather than combined chemotherapy should be considered to attain survival benefit and a better quality of life for patients .
no additional adverse events were observed in our study compared with previous results , for example , cardiotoxicity was evident in 3/90 ( 3% ) patients in our study , which was similar to a report of single agent use of trastuzumab in which 2% of patients exhibited cardiotoxicity .
the most common treatment - related adverse events were chill and fever , which were similar to another published result .
in conclusion , trastuzumab combined with chemotherapy was active and well tolerated as a first - line treatment for patients with her2-overexpressing advanced breast cancer . even for patients who progressed upon trastuzumab treatment , continued trastuzumab treatment still showed efficacy but not as good as that observed for first - line therapy .
earlier administration and longer duration of trastuzumab treatment tended to have more clinical benefits for advanced breast cancer patients .
furthermore , trastuzumab combined with a single chemotherapy agent delivered similar efficacy compared with combined chemotherapy , and should be considered as an option to achieve survival benefit and a better quality of life for patients .
 objectiveto observe the efficacy and safety of trastuzumab combined with chemotherapy in patients with human epidermal growth factor receptor 2 ( her2)-overexpressing advanced breast cancer.methods a total of 90 patients with her2-overexpressing advanced breast cancer were enrolled in this study . 
 all patients were diagnosed with ductal invasive breast cancer by pathological analysis , and were aged between 3173 years with a median of 51 years . 
 her2-positivity was defined as 3(+ ) staining in immunochemistry or amplification of fluorescence in situ hybridization ( fish , ratio 2.0 ) . 
 trastuzumab was administered in combination with chemotherapy as first - line treatment and beyond progression as a secondline , third - line , and above treatment in 90 , 34 , 14 , and 6 patients , respectively . 
 the chemotherapy regimen was given according to normal clinical practice . 
 the response rate was evaluated every two cycles , and the primary endpoints were progression - free survival ( pfs ) and overall survival ( os ) . 
 survival curves were estimated by using kaplan - meier graphs and were compared by using log - rank test statistics . 
 multivariate analysis was done using cox s proportional hazards regression model , and the level of significance was p<0.05.results all 90 patients received at least one dose of trastuzumab , and efficacy could be evaluated in 85 patients . 
 the median follow - up was 50 months . in total , 72 ( 80.00% ) patients had visceral metastasis , and 43 ( 47.78% ) patients had progressed after one or more extensive chemotherapy regimens for metastatic diseases . 
 the median pfs for first - line trastuzumab was 10 months ( range , 259 months ) , and the median os after metastasis or initially local advanced disease was 22 months ( range , 2116 months).conclusions trastuzumab combined with chemotherapy was active and well - tolerated as a first - line treatment and even beyond progression in her2-overexpressing advanced breast cancer as a second - line or third - line treatment . 
 however , its efficacy is certainly less beyond this point . 