breast cancer is the second most common cancer worldwide , with more than one million new cancer cases annually . metastatic breast cancer ( mbc ) accounts for 20%-30% of all breast cancer cases and remains incurable ; therefore , systemic therapy plays an essential role in the treatment of mbc . among systemic therapies , endocrine therapy ( et ) because et is as effective as chemotherapy but less toxic , it should be recommended first in patients with hr - positive mbc except in cases of rapidly progressive disease . aromatase inhibitors ( ais ) are commonly used in practice in adjuvant and palliative settings . ais inhibit the aromatase enzyme , resulting in interruption of estrogen synthesis and suppression of tumor growth [ 4 - 7 ] . currently , there are three clinically available third - generation ais ; two reversible nonsteroidal ais , letrozole and anastrozole ; and one irreversible steroidal ai , exemestane . all three agents are at least as effective as tamoxifen in postmenopausal patients with hr - positive mbc [ 4 - 6 ] . a randomized phase iii clinical trial to compare letrozole with tamoxifen as first - line treatment showed that letrozole was superior to tamoxifen in terms of objective response rate ( orr ) , time to progression , and overall survival ( os ) . for this reason , there has been no satisfactory clinical data describing letrozole , particularly in korean patients . therefore , we investigated the efficacy and toxicity of letrozole as a first - line treatment for postmenopausal patients with hr - positive mbc . we searched all patients who received letrozole as a palliative treatment regardless of ordinal lines of therapy between january 2001 and december 2012 ( fig . 1 ) . a total of 407 patients met these criteria . among the 407 patients , 230 who received prior chemotherapy and 90 treated with a second or further lines of treatment were excluded from our analysis . menopause was defined as follows : prior bilateral oophorectomy , age > 60 years , age < 60 years with amenorrhea for 12 or more months in the absence of chemotherapy , tamoxifen , toremifene , ovarian suppression , or follicle - stimulating hormone / estradiol in the postmenopausal range . this protocol was reviewed and approved by the institutional review board of seoul national university hospital ( snuh ) ( irb no . we reviewed the medical records of all patients for the following characteristics : age , disease status , hr status , human epidermal growth factor receptor 2 ( her-2 ) status , ki-67 status , adjuvant treatments , date of recurrence , cancer antigen 15 - 3 level , number of metastatic organs , and dominant metastatic site . estrogen receptor ( er ) or progesterone receptor ( pr ) positivity was defined as staining for er or pr  1% of tumor cells by immunohistochemistry ( ihc ) . positivity was defined as an ihc of 3 + or 2 + and her-2 fluorescence in situ hybridization  positive . the high level of ki-67 was defined as an ihc of ki-67  14% of tumor cells . the treatment response was evaluated according to the response evaluation criteria in solid tumors ver . the grading of toxicity was recorded according to the national cancer institute common toxicity criteria for adverse events ( nci - ctcae ) ver . 4.0 . et - sensitive was defined as a relapse after  1 year of completion of adjuvant et . disease - free interval ( dfi ) was calculated from the day of curative resection to the date of tumor recurrence . progression - free survival ( pfs ) was measured from the first day of letrozole treatment until tumor progressions or death of any cause . os was calculated from the first day of letrozole treatment to patient death or the last date of follow - up . orr was defined as the proportion of patients with either a complete response or a partial response . the clinical benefit rate ( cbr ) was defined as the proportion of patients achieving the best overall response of complete response , partial response , or stable disease lasting for at least 6 months . all patients received 2.5 mg letrozole once a day until disease progression or withdrawal due to toxicity or patient s decision . tumor response was evaluated using the appropriate imaging modalities at least every 2 months in the first 6 months and every 3 months thereafter , or whenever there was clinical evidence of disease progression . categorical variables were compared with the pearson s chi - square test or fisher exact test , as appropriate . the log - rank test was used to compare the probability of survival between subgroups . multivariate analysis was performed using the cox proportional hazards model , and hazard ratios were calculated using a 95% confidence interval . all analyses were conducted using the pasw ver . 18.0 software package ( spss inc . , chicago , il ) . we searched all patients who received letrozole as a palliative treatment regardless of ordinal lines of therapy between january 2001 and december 2012 ( fig . 1 ) . a total of 407 patients met these criteria . among the 407 patients , 230 who received prior chemotherapy and 90 treated with a second or further lines of treatment were excluded from our analysis . menopause was defined as follows : prior bilateral oophorectomy , age > 60 years , age < 60 years with amenorrhea for 12 or more months in the absence of chemotherapy , tamoxifen , toremifene , ovarian suppression , or follicle - stimulating hormone / estradiol in the postmenopausal range . this protocol was reviewed and approved by the institutional review board of seoul national university hospital ( snuh ) ( irb no . we reviewed the medical records of all patients for the following characteristics : age , disease status , hr status , human epidermal growth factor receptor 2 ( her-2 ) status , ki-67 status , adjuvant treatments , date of recurrence , cancer antigen 15 - 3 level , number of metastatic organs , and dominant metastatic site . estrogen receptor ( er ) or progesterone receptor ( pr ) positivity was defined as staining for er or pr  1% of tumor cells by immunohistochemistry ( ihc ) . positivity was defined as an ihc of 3 + or 2 + and her-2 fluorescence in situ hybridization  positive . the high level of ki-67 was defined as an ihc of ki-67  14% of tumor cells . the treatment response was evaluated according to the response evaluation criteria in solid tumors ver . the grading of toxicity was recorded according to the national cancer institute common toxicity criteria for adverse events ( nci - ctcae ) ver . 4.0 . et - sensitive was defined as a relapse after  1 year of completion of adjuvant et . disease - free interval ( dfi ) was calculated from the day of curative resection to the date of tumor recurrence . progression - free survival ( pfs ) was measured from the first day of letrozole treatment until tumor progressions or death of any cause . os was calculated from the first day of letrozole treatment to patient death or the last date of follow - up . orr was defined as the proportion of patients with either a complete response or a partial response . the clinical benefit rate ( cbr ) was defined as the proportion of patients achieving the best overall response of complete response , partial response , or stable disease lasting for at least 6 months . all patients received 2.5 mg letrozole once a day until disease progression or withdrawal due to toxicity or patient s decision . tumor response was evaluated using the appropriate imaging modalities at least every 2 months in the first 6 months and every 3 months thereafter , or whenever there was clinical evidence of disease progression . categorical variables were compared with the pearson s chi - square test or fisher exact test , as appropriate . the log - rank test was used to compare the probability of survival between subgroups . multivariate analysis was performed using the cox proportional hazards model , and hazard ratios were calculated using a 95% confidence interval . all analyses were conducted using the pasw ver . 18.0 software package ( spss inc . , the mean age at diagnosis of the metastatic or recurrent disease was 59.310.5 years ( median , 59.3 years ; range , 36.4 to 85.7 years ) . overall , 54 patients ( 64.3% ) had both er- and pr - positive tumor , while 27 ( 32.1% ) and three ( 3.6% ) had er - positive /pr - negative tumor and er - negative / pr - positive tumor , respectively . ki-67 could be determined , 10 ( 11.9% ) had a high level of ki-67 . moreover , 34 patients ( 40.5% ) had bone - dominant metastasis and 21 patients ( 25.0% ) had lymph node or soft tissue metastasis . among 48 patients who received adjuvant tamoxifen , 14 ( 29.2% ) had et - sensitive tumors . adjuvant et data were insufficient for 26 patients ; therefore , only 48 ( 64.9% ) received tamoxifen as an adjuvant et . moreover , only three patients received anastrozole following tamoxifen as sequential treatment , while 58 ( 78.4% ) received adjuvant chemotherapy . additionally , 60 patients ( 81.1% ) had a dfi > 2 years , and 14 patients ( 29.2% ) were et - sensitive in the adjuvant et group . the median dfi in et - sensitive patients was 8.95 years ( range , 6.25 to 18.3 years ) , while the median pfs and median os were longer in the et responsive group than the non - responsive group ; however , these differences were not statistically significant ( median pfs , 12.3 vs. 34.1 months ; p=0.266 ; median os , 52.6 vs. 74.0 months ; p=0.262 ; log - rank test ) . the median follow - up was 71 months , and the median duration of treatment was 17.1 months . the most common reasons for discontinuing letrozole were disease progression ( 97.6% ) , followed by drug toxicity ( arthralgia grade 3 , 2.4% ) . median pfs and os were 16.8 months ( 95% confidence interval [ ci ] , 9.8 to 23.8 ) and 56.4 months ( 95% ci , 38.1 to 74.7 ) , respectively ( fig . 2 ) . shorter pfs and os were seen in patients with a dfi  2 years or initial metastasis or symptomatic visceral disease ( fig . 3 ) . subgroup analysis revealed that the orr for patients with a dfi > 2 years was significantly higher than that of patients with a dfi  2 years ( 43.3% vs. 14.3% , p=0.044 ) ( table 3 ) . univariate analysis revealed that short dfi (  2 years ) , initial metastasis and symptomatic visceral metastasis were significantly associated with short pfs ( table 4 ) . upon multivariate analysis , short dfi (  2 years ) , initial metastasis and symptomatic visceral metastasis also significantly influenced pfs ( table 4 ) . the observed toxicity in our study was limited , with most adverse events being mild to moderate . only one patient ( 3.2% ) had a left proximal humerus fracture related to osteoporosis , while two ( 6.4% ) had newly detected osteoporosis while using letrozole as defined by the nci - ctcae ver . the mean age at diagnosis of the metastatic or recurrent disease was 59.310.5 years ( median , 59.3 years ; range , 36.4 to 85.7 years ) . overall , 54 patients ( 64.3% ) had both er- and pr - positive tumor , while 27 ( 32.1% ) and three ( 3.6% ) had er - positive /pr - negative tumor and er - negative / pr - positive tumor , respectively . ki-67 could be determined , 10 ( 11.9% ) had a high level of ki-67 . moreover , 34 patients ( 40.5% ) had bone - dominant metastasis and 21 patients ( 25.0% ) had lymph node or soft tissue metastasis . among 48 patients who received adjuvant tamoxifen , 14 ( 29.2% ) had et - sensitive tumors . adjuvant et data were insufficient for 26 patients ; therefore , only 48 ( 64.9% ) received tamoxifen as an adjuvant et . moreover , only three patients received anastrozole following tamoxifen as sequential treatment , while 58 ( 78.4% ) received adjuvant chemotherapy . additionally , 60 patients ( 81.1% ) had a dfi > 2 years , and 14 patients ( 29.2% ) were et - sensitive in the adjuvant et group . the median dfi in et - sensitive patients was 8.95 years ( range , 6.25 to 18.3 years ) , while the median pfs and median os were longer in the et responsive group than the non - responsive group ; however , these differences were not statistically significant ( median pfs , 12.3 vs. 34.1 months ; p=0.266 ; median os , 52.6 vs. 74.0 months ; p=0.262 ; log - rank test ) . the median follow - up was 71 months , and the median duration of treatment was 17.1 months . the most common reasons for discontinuing letrozole were disease progression ( 97.6% ) , followed by drug toxicity ( arthralgia grade 3 , 2.4% ) . median pfs and os were 16.8 months ( 95% confidence interval [ ci ] , 9.8 to 23.8 ) and 56.4 months ( 95% ci , 38.1 to 74.7 ) , respectively ( fig . 2 ) . shorter pfs and os were seen in patients with a dfi  2 years or initial metastasis or symptomatic visceral disease ( fig . subgroup analysis revealed that the orr for patients with a dfi > 2 years was significantly higher than that of patients with a dfi  2 years ( 43.3% vs. 14.3% , p=0.044 ) ( table 3 ) . univariate analysis revealed that short dfi (  2 years ) , initial metastasis and symptomatic visceral metastasis were significantly associated with short pfs ( table 4 ) . upon multivariate analysis , short dfi (  2 years ) , initial metastasis and symptomatic visceral metastasis also significantly influenced pfs ( table 4 ) . the observed toxicity in our study was limited , with most adverse events being mild to moderate . only one patient ( 3.2% ) had a left proximal humerus fracture related to osteoporosis , while two ( 6.4% ) had newly detected osteoporosis while using letrozole as defined by the nci - ctcae ver . upon meta - analysis , ais showed similar efficacy and less toxicity than chemotherapy . the phase iii trials   demonstrated that anastrozole or letrozole was superior to tamoxifen as a first - line treatment in postmenopausal patients with mbc . based on both meta - analysis and phase iii trials , anastrozole or letrozole is the standard first - line therapy in postmenopausal patients with hr - positive mbc . however , most ai trials in mbc have been tested in western patients , not asian patients , and there have not been any data relevant to ais generated in hr - positive mbc to date , particularly in korean patients . moreover , only 40% of korean patients with breast cancer are postmenopausal , which seems to be lower than in western countries . as a result , it is not easy to perform a large - scaled study for ais , particularly in korean postmenopausal patients . to the best of our knowledge , even though this is a retrospective analysis , our study has the largest scale of analysis for letrozole as a first - line treatment in korean postmenopausal patients with hr - positive mbc . in our study , pfs , os , and orr were 16.8 months , 56.4 months , and 36.9% , respectively , which is more favorable than in other studies . moreover , short dfi and symptomatic visceral metastasis were significantly related to poorer clinical outcomes ( table 4 , fig . 3 ) . unfortunately , we found no dfi data in phase iii trials of and therefore could not compare them with our study directly . it is important to point out that even in the po25 study , only the median dfi ( 5.9 years ) was given . in our study , categorization of dfi was based on two years and the median dfi was 6.1 years ( range , 0.1 to 37.4 years ) . moreover , it is difficult to compare these values directly , because no previous studies divided patients into symptomatic and asymptomatic visceral metastasis . rather , most studies conducted to date have used nonvisceral and visceral metastases to separate the dominant metastasis . particularly , in visceral metastasis , only liver involvement was considered , not the symptoms . therefore , our study is unique in that it confirms symptoms as an important factor . a randomized phase iii ( po25 ) trial to compare letrozole with tamoxifen in postmenopausal patients with mbc showed better clinical benefits in letrozole . however , pfs and os in our study were better than in other trials , including the po25 study . this result may have occurred because the proportion of patients with initial metastasis at diagnosis was much lower than in other phase iii studies ( table 5 ) , and most enrolled subjects were recurrent cases ( 88.1% ) in the present study . the disease burden of recurrent cases may have been smaller at the time of diagnosis since it was detected early through routine regular follow - up examination . the rate of dominant visceral metastasis was greater in the po25 study ( 43% ) than in our study ( 34.6% ) . moreover , there were fewer patients with relatively adverse dominant metastatic sites such as liver involvement in this study ( table 5 ) . in addition , one prior chemotherapy regimen for the treatment of metastatic disease was permitted in the po25 trial , whereas our patients received letrozole treatment as their first - line therapy in the metastatic setting . it is also possible that the patients who were selected to be treated with first - line et instead of chemotherapy had a tumor with a more indolent nature . therefore , our results may show better survival than those of previous studies . even in the group with visceral metastasis , patients with no symptoms had a median pfs four times longer ( 40.6 months vs. 8.8 months ) and a median os three times longer ( 89.5 months vs. 24.2 months ) than those with symptoms ( fig . moreover , patients with a dfi  2 years or initial metastatic diseases also showed shorter survival than those without . cytotoxic chemotherapy may be preferred for patients of a relatively young age , with short dfi , with initial metastasis or in need of rapid symptom control . therefore , any of the third generation ais may be used for front - line treatment of hr - positive mbc in postmenopausal patients without visceral crisis . treatment decisions are based on symptoms and disease severity ( e.g. , impending visceral crisis ) , dfi , patient age , performance status , sites of disease and comorbidities . other important concerns include patient preferences , maintaining or improving quality of life , and minimizing treatment toxicities . even if patients had symptoms or metastatic diseases initially , an anti - hormone therapy would be useful when tumor tissues were revealed as strongly er positive or it is difficult to proceed with chemotherapy because of old age . in our study , although patients had the above risk factors , they were treated with et if they were elderly , had lower eastern cooperative oncology group performance scores , or did not want chemotherapy . to date , there has been no evidence of concurrent cytotoxic chemotherapy and cytostatic et resulting in improved survival among advanced breast cancer patients . therefore , we recommend et and chemotherapy be performed sequentially to fit individual patients situations . some tumors harbor intrinsic resistances to endocrine agents , and in the metastatic setting , all tumors ultimately acquire resistance to et . in this study , there were no statistically significant differences in treatment response and survival between patients who had recurred after  1 year of completion of adjuvant et and those who had not . patients with previous et ( tamoxifen ) were included in the phase iii trials shown in table 5 , and third generation ais drew favorable clinical outcomes . moreover , the past tamoxifen treatment history did not affect the ai effect in any of the studies summarized in table 5 . there are different resistance mechanisms of tamoxifen and letrozole in genome - wide analysis ; therefore , these findings suggest that there no cross - resistance between these mechanisms recent studies of paloma-1 , and turner et al .   demonstrated that endocrine monotherapy had limited efficacy in patients with disease progression after previous exposure to et , irrespective of clinically or molecularly defined endocrine sensitivity , suggesting a need for the routine use of more effective combination regimens . in our study , the clinical outcomes with no statistically significant difference according to et - responsiveness might have occurred because of the relatively small sample sizes . therefore , further studies and validation are warranted . first , the retrospective design made it difficult to compare functional status , symptoms , and toxicity profiles among patients . second , the enrolled patients were selected from a single institution in korea , and the relatively small sample size may limit the statistical power to derive significant outcomes and correct the differences in subgroup characteristics . despite these limitations , our analysis investigated a homogeneous patient population with a large case series of postmenopausal women treated with the first line letrozole that were regularly evaluated during and after treatment . however , the characteristics of korean patients differ from those of western patients in terms of age , menopausal status and disease status at first diagnosis . therefore , a prospective clinical trial to reveal the efficacy and toxicity of ais in korean patients is warranted .
purposeletrozole showed efficacy and generally favorable toxicities , along with the convenience of oral administration in postmenopausal patients with hormone receptor ( hr)positive metastatic breast cancer ( mbc ) . to the best of our knowledge 
 , there have been no reports of the clinical outcomes in korean patients , although letrozole is widely used in practice . 
 therefore , this studywas conducted to affirm the efficacy and toxicities of letrozole in korean patients.materials and methodsthis study retrospectively analyzed 84 hr - positive mbc patients who had been treated with letrozole from january 2001 to december 2012 . 
 clinicopathological characteristics and treatment history were extracted from medicalrecords . 
 all patients received 2.5 mg letrozole once a day until there were disease progressions or unacceptable toxicity . 
 progression - free survival ( pfs ) was the primary endpoint , and secondary endpoints were overall survival ( os ) , objective response rate ( orr ) , and toxicity.resultsthe median age of the subjects was 59.3 years . 
 letrozole treatment resulted in a median pfs of 16.8 months ( 95% confidence interval [ ci ] , 9.8 to 23.8 ) and a median os of 56.4 months ( 95% ci , 38.1 to 74.7 ) . 
 the orr was 36.9% for the 84 patients with measurable lesions . 
 multivariate analysis revealed symptomatic visceral disease ( hazard ratio , 3.437 ; 95% ci , 1.576 to 7.495 ; p=0.002 ) and a disease - free interval  2 years ( hazard ratio , 2.697 ; 95% ci , 1.262 to 5.762 ; p=0.010 ) were independently associated with shorter pfs . 
 however , sensitivity to adjuvant hormone treatment was not related to pfs . 
 letrozole was generally well tolerated.conclusionletrozole showed considerable efficacy and tolerability as a first - line treatment in postmenopausal patients with hr - positive mbc .