breast cancer is the second leading cause of cancer deaths in women today after lung cancer .
metastatic breast cancer ( mbc ) is deemed incurable and median survival for patients with cancer that is estrogen receptor ( er ) negative or no longer hormonally responsive is only 18 to 24 months [ 1 , 2 ] . a variety of molecularly targeted drugs have been developed for mbc , but to date only , trastuzumab ( herceptin , genentech , ca , usa ) has shown an overall survival ( os ) benefit of several months [ 35 ] . clearly , more effective treatment strategies and/or improved patient selection are urgently needed .    in the 1990s ,
high dose chemotherapy followed by autologous stem cell transplantation ( hd - asct ) was pioneered to improve survival .
the initial feasibility studies in small cohorts of patients with advanced stage disease showed improved survival when compared to historical controls [ 69 ] .
subsequent prospective randomized clinical trials comparing hd - asct to standard chemotherapy resulted in improved pfs , but failed to demonstrate os benefit [ 1014 ] .
the results of the last trial of these series with 386 patients with metastatic breast cancer employing hd - asct were reported most recently and confirmed the results of earlier studies .  
all together , the lack of convincing survival data at the expense of high toxicity resulted in the demise of hd - asct as a treatment modality of mbc .
however , while the vast majority of patients with mbc will succumb to their disease within a relatively short period of time , 510% of patients live longer than 5 years , and observational data suggest that 13% of patients treated with conventional chemotherapy and/or hormonal manipulation may experience long - term survival beyond 1015 years [ 1621 ] .  
quite surprisingly , the most impressive long - term survival rates in excess of 10% were reported with hd - asct [ 2224 ] .  
response to treatment , site of metastases , hormone receptor status , performance status , and short initial disease - free interval were important prognostic factors for survival after hd - asct and corresponded to prognostic factors known from treatment with conventional , less aggressive therapies [ 2527 ] .
we have studied long - term survival rates as well as the distinct disease- and patient - related characteristics that would be predictive of long - term survival in a cohort of patients with mbc , who were treated at our institution between 1989 and 1999 .
records of all patients in the bone marrow transplant registry at ucsd treated with hd - asct for mbc between 1989 and 1999 were retrospectively reviewed .
patients were followed for a median of 65 months from diagnosis ( range 10.4255.0 months ; quartiles 36.7109.3 months ) .
age , race , stage at diagnosis , histology , estrogen receptor ( er ) and menopausal status , body mass index ( bmi ) in kg / m   at the time of hd - asct , time to transplant and death , site of metastasis , and disease status prior to hd - asct were extracted .   since all transplants were carried out prior to routine assessment of her-2/neu receptor status , this information was not part of our analysis .
menopause was defined clinically by absence of menstruation for more than 12 months ( http://www.cancer.gov/ ) .
high dose chemotherapy prior to stem cell support was platinum based in combination with thiotepa / etoposide , ifosfamide / etoposide , cyclophosphamide / bcnu , cyclophosphamide / mitoxantrone , or cyclophosphamide / thiotepa .
body surface area was allowed to exceed 2  m. ten patients received hd - asct in first line ; all other patients received at least one line of treatment prior to hd - asct ( median 1 ; range 04 ) .
the other 89 patients received peripherally mobilized stem cells , 23 of which received grafts supplemented with harvested bone marrow cells .
mobilization was achieved with granulocyte- or granulocyte / macrophage - colony stimulating factor   with or without cyclophosphamide .
extent of metastatic disease was determined within 12 weeks prior to and within 612 weeks after hd - asct by imaging and physical exam .
thereafter , assessment of disease status was prompted by patient symptoms and carried out at physicians ' discretion .
patients were grouped according to site of metastasis  :  in visceral or bone metastasis , or local or nodal recurrence .
if multiple sites of metastasis were present , assignment to one metastatic site was prioritized as follows : visceral > bone > nodal > local .
complete response ( cr ) , partial response ( pr ) , stable disease ( sd ) , and progressive disease ( pd ) were determined according to recist criteria .
multiple linear regression models were used to explore the association between a continuous outcome and predictors of interest .
cox models were used to identify independent   predictors of a time - to - event variable and schoenfeld tests were used to test for proportional hazard assumptions .
predictors of interest with p < 0.2 in the univariate analysis were included in an initial model and a manual backward selection was made based on the wald test p values .
median age at initial diagnosis was 43 years ( quartiles 3849 ) and 47 years ( quartiles 4143 ) at metastasis .  
median time from initial diagnosis to documentation of metastasis was 29 months ( quartiles 16.663.7 ) , and from metastasis to hd - asct 6.6 months ( quartiles 4.516.6 ) , respectively .
twelve patients received hd - asct as their first line of treatment , whereas 84 patients had at least one prior line of chemotherapy for metastatic disease ( 48 patients with 1 line , 24 with 2 lines , 10 patients with 3 lines , and 2 patients with 4 lines of chemotherapy ) .
median bmi at metastasis was 25 ( quartiles 21.429.6 ) and 24% of patients were obese ( bmi > 30 ) .
for all patients ( n = 96 ) , median pfs and os were 3.9 years ( ci 2.95.4 ) and 5.6 years ( ci 4.17.4 ) after initial diagnosis , and 1.6 years ( ci 1.31.9 ) and 2.7 years ( ci 2.33.9 ) after diagnosis of metastatic disease , respectively ( figures 1(a ) and 1(b ) ) .
survival rates at 10 years were 24.5% ( ci 17.234.9% ) from diagnosis and 14.4% ( ci 8.7 , 23.9% ) from when metastatic disease was diagnosed .  
as depicted in figure 2 , pfs and os differed significantly for patients with a bmi  30 and > 30 . at diagnosis , median pfs for patients with bmis
 30 ( n = 73 ) and > 30 ( n = 23 ) was 4.4 ( ci 3.66.7 ) and 2.5 years ( ci 1.74.9 ) , and median os was 7.1 ( ci 4.48.7 ) and 3.2 years ( 2.416.75 ) , respectively ( figure 2(a ) and 2(c ) ; all p values   = 0.001 ; univariate ) .  
once metastasis was diagnosed , median pfs for patients with bmis  30 and > 30 was 1.8 ( ci 1.442.77 ) and 1.04 years ( 0.91.96 ) years , and median os was 3.20 ( ci 2.424.30 ) and 2.30 years ( ci 1.564.96 ) , respectively ( figure 2(b ) and 2(d ) ; all p values  < 0.02 ; univariate ) .
ethnicity , stage at diagnosis , histology , site of metastasis , remission prior to hd - asct , menopausal status , ages at hd - asct and at diagnosis ( < age 40 versus  age 40 ) , bmi (  30 versus > 30 ) , and er status were evaluated as independent predictors of pfs and os .   in a univariate analysis , bmi , stage at initial diagnosis , and histology were predictive of time from initial diagnosis to metastatic disease ( all p values  < 0.01 ) .
as depicted in table 2 , only the initial stage at diagnosis and bmi were confirmed as independent predictors in a multivariate multilinear regression analysis .  
time to metastasis was significantly shorter for patients with a bmi > 30 ( table 2 ) .
median time to metastasis was 1.14 years for patients with a bmi > 30 compared to 1.85 years for patients with a bmi  30 ( p < 0.04 for time to metastasis ) .
times to metastasis were similar for stage i or ii disease ( approximately 2 years ) , but time to metastasis shortened significantly compared to stage i or ii disease when stage iii was present at diagnosis ( 0.72 years , p < 0.0006 ) . stage at diagnosis , er - status , site of metastasis , remission status prior to hd - asct , and bmi were considered for multivariate analysis since univariate p values were  < 0.02
. only bmi , stage at diagnosis and site of metastasis were confirmed to be independent predictors of survival at the time of metastasis ( table 3 ) .
patients with a bmi > 30 had a significantly higher hazard of progression and death compared to patients with a bmi  30 ( hr for progression  =  2.23 ; p = 0.005 ; hr for death   =  1.82 ; p = 0.04 ) . also ,
once metastasis was diagnosed , hazards of progression and death increased significantly with increasing stages present at diagnosis ( compared to stage i all p values  < 0.05 ; table 3 ) or with visceral disease .
in the 1990s , high hd - asct was thought to be a beneficial treatment option in mbc , based on the hypothesis that significant dose escalation would improve the efficacy of chemotherapy .
hd - asct was abandoned . since cure could not be achieved with aggressive treatment , the school of thought changed and sequential single agent chemotherapy with or without biological targeted therapies and /or hormonal manipulation in er+ patients has become the preferred way of symptom control [ 2 , 29 ] .  
however , a proportion of patients with mbc can achieve long - term survival which has been reported to exceed 10% with more aggressive chemotherapy such as hd - asct [ 2224 ] .
we were specifically interested if such high percentages of survival could be maintained beyond 10 years , at which point it is possible that at least some of these patients may be cured of their disease .
second , we studied the patient- and disease - specific characteristics predictive of survival . for both questions we analyzed our institutional cohort of 96 patients with mbc who had received hd - asct as part of their treatment algorithm .  
since the last patient was transplanted in 1999 , each patient had a minimum follow - up of 10 years .  
survival rates at 10 years were 24.5% from initial diagnosis and 14.4% from when metastatic disease was diagnosed .   
second , and most surprisingly , in univariate and multivariate analyses , obesity was the only patient - related factor associated with significantly shorter os and pfs from initial diagnosis and from when metastasis was diagnosed .
obesity has previously been reported as a risk factor for survival in patients diagnosed with earlier stages of breast cancer [ 3032 ] and seems associated with higher stages at diagnosis , but , to the best of our knowledge , this is the first study reporting obesity as a risk factor for survival in patients with mbc .  
other patient - related factors such as age , ethnicity , and menopausal status were not significant .
weights and obesity status were not available to us at the time of initial diagnosis , but recorded at the time of metastasis prior to first treatment .
the median interval between initial diagnosis and time to metastasis was only approximately 3 years and can probably be considered a time frame where major weight changes are not expected to occur for the majority of patients .
we therefore felt comfortable to use the weight obtained at metastasis as the representative personal weight for each patient .  
third , among disease - related characteristics , stage at diagnosis was an independent predictor of time to metastasis .
neu was not part of the analysis since it was not routinely tested prior to 1999 . at the time of metastasis , in addition to stage at diagnosis , visceral metastasis also became an independent predictor of a higher hazard for progression and , suggestively , shortened os .
higher stages at diagnosis are known to be associated with shorter time to recurrence and poorer survival [ 35 , 36 ] , and increased likelihood of occult metastasis in permissive niches such as the bone marrow and/or biologically more aggressive forms of cancer with increased burden of disease were suggested as plausible explanations for poorer survival at higher stages [ 37 , 38 ] .   also , visceral metastasis has been reported before as a predictor of poor survival in mbc [ 2527 ] .  
the association of poorer outcomes with higher stages at initial diagnosis or visceral metastasis seems uniformly accepted , and our study supports these previous findings . the most important and novel finding was the negative effect of obesity on survival in mbc , and its importance as independent predictor of time to metastasis and progression . to the best of our knowledge ,
these results provide first strong evidence that elevated bmi may contribute significantly to poor survival in mbc and these data were ascertained in the setting of hd - asct . while it has been reported that obesity is associated with higher stages of breast cancer at diagnosis , and that obesity negatively impacts various outcome factors in earlier stages of breast cancer [ 3032 ] , the effects of obesity
have not been directly studied in mbc . specifically in respect to locoregional breast cancer , two prospective studies identified obesity as an independent risk factor for overall mortality , distant and contralateral recurrence , and death from breast cancer [ 31 , 32 ] .
similar findings for all presentations of breast cancer ( some of which had mbc ) were reported in the prospective analysis of case - control studies on environmental factors and health ( pace ) study . in general , it is increasingly recognized that obesity and cancer are linked and that obesity not only confers a higher risk of cancer incidence but also increases cancer mortality as demonstrated in three large population - based cohort studies [ 3941 ] .  
the reasons are poorly understood , but tumor growth stimulation by adipokines released from fatty tissue , inflammation [ 4244 ] , and especially in the case of breast cancer increased estrogen levels in obese postmenopausal females fueling tumor growth [ 45 , 46 ] are implicated . also , adjuvant undertreatment of obese patients , if chemotherapy is not strictly weight - based [ 4749 ] , is increasingly recognized as important for early relapse . against physicians ' beliefs , chemotherapy in the obese is well tolerated , and , while dose increases proportional to weight do not confer a higher risk for toxicity [ 49 , 50 ] , under - dosing in the obese breast cancer patient receiving adjuvant chemotherapy demonstrated increased risk for recurrence , shorter dfs or os [ 51 , 52 ] . despite these data , two recent surveys show that only 25% of breast cancer patients receive strictly weight - based dosing during adjuvant chemotherapy and that 19 of 44 cooperative group trials used dose limits for the obese [ 47 , 48 ] .   in our study population ,
doses of previous adjuvant regimens were unknown , and suboptimal adjuvant treatment can not be ruled out as a reason for faster time to metastasis in the obese .
however , agents used for treatment in the metastatic setting and for hd - asct were dosed by actual body weight , and body surface areas were allowed to exceed 2  m , such that underdosing does not appear to be the main reason for poorer outcome parameters .
further study limitations are absence of her-2-neu as important prognostic marker , since it was not routinely available in the era of hd - asct , and patient population diversity
.   selection bias may be present since not every patient deemed a candidate for hd - asct may have been referred or proceeded to hd - asct .
factors such as , but not limited to , physicians ' or patients ' treatment preferences , patients ' performance status and socioeconomic status may have interfered .   until now , obesity and its effect on outcomes in mbc have not been examined in depth , and this is the first report to implicate obesity in poorer outcomes . while this observation was made in the setting of hd - asct , conclusions about the contribution of hd - asct to long - term survivorship
can not be made , given retrospective study design , diverse study patient population , and mixed treatment algorithms .
however , our results demonstrate that ultra - long - term survivorship can be achieved in the setting of more aggressive chemotherapy with hd - asct and that obesity was deleterious in mbc . in contrast to mbc ,
correction of unhealthy life - style behavior associated with obesity is the subject of intense exploration after adjuvant treatment for breast cancer , where patients are officially recognized as  breast cancer survivors .
   results from the women 's healthy eating and living ( whel ) study   suggest that obese patients can experience significant overall survival benefit if compliant with a combination of diet and exercise .
we believe that our findings generate the hypothesis that obesity may be a potentially correctable patient - related adverse survival factor in mbc and , similar to approaches for locoregional stages of breast cancer , can serve as a target for intervention given the prospect of long - term survival in certain settings .
 the purpose of the study was to identify predictors of long - term survival in metastatic breast cancer ( mbc ) . 
 a cohort of 96 patients , who received high - dose chemotherapy with autologous stem cell support ( hd - asct ) as part of their treatment , was analyzed . 
 percent long - term survival at 10 years was 
                 24.5% ( ci 17.234.9% ) when metastasis was diagnosed and 14.4% ( ci 8.723.9% ) when mbc was diagnosed . 
 survival was impacted significantly by body mass index ( bmi ) . 
 median overall survival from initial diagnosis or from time of metastasis for patients with bmis 
                 30 and > 30 ( obese ) was 7.1 ( ci 4.48.7 ) and 3.2 years ( 2.416.75 ) , respectively , or 3.2 or 2.3 years ( all p = 0.02 ) . also , obesity was the only independent patient - related predictor of time to metastasis and of survival . 
 while obesity is linked with poor outcomes in earlier stages of breast cancer , this has not been previously reported for mbc . 
1. Introduction
2. Methods
3. Results
4. Discussion