Importance of Metastasis Site in Survival of Patients with Breast Cancer

  

    
Multivariate analysis
    
P value
    
Hazard ratio
    
95% confidence interval
  
  

    
Menopause status
    

    

    

  
  

    
Postmenopause vs premenopause
    
0.023
    
2.07
    
1.11-3.85
  
  

    
Diabetetes mellitus
    

    

    

  
  

    
Yes vs no
    
0.006
    
2.71
    
1.37-6.29
  
  

    
Lymphovascular invasion
    

    

    

  
  

    
Positive vs negative
    
0.004
    
7.71
    
1.39-5.30
  
  

    
Grade
    

    

    

  
  

    
Grade 3 vs grade 1-2
    
0.017
    
2.09
    
1.14-3.84
  
  

    
Hemoglobin
    

    

    

  
  

    
≥12 g/dL vs <12 g/dL
    
0.001
    
0.34
    
0.17-0.63
  
  

    
Bone metastasis
    

    

    

  
  

    
Yes vs no
    
0.018
    
0.50
    
0.28-0.88
  
  

    
The number of metastasis
    

    

    

  
  

    
Multiple vs single organ
    
0.018
    
2.14
    
1.14-3.99
  

Table 4:  The independent prognostic factors that affected the survival time of the patients after development of metastasis.

Discussion

The overall survival duration of patients with breast cancer has significantly increased, parallel to the recent advances in early diagnosis techniques and adjuvant treatments. However, patients who develop metastasis still have varied survival durations. Some patients may die in a very short time, while some others may live with the metastasis for many years. Therefore, metastatic breast cancer patients represent a heterogeneous group that involves different clinical entities. Due to the differences in survival durations, determining the prognostic factors for this patient group is of great importance.

Bone metastases represent the most common metastasis seen in patients with breast cancer. The bones are primarily the first site of metastasis in this patient group. After development of bone metastasis, patients generally have longer survival durations compared to the patients with other metastatic sites. The median survival of patients after development of bone metastasis is approximately two years and 20% of these patients live longer than five years [9]. In their study including 248 breast cancer patients with bone metastases, Yavas et al. reported that the median survival duration after the development of metastasis was 24 months. It was reported in the same study that the first site of metastasis was the bone in the majority of the patients [10]. In 110 breast cancer patients having bone metastasis alone (having no metastasis at any other region), Ahn et al. reported the median survival as 55.2 months [11]. In the current study, patients developing bone metastasis were seen to have statistically significantly longer survival after the development of metastasis, compared to the patients with brain, liver, or lung metastases. However, patients with locoregional relapse and patients with bone metastasis had similar survival times. Both sites had the longest survival durations; median survival: 32 and 31 months, two-year survival: 57% and 63%, and five-year survival: 24% and 22%, respectively.

Stereotactic radiosurgery or surgical applications may extend the survival time in a limited number of tumors; however, the survival in these patients is still very low after the development of brain metastasis. The one-year survival rate after development of brain metastasis is approximately 20% [12]. In a study performed by Niwinska et al. [13] in 222 breast cancer patients with brain metastasis, median survival of patients was found to be 7.5 months. Results of the present study also showed that the patients have quite a low survival duration after the detection of brain metastasis (median survival: seven months, two-year survival: 20%, five-year survival: 0%). Compared to the survival duration of patients developing bone, lung, liver metastasis, or locoregional relapse, patients with brain metastasis had statistically significantly shorter survival.

Like brain metastasis, hepatic metastasis is also generally associated with poor prognosis in patients with metastatic breast cancer. In 500 metastatic breast cancer patients having liver metastasis, Pentheroudakis et al. showed that median survival time was 16 months and five-year survival was 8.5% [14]. In the present study, the median survival of patients with liver metastasis was 13 months, and their two-year and five-year survival rates were 30% and 12%, respectively. When compared to the survival durations with other organ metastases, patients with liver metastasis were seen to have significantly shorter survival compared to the patients with bone, lung metastasis or locoregional relapse, and significantly longer survival compared to the patients with brain metastasis.

The lungs are also a common site of metastasis in patients with metastatic breast cancer. Kawano et al. performed a study in patients with hormone positive stage IV breast cancer (69 patients) and reported the median survival in patients with lung metastasis to be 37 months [15]. In the present study, patients with lung metastasis had a median survival of 25 months, and their two-year and five-year survival rates were 51% and 12%, respectively. Patients with lung metastasis had shorter survival times compared to the median and two-year survival in patients with bone metastasis or locoregional relapse, and longer survival compared to the patients with liver or brain metastasis. However, their five-year survival rate was similar to the rate in patients with liver metastasis.

Most researchers believe that the age of the patient at diagnosis is a prognostic factor affecting the survival. In the study performed by Largillier et al. [16] in 1038 patients with metastatic breast cancer, it was reported that the survival of patients above 50 years of age was shorter than the survival of patients aged below 50 years (median survival 20 and 31 months, respectively). Some studies have shown that premenopausal women had better prognosis than the postmenopausal women [2]. However, other studies do not support this finding [17,18]. In the present study, the univariate analysis showed that patients’ age above 50 years and postmenopausal status affected the prognosis in a negative way; however, the multivariate analysis showed that only menopausal status was an independent prognostic factor. Some researchers associated the poor prognosis seen in patients with older ages to the comorbidities present in this patient group [7]. The current results showed that patients with comorbidities did not have significantly different survival rates; however, patients with diabetes had shorter survival than the other patients. Additionally, presence of diabetes mellitus was found to be an independent prognostic factor. Different from the present study, in their study including 557 patients with metastatic breast cancer, Jung et al. revealed that the presence of hypertension was an independent prognostic factor associated with mortality and they did not show a relation between the presence of diabetes mellitus and survival [18]. Some studies showed that poor performance status of the patients is among the factors that negatively affect the prognosis [19,20]. In the present study, the univariate analyses demonstrated that the performance status was a factor affecting prognosis; however, such an affect was not confirmed by multivariate analyses.

Tumor biology is known to play a significant role in the disease prognosis and patient survival. Furthermore, various studies have shown that various parameters that play roles in tumor behaviors, such as tumor differentiation, lymphovascular invasion, and perineural invasion, and have effects on the prognosis. In their study comparing breast cancer patients who had metastasis at diagnosis and who developed metastasis later (370 patients), Jimeno et al. confirmed the relationship between survival and grade. According to that study, the poorly differentiated tumors continue their negative effects on survival even after the metastasis (median survival 37 vs. 21 months) [21]. In a study performed by Liu et al., the results in 135 patients with metastatic breast cancer were found similar to the above mentioned study; median survival was 29 months for grade 1 tumors, and 19 months for grade 2 and 6 months for grade 3 tumors [22]. The results of the present study also showed that the survival was negatively affected in patients having poorly differentiated tumors with lymphovascular invasion. Additionally, tumor grade was encountered as an independent prognostic factor in the multivariate analyses.

Both the hormone receptor status and HER2 status in patients with breast cancer have significant roles in the treatment decision and patient prognosis. Several studies have shown that ER- and/or PR- status is associated with poor treatment response and increased mortality risk in patients with metastatic breast cancer [7,23-25]. Takeuchi et al. performed a study in 345 Japanese women who had their first recurrence, and showed that ER- and PR- statuses were poor predictive factors for mortality [25]. Similarly, Jun et al. reported that both ER- and PR- status is associated with mortality in the multivariate analyses [18]. On the other hand, Chang et al. reported that only PR- status was an independent prognostic factor [7]. Ryberg et al. [26] performed a survival analyses in 469 metastatic breast cancer patients who were treated with epirubicin-based chemotherapy and reported ER- status to be a poor prognostic factor. However, different from the other studies, the current results did not show such a strong relation between the survival and hormone receptor status. Only the univariate analyses showed that ER+ status had positive effects on survival, but no statistical significance was seen in the multivariate analyses.

HER2 is a pro-oncogene and its overexpression is known to be associated with poor survival and prognosis in early stage diseases [27,28]. Its role in metastatic disease is yet to be discovered. The present study did not show a statistically significant relation between HER2 and survival; however, there are studies reporting that HER2 is a prognostic factor for survival. In their study, Yung et al. confirmed the relation between HER2+ status and mortality [18]. In the study performed by Ren et al. in 194 patients with metastatic breast cancer at diagnosis, different from the above mentioned study, a statistically significant relation was not observed between the survival and the absence of HER2 overexpression; however, this patient group was shown to have a slightly longer survival than the other patients [29]. Largillier et al. [16] have reported that median survival was not different between the patients with HER2+ and HER2- tumors; median survival was 22 and 29 months, respectively. This study also showed that HER2 status does not affect survival.

Several studies have investigated the effects of the time for metastases development and its localization on survival. These studies have generally shown that patients with longer intervals of metastasis development also had longer survival times [7,18,21,22,25]. Jimeno et al. [21] reported that the interval for metastasis development (<24 months vs. ≥24 months) has significant effects on the survival according to a univariate analysis. Chang et al. [7] grouped the interval for metastasis development as <12 months, 12-60 months, and >60 months and they obtained significant results in terms of survival. However, in the present study, no significantly different survival rates were observed when the interval for metastasis development was stratified as 12 and 24 months (<12 vs ≥12 months, <24 vs ≥24 months). The interval for metastasis development was not considered to be a prognostic factor in the current study.

Some studies report that similar to the interval for metastasis development, the number of metastasis, and localization of metastasis also affect survival [17,18,21,29]. Jimeno et al. [21] assessed the number of sites with metastasis development along with the interval for metastasis. Their results showed a statistically significant difference in the survival rates between the cases with single organ metastasis and multiple organ metastases. Additionally, the presence of ≥2 organ metastases was considered to be a poor prognostic factor. Similarly, in the present study, the number of metastases was found to be a prognostic factor affecting the survival in both univariate and multivariate analyses. In the study performed by Jun et al., presence of brain, bone, and liver metastases was observed to represent the prognostic factors that statistically significantly the survival, both in the univariate and the multivariate analyses [18]. Liu et al. [22] reported that the presence of liver metastases represented a poor prognostic factor. The present study revealed that the presence of bone, liver, and brain metastasis was among the factors affecting survival. Patients with bone metastasis had longer survival than the patients having metastasis in the other organs, and bone metastasis was also shown to be a good prognostic factor based on the multivariate analyses.

Although not always, the levels of tumor markers such as CEA and Ca15.3 can be elevated in patients with metastatic breast cancer after development of metastasis. The level of increase in tumor markers varies between the patients. In their study comparing the predictive and prognostic value of circulating tumor cells and tumor markers (CEA, CA15.3 and lactate dehydrogenase) in patients with metastatic breast cancer, Pierga et al. [30] showed that CEA and Ca15.3 levels above the normal interval were poor prognostic factors for progression-free survival according to the univariate analysis. In the current study, the researchers also assessed the effects of elevated tumor marker levels on survival. Based on the univariate analyses, only the level of Ca15.3 that is above the normal interval was found to be a prognostic factor affecting survival. CEA levels above the normal interval did not affect survival.

It was shown that the hemoglobin levels measured at diagnosis can be associated with prognosis in many cancer patients [31-34]. A decrease can be expected in the hemoglobin levels of the patients with metastatic disease, since these patients receive strong treatments and it is highly possible that their hemodynamic balance may be altered. The results of this study show that hemoglobin levels in patients with metastatic breast cancer are strongly associated with the prognosis.

Conclusion

The results of the present study support the claim that patients with bone metastasis have the best survival rates, whereas the patients with brain metastasis have the shortest duration of survival. The duration of survival in patients with metastatic breast cancer greatly varies according to the localization of metastasis. The study results showed that among all the prognostic factors that play significant roles on the survival of patients with metastatic breast cancer, post-menopause, presence of diabetes mellitus, lymphovascular invasion positivity, high disease grade, and multiple organ metastases represent the poor independent prognostic factors; whereas the presence of bone metastasis is a good independent prognostic factor.

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