Background
Breast cancer has a relatively favorable prognosis compared with other cancers, such as lung, colon, ovarian and pancreatic cancers. Approximately 80% of women with primary breast cancer are expected to survive for at least 10 years after the operation (mastectomy or breast-conserving surgery) [
1,
2]. However, of patients who have a relapse after the operation, or patients who were initially diagnosed with metastatic breast cancer (MBC), only about 5% survive for more than 10 years [
3,
4]. Since women with MBC are unlikely to be cured from the disease, palliative therapy is taken into account for these patients for the purpose of prolongation of their survival, with maintenance of quality of life. There have been many clinical trials to assess the efficacy and safety of anti-cancer cytotoxic agents in metastatic settings of breast cancer [
5‐
11]. In a first-line chemotherapy in this setting, both anthracyclines and taxanes are expected to have favorable activity, that is, response rates of 40 to 60% and survival of over two years, either by monotherapy or in combination with each other. In contrast, the efficacy of chemotherapy is not satisfactory in the second or later lines [
12‐
19]. There are several possible reasons for these results, such as resistance to drugs, attenuated physical condition of the patients and less availability of drugs to use because of prior drug usage.
Although the aim of treatment for MBC is control of the disease and disease-related symptoms, treatment can occasionally achieve progression-free or disease-free long-term survival in patients with MBC [
3,
20,
21]. Many factors are thought to be responsible for determining the survival term in MBC. Patient factors such as age, menopausal status, performance status, disease-free interval (DFI) and treatment that patients have received or are receiving are associated with prognosis. Further, tumor characteristics such as site of disease, number of disease sites, tumor grade, hormone sensitivity, human epidermal growth factor receptor-2 (HER2) status and other biological characteristics are likely to be responsible. However, the factors that are critical in predicting a patient’s survival remains to be determined. If factors involved in long-term survival of patients with MBC are identified, they would be helpful for physicians to make a decision regarding the choice of treatment strategy and avoiding ineffective and harmful interventions in daily clinical practice.
The aim of this study was to determine the factors responsible for long-term survival of patients with MBC. We retrospectively compared clinicopathologic features and clinical outcomes for patients with MBC who survived for a long period with those who did not survive for a long period.
Discussion
Although the aim of treatment for MBC is control of the disease and disease-related symptoms, progression-free or disease-free long-term survival is occasionally observed following systemic treatment in patients with MBC [
3,
20,
21]. However, who is expected to be a long-term survivor, or what strategy is the best for long-term survival, remains to be determined. In this study, we attempted to determine what prognostic factors are responsible for long-term survival by retrospectively comparing clinicopathologic features and clinical outcomes of patients with MBC who had survived for 50 months or more after diagnosis of MBC with patients with MBC who had died within 50 months after diagnosis. Of 70 patients with MBC who had received chemotherapy at our hospital between November 2005 and September 2011, patients who survived 50 months or more accounted for 38.6%, and patients who died within 50 months accounted for 40%. In terms of baseline clinicopathologic features associated with survival of the patients studied, the proportion of patients with longer DFI and the proportion of patients with hormone-sensitive tumors were significantly higher in long-term survivors, but the proportion of patients with triple negative tumors was significantly lower in long-term survivors (Table
1). Lower tumor grade seemed to show a trend for long-term survival, although there was no statistically significant difference between the two groups. In contrast, the number of prior chemotherapeutic regimens the patients had received was not lower in long-term survivors than in non-long-term survivors, and there was no relationship of metastatic sites, number of disease sites, prior chemotherapy regimens or chemotherapy line between the two groups. These findings suggest that long-term survival might be associated with slowly growing luminal A-subtype tumors.
As chemotherapy used in adjuvant settings, anthracyclines and taxanes are included in standard regimens because of abundant evidence from many clinical trials over the past several decades showing significant reduction in the risk of relapse or death from the disease [
25‐
28]. In contrast, there is no standard regimen recommended in metastatic settings. In many cases of MBC, anthracyclines and taxanes had already been administered in adjuvant settings. Therefore, physicians often have difficulty in choosing a regimen among agents for which clinical studies have demonstrated their feasibility. In cases of life-threatening metastatic lesions or cases of rapidly growing tumors, regimens that are expected to control lesions quickly, such as taxanes in combination with either gemcitabine, capecitabine or bevacizumab, should be utilized [
28‐
33]. However, many patients show progression of disease during or after receiving these cytotoxic regimens, even if favorable combinations are chosen. We previously demonstrated that long-term administration of one regimen was essential for favorable outcomes of treatment for MBC [
34]. To prolong the duration of treatment or the TTF, chemotherapeutic regimens that are less toxic as well as effective are considered. Metronomic chemotherapy is defined as continuous or frequent treatment of low doses of anticancer agents, and is usually used for palliative care in patients who have been heavily pretreated with cytotoxic drugs, or patients who have poor performance status [
35]. Interestingly, metronomic chemotherapy used for palliation has been reported to result in favorable tumor responses and prolonged survival in some cases [
36‐
39]. In this study, the proportion of patients who received a metronomic regimen as the most effective regimen was two thirds of long-term survivors (65.3%), which was double that of non-long-term survivors (Table
1). Of 15 patients who were treated with metronomic regimens in the long-term survivors group, nine (60%) received the regimen for more than two years, and one had not received the regimen for two years but was continuing to receive the regimen at the time of analysis (data not shown). Metronomic regimens may therefore have greatly contributed to prolongation of the duration of treatment in this group.
The proportion of patients who showed favorable tumor responses to, or those who showed clinical benefit from, the most effective regimen in long-term survivors was three times (83%) and five times (100%) higher than in non-long-term survivors, respectively (Table
2). The median TTF was more than two years and TTP was approximately three years in long-term survivors. These data indicate that long SD or better tumor response (PR or CR) to treatment for MBC at least once and continuation of treatment with one regimen for more than two years are needed for long-term survival. TTP and OS after the most effective regimen were significantly longer in long-term survivors than in non-long-term survivors (Table
2, Figures
2 and
3). However, in contrast to our expectation, the number of chemotherapeutic regimens for breast cancer, for MBC or after receiving the most effective regimen did not differ between the two groups. Furthermore, to exclude the possibility that the prognostic factors described above resulted from a relatively short observation period in which the outcomes of the patients were compared, we performed an exploratory analysis comparing prognostic factors of patients who survived 60 months or more and patients who died within 60 months after diagnosis of MBC. As a result, all factors identified from baseline characteristics and clinical outcomes of the patients by the comparison did not differ from those that we compared at 50 months after diagnosis of MBC, except for number of prior regimens for MBC (Tables
4 and
5).
Acknowledgements
This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (grant numbers: 10671249, 13671380, 14571262 and 15591340).
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
KK was involved in the design of the study and acquisition, analysis and interpretation of data and drafted the manuscript. SH, CM and SN participated in the design of the study and performed the statistical analysis. HT and HH conceived of the study and helped to draft the manuscript. MO, NFH and MD participated in the design of the study and helped to draft the manuscript. KT and HY contributed to analysis and interpretation of data and helped to draft the manuscript. All authors read and approved the final manuscript.