|
 
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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 13
| Issue : 5 | Page : 778-784 |
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Clinicopathological features and prognostic evaluation of bone metastasis in triple-negative breast cancer
Anqi Luo, Fang Wu, Rui Han, Shangke Huang, Yujiao Zhang, Xin Jing, Xinhan Zhao
Department of Medical Oncology, School of Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| Date of Web Publication | 13-Dec-2017 |
Correspondence Address:
Xinhan Zhao
Department of Medical Oncology, School of Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 227 Yanta West Road, Xi'an, Shaanxi 710061
P.R. China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jcrt.JCRT_543_17
Background: Bone metastases (BMs) are common for breast cancer patients. However, triple-negative breast cancer (TNBC) with BM is relatively rare and few data on it are available. In this study, we aim to investigate the incidence and clinicopathological features and to evaluate the prognosis of TNBC patients with BM.
Materials and Methods: A total of 616 patients with TNBC (120 out of them had BM) between 2007 and 2011 were involved in the study. Clinicopathological characteristics were statistically analyzed.
Results: A total of 120 (19.5%) patients developed BM with a median age of 53.1 years. The median overall survival (OS) was 40 months, and the 5-year OS rate was 37.3% in TNBC patients with BM. Patients without BM had longer survival time than those with BM (P < 0.001). In the univariate analysis, lymph nodes metastasis, tumor Stage III-IV, multiple BMs, and coexistence of visceral metastasis were correlated to a poor prognosis (P = 0.020; P < 0.001; P < 0.001; P < 0.001). Moreover, multivariate analysis demonstrated that tumor stage, number of BM, and visceral metastasis were significantly independent factors for OS (P < 0.001; P < 0.001; P < 0.001).
Conclusions: Tumor Stage III-IV, multiple BMs, or coexistence of visceral metastasis were associated with poor prognosis for OS in TNBC patients with BM. These associations may contribute to prevention, early detection, and goal-directed treatment of bone metastatic TNBC.
Keywords: Bone metastasis, breast cancer, prognosis, survival, triple negative
How to cite this article:
Luo A, Wu F, Han R, Huang S, Zhang Y, Jing X, Zhao X. Clinicopathological features and prognostic evaluation of bone metastasis in triple-negative breast cancer. J Can Res Ther 2017;13:778-84 |
How to cite this URL:
Luo A, Wu F, Han R, Huang S, Zhang Y, Jing X, Zhao X. Clinicopathological features and prognostic evaluation of bone metastasis in triple-negative breast cancer. J Can Res Ther [serial online] 2017 [cited 2022 Mar 8];13:778-84. Available from: https://www.cancerjournal.net/text.asp?2017/13/5/778/220479 |
| > Introduction | |  |
Breast cancer is more common in women in recent years due to changes of the environment and lifestyle.[1],[2] It is the leading global cause of cancer death in women, which accounts for 14% of cancer deaths every year.[3] Based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2), breast cancer is classified into several intrinsic molecular subtypes: luminal A, luminal B, HER-2, and triple negative. Among them, triple-negative breast cancer (TNBC) is defined as lack of the expression of ER, PR, and HER-2.[4] It is well established that TNBC is a more aggressive type due to high likelihood of metastasis and poor prognosis.[5] TNBC was supposed to have the preference to metastasis to brain and visceral organs such as lung and liver rather than bone compared to other breast cancer subtypes.[6] However, bone is thought to be the most common site of advanced breast cancer and the incident rate is nearly 80%.[7],[8] In spite of better prognosis and outcome, patients with bone metastasis (BM) have increased susceptibility to have such complications as pathologic fracture and spinal cord compression which decrease the quality of life.[9]
Breast cancer patients with BM are prone to get a longer survival than other metastatic sites and have excellent clinical outcomes.[10] Nevertheless, TNBC patients with BM survive a shorter time than other subtypes.[11] It has been elucidated that different breast cancer phenotypes are prognostic for patients' survival from the time of diagnosis of primary tumor.[12] In a recent multicenter retrospective cohort study including 111 patients with symptomatic spinal bone metastatic breast cancer, Bollen et al. reported that the median survival time in TNBC patients with spinal BM was shorter than patients with spinal BM from breast cancer with a receptor positive phenotype.[13] It should be noted that recent studies have showed clinical characteristics and prognostic factors associated with bone metastatic breast cancer or TNBC separately, and TNBC with BM is less well-demonstrated. It is crucial to investigate the clinical features and survival outcome of TNBC patients with BM, especially in Asian populations.
Therefore, in this study, we estimated the incidence of BM in TNBC patients, retrospectively analyzed the clinicopathological characteristics of the triple-negative bone metastatic breast cancer, and compared the clinical features and survival between TNBC patients with and without BM. Moreover, we evaluated prognostic factors related to the overall survival (OS) of bone metastatic TNBC patients so as to guide goal-directed therapy for patients.
| > Materials and Methods | | |
In this retrospective study, patients diagnosed with TNBC by medical records and pathology reports from May 1, 2007, to May 1, 2011, were included. Excluding from the analysis were male patients, the patients without complete record data, the patients did not undergo follow-up, or the patients had another malignant tumor alone with breast cancer. The quality of the cancer registry database was reviewed and approved by the Ethics Committee of our institution. Among the 616 TNBC patients, 120 patients formed the BM group and 406 patients made up non-BM group. The remaining including 90 TNBC patients who had other metastatic sites would not be discussed in the study. We defined patients with BM who went through emission computed tomography (CT) screening showing abnormal radionuclide uptake and then confirmed by other imaging methods including X-ray, CT, and magnetic resonance imaging (MRI) scans and/or biopsy. Non-BM group was defined as those who without any metastases such as metastasis to bone, liver, brain, lung, or others demonstrated by MRI and CT scans. The following clinical and pathological variables include age, family history, tumor size, menopausal status, lymph node metastasis, tumor stage, histologic grade and histology, bone metastatic characteristics (including number of BM, distribution, skeletal-related events [SREs], and along with visceral metastasis or not), and therapies (including surgery, chemotherapy, endocrine therapy, radiotherapy, and bisphosphonate). Clinical staging was based on the sixth edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual.[14] ER status and PR status were assessed using immunohistochemistry (IHC) and were considered positive when staining results showed 10% or more cells. HER-2 positivity was defined as an IHC score of 3+ and fluorescence in situ hybridization was considered when the score was 2+. Histologic grade was defined on the bases of the Black's Nuclear Grading System with modification of numbers that I was used to represent well-differentiated tumors, II represented moderately differentiated tumors, and III represented poorly differentiated tumors. In addition, we defined the de novo BM as the patients who had BM detected during the initial diagnosis of TNBC. We defined the recurrent BM as the patients who develop BM after receiving treatment of the primary TNBC. The single metastasis was defined as one BM confirmed by imaging methods and/or biopsy, and the multiple metastases was defined as two or more bone metastatic sites. Ratings of level of pain were accessed on a numeric rating scale from 0 to 10. 0 represents no pain. Pain scores from 1 to 3, 4 to 6, and 7 to 10 represented mild, moderate, and severe pain, separately.
The patients were followed up from the exact diagnosed date to the date of death or May 1, 2016. Details of follow-up were obtained through telephone communication, outpatient review, and letters. OS was measured from the date of diagnosis of TNBC with or without BM to the date of last follow-up or death, whichever occurred first. The date of death was confirmed from medical records or death certificates.
Statistical analysis was performed with SPSS software, version 22.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics in terms of mean, median, range, and percentiles were applied to all parameters. Continuous variables were assessed by using the independent t-test. Association between categorical variables was assessed using the Chi-square test when appropriate. Kaplan–Meier survival analysis with a log-rank test was carried out to estimate OS. Each established variable was analyzed for its association with OS using the univariate Cox's regression analysis. The multivariate analysis to determine the association between significant independent variables, and OS was performed with the Cox proportional hazards regression model and it was used to compute hazard ratio (HR) and 95% confidence interval. In the tests, P < 0.05 was considered statistically significant.
| > Results | | |
Among the 616 TNBC patients, BM developed in 120 cases (19.5%) [Figure 1]. The clinical and pathological characteristics of TNBC patients with or without BM are summarized in [Table 1]. The median age at diagnosis in the BM group was 53.1 years (range, 30.0–75.0 years), and 32.5% of patients were diagnosed before the age of 50 years, while in the non-BM group, the median age was 48.0 years (range, 28.0–75.0 years). It was found significant differences between the groups in age at diagnosis (P = 0.001). A positive family history was found in 7.5% of the BM group and 8.6% of the non-BM group (P = 0.697). Results showed that patients in the BM group were more likely to be postmenopausal than the non-BM group (64.2% vs. 35.8%, P = 0.034). The tumor size (P = 0.296), number of metastatic lymph nodes (P = 0.319), and histologic grade (P = 0.438) did not differ significantly between the groups. The median tumor size was 3.56 cm in the BM group and 3.35 cm in the non-BM group. More than half of the patients in both groups had positive lymph nodal metastasis (57.5% vs. 55.9%). The majority of patients in two groups were at III histologic grade which accounted for 92.5% in the BM groups and 88.9% in the non-BM group. More patients in the BM group were at III and IV stage at diagnosis (55.0% vs. 29.5%, P < 0.001). Patients in the BM group included 108 cases of invasive ductal carcinoma (90.0%), three cases of invasive lobular carcinoma (2.5%), three cases of mix ductal and lobular carcinoma (2.5%), and six cases of (5.0%) other type. The two groups did not differ in the treatment modalities. As for primary surgery, 36 (90.0%) patients in the BM group and 354 (87.2%) patients in the non-BM group had undergone modified radical mastectomy (P = 0.564). Most patients in both groups received chemotherapy (95.0% vs. 94.6%, P = 0.858), but few patients received endocrine therapy (4.2% vs. 2.2%, P = 0.328). 48 (40.0%) patients in the BM group and 154 (37.9%) patients in the non-BM group were treated with radiotherapy (P = 0.682). | Figure 1: The inclusion diagram of breast cancer patients. TNBC=Triple-negative breast cancer, BM=Bone metastasis
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 | Table 1: Clinicopathological characteristics of triple-negative breast cancer patients with and without bone metastasis
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[Table 2] shows the characteristics of TNBC patients with BM. Patients with BM seemed more likely to be diagnosed with the recurrence group (85.8%) rather than the de novo group (14.2%). Multiple lesion (62.5%) was more prevalent in bone metastatic patients than the single one (37.5%). The most common site of BM was the spine (63.3%), and the second most common site was the pelvis (28.3%). Almost half of the patients (50.8%) had bone pain. Within the whole patients with bone pain (n = 61), 12 (19.7%) women had mild pain, 30 (49.2%) women had moderate pain, and the remaining (31.1%) women had severe pain. Fifty-seven patients developed visceral metastasis at or after the diagnosis of BM. Among the 105 patients who managed with bisphosphonates, almost four-fifths of them received zoledronic acid and the rest of them received pamidronic acid. For the patients diagnosed with BM, 47.5% of them experienced SREs. Radiation to bone (47.5%) was the most common SREs, followed by pathological fracture (15.8%) and orthopedic surgery to bone (5.8%), and the remaining were spinal cord compression (3.3%) and hypercalcemia (3.3%). | Table 2: Clinical characteristics of triple-negative breast cancer patients with bone metastasis
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Patients were followed up for 0.5–102 months in this study. The survival percentage for BM group was 15.0% (18/120 patients) at the end of follow-up. The median OS was 40 and 63 months for TNBC patients with and without BM. OS rates for patients with BM were 85.0%, 52.5%, and 37.3% at 1 year, 3 years, and 5 years of diagnosis, respectively. Patients without BM had longer OS compared to patients with BM (P < 0.001). The survival curves of the TNBC patients with and without BM are shown in [Figure 2]. | Figure 2: Overall survival curves of triple-negative breast cancer patients with and without bone metastasis
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In the univariate analysis, patients with tumor Stage I-II, single BM with or without lymph nodes metastasis, or visceral metastasis had longer survival time after BM than patients with tumor Stage III-IV, multiple BMs, lymph nodes metastasis, or coexistence of visceral metastasis (P < 0.001; P < 0.001; P = 0.020; and P < 0.001, respectively). However, other factors including age, family history of breast cancer, histologic grade, histology, primary surgery, chemotherapy, radiotherapy, and bisphosphonate were not statistically significant in OS as shown in [Table 3]. Multivariate analysis demonstrated that tumor stage (HR, 0.144; P < 0.001) was independently correlated with survival time. Furthermore, number of BM and coexistence of visceral metastasis were significantly independent prognostic factors for OS in TNBC patients with BM (HR, 0.088 and 0.024, respectively; P < 0.001 for both). The independent prognostic factors that impacted on the OS after the diagnosis of BM are shown in [Table 4]. The survival curves for each of the three individual prognostic variables can be seen in [Figure 3]. | Table 3: Univariate analysis of clinicopathological factors for overall survival
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 | Table 4: Multivariate analysis of prognostic factors for overall survival
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 | Figure 3: Kaplan–Meier overall survival curves for triple-negative breast cancer patients with bone metastasis. (a) Tumor stage at bone metastasis diagnosis, (b) number of bone metastasis, and (c) accompany with visceral metastasis
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| > Discussion | | |
TNBC has unique biology, aggressive, and early pattern of metastasis, generally poor prognosis, and the incidence of TNBC is quite different in ethnicity that African-American women were reported to have the highest prevalence of TNBC.[15],[16] In the present study, the prevalence of TNBC was 15.8% which was in accordance with the previous studies.[17],[18] A latest study including 2569 TNBC patients in America by Lin et al. suggested that bone was not the most common metastatic sites in TNBC patients.[18] In contrast, recent researches showed that the majority of metastasis in breast cancer was bone.[6],[19] In our study, BM accounted for 19.5% of the TNBC patients, and the percentage was approximately consistent with the recent analysis.[20] Moreover, Lin et al. showed that among the 116 TNBC patients, 24% of them were noted to have a BM at the time of first metastatic presentation and 42% of them were with BM at the time of initial and subsequent recurrence during follow-up.[21] As is known to all that TNBC affects younger women, however, patients with BM are mostly elderly and ambiguous results in several studies have noted that whether younger age was relevant to poor prognosis.[22] Most patients included in our study were older than 50 years and younger patients were associated with an increased risk of death although statistically significant difference was not observed in different age groups. It should be further investigated in the future studies. To make a better evaluation of TNBC patients with BM, we compared the clinical and pathologic characteristics between TNBC patients with and without BM. We illustrated that patients with BM were deemed to have such features as older age, higher tumor stage, positive metastatic lymph nodes, and invasive lobular histology.
According to our study, most patients were diagnosed with multiple BMs and the most common metastatic site for bone was spine which was similar to the previously published literature.[11] It is known to all that bone pain and SREs are closely related to patients' living quality and add extra burden to patients in some way. Our results showed that half of the patients suffered bone pain and 47.5% of them had SREs. Jensen et al. indicated that 43.2% of 178 patients who presented with BM at the time of breast cancer diagnosis developed an SRE which was congruent with our analysis and the incidence rate of SREs was highest in the 1st year after BM diagnosis.[23] Moreover, some researches showed higher rates of SREs in BM patients which may due to the lack of bisphosphonate or other treatments.[24]
Several studies have reported that TNBC was an aggressive phenotype and TNBC patients with BM were associated with poor survival outcome compared to other subsets of breast cancer with BM.[13] Katarzyna et al. revealed that the risk of metastasis to the bone in TNBC patients was the highest in the first 2–3 years but then fell slightly, and the median OS was only 5.5 months which was shorter compared to our study. One possibility was that half of patients in Katarzyna's study did not receive adjuvant radiotherapy and almost two-third of them have received systemic therapy after recurrence, but nearly all patients in our study received such therapies.[25] In addition, Lee et al. have demonstrated the median OS of TNBC patients with BM was 40 months which was in agreement with our results.[11] Among the clinical factors related to OS after BM, tumor stage, number of BM, lymph nodes metastasis, or visceral metastasis, at the univariate Cox's regression analysis, were considered as prognostic factors for OS. Furthermore, in the multivariate Cox's regression analysis, tumor stage, number of BM, or visceral metastasis was independently correlated to OS in TNBC patients with BM. In our study, the survival time of patients with higher tumor Stage (III-IV) was much shorter than patients with lower tumor Stage (I-II). Emerging data indicated that single BM was identified as a favorable prognostic factor for survival and patients with single BM had a more preferable prognosis than patients with multiple BMs.[11] The findings were equivalent to our report. In addition, bone metastatic patients who developed visceral metastasis at the time of primary breast cancer diagnosis or during follow-up were also associated with a poorer survival outcome.
Due to the lack of ER, PR, and HER-2, bone metastatic TNBC patients could not benefit from hormonal agents or trastuzumab-based therapy. Even though, in recent years, molecularly targeted agents have been investigated in the treatment of metastatic TNBC such as monoclonal antibodies against vascular endothelial growth factor and poly ADP-ribose polymerase inhibitors, there are no specific targeted therapy for metastatic TNBC patients.[26],[27] Therefore, TNBC patients with BM receive surgery, chemotherapy, radiation, and bone-modifying agents alone or in combination to get maximum therapeutic effect and minimum side effects. In our study, 107 patients were treated with modified radical mastectomy, while the rest received breast conservative surgery. However, several studies demonstrated that TNBC patients who received breast conservative surgery had the same OS and local and regional recurrence rates as patients who had a mastectomy.[28],[29] Chemotherapy is recommended for TNBC patients, and platinum-based chemotherapy is the mainstay of treatment for patients with metastatic TNBC. Ninety-five percent TNBC patients with BM received chemotherapy in this study and were found to have better outcome than patients who did not have it. For TNBC patients with BM, bisphosphonates have been shown to relieve bone pain, reduce the incidence of SREs, and also possess antitumor activity.[30] Therefore, it has been the routine use for patients with BM. In addition, denosumab, a human monoclonal antibody against RANKL therapy, has been applied in the clinic because of its effect on delaying the first SREs after BM and the long-time effects should be noticed.[31]
However, this study was limited by the number of bone metastatic patients. Moreover, this is a single-center retrospective study, and the selection of patients involved in this study was not completely random. In addition, treatments such as chemotherapy, radiotherapy, endocrine therapy, and bone-modifying agents had improved the outcome of patients with BM and had an impact on the survival time. Finally, we could not illustrate the effects of some new metastatic sites on the outcome of bone metastatic patients.
| > Conclusions | | |
The present study has suggested that the incidence of BM in TNBC was 19.5%. Shorter survival was observed in patients with lymph nodes metastasis, higher tumor stage, multiple BMs, or concurrently visceral metastasis, and the aforementioned three factors including tumor stage, number of BM, and visceral metastasis were independent prognostic factors for OS in bone metastatic TNBC patients. Early detection and treatment for such high-risk patients might promote better outcome and prolong their survival time. Further studies with larger size of BMs patients will be required to confirm clinical factors bound up with bone metastatic TNBC and novel-targeted therapy could be investigated to improve the poor prognosis of this challenging entity.
Acknowledgments
We would like to thank the Department of Oncology, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, for offering advice on data analysis. We are grateful for all participants included in the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]
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