Breast Subtypes and Prognosis of Breast Cancer Patients With Initial Bone Metastasis: A Population-Based Study

Background Metastatic breast cancer (MBC) is a highly heterogeneous disease and bone is one of the most common metastatic sites. This retrospective study was conducted to investigate the clinical features, prognostic factors and benefits of surgery of breast cancer patients with initial bone metastases. Methods From 2010 to 2015, 6,860 breast cancer patients diagnosed with initial bone metastasis were analyzed from Surveillance, Epidemiology, and End Results (SEER) database. Univariate and Multivariable analysis were used to identify prognostic factors. A nomogram was performed based on the factors selected from cox regression result. Survival curves were plotted according to different subtypes, metastatic burdens and risk groups differentiated by nomogram. Results Hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) positive patients showed the best outcome compared to other subtypes. Patients of younger age (<60 years old), white race, lower grade, lower T stage (<=T2), not combining visceral metastasis tended to have better outcome. About 37% (2,249) patients received surgery of primary tumor. Patients of all subtypes could benefit from surgery. Patients of bone-only metastases (BOM), bone and liver metastases, bone and lung metastases also showed superior survival time if surgery was performed. However, patients of bone and brain metastasis could not benefit from surgery (p = 0.05). The C-index of nomogram was 0.66. Cutoff values of nomogram point were identified as 87 and 157 points, which divided all patients into low-, intermediate- and high-risk groups. Patients of all groups showed better overall survival when receiving surgery. Conclusion Our study has provided population-based prognostic analysis in patients with initial bone metastatic breast cancer and constructed a predicting nomogram with good accuracy. The finding of potential benefit of surgery to overall survival will cast some lights on the treatment tactics of this group of patients.


INTRODUCTION
Breast cancer is the most commonly diagnosed malignant tumor and the leading cause of cancer death among females worldwide, accounting for 24.2% of all new cases and 15.0% of cases of death (1). Approximately 5-8% of breast cancer patients demonstrate distant metastasis at first diagnosis (2). De novo stage IV breast cancer is usually considered an incurable disease. The overall 5-year breast cancer specific survival (BCSS) of de novo stage IV breast cancer patients is about 27%. However, with the advance of systemic therapy and local treatment, the prognosis has been largely improved (3,4).
Metastatic breast cancer (MBC) is a highly heterogeneous disease with a wide range of clinical manifestation from solitary to multiple visceral involvements. Metastatic pattern is highly correlated to breast cancer subtype. Patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR + /HER2 − ) disease were reported to have more bone metastasis, patients with HR − /HER2 + tumors had more liver metastasis, whereas brain and lung metastasis were more likely to occur in HR − /HER2 − patients (5,6). Bone metastases, whether oligometastatic or combined with metastasis to other sites, were most commonly diagnosed, representing around 70% in MBC patients (7,8). Patients with bone metastasis exhibited preferred prognosis compared with visceral metastasis due to different metastatic pattern of different subtypes (6,9). Even though, different subtypes and metastatic patterns presented divergent outcomes. Previous analysis showed that patients of bone-only metastasis and HR + /HER2 − subtype better overall survival (OS) (10,11).
Therapeutic goals in MBC are usually maintenance of quality of life and palliation of symptoms. Generally, systemic therapy is the primary choice including chemotherapy, targeted therapy, endocrine therapy and immune therapy. It is still controversial about the role of surgery in metastatic patients. Therefore, surgery for MBC patients is a choice but not a preference for now with the existing evidence. Subgroup analyses of several retrospective trials have suggested a prolonged survival time for bone metastatic patients, while others turned out just the opposite.
The purpose of our study was to investigate the prognostic factors of de novo stage IV breast cancer patients with bone metastasis and if surgery of the primary site could benefit them.

Data Collection
The data were extracted from the SEER database. Patients diagnosed of breast cancer with de novo bone metastasis from 2010 to 2015 with active follow-up, valid survival time, known subtype information, known American Joint Committee on Cancer (AJCC) system stage, de novo bone involvement, known visceral metastatic status, known surgery of the primary site, known cause of death were included. Patients with other malignant comorbidities were excluded to eliminate the effect of other malignancy to OS. Occult breast cancer patients (T0), undefined T and N stage patients were excluded from the analysis. Patients diagnosed only in autopsy and death certification were also excluded. At last, 6,860 patients were included in the analysis.
Before initiating this study, we submitted a data-use agreement to the SEER program and were officially granted access to the database. The variables extracted were age at diagnosis (<60 and ≥60 years old), race (white, black, other >and unknown), gender (female and male), year of diagnosis (2010,2011,2012,2013,2014,2015), breast subtypes (HR + /HER2 − , HR + /HER2 + , HR − / HER2 + and HR − /HER2 − subtypes), grade (I, II, III, IV, unknown),  derived American Joint Committee on Cancer (AJCC) T stage  (T1, T2, T3, T4), derived AJCC N stage (N0, N1, N2, N3), marital status at diagnosis (married, unmarried and unknown), insurance status (insured, uninsured and unknown), brain metastasis status at diagnosis (yes or no), liver metastasis status at diagnosis (yes or no), lung metastasis status at diagnosis (yes or no), SEER causespecific death classification (alive or dead of other cause and dead attributable to this cancer), vital status (alive and dead), survival time and surgery information of primary site.

Statistical Analysis
The frequency and proportion of the baseline characteristics in the study cohort were by described by chi-square test. OS and BCSS were both calculated to evaluate prognosis. Univariate analysis was performed with variables including age, sex, race, grade, subtype, T stage, N stage, marital status, insurance status, visceral metastases and surgery or not. The statistically meaningful (p <0.05) variables were taken into the multivariable Cox analysis to determine the independent prognostic factors of patients with bone involvement. Kaplan-Meier survival curves were plotted to estimate the OS and BCSS. Log-rank test was applied in comparing survival. A nomogram model based on the statistically significant factors in multivariate analysis was plotted to predict a patient of specific characteristic. A concordance index (c-index) was calculated to evaluate the performance of the nomogram. Calibration curves were plotted to evaluate the consistency between predicted and actual overall survival at 3 and 5 years, respectively. The cutoff values were generated by X-tile software (3.6.1; https://medicine.yale.edu/lab/ rimm/research/software). All statistical analyses were carried out with R software (version 3.6.1; http://www.R-project.org). A twotailed p <0.05 was considered statistical significant.

Univariable and Multivariable Analysis
In univariate analysis, we found that patients of older age, black race, higher grade tumors, HR − /HER2 − subtype, high T stage (T >2), unmarried status, uninsured status, visceral involvement (brain, liver or lung), no primary tumor surgery displayed worse OS ( Table 2).

Benefits of Primary Tumor Surgery in Patients Subdivided by Molecular Subtypes and Metastatic Sites
Similarly, the analysis of BCSS showed consistent results.

DISCUSSION
With huge diversity and heterogeneity, the prognosis and treatment tactics of de novo stage IV breast cancer should be tailored in the light of their clinicopathological features, metastatic burden and even social status. The current study reported the prognosis of this group of patients with bone metastases according to different molecular subtypes as well as potential benefits of surgery of the primary tumor. To our knowledge, this analysis is the first population-based, retrospective, prognostic and predictive survival analysis and the first one to explore the surgical benefits of this group of patients based on subtypes and metastatic burdens. The prognostic nomogram we generalized included all the independent risk factors and show a good accuracy and accordance in predicting the survival rate of each case. The risk stratification model further differentiated patients of distinct risk subgroups, which provides critical information for indicating outcomes and facilitates individualized treatment choices. In this analysis, several features associated with improved outcome were identified, including HR-/HER2 + subtype, age <60 years old, white race, lower grade, lower T stage (T ≤ T2), no concurrent visceral metastasis, married and insured status. Patients of HR+/HER2-subtypes usually present preferred prognosis among all subtypes but in our analysis, patients of HR + /HER2 + subtype (1,192/6,860) demonstrated the best outcome among all subtypes in our analysis. Similar results were reported in previous studies involving patients with various sites of metastasis. In a multicenter study held in Netherlands, the HR + /HER2 + subtype was associated with the longest survival after diagnosis of distant metastasis (HR + / HER2 + vs HR + /HER2 − : HR = 0.64, 95% CI = 0.45-0.92, p = 0.02) (12). In another SEER-based analysis, HR + /HER2 + tumor was reported to have the best prognosis (HR + /HER2 + vs HR + / HER2 − : HR=0.85, 95% CI = 0.77-0.94, p <0.05) (13). We postulated that several reasons may contribute to the favorable survival of HR + /HER2 + subtype. First of all, different subtypes demonstrated a totally distinguished metastatic pattern. In another SEER-based study, HR + (both HER2 − and HER2 + ) was significantly associated with an elevated bone metastasis and better prognosis (11). Intrinsic biological characteristics and metastatic propensity of HR-positive subtype mainly contributes the good prognosis. In our subgroup analysis, we found that in different metastatic burdens, most patients with HR-positive tumors have better prognosis than those with HR-negative tumors, except patients with bone and brain metastasis (HR = 0.79, 95%CI = 0.51-1.24, p = 0.31). Secondly, the development of HER2 targeted therapy has evolved greatly. Trastuzumab, a humanized monoclonal antibody targeting HER2, reduced 44% of death risk in women with HER2+ disease compared with that of HER2-disease who did not received HER2-targeted therapy in the metastatic setting (14). In CLEOPATRA trial, the addition of pertuzumab to trastuzumab and docetaxel further improved OS in patients with HER2 + MBC (HR = 0.66, 95% CI 0.52-0.84, p = 0.0008) for first-line treatment (15). In progressed patients, trastuzumab emtansine could improve OS compared with capecitabine and lapatinib for second-line treatment as reported in EMILIA trial (HR = 0.75, 95% CI 0.64-0.88) (16). Thirdly, HR-positive breast cancers might display more indolent biological features than HR-negative tumors (17), and options for endocrine therapy have expanded in the last two decades. For postmenopausal patients, aromatase inhibitors (AIs) are recommended first-line endocrine therapy with or without cyclin dependent kinases 4/6 inhibitors. Multi-line endocrine modalities were available after progression or endocrine resistance in metastatic HR-positive breast cancer (18)(19)(20)(21)(22). Fourthly, in preclinical researches, the inhibition of HER2 could also improve endocrine sensitivity by crosstalk between HER2 and HR (23,24). In clinical trials, the PERTAIN and ALTERNATIVE trial showed that the combination of HR and HER2 targeting therapy offers an effective and safe regimen (25,26).
Surgery of the primary site of de novo MBC is a controversial topic with conflicting evidences. Many retrospective analyses of large cohort such as SEER and national cancer database (NCDB) or monocentric database have proven a better outcome of primary surgery in selected patients (5,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). However, retrospective results are usually undermined for selection bias (37). Several prospective trials have also addressed this issue. A multicenter Turkish trial MF07-01 showed a statistically significant improvement in surgery arm in 5-year follow-up, especially in patients with ER/PR (+) or HER2(−) tumor, solitary bone metastasis or younger age (<55 years old) (38). An Indian randomized controlled trial in patients responsive to first-line treatment also showed that surgery could not improve OS (39). However, these prospective trials were also questioned for insufficient chemotherapy, deviation from contemporary practice, insufficient adapted p value and so on (27,40,41). In spite of these contradictory results, the present study suggested that in well-selected patients, primary surgery might be considered one of the treatment options.
Metastatic burden is another critical factor when making surgical decisions. The current study indicated that apart from patients with bone and brain metastasis, patients of other Liu et al.

Prognosis of MBC Patients
Frontiers in Oncology | www.frontiersin.org December 2020 | Volume 10 | Article 580112 metastatic patterns might benefit from surgery. Likewise in a subdivision analysis of M1 patients, preferred prognosis was seen across all subdivisions after surgery except M1c category which is defined as brain involvement or multiple visceral metastasis (42).
When it comes to molecular subtype, previous studies showed less benefit of surgery in metastatic triple-negative breast cancer (TNBC) patients. However, patients with bone metastatic TNBC in our cohort exhibited improved survival after primary surgery. Previous study in well-selected and risk-stratified patients demonstrated similar results in TNBC tumors (43). In summary, MBC is no more a contradiction to primary surgery, specified risk-subdivision should be employed to better screen appropriate patients for customized therapy to bring along maximum benefit.
There are some limitations of this research though. The SEER database covers about 30% of the USA population, which offers a highly representation of a general situation but on the other hand, makes it immature to apply in Asian and Chinese population on the basis of ethnic differences. In SEER database, significant confounding prognostic factors like complications, detailed treatments, treatment sequence, treatment duration, margin status, recurrence score cannot be attained, which will greatly affect the applicability of the study in real-world cases. Even though the nomogram achieved acceptable prediction and risk stratification efficacy, it lacked external validation to further enforce the reliability. The result of our analysis should be interpreted with caution and applied in well-selected cases.
In conclusion, the current study identified potential prognostic factors in predicting survival in patients with de novo MBC with bone metastasis and suggested primary surgery might increase survival in selected subgroup of patients. The nomogram we constructed provided a quantitative method to predict survival of individuals and well differentiated patients of different risk subgroups.

DATA AVAILABILITY STATEMENT
Publicly available datasets were analyzed in this study. This data can be found here: Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov/).

AUTHOR CONTRIBUTIONS
DL and JW contributed equally to the study design, data collection, statistical analysis and manuscript writing. LZ conceptualized the study and was involved in result interpretation and manuscript writing. CL, LA, and SD helped with data collection. All authors contributed to the article and approved the submitted version.