Bone metastases are the most common distant metastatic site in breast cancer, and severe complications, low quality of life, poor prognosis and significantly decreased survival rates are often associated with the occurrence of bone metastases [16]. Our study analysed recently available data on the subtypes of stage IV patients with bone metastatic breast cancer from the SEER registries in an attempt to analyse differences in the effects of the breast cancer subtype and other factors on patient prognosis.
Bone metastasis is most abundant among the HR+ subtypes, and the distribution of tumour subtypes in stage IV patients in our study was similar to that in other studies in the published literature [12, 19, 20]. Our study identified that stage IV patients with HR+/HER2- breast cancer are the most prone to bone metastasis, followed by those with HR+/HER2+ breast cancer. HR-/HER2- breast cancer has a particular propensity to metastasize to the brain and lung; brain metastasis is more common in this subtype than in the other subtypes, and bone metastasis is relatively less likely to occur, which is consistent with the findings of previous research [21]. This may be due to the different molecular subtypes of breast cancer leading to different metastasis sites due to their special molecular biological characteristics.
The median OS for the entire cohort was 38 months, which is similar to that in Kuchuk’s study, which reviewed 294 electronic records of metastatic breast cancer patients and found that the median OS from bone metastasis diagnosis was 40 months in bone metastasis patients [22]. The median OS was 46 months for stage IV patients with only bone metastases and 24 months for those with bone and other site metastases in our study, which was similar to the survival reported by previous authors in recent years [8]. A study of 815 patients with de novo or recurrent metastatic breast cancer identified that patients with visceral metastases and those with multiple metastatic sites had worse OS, findings consistent with our results [23]. The five-year survival rate was 33.9%, which is similar to that in previous studies, which showed that 24–39% of patients lived five years after the diagnosis of bone metastases [5]. This may be because the subjects of this study were menopausal women, while there was no limitation on the age of the previous study subjects; moreover, the proportion of elderly patients was large and their prognosis was poor, and with the improvement of treatment methods in recent years, the prognosis of patients has been improved.
Our study showed that the five-year survival rate of HR+/HER2+ stage IV patients was the highest, reaching 5.6 times that of HR-/HER2- patients. Stage IV patients with HR+/HER2+ breast cancer had the longest median survival period. Although our study showed that the incidence of bone metastasis in HR-/HER2- breast cancer patients was low, stage IV patients with HR-/HER2- tumours had the worst prognosis. With the shortest median survival time, the OS of stage IV patients with HR-/HER2- breast cancer was significantly lower than that of stage IV patients with other molecular subtypes. The large difference in prognosis observed across all tumour subtypes confirms that breast cancer is a heterogeneous disease, even in the specific group of patients with bone metastases. The improvements in OS seen in HER2+ patients could be explained in part by the efficacy of HER2-targeted agents. In Dawood’s large-scale, randomized study of 2019 women with metastatic breast cancer, HER2+ patients who received trastuzumab had an improved prognosis compared with HER2- patients [24]. However, HR-/HER2- is an invasive subtype, with the characteristics of rapid progression, strong aggressiveness, a high degree of malignancy, easy occurrence of distant metastasis, and rapid relapse [25-27]. Therefore, our study included tumour subtype as a prognostic factor and provided evidence of a clear association of age, race, marital status, insurance, tumour grade, histology, subtype, and visceral metastases in bone metastasis patients with OS. This was similar to the findings of a previous study. The Denmark data were from population-based health registries that included all women diagnosed during 1999–2011 with regional or stage II/III breast cancer and showed predictors of recurrence, metastases, and mortality, including age, hormone receptor status, and stage at diagnosis [28]. Ahn’s study showed that ER-negative status and bone metastasis combined with visceral metastasis are risk factors for OS [8]. Iqbal J’s study showed that in US women diagnosed with invasive breast cancer, survival varies by race and ethnicity, and black women are more likely to die from breast cancer within 7 years than non-Hispanic white or Asian women [29]. A previous study observed that Hispanics and non-Hispanic blacks were more likely to have ER-positive and PR-negative tumours than non-Hispanic whites [30]. However, in our study, we found no interaction between subtype and race.
The protective effect of marriage on survival can be explained by these patients gaining better economic resources and having greater social support in marriage [31]. Although some factors have been found in previous studies, no covariates have been adjusted for other factors, or fewer covariates have been adjusted. We used a Cox proportional hazards regression model adjusting for all the factors, which demonstrated that tumour subtype was a prognostic factor. Therefore, in clinical and nursing work, doctors and nurses can carry out different treatments and nursing work for different patients according to age, race, marital status, insurance, tumour grade, histology, subtype, and visceral metastases. In addition, we found that there was an interaction between subtype and multiple visceral metastases, which suggests that we should pay attention to the risk of visceral metastasis in patients with different subtypes. Future studies are recommended to explore the mechanism of molecular subtype and metastasis site as well as the influence of their interaction on the outcome and management of patients.
We acknowledge that the study has some limitations. The SEER database does not provide information on the expression status of Ki-67; the Ki-67 index value is a prognostic factor in primary breast cancer and is a proliferation marker that also distinguishes between luminal A and luminal B breast cancer [32]. Breast cancer is generally divided into luminal A and luminal B according to HR/HER2 status and Ki-67 in the course of clinical diagnosis and treatment [33]. This may contribute to some disparities between our investigation and clinical applications. We do not have information regarding the radiotherapy or systemic treatments of this cohort, which may contribute to some of the differences observed in survival according to prognostic variables. Additionally, the pathological data could not be centrally reviewed and were collected from different local pathology laboratories.