Symptomatic bone marrow metastases (BMM) are the hematogenous spread of circulating tumor cells and the invasion of highly vascularized bone marrow. They manifested as hematopoietic function suppression, such as anemia, thrombocytopenia, and abnormal coagulation (1). Diffuse bone marrow involvement leading to profound cytopenias is rare in solid malignant tumors of nonhematologic diseases (2). Xiao et al. retrospectively analyzed 10,122 solid tumor bone marrow biopsy samples and found that lung, gastric, and breast cancer patients were prone to bone marrow infiltration (3). Although the specific mechanism of breast cancer BMM is not fully understood. It has been confirmed that bone marrow adipocytes (BMAs) and adipokines secreted by breast cancer cells are essential mediators in promoting breast cancer metastasis (4). BMAs secrete cytokines such as leptin, adiponectin, IL-1β, IL-6, TNF-α, and VEGF to promote breast cancer cell metastasis (5). BMAs can also release cytokines to activate dormant mesenchymal stem cells (MSCs) and cancer stem cells (CSCs) to increase their proliferation and promote breast cancer BMM (6).

Current literature suggests that chemotherapy prolongs survival in breast cancer patients with BMM (7, 8). Chemotherapy, however, can promote the growth of BMAs in the bone marrow, especially in the sacrum (9). Increased BMAs will further promote tumor cell escape and bone destruction around the tumor to promote tumor progression. At the same time, the adverse reactions of chemotherapy agents affected the patient’s quality of life (4). Kopp et al. found that the initial chemotherapy of BMM alleviated the patient’s cytopenias but did not significantly improve the patient’s prognosis (2). Only one case report highlights the positive role of anti-HER2 therapy in breast cancer BMM (10). Furthermore, there is a lack of large-scale studies on the prognosis of treatment regimens other than chemotherapy.

Therefore, we conducted a retrospective analysis based on our center’s cases to investigate the clinical characteristics of breast cancer BMM, the prognosis of patients with different treatment methods, and the risk factors affecting the prognosis.

Clinically relevant bone marrow carcinomatosis (that causes severe cytopenia) is a rare event in patients with breast cancer, with a reported incidence of only 0.17% (2). We retrospectively reviewed 733 patients with advanced breast cancer and found that 33 (4.5%) developed bone marrow metastases, which is higher than previously reported studies and may be related to aggressive bone marrow biopsy and vigilance for patients presenting with anemia and unexplained febricity. Our study found that the median age of patients with bone marrow metastases was 49.5 years old (29–68 years), the pathological type was invasive ductal carcinoma, the molecular type was HR positive/HER2 negative, the Ki-67 index was highly expressed, and histological grades 2–3 were more common, which is similar to the clinical features of breast cancer patients with BMM in a retrospective study by Abdullah Sakin et al. (2, 7). All our patients’ clinical manifestations presented with fatigue, consistent with reported studies (11, 12). There were 25 patients with fever; we performed relevant tests for etiology, and all were negative. Empirical antibiotic therapy did not significantly improve the patient’s symptoms, and immediately we performed a bone marrow aspiration biopsy which revealed BMM. Xiao et al. also reported the phenomenon of unexplained febricity in BMM patients with solid tumors (3). We found that all patients had BMM accompanied by bone metastases. The reported articles did not analyze the specific sites of bone metastases. We found that the weight-bearing bone (spine, 26 cases) was the most common site of metastasis, which may be because the level of CXC3L1/CXC3R1 in the spine bone is higher than that in other bones, which can promote the adhesion and migration of breast cancer cells (13).

We summarized the literature on breast cancer BMM retrieved from PubMed ( Table 4 ). The published kinds of literature are mainly case reports. After BMM, chemotherapy is the first choice (11, 14–16). Although some patients’ diseases were controlled, some reports mentioned that chemotherapy-related adverse events led to dose reduction or even discontinuation (11). Turner et al. found that CDK4/6 inhibitor combined with ET can significantly improve the survival of hormone receptor-positive breast cancer patients with visceral metastases (not visceral crisis) (19). Giovanna Garufi et al. reported a patient with hormone receptor-positive breast cancer with BMM who received letrozole in combination with palbociclib and leuprolide and achieved a 26-month sustained complete remission (17). Sakin et al. retrospectively studied 30 patients with breast cancer BMM who had received chemotherapy and had a median OS of only 6 months (7), which is shorter than the median OS of 18 months in our study. Among the 25 patients with HR⁺/HER2⁻ in our research, we were pleasantly surprised to find that the median PFS of 13 patients treated with endocrine therapy was 11 months, which was significantly better than the chemotherapy group of 2 months (Log-rank p = 0.021). The maximum PFS was 22 months, and the patient had progressive disease at our follow-up cutoff. The median OS was 23 months longer than the chemotherapy group (5 months). We found that the prognosis of patients in the ET group was significantly improved. The multivariate Cox regression results found that higher ECOG scores and higher age were risk factors affecting the OS of patients, which was consistent with the reported results (2). We counted the AEs after the patients received the two treatment regimens and found that the incidence of AEs of grades≥3 in patients receiving ET was significantly lower than in the chemotherapy group. The proportion of patients with dose reductions due to AEs was also lower in the ET group. Furthermore, no treatment-related SAEs occurred in either group. Indicates that ET may become the most effective and safest treatment option for HR⁺/HER2 patients with BMM, and the sample size should be expanded for further research in the future.

To the best of our knowledge, a larger number of patients with symptomatic BMM were included in this study. The clinical characteristics, prognosis, and adverse events were described in detail. We believe that our current study represents the first thorough evaluation of the efficacy and safety of CDK4/6 inhibitor combined with ET applied to patients with symptomatic BMM and provides valuable information for optimizing therapy.

However, there are limitations to this study. Given the limitations inherent to a retrospective, single-center, small sample size study associated with the challenges in identifying patients considered to be in BMM, our results need to be validated in appropriately designed prospective multicenter prognostic studies and clinical trials comparing different treatment modalities for patients with this condition.

When breast cancer patients present with anemia and fever despite a negative etiological test, BMM should take this into account. For HR⁺/HER2⁻ patients with good physical status and can receive active treatment, CDK4/6 inhibitors combined with endocrine therapy can be used to control disease progression, improve quality of life, and prolong survival.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

RY: writing—original draft; review and editing. GL: writing—review and editing. ZL: writing—review and editing. LJ: methodology, funding acquisition, writing—review and editing. JC: conceptualization, methodology, supervision, writing—original draft; review and editing. All authors contributed to the article and approved the submitted version.