Advanced PA is dominant by BM, which usually be osteogenic lesions, causing structurally disturbed and unstable osteogenic changes25. The pathogenesis of prostate cancer bone metastases is now thought to include two major mechanisms: metastasis to the spine via the Baston spinal venous plexus and Paget’s seed and soil theory; nevertheless, the specific mode of action is still being investigated. In 2020, PA have affected roughly 1.41 million men globally, accounting for 30.7% of all cancers diagnosed1. The most prevalent location of PA distant metastasis is the bone. It was reported that the incidence of BM was about 3%–10% in patients who were initially diagnosed with PA in developed countries, while it could reach 27% in developing countries26,27. This study found that the probability of BM in patients with PA was 3.1% (4147/132,601), which is comparable with results from previous research. Since early PA symptoms are similar to those of benign prostatic hyperplasia, many individuals have BM when they are first diagnosed. Patients with only BM have a better prognosis than those with multiple sites. However, until patients have BM, their OS will decrease rapidly, with 1- and 5-year survival rates of 47% and 3%, respectively12. BM patients are often untreatable with standard treatments (surgery, radiation, and chemotherapy) and may experience a succession of skeletal-related events which diminish their quality of life23. Therefore, we must discover the effective risk and prognostic factors for BM in patients with PA for early diagnosis, to facilitate early prevention, and to assess the prognosis of BM in patients with PA. In this study, we constructed a diagnostic nomogram to predict BM in newly diagnosed PA patients and a prognostic nomogram for BM patients. By obtaining data on several key accessible variables on the nomogram, diagnosis-related and prognosis-related scores can be calculated, thus facilitating further clinical assessment and management.
Based on the seed and soil theory, PA disseminates to bone via the hematogenous route, and the microenvironment of bone provides a particularly fertile environment for tumor cell proliferation and progression28. PA cells have a subtle tendency to bone, and in an autopsy study, 90.1% of individuals who died of PA were diagnosed with metastatic cancer to bone29. However, PA metastasis to the bone is a complicated progression, and its exact mechanisms remain unknown. It has been shown that bone-derived chemokines operate as chemoattractants for circulating PA cells, which, upon arriving in bone, are exposed to elements within the bone microenvironment that promote the establishment of metastasis. The release of growth factors by tumor cells may directly promote osteoblast activity, leading to a rise in receptor activator of NF-(kappa )B (RANK) ligands expression. This overproduction of RANK ligand then mediates a vicious cycle of tumor growth and bone destruction by promoting the formation, function, and survival of osteoclasts, which results in excessive bone reabsorption, and the release of growth factors from the bone matrix, which may perpetuate tumor activity30,31. Additionally, as for clinical characteristics, research discovered that BM in PA patients had a substantial correlation with PSA32, T-stage33, and ISUP groups34. When PSA <10ng/ml, the frequency of bone metastases in PA patients was found to be close to zero; when PSA >20ng/ml, the probability of bone metastases was reported to be over 70%32. According to the European Urological, the risk of newly diagnosed PA patients were stratified into low risk (Gleason score (le )7, T1–T3, and PSA <10ng/ml, with T1 patients considered low risk regardless of PSA value), intermediate risk (Gleason score (le )7, T2/T3, and PSA >10ng/mL), or high risk (Gleason >7 score)35. The Gleason score has been utilized for half a century to estimate the prognosis of PA patients and to guide treatment decisions. The grading system has been the subject of extensive research, which has influenced its use in clinical practice. Subsequently, ISUP convened several consensus to modify both the grading standards and the manner in which grades were presented in accordance with the Gleason score36,37. Ultimately, to more effectively communicate the prognostic significance of PA, the ISUP Consensus Conference established a five-grade grading system, with grades 1 to 5 based on Gleason scores (le )6, (3+4=7, 4+3=7, 8), and 9–10, respectively. In this study, we used clinical data from the SEER database for analysis to identify eight predictors of BM in PA patients, namely, age, PSA, T classification, N grade, brain metastases, liver metastases, and lung metastases. The association between PSA value, T grade and ISUP grade and BM in PA patients has been confirmed in previous research. Surprisingly, however, T3 stage PA patients had the least risk of BM. We hypothesize that it may be connected to the PSA value; when PSA <10 ng/ml, patients with stage T1–T3 belong to the low risk group in total. Meanwhile, our research revealed that older individuals, N1 stage, brain metastases, liver metastases, and lung metastases were more likely to develop BM. We speculate that this is owing to the weakened immune of elderly patients, which makes them susceptible to BM. Moreover, we found lymph node, brain metastasis, liver metastasis and lung metastasis are risk factors for synchronous BM.
Currently, there is no curative therapy for PA patients with BM, and SERs are highly prevalent; therefore, early detection of BM is crucial for patients to receive appropriate treatment to reduce the inconvenience and pain caused by various complications, allowing them to live with tumors for an extended period of time. To date, the majority of research focused only on independent risk variables, and only one realistic model has been developed to predict the risk of BM in PA patients38. In the prior model, practitioners were required to precisely estimate the prostate’s volume to forecast BM, which was impractical for treatment. To answer this deficiency, we developed a novel web-based nomogram based on eight independent predictors and demonstrated excellent performance with ROC curves, calibration curves, and DCA, which may improve the current state of risk assessment and enable more accurate personalized clinical decision making.
Most PA patients with BM didn’t exhibit overt clinical symptoms in the early stages, and some individuals might not be identified until they present with impaired limb movement, bone pain and pathologic fractures39. The spine is the most typical location for BM, which may induce spinal discomfort, radiating pain, limb paralysis, and even paraplegia in extreme cases. Patients with extensive BM may also have systemic symptoms, including weariness, wasting, anemia, and possibly multiorgan system failure. In addition, hypercalcemia may affect numerous physiological systems, such as the neurological system, cardiovascular system, digestive system, urinary system, and even tumor cachexia. Although SREs are commonly used to describe the specific symptoms of BM in current clinical practice, the concept of SREs originated in early clinical studies of bone-modifying drugs and was only used as a clinical endpoint to assess the efficacy of drug therapy, including four types of pathological fractures, spinal cord compression, bone surgery, and bone radiotherapy40. Although there is a correlation between SREs and clinical symptoms, the subjective evaluation procedure and the fact that it may be altered in the short term make it inappropriate as an endpoint in clinical trials. Therefore, OS was chosen as the outcome measure for BM patients. At present, the primary objectives of treating PA patients with BM are to prevent and minimize the incidence of SREs, alleviate the pain caused by BM, and enhance the quality of life of the patients. Our research found that OS in PA patients was associated with five factors: age, marital status, PSA value, ISUP group, and liver metastases, rather than treatment methods such surgery, chemotherapy, or radiation therapy. Furthermore, using ROC curves, calibration curves, and DCA validation, it was shown that the nogram may provide new opportunities for individualized evaluation and clinical decision-making. This conclusion is comparable to the metastatic PA model developed by Jiang et al.41. It seems that younger, married, lower PSA levels, lower ISUP grades, and without liver metastases individuals achieved better OS. However, grade 3 of the ISUP had a higher OS than grade 2, which is unexpected. This may be because both have comparable Gleason scores and largely intact prostate tissue. Nonetheless, ISUP grade 3 had a higher OS than grade 2, which may be due to the fact that both grades have comparable Gleason scores and partly intact prostate tissue. In addition, Hu et al.42 established the prognostic nomogram of PA patients with BM using six genes signatures, which is more costly and cumbersome than our model.
Our study has a significant advantage compared with previous similar studies. First, the subject of our study is not consisted with previous research. The majority of previous research focused on the risk and prognosis of PA patients with BM38,39,41. However since PA is a heterogeneous disease with various biological traits for different pathological subtypes, we selected PA as our study topic. Second, our study had a considerable sample size, and to the best of our knowledge, it was the largest sample size focusing on PA patients with BM. Third, we developed two practical web-based tools to aid clinicians in their daily work by allowing for more efficient and easy prediction of BM risk and prognosis in PA patients.