In fact, a lot of prostate cancer patients are already in the middle and advanced stages of the disease at the time of consultation, losing the chance of radical surgery and having to opt for endocrine therapy. Clinical observation has found that, although endocrine treatment can improve patient survival rates, its long-term effects vary greatly (12). Because the occurrence mechanism of CRPC will be extremely complex and there is no effective treatment (13), once the patient advances to the CRPC stage, treatment is extremely difficult and prognosis is extremely poor. Therefore, we judge the prognosis by analyzing the risk factors that may affect early progression to CRPC (within 18 months after endocrine treatment) and use this to guide treatment.
In the comparison between the sensitive and drug-resistant group, we found that the shorter the TTN, the more likely PC was to become CRPC (p < 0.031). TTN refers to the time when the PSA level drops to the lowest value after endocrine treatment. As one of the early authors of this concept, Cooper EH argued that the TTN is closely related to prostate cancer progression (14). Sasaki's study showed that the longer TTN and the lowest point of PSA mean the lower risk of prostate cancer progression (15). Unlike the Sasaki's study, the PSA nadir value showed significant differences in our univariate test (p < 0.001), but there was no statistically significant difference in our multivariate analysis (p = 0.098; overall risk [OR] = 2.029; 95% CI (0.877–4.696)). This could be a pseudo-association between numerous exposure factors and outcome (occurrence of CRPC), where exposure factors are indirectly associated with outcome, which is a side-effect of the fact that the length of time to reach the minimum PSA is more correlated with CRPC progression than, for example, high or low changes in PSA values, but cannot be excluded because of a single center, small sample.
We found that the LDH levels are significantly increased in a variety of malignant tumors, and the relevant literature shows that LDH plays a crucial role in tumor metabolism, proliferation, invasion and metastasis (16). Some studies have shown that LDH levels have important prognostic value for many solid tumors (such as liver cancer and renal clear cell carcinoma ) (17–18). The results of our study confirmed that the higher the serum LDH before endocrine treatment, the greater the possibility of progression of CRPC. Indeed, Since the 2004 year when Halabi included LDH as a prognostic model for predicting survival in metastatic CRPC patients (19) to the recent continuously updated and adjusted of this model by Armstrong et al. (20), LDH was included almost every time in the prognostic model for CRPC patient .Therefore, value of LDH for predicting the prognosis of CRPC patients is recognized in literature. Furthermore, recent studies by Heck have also demonstrated that in treating prostate cancer patients with organ metastasis, elevated LDH is related to a worse prognosis for prostate cancer patients with organ metastases (21).
In the comparison between the early and late drug-resistant group, we also found that the correlation between TTN and onset of CRPC was statistically significant; that is, the shorter the TTN, the shorter the time for progression of CRPC. Research has shown that the dynamic change index of PSA is a common indicator used to predict the time of CRPC progression, and the widely accepted view is that the faster the rate of PSA decline, the better the prognosis (22). In recent years, more evidence has suggested that longer TTN was closely associated with longer periods of progression-free survival (23–24). Morote et al. found that the faster the PSA decreased to the lowest value, the shorter the progression-free survival and Overall survival (OS) (25). The value of TTN > 12 months after ADT is reported to be the most important early predictor of prolonged survival in prostate cancer patients with bone metastasis (26). Although it is generally believed by most clinicians that a sharp decline in PSA is always associated with a better response, our study suggests that a longer time taken to achieve a minimum PSA may represent a state of sustained androgen sensitivity following ADT treatment. However, the decline in PSA in a short period of time may be due to endocrine therapy inhibiting androgen receptor-mediated PSA expression levels in HSPC cells. Thus, there is a shorter time to achieve minimum PSA and accelerated death of HSPC cells, which may induce the growth and proliferation of hormone-resistant prostate cancer cells which progress to CRPC (13).
Meanwhile, we also found that higher serum LDH levels prior to endocrine therapy suggested a shorter time for progression to CRPC. The study showed that higher LDH levels before ADT was closely related to poor OS and progression-free survival (PFS), and subgroup analysis confirmed that increased LDH baseline levels accelerated disease progression in CRPC patients and HSPC patients (27). This was also confirmed by the previous study, in which among the 442 CRPC patients included, the median OS was 40.7 months (95% CI; 36.8–44.0) and the median OS in patients with elevated LDH was only 30.6 months (95% CI 27.6–36.5) (28). Scher et al. also found that the combination of LDH with other biomarkers (e. g., PSA or CTC counts) also provides evidence for improving the risk stratification of disease and extending the period of disease progression (29). The specific mechanism of the role of LDH in tumor progression is unclear. The massive production of lactic acid leads to increased local acidity in the tumor microenvironment, which is harmful for normal cells and beneficial for tumor cells. Therefore, at the early hormone-sensitive stage, the mechanism may be associated with a reversible reaction of lactic acid dehydrogenase catalyzing the conversion of pyruvate to lactate, which plays a key role in the glycolysis of tumor cells (30).
Furthermore, our study found that a higher PLR before endocrine therapy suggested a shorter time for progression to CRPC. PLR, a biomarker of the systemic inflammatory response, has been shown to have a predictive value in assessing the presence and progression of cancer (e. g., ovarian cancer and colorectal cancer) and in response to drug therapy (31–32). Recently, there has also been more evidence that inflammation may play an important role in the development and progression of prostate cancer (33–34). Wang et al. found that high PLR is an independent prognostic factor for PFS and OS in prostate cancer ADT treatment and could predict a poor prognosis in patients with a GS > 7 or bone metastases (34). Our study differed from Wang et al. in that it found no difference in PLR in the drug-sensitive and drug-resistant group, but PLR differences between the drug-resistant group, which may be related to insensitive PLR responses to low-tumor loads. The data from this study showed PLR = 185.71 ± 87.72 in sensitive Group And PLR = 153.22 ± 63.26 in late resistant group, which was relatively similar. However, PLR in the early resistance group = 216.15 ± 156.25, which increased significantly and fluctuated greatly. However, this finding is not conclusive due to the single-center and small-sized sample. The mechanisms underlying our observations were unclear. The elevated PLR reflects an elevated platelet-dependent pro-tumor response (35) and a reduced lymphocyte-mediated antitumoimmune response (36), both of which may contribute to cancer progression and adverse outcomes. There are fewer studies of PLR in the prognosis of prostate cancer treated with ADT, and the use of PLR in the prediction of time to progression of CRPC is, to our knowledge, the first of its kind.
Finally, by comparing the survival curves of different group of CRPC patients, we found that TTN, LDH, and PLR not only have value for the prognostic value of CRPC at both time intervals of 24 and 18 months, but also play a role in CRPC progression-free survival. The ROC curve showed that the predictive value of TTN (AUC 0.852) (95% CI 0.768–0.942, p < 0.001) was much higher than that of PLR (AUC 0.631) or LDH (AUC 0.647) and that the AUC value of TTN combined with PLR and LDH increased to 0.958 (95% CI 0.911–0.997, p < 0.001). Moreover, our correlation analysis also found that TTN was inversely correlated with tumor M stage (r = -0.343; p = 0.001) and positively associated with hemoglobin (r = 0.301; p = 0.004). There was also a positive correlation between PLR and NLR (r = 0.784; p < 0.001).
This study has certain limitations. First, our study was conducted at a single institution with a small sample size of 90 patients with a short-term follow-up time of 3 to 60 months and a mean follow-up time of 24.75 months. It has been shown that NLR (20), a biomarker of the systemic inflammatory response, and the liver function marker AST (37), are associated with a poor prognosis of CRPC. Our study was considered in the context of current research, but they had not been found to be statistically significant, possibly due to the study involving fewer cases and being limited to a single-center study. Therefore, to provide better evidence, our results require testing with a larger sample, preferably a multicenter cohort. Second, data collected from the HIS system did not cover all of the available clinical and pathological information, and information on immunohistochemical data and other biomarkers (e. g., AR-V7, circulating tumor cells, etc.).