Chromogranin A interest in monitoring castration-resistant prostate cancer
Prostate cancer (PC) is second highest incidence most diagnosed cancer globally in men, with an estimated 1.4 million diagnoses worldwide in 2020. (1)
Systemic therapy, based on androgen deprivation, is standard primary treatment for advanced PC. Despite adequate therapy, the disease eventually progresses to castration-resistant prostate cancer (CRPC). (2)
In metastatic PC, standard first-line therapy combines androgen deprivation therapy (ADT) with therapies targeting the androgen-receptor (AR) pathway, including abiraterone, apalutamide, and enzalutamide. (3)
Neuroendocrine differentiation (NED) is an alternative AR-independent mechanism of resistance to cancer therapeutics like androgen deprivation agents. This resistance manifests, after exposure to multiple treatments, by a histological change from an adenocarcinoma to a neuroendocrine histology, ultimately developing into a neuroendocrine prostate cancer (NEPC).
NEPCs, which includes both pure small-cell carcinoma and mixed adenocarcinoma-neuroendocrine tumors, are characterized by a diminished secretion of prostate-specific antigen (PSA), often accompanied by expression of neuroendocrine markers, such as chromogranin A (CgA), synaptophysin, and neuron specific enolase (NSE).
De novo small-cell PC, an extremely aggressive histological variant of PC, is extremely rare: occurring in fewer than 1% of men with untreated PC. While NEPC is rarely diagnosed de novo, about 10-17% of patients with metastatic CRPC have been reported to progress with treatment emergent NEPC when treated with new hormonal agents. (4)
Chromogranin A (CgA) is the main constituent of secretory granules of neuroendocrine cells. In these cells, CgA regulates the storage and secretion of hormones and neuropeptides and is a precursor to biologically active peptides. (5)
Elevated levels of CgA in men with PC may suggest the emergence of neuroendocrine tumor cells or progression of pre-existing neuroendocrine tumors or sub-populations. Transdifferentiated NEPC cells—like normal neuroendocrine cells—produce, store, and secrete CgA. (6)
The value of CgA as a prognostic and therapy-predictive biomarker in the localized and mCRPC settings has been tested and is still being discussed. (7-13)?
A recent analysis of serum CgA levels before and after treatment with either radical prostatectomy, chemotherapy (docetaxel), or hormonal therapy (abiraterone or enzalutamide) was reported. The analysis included 395 men with PC that were divided into 3 cohorts according to treatment: the radical prostatectomy, docetaxel, and the combined abiraterone or enzalutamide [TS1]?[KS2]?cohorts. Men with localized and hormone-na?ve PC were included in the radical prostatectomy cohort; while those with mCRPC were included in the docetaxel and abiraterone/enzalutamide cohorts. (14)
CgA levels, at baseline, were approximately 3-fold higher in the docetaxel and abiraterone/enzalutamide cohorts, including men with mCRPC, compared to the RPE cohort, including men with localized PC. The median baseline CgA level was 111.1 ng/mL in the docetaxel cohort and 149.9 ng/mL in the abiraterone/enzalutamide cohort. This is in line with previous observations that neuroendocrine differentiation status significantly progresses during ADT and is associated with an increase in serum CgA levels. (Figure 1)
This study also suggests baseline cut-offs for CgA to predict outcome (i.e.overall survival) at 168.0 ng/ml in patients treated with docetaxel chemotherapy and at 81.2?ng/ml in patients treated with abiraterone or enzalutamide.
Furthermore, it shows that high baseline CgA and CgA increases after 3 month of hormonal treatment were significantly associated with shorter overall survival in patients treated with abiraterone or enzalutamide and might indicate resistance to therapy related to neuroendocrine differentiation (Fig.2B).
A recent systematic analysis of clinical studies that assessed CgA levels suggests that CgA may be a useful biomarker for monitoring disease evolution and for guiding treatment in men with mCRPC.15?(Figure 3)
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In conclusion, the presence or progression of neuroendocrine differentiation is reflected by serum CgA levels. NED significantly progresses during ADT. High baseline CgA levels and increased CgA levels after 3 months of hormonal treatment with Abiraterone or Enzalutamide are significantly associated with shorter overall survival, suggesting NED-related resistance to therapy. Systematic CgA assessments in clinical practice, at baseline and during treatment, may be useful for monitoring disease evolution and assisting physicians with choosing and modifying therapy.
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References
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