Advanced Prostate Cancer Is a Disease That Predominantly Resides in the Bones

In the early stages of advanced prostate cancer, malignant cells shed from the primary tumour, migrate locally, invade blood vessels, and may disperse widely in the body. Once in the bloodstream, the chances of metastatic cells surviving in many regions of the body outside of the primary tumour (i.e., the “Homeland”) are low due to the rigorous characteristics of lymphatic and blood circulatory systems and the host defense mechanisms.Prostate cancer cells (the “seeds”) in the bloodstream need to settle in an appropriate “soil,” and so they preferentially migrate to bone (the “Hostland”;

Figure 1

). These malignant cells invade and eventually proliferate in the bones of the axial skeleton, such as the ribs, pelvis, and spine, where red marrow is most abundant,although metastases in the long bones and skull are not uncommon.

Prostate cancer cells (the “seeds”) in the bloodstream need to settle in an appropriate “soil,” and so they preferentially migrate to bone.

Figure 1. Prostate Cancer Has an Affinity to Metastasize to Bone

^{Adapted from Pienta KJ}^{et al}^. 2013

Prostate cancer cells leave the primary tumour (the “homeland”) and enter in the bloodstream, where soluble factors aid in their preferential migration to bone (the “hostland”).
Once a prostate cancer cell reaches the skeleton, it still needs to invade the bone and proliferate.
The bone matrix is rich in factors that stimulate the growth of tumour cells and promote a vicious cycle of metastases and bone pathology.
Physical factors in the bone microenvironment, including a supportive vascular system, may also enhance tumour growth.
The physical characteristics of bone tissue – including a supportive vascular system in the axial skeleton, thin sinusoidal walls, a direct venous system from prostate to bone, and slow circulation – can facilitate the attraction and migration of tumour cells to bones.Prostate cancer cells that migrate to the skeleton attach to the endosteal surface and colonize bone. Paget’s hypothesis then predicts that the growth of tumour foci tends to be the direct result of a specific organ’s microenvironment.
The bone microenvironment, made up of osteoclasts, osteoblasts, the mineralized bone matrix, and many other types of cells, is highly favourable for tumour invasion and growth. The bone matrix is rich in factors that stimulate the growth of tumour cells and promotes a vicious cycle of metastases and bone pathology (Figure 1
).Bone is an extremely fertile “soil” for prostate cancer “seeds” because a variety of growth factors stored in the matrix are readily released in their active form into the bone microenvironment during the process of physiologic bone remodeling. Many cytokines and growth factors are locally released from bone, providing an excess supply of nutrients that can help survival, growth, and spread of the tumour cells.

Figure 2. Distribution of Sites of Metastases in 2,607 Men Diagnosed With Stage IV Prostate Cancer Within the SEER–Medicare Database Between 1991 and 2009

Distribution of Sites of Metastases in 2,607 Men Diagnosed With Stage IV Prostate Cancer Within the SEER–Medicare Database Between 1991 and 2009

^{Adapted from Gandaglia G}^{et al}^. 2015

Studies have shown that approximately 90% of men with advanced prostate cancer will develop bone metastases.This incidence was demonstrated in an autopsy study of 1,589 men who had either prostate cancer at autopsy or a history of prostate cancer that was previously treated. In addition, a Surveillance, Epidemiology, and End Results (SEER) database analysis of patients diagnosed with stage IV prostate cancer between 1991 and 2009 also revealed that the majority of patients had bone metastases (91.1%;

Figure 2

). The results showed that while 2.8% of men had lymph node metastases, and 6.1% had visceral metastases, 80.2% had bone metastases, with bone and visceral metastases present in another 10.9% of patients. (Figure 2
)

Studies have shown that approximately 90% of men with advanced prostate cancer will develop bone metastases.

Bone Metastases May Demonstrate Variable Migratory Pathways

The majority of men with clinically localized prostate cancer who develop bone metastases do so many years following removal of the primary tumour. This indicates a lag between initial therapy and the biochemical recurrence, the first indication of future overt metastasis. It is hypothesized that metastatic prostate cancer cells can remain dormant in the bone marrow for several years prior to turning to a proliferative phenotype, a transformation that drives metastatic progression.
The genomic evolution of CRPC, from initial tumorigenesis through the acquisition of metastatic potential to the development of castration resistance, has been revealed by whole genome sequencing.
Results from genomic studies support the theory of progression to a proliferative phenotype following dormancy in the bone marrow, as monoclonal and polyclonal metastatic tumour cells are observed to preferentially and frequently migrate between sites distant from the primary tumour (Figure 3
). The “seed and soil” hypothesis states that metastatic potential is not a property of the primary tumour as a whole, but is acquired as a rare event inside the tumour. Genomic studies also support this hypothesis, as separate waves of metastatic invasion directly from the primary tumour have not been observed.

Figure 3. Bone Metastases May Demonstrate Variable Migratory Pathways

^{Adapted from Gundem G}^{et al.}²⁰¹⁵

Body maps show the seeding of all tumour sites from one patient in the genomic sequencing study. Seeding events are represented with colour-coded arrows and with double-heads when seeding could be in either direction. When the sequence of events may be ordered from the acquisition of mutations, arrows are numbered chronologically. Subclones on branching clonal lineages are labeled with the same number but with different letters, e.g., 1a and 1b. Results from these genomic studies support the theory of progression to a proliferative phenotype following dormancy in the bone marrow, as monoclonal and polyclonal metastatic tumour cells are observed to preferentially and frequently migrate between sites distant from the primary tumour.

Bone Metastases Are Associated With Higher Mortality

Bone metastasis indicates a poor prognosis in men with prostate cancer.The 1-year survival rate in a cohort study was 87.0% (95% CI: 86.5-87.4) in men with prostate cancer without bone metastasis, 47.4% (95% CI: 44.1-50.6) in men with bone metastasis but no skeletal-related events (SREs), and 39.9% (95% CI: 35.6-44.2) in men with bone metastasis and SREs. Respectively, corresponding 5-year survival rates in these groups were 55.8% (95% CI: 54.9-56.7), 2.7% (95% CI: 2.2-3.4) and 0.7% (95% CI: 0.6-1.0).

Figure 4

shows the survival probabilities at 1, 5, and 7 years in 3 distinct cohorts of patients with prostate cancer from the cohort study. The men were identified from 1999 through 2007 in the Danish National Patient registry.

Progression From Bone to Multiple Metastatic Sites Decreases Survival in CRPC

The location and the number of metastatic sites in patients with prostate cancer may have prognostic implications.

Figure 4. Bone Metastases Lead to Poor Survival

^{Of the 23,087 patients with initial diagnosis of prostate cancer, 22,404 had no bone metastases, 569 presented with bone metastases but no SRE and 114 presented with bone metastases and SRE.}

^{Adapted from Norgaard M}^{et al}^. 2007

The role of the metastatic phenotype on mortality in men with stage IV prostate cancer was examined in 3,857 men from the SEER database who presented with metastatic prostate cancer between 1991 and 2009. At diagnosis, 611 patients (15.8%) were identified as having 2 or more metastatic sites. In addition, 108 patients (2.8%) were recorded as having lymph node metastases, 3,093 (80.2%) had bone metastases, 234 (6.1%) had visceral metastases, and 422 (10.9%) had bone plus visceral metastases. Progression from bone to multiple metastatic sites is associated with increasing mortality (

Figure 5

Patients who had bone metastases alone had a 1.5-fold higher probability of dying versus men with lymph node involvement only (𝘱=0.02).

The site of metastases, after adjusting for confounders, was observed to be an independent prognostic factor. Of note, patients who had bone metastases alone had a 1.5-fold higher probability of dying versus men with lymph node involvement only (p=0.02).Men with bone plus visceral metastases had a 1.3-fold higher probability of dying compared with men who only had bone metastases (p<0.001).

Figure 5. Progression From Bone to Multiple Metastatic Sites Decreases Survival in CRPC

^{Kaplan-Meier curve depicting time to overall mortality after stratifying patients according to the site of metastases.}

^{Adapted from Gandaglia G}^{et al}^{. 2015.}

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