Bone metastases, prostate cancer and theranostics
Bone metastases, prostate cancer and theranostics
Bone metastases are a common secondary cancer of many cancer types, such as breast (70%), prostate (85%), lung and kidney cancer (40%), due to the unique bone microenvironment. Tumors mostly metastasize to axial skeleton (i.e. bones of the trunk and pelvis) rather than to appendicular skeleton (limbs and girdles) along the distribution of the red bone marrow.
This highly vascular tissue contains blood-forming stem cells and an active microenvironment that promotes cellular growth. The process is not yet fully understood, but the bone environment is replete with growth factors which cancer cells hijack and exploit for their own benefit. The healthy bone undergoes a constant remodeling process, where bone destruction (resorption) and new bone formation are perfectly balanced. So it is also a rich source of calcium released as a consequence of constant bone destruction. Cancer cells express calcium-sensing receptors, and this constant supply of calcium seems to provide fertile soil for tumor growth. The unique immune environment in the bone with its multiple inhibitory and stimulatory effects on cells might also lead to proliferation of metastases. It is likewise possible that the slow blood flow in the red bone marrow facilitates the attachment of cancer cells to the bone surface.
On top of it, in osteoblastic metastasis’s types (more on it below), studies have detected the cancer cell ability to osteomimicry, i.e. ability of cancer cells to disguise themselves as bone by expressing bone-specific proteins. The body confuses them with healthy bone cells and instead of killing “nurtures” them.
Metastatic spread initiates early in the disease process, even before the primary tumor becomes clinically detectable, and may remain dormant for years. The signals that eventually trigger tumor cells to “wake up” are still poorly understood and are under intense scrutiny. Interactions between multiple cells in the bone microenvironment that maintain the dormancy and prevent its subsequent escape from quiescence are currently the target of clinical research.
Phenotypes of bone metastases
Bone metastases can be of osteoblastic phenotype, i.e. triggering new bone formation, or osteolytic phenotype, i.e. destroying the normal bone. Most metastases are mixed showing signs of both types, but with one being predominant. Breast cancer tends to result in the osteolytic bone metastases. Prostate cancer is unique in its ability to stimulate abnormal new bone formation, i.e. osteoblastic type. Lung cancer bone metastases tend to be osteolytic.
Diagnostics of bone metastases
Bone metastases are often diagnosed at an advanced stage with bone lesions already quite significant. Major symptoms are bone pain that is often poorly localized and worse at night; pathological fractures, hypercalcemia (excessive calcium levels in blood) and spinal cord compression; blood count may show anemia, thrombocytopenia (low blood platelet count) or leukopenia (decrease in leukocytes). A timely and precise diagnosis of metastatic bone disease is crucial because of its major clinical consequences.
Standard-of-care imaging methods, such as X-ray, CT scan and radionuclide bone scintigraphy are routinely used for detection. But these methods mainly depict the reaction of the surrounding tissues to the presence of cancer cells. Biomarkers in blood and urine reflect the ongoing rates of bone resorption and formation in the body as a whole and do not provide information specific to individual bone lesion sites.
The evaluation of the effects of treatments is just as important for routine clinical practice. Bone is the only metastatic site with distinct criteria for evaluating response to treatment, which are based on bone repair and destruction rather than on changes in tumour volume. Standard-of-care imaging methods are not very suitable for the treatment evaluation either. There is a now well-recognized phenomenon of initial “flare response” to the therapy of metastatic disease. This initial deterioration detected by the conventional imaging methods often leads to an incorrect assessment that treatment has been ineffective and consequent premature treatment discontinuation, whereas such initial deterioration is in fact followed by a subsequent improvement.
Radioligand Lutetium-PSMA therapy in treating metastatic prostate cancer
Detection of overexpression of PSMA (prostate specific membrane antigen) on the surface of prostate cancer cells has been indeed revolutionary in the treatment of metastatic prostate cancer (mPC). Theranostics as applied to mPC combines an imaging biomarker (PSMA-PET/CT with fluorine-18 or gallium-68) to detect and depict the tumor foci regardless of their location (any soft or bone tissue) and thereby predict the treatment response, and another radioligand (labelled with lutetium-177 or Actinium-225) to directly target and destroy the cancer cells. PSMA-PET/CT is also the most precise treatment evaluation tool to date. Read more about the diagnostics and therapy on our web site.
Therapy response example after 3 sessions of radioligand PSMA therapy with Lutetium-177 and 4-week intervals in-between
PSMA PET/CT January 2021
PSA 77 ng/ml
Metastasized castration resistant prostate cancer after several antihormonal treatments (1st & 2nd generation) and immunotherapy
PSMA PET/CT December 2021
PSA 0,05 ng/ml
After 3x 177Lutetium PSMA ligand therapy January to March 2021 and no further therapy thereafter
Bibliography: Coleman, R.E., Croucher, P.I., Padhani, A.R. et al. Bone metastases. Nat Rev Dis Primers 6, 83 (2020). https://doi.org/10.1038/s41572-020-00216-3