Diagnostics of metastatic disease

Diagnosing metastatic disease requires a combination of advanced imaging techniques and tissue biopsies to accurately detect cancer spread and guide treatment decisions. The main goals are to identify where the cancer has spread, assess the extent of the disease, and gather molecular data to inform whether the tumor has genetic aberrations that can be addressed with targeted therapies. Here are the key diagnostic tools used:

Computed Tomography (CT)

Computed Tomography (CT) is one of the most widely used imaging methods in oncology. It provides detailed cross-sectional images of the body, allowing clinicians to visualize the size, shape, and location of tumors, as well as any potential metastases to organs such as the lungs, liver, or bones, 2010). CT scans are especially useful for staging cancer and monitoring treatment response, making them a standard tool in the diagnostic workup for cancers.

Positron Emission Tomography (PET)

Positron Emission Tomography (PET), typically combined with fluorodeoxyglucose (FDG), highlights areas of increased metabolic activity. Cancer cells often have higher glucose uptake, which makes FDG-PET particularly effective at detecting metastatic disease, even before it becomes apparent on a CT scan. PET imaging is invaluable in assessing cancer spread to lymph nodes and distant organs, and is often used in conjunction with CT for better anatomical localization of these metastases. Indeed, the integration of PET/CT has become a pivotal advancement in cancer diagnostics. For instance, PET/CT is highly effective in detecting lung cancer metastases, helping to stage the disease and assess whether it has spread to distant sites like the adrenal glands or bones. Moreover, PET/CT-guided biopsies enable clinicians to precisely target suspicious lesions, providing better diagnostic yield and reducing the chances of false-negative results. A caveat of this technique is its resolution: it will only pick up metastases that have a volume of at least 0,5cm3 (=0,5×1012 µm3) which is hughe when one knows that a tumor cell will be in the order of 10-30 µm3.

Magnetic Resonance Imaging (MRI)

Magnetic Resonance Imaging (MRI) provides excellent soft tissue contrast and is especially useful in detecting brain, liver, and spinal metastases, picking up lesions up to 1mm. While PET/CT is useful in most parts of the body, MRI is the gold standard for detecting brain metastases, given its superior resolution in brain tissue. MRI is particularly effective at detecting small brain metastases that might be missed on CT or PET, making it the imaging method of choice for patients with neurological symptoms or cancers that commonly metastasize to the brain, such as lung cancer and melanoma. MRI is also relevant for imaging metastases in patients with suspected spinal cord compression, which can be a medical emergency.

Biopsies

Biopsies are critical for confirming the diagnosis. Not only may they confirm the cancer’s spread, but they also provide histological and molecular data that guide treatment. In particular, molecular profiling from tumor biopsies can detect mutations (e.g., EGFR, BRAF, or ALK gene mutations) that guide treatment decisions for targeted interventions that will likely be effective for these cancers.

Liquid biopsies

A more recent development in the detection of metastatic disease is the use of liquid biopsies, which analyze for instance circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) in the blood. These minimally invasive tests provide real-time information on the molecular landscape of the tumor and can, in particular, be useful for monitoring treatment response and evolving resistance mechanisms, detecting minimal residual disease (MRD) or early signs of metastasis. The sensitivity of these assays still is a matter of debate. For instance, MRD sensitivity has to be in the order of 0.0001%. This can only be achieved with whole genome sequencing and a tumor-informed assay.

Conclusion

The diagnostic process for metastatic disease has greatly evolved, with the integration of advanced imaging techniques like CT, MRI, PET/CT, and molecular biopsies providing a comprehensive approach. These tools not only help in identifying and characterizing metastatic lesions but also play a crucial role in guiding treatment strategies, including targeted therapies and immunotherapy. Emerging methods like liquid biopsies represent the future of non-invasive cancer diagnostics, offering real-time insights into tumor behavior and response to treatment. Understanding how to utilize and interpret these diagnostic methods is key for optimizing patient outcomes in metastatic cancer care. In the following patient case, we will reflect on the use of some of these strategies.

Further reading

• Fass L. Imaging and cancer: a review. Mol Oncol. 2008 Aug;2(2):115-52. doi: 10.1016/j.molonc.2008.04.001.
• Epub 2008 May 10. Erratum in: Mol Oncol. 2022;16(15):2896. doi: 10.1002/1878-0261.13283.
• Hussain S, Mubeen I, Ullah N, Shah SSUD, Khan BA, Zahoor M, Ullah R, Khan FA, Sultan MA. Modern Diagnostic Imaging Technique Applications and Risk Factors in the Medical Field: A Review. Biomed Res Int. 2022;2022:5164970. doi: 10.1155/2022/5164970.
• de Jager VD, Timens W, Bayle A, Botling J, Brcic L, Büttner R, Fernandes MGO, Havel L, Hochmair MJ, Hofman P, Janssens A, Johansson M, van Kempen L, Kern I, Lopez-Rios F, Lüchtenborg M, Machado JC, Mohorcic K, Paz-Ares L, Popat S, Ryška A, Taniere P, Wolf J, Schuuring E, van der Wekken AJ. Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries. Lancet Reg Health Eur. 2024;38:100838. doi: 10.1016/j.lanepe.2024.100838.
• Choi HY, Chang JE. Targeted Therapy for Cancers: From Ongoing Clinical Trials to FDA-Approved Drugs. Int J Mol Sci. 2023;24(17):13618. doi: 10.3390/ijms241713618. Alix-Panabières C, Pantel K. Liquid Biopsy: From Discovery to Clinical Application. Cancer Discov. 2021;11(4):858-873. doi: 10.1158/2159-8290.cd-20-1311.
• Lone, S.N., Nisar, S., Masoodi, T. et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer 21, 79 (2022). doi: 10.1186/s12943-022-01543-7.