Despite the significant advances in cancer diagnostics to date, there are still many challenges and limitations in the field. These include accuracy of diagnosis, early detection, and the level of invasiveness. In some instances, the diagnostic procedure is highly invasive, requiring patients to undergo risky surgical procedures to get a diagnosis. Some methods, e.g., biopsies and cytology aspiration are speculated to cause tumour seeding resulting in metastasis, an event where cancer cells dislodged from the tumour site are introduced to the lymphatic system and/or bloodstream and go on to establish independent tumour sites resulting in the spread of cancer(1). Although the theory of tumour seeding is controversial and the occurrence is considered rare, it is still a potential risk. Non-invasive methods of diagnosis such as CT scans can be costly and expose patients to high levels of radiation (2)
Not all tumours are the same and as such, the choice of diagnostic tool may vary, even for types of cancers affecting the same organs. The rate of progression, metastatic ability, malignancy, and genetic information varies between cancer cell types. This makes cancer diagnosis complex, especially in the early stages as there is no accurate way to extrapolate and predict progression (3).
Imaging techniques are powerful tools in determining the physical aspects of a tumour, e.g., the precise location and size of a tumour (see Figure 1), but do not give any information on the progression and metastasis (3).
Figure 1: CT scan image showing a tumour caused by lung cancer (4)
This also applies to mammograms which are used for routine breast cancer screening. As everyone has different breast structures and density, this can interfere with diagnosis, resulting in:
- Overdiagnosis - When benign tumours are interpreted as potentially life-threatening resulting in patients undergoing invasive procedures such as tissue biopsy, which may require hospitalisation and increase the risk of secondary infection on the open wound (1).
- False Positives - When cancer (or suspected cancer) is diagnosed leading to further invasive testing that is not required - this is common in breast cancer screening. Further testing includes a diagnostic mammogram, ultrasounds and sometimes MRIs or biopsies to determine if the change or abnormality is in fact cancer.
- False Negatives – These occur frequently due to limitations in the sensitivity of diagnostic tools. This is particularly an issue in early diagnosis where the physiological changes are below the limit of detection. It is estimated that 1 in 5 cases of breast cancers go undiagnosed
A solid biopsy is a sample of a tumour that is extracted and sent to a laboratory for testing. Due to the invasive nature of the procedure, this method cannot be used to monitor cancer progression and is not a viable option for the diagnosis of high-risk patients.
The sample size extracted can vary depending on the method used: for example, use of a dermal punch to cut a sample of skin out for melanomas, to open surgery for extraction of large sections of organs. Sometimes, the availability of adequate amounts of tissue is limited which can also hinder the diagnosis and characterisation of cancer. If a biopsy is taken for imaging testing, it is cut into thin slices, frozen then tested. This also relies on the expertise of trained medical staff. These trained professionals rely on their personal experience and look at hundreds of image results daily, creating a large gap for human error (6).
A liquid biopsy is based on the detection of cell-free DNA from tumour DNA in bodily fluids.
Accurate results are crucial to monitor a patient’s condition and make informed timely decisions on patient care. Technical limitations of laboratory testing restrict its ability to accurately diagnose cancer. It is, however, a much less invasive method of cancer diagnoses than solid biopsy extraction and testing.
Tumour cells take over normal cellular mechanisms to support the growth of cancer. The concentration of these markers in the blood is much higher in cancer patients compared to normal physiological conditions. However, biomarkers are not entirely specific to cancer and can be elevated due to other non-cancerous conditions; for instance, multiple myeloma increases the level of serum proteins which can interfere with cancer diagnoses. Therefore, liquid biopsy cannot be relied upon as a sole diagnostic tool for cancer (7).
Cancer cells are not always uniform within a tumour cell: they undergo infinite proliferation meaning the chance of mutations occurring is high. In biopsies, there is great potential to miss mutations in other areas of a tumour as only a small sample is extracted for testing: this can impact the next steps of patients’ care as medical professions don’t have the complete picture of all mutations to make informative diagnoses and effective treatment plans. Especially in cases where mutations can impact the effectiveness of treatments or where cancer has spread beyond the point of origin (6).
Figure 2: Representing types of liquid biopsy tests and their purpose at specific points of cancer diagnosis (8).
An ideal tumour marker test:
- High positive and negative predictive values to give clearly defined reference levels to differentiate normal and abnormal
- Inexpensive and simple compared to the current complex, expensive equipment
- Patient acceptability and validation from clinical trials
The ideal tumour marker test does not exist due to challenges in diversity between individual cancer progression and current technology available. A lack of standardised test guidelines due to variability in laboratory methods for tumour markers makes it difficult to compare different methods. Additionally, non-routine cancer markers may contribute to a misdiagnosis or delay in treatment, especially markers that aren’t directly linked to specific cancer (7).
Molecular diagnostics are great for diagnosing cancer but are limited due to our lack of knowledge of specific tumour biomarkers for each cancer type. These tests are usually conducted using PCR or NGS testing and can detect a single molecule of tumour-specific DNA within the presence of nucleic acids. DNA tests usually rely on cancer-driving mutations in the gene and are less prone to false- and positive- results compared to analysing the known protein markers that are tissue-specific rather than tumour-specific markers. Tests like PCR require expensive equipment and enzymes as well as trained laboratory professionals: there is potential to adopt these tests for smaller, inexpensive point-of-care (POC) tests. (9).
Electrochemistry tests have the advantage over PCR of being suitable for miniaturisation. PCR also requires skilled personnel and expensive equipment to operate the tests: these have limited availability in low-resource areas. Compared to PCR and DNA sequencing methods, electrochemistry technology can detect ctDNA, simpler, faster, sensitive and specific compared to the lab-based methods. These can be made low-cost and portable: ideal for resource-limited areas (10). Our sensors are robust and reproducible meaning they are suitable for mass production without affecting quality: ideal for POC devices.
Current methods are largely effective in diagnosing and monitoring cancer. However, due to limitations in technology and understanding of cancer, misdiagnosis frequently occurs. This leads to unnecessary tests and treatment that may harm a patient’s physical and mental health. As we advance in medical innovation and deepen our understanding of the disease, these limitations inspire novel technology to increase limits of detection, enhance sensitivity and specificity to produce better sensors.
Our Gii-Sens can translate existing test formats, like PCR, into POC without compromising performance. Get in touch with us today if you are developing an electrochemistry based POC device.
- Etzioni R, Gulati R. Recognizing the Limitations of Cancer Overdiagnosis Studies: A First Step Towards Overcoming Them. J Natl Cancer Inst. 2015 Nov 18;108(3):djv345. doi: 10.1093/jnci/djv345. PMID: 26582245; PMCID: PMC5072370.
- Ilié M, Hofman P. Pros: Can tissue biopsy be replaced by liquid biopsy? Transl Lung Cancer Res. 2016 Aug;5(4):420-3. doi: 10.21037/tlcr.2016.08.06. PMID: 27655109; PMCID: PMC5009092.
- Sokolenko AP, Imyanitov EN. Molecular Diagnostics in Clinical Oncology. Front Mol Biosci. 2018 Aug 27;5:76. doi: 10.3389/fmolb.2018.00076. PMID: 30211169; PMCID: PMC6119963.
- Campuzano, S., Serafín, V., Gamella, M., Pedrero, M., Yáñez-Sedeño, P., & Pingarrón, J. M. (2019). Opportunities, Challenges, and Prospects in Electrochemical Biosensing of Circulating Tumor DNA and its Specific Features. Sensors (Basel, Switzerland), 19(17), 3762. https://doi.org/10.3390/s19173762