Simplifying Cancer Detection using point-of-care Technologies

Current Scenario & Challenges in Cancer Detection

Approximately 1 in 6 people die of cancer. Multiple factors are expected to fuel the demand for innovative diagnostic solutions in cancer diagnosis. These factors are listed in Exhibit 1 below:

Growing incidence and economic burden:

As per WHO estimates, there were ~17 million newly diagnosed cases of cancer and 9.5 million deaths around the globe in 2018. In 2010, the estimated annual cost for cancer care was ~USD 1.6 trillion. By 2040, the global burden is expected to reach 27.5 million new cases and 16.3 million cancer deaths, primarily due to the aging population. According to the Institute of Health Metrics and Evaluation (IHME) statistics, the prevalence of cancer was found to be comparatively high in the United States (refer to Exhibit 2). Additionally, the prevalence of cancer is on the rise in developing countries.

Need for early diagnosis for the betterment of survival rates:

There exists variation in the survival rate and ease of diagnosis among different cancer types. The need for early diagnosis is evident from the fact that survival rates decrease by ~30-40% after cancer spreads from the site/organ of origin to other body parts. In cancers with low survival rates such as lung, prostate, colon, pancreas, and liver, early diagnosis becomes much more critical. Additionally, some cancers such as brain cancer and Non-Hodgkin lymphoma are fatal and at the same time hard to diagnose. Exhibit 3 given below shows estimated cancer deaths in both males and females in the US, in 2019.

Heterogeneous nature of cancer:

Multiple factors such as the aging population, unhealthy habits, and carcinogenic environmental exposure are expected to contribute to the rising incidence of cancer. There exists a huge disparity in causes for different types of cancers and individual occurrences.

As per the American Cancer Society Surveillance report, variation in cancer prevalence is observed on the basis of age, gender, and ethnicity, thereby making the diagnosis of cancer complex and propelling the need for dynamic and personalized tests. For e.g., i) in the US, cancer prevalence is comparatively high for the middle-aged group (55-80 years). ii) Pre-existing co-morbidities often complicate the diagnosis and treatment of cancer at older ages (refer to Exhibit 4).

Limitations to existing cancer detection techniques:

• Most of the current cancer detection methods are lab-based, invasive, time-consuming, and expensive. There are several instances wherein patients forgo basic screening on account of the impact on the quality of life due to the current diagnostic test characteristics.
• In lab-based tests, due to the involvement of multiple and separate pre and post-analytical stages, such as sampling, labeling, etc., there are high chances of manual errors.
• According to WHO, 70% of deaths from cancer occur in low- and middle-income countries. In addition, there is a lack of access to healthcare infrastructure having the required diagnostic capabilities in these areas.
• The requirement of highly trained lab practitioners for cancer detection and a shortage of the same may impact the implementation of improvised diagnostic measures.

The development of effective Point-of-Care (POC) diagnostic solutions can play a significant role in addressing the above-mentioned challenges.

Leveraging Multiple Technologies from POC Application

Transitioning of diagnostics from centralized or hospital-based laboratories towards POC can only be facilitated, if the developed POC solution is portable, easy-to-use, and reduces the overall cost burden. In the review article, ‘The Role of Affordable, Point-of-Care Technologies for Cancer Care in Low- and Middle-Income Countries’, Karen Haney (National Cancer Institute) and her team points out that the need for POC solutions has resulted in the exploration and commercialization of molecular diagnostic tools and innovative technologies in optical imaging (refer Exhibit 5).

Additionally, with the advancement of separation and sequencing technologies, the concept of liquid biopsy is gaining significance. In a liquid biopsy, only a few drops of the liquid sample (blood, urine, saliva, etc.) is taken in place of tissue for cancer detection.

Imaging technology:

Imaging plays a central role in the comprehensive cancer care continuum, right from the screening stage – diagnosis to treatment cycles and follow-ups. On account of its very nature, imaging technology-based solutions are well-suited for providing rapid results. Both in-vitro and in-vivo portable imaging solutions are under research/commercial development. Miniaturization of the imaging device and price reduction are supported by the adoption of innovative technologies, such as optical Micro-electromechanical Systems (MEMS), optical fibers, etc. In addition, advancement in smartphone technology fitted with high-resolution optical lenses has provided a ubiquitous platform for cost-effective and easy-to-use POC solution development.

• Ultrasounds that were initially considered bulky and costly are presently made portable for ready availability and cost-effectiveness. Established players such as GE and Siemens have portable ultrasound products in their portfolio. For e.g., GE Healthcare introduced VSCAN in 2010, and MobiSante introduced MobiUS TC2 in 2013.
• Portable Microscopy: Presently, hardware modifications are allowing for a compact design. Ultra-compact objectives and thin filters are enabling the development of advanced, field-portable microscopy systems. For e.g., in 2014, Edmund Optics launched TECHSPEC assemblies. Market players are leveraging Light-emitting Diodes (LEDs) for fluorescence microscopy, providing the ease of switch between fluorescence excitation and Brightfield (BF) illumination. While special eyecups on the microscope eliminate the need for a dark room, these microscopes can also run on battery packs facilitating their use in the areas where there is no main power supply. In 2014, ZEISS and the Foundation for Innovative New Diagnostics (FIND) developed PrimoStar iLED. Researchers at MIT developed diffraction diagnosis systems to convert smartphone camera into a powerful microscope in 2015.

• The Pocket Colposcope: Duke University’s Tissue Optical Spectroscopy Lab and 3rd Stone Design developed a pocket colposcope in 2017; this instrument has a unique portable design, allowing it to reach closest to the cervix point, without the need of a high-resolution viewing system. It can also be attached to a laptop for real-time analysis and provides results at par with lab-based tests.

Molecular Diagnostics

The discovery of new bio-markers has propelled the need for POC detection in oncology indication. Still, the major challenge lies in purifying/concentrating the required biomarkers in limited samples, without the use of lab centrifuge. Technologies such as liquid biopsy, portable sequencing, and implantable biosensors are contributing to the development of POC diagnostic solutions for cancer.

• Liquid Biopsy: In the current treatment protocol, a number of re-biopsies are required to assess the status of the ever-changing tumor. This results in increased associated expenditure costs, such as hospitalization, surgery, etc., and thus, remains a key challenge for both the patient and the care-giver. With the development of technologies in liquid biopsy, the screening process is expected to change completely by making it minimally invasive with the requirement of a single drop of sample, such as blood, saliva, urine, etc. This technology uses circulating tumor cell biomarkers for cancer detection. Grail and Guardant Health are two companies at the forefront of liquid biopsy development. Guardant Health liquid biopsy solution has been on sale as a lab-developed test since 2014; the company plans to file for FDA approval by 2020. Another company named Two Pore Guy has also been actively working on its nanopore-based sensor system for a detecting point mutation in KRAS G12D in collaboration with the University of California. Several established players in the field of cancer diagnostics and technology firms with data capability are actively pursuing developments in this space. A few of them are listed below:
• In 2018, Abbott decided to partner with Angle on a liquid biopsy study for breast cancer.
• Grail (a spin-off from Illumina) since 2016 has managed to raise USD 1.5 billion in funding for its liquid biopsy development.
• Microsoft has contributed its machine learning and computing capabilities as well as an equity investment in Adaptive Biotechnologies to develop blood-based diagnostics.
• Miniaturization of Polymerase Chain Reaction (PCR): Researchers are integrating solar sources with microfluidics (KS-Detect – Validation of Solar Thermal PCR) to eliminate power requirements for nucleic acid amplification. This can prove to be of high value in the resource-limited region having a limited/irregular power supply. Further, players are working on the integration of PCR with a smartphone, thereby making the diagnostic process simple as the device would not only control the action but also receive data, carry out automated analysis, and transmit the results.
  • Implantable Biosensors: Implantable bio-sensors are expected to play an imperative role in the monitoring of vitals both, for cancer detection as well as recovery progress. For e.g., measuring body temperature is important for monitoring the effect of chemotherapy, and in this scenario, a biosensor can be useful for the real-time updates. Fouling has been one of the major challenges for the application of man-made biosensors. In 2019, the research team at Lawrence Livermore Laboratories developed a pH sensor coated in the anti-fouling lipid bilayer. Implantable biosensors encompass the potential to monitor the efficacy of cancer treatment by determining the fluid pressure/acid-base balance in a tumor.
  • Use of CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a natural genome editing tool that is used for diagnostic purposes; it has the potential to detect single nucleotide base mutation in cancer, thus providing a high level of accuracy. The paper-based prototype is already developed for infectious diseases and extension of the same in the near future can be seen for associated cancers, such as cervical, oral, etc. However, this technology is still in the research phase, and further clinical developments would be needed.
  • Multiplex POC Detection: Developments in microfluidics have paved the way for designing of efficient lab-on-chip solutions, which can detect multiple analytes/biomarkers using single samples. These miniaturized solutions are both rapid and cost-effective due to the low consumption of reagents and manpower.

  Benefits & Challenges for POC Technology Adoption

  POC technology is expected to offer a number of benefits over the traditional processes. Further, the case for breast cancer detection helps elucidate the same. As per the WHO statistics, less than 4% of the population is screened, and millions of women die due to breast cancer.

  Traditional Processes: Typically, breast cancer is detected using the ELISA test and mammography. For ELISA testing, the lab process involves the use of expensive and bulky equipment for different processes, which include blood separation, mixing, incubation, and test reading. Although there is an economy of scale, accessibility remains a major challenge, specifically in developing countries. Moreover, in mammography (which is considered as the gold standard), the accuracy level varies between 45% and 90%, depending on the reading ability and experience of the medical personnel. Mammography is also considered painful, requires disrobing, and exposes the patient to radiation side-effects.

  POC Solutions: POC solutions help overcome geographical, cultural, and economic barriers. In 2017, POC Medical Incorporation launched the Pandora CDx-MammoAlert, a microfluidic rapid POC test that detects the presence of 48 serum biomarkers and seeks to replace the laboratory-based test. The system offers results in 30 minutes; the data is stored in the cloud and can be accessed from a remote location for quick and early decision making. Exhibit 5 depicted below highlights key benefits of POC solutions:

  Although POC offers multiple benefits, a number of adoption challenges need to be addressed for higher clinical adoption. Exhibit 6 highlights some of the key challenges:

  References

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