In spite of advances in the diagnosis and treatment of breast cancer, it still continues to be a predominant cause of death among women all around the world. Early detection is imperative to have a control over the pain and emotional impact, and also to improve survival rates and lessen the healthcare burden. Hence, as much as the scientists are trying for a possible cure, an equal effort is also going into developing efficient standalone or adjunct early detection modalities and to reduce healthcare costs.  There is a need for better access to screening technologies.

There are many breast imaging systems available in the market to facilitate diagnosis of breast abnormalities. Some of them are used for screening, some are used for diagnosis, and some are used for adjunctive evaluation.  Some are too limited and expensive for screening.  Below is a brief summary of the pros and cons of the available technologies:

Mammography (MMG)

  • Most widely used imaging modality
  • Good cancer detection accuracy in fatty breast tissue
  • Effective in detecting microcalcifications, but limited in cases of dense breasts due to opacification
  • Use of ionizing radiation
  • Discomfort during breast compression
  • Reduced cancer detection accuracy in dense breasts
  • Reduced usage in young women
  • Subjective interpretation based on radiographer experience

Ultrasound

  • No ionizing radiation
  • No breast compression
  • Microcalcifications are not easily visualized
  • Subjective interpretation based on radiographer experience
  • Very Expensive, very time consuming, not approved for general screening

Magnetic Resonance Imaging

  • No ionizing radiation
  • No breast compression
  • High sensitivity
  • Microcalcifications are not easily visualized
  • Time consuming, not approved for general screening
  • Long acquisition time
  • Requires patients to remain still during the scan as images are susceptible to motion artefacts
  • Expensive
  • Less specificity

Breast Thermography

  • No ionizing radiation
  • No breast compression
  • One-time thermal image of the breast tissue
  • Accuracy is highly dependent upon the operator and interpretations are difficult and are of limited value
  • Stable indoor environment with ambient temperature and humidity conditions are vital for good accuracy
  • Does not take into account the chaotic fluctuations of skin surface temperature over a period of time that is important for better interpretation

*Breast Density Challenge*

Dense Breast Tissue (DBT) makes mammography hard to read.  Over 40% of women have DBT, which leads to missed cancers that are discovered at later stages, resulting in more invasive treatments and a poor prognosis. Women with higher density breast tissue are considered to have a higher risk of breast cancer. Recently, the FDA proposed specific language that would explain how Breast Density can influence the accuracy of mammography.     

What is needed?

  • An adjunct modality for effective breast health monitoring to detect breast tissue abnormalities early
  • Tissue density independent solution
  • Suitable for use by young women
  • Radiation-free
  • Comfortable and easy to use
  • Affordable
  • Non-invasive

Cyrcadia Health has developed such an adjunct solution for breast cancer screening called the AprisTM TM (formerly known as the Circadian Biometric Recorder (CBRTM TM)

Scientific Background

The global impact of breast cancer is huge and is increasing. According to the Global Cancer Observatory (GCO) and the International Association of Cancer Registries (IACR), breast cancer is the second most common cancer in the world and the most frequent cancer among women [1].  Therefore, for better survival rate and less aggressive treatments, it is important to detect any abnormal changes in the breast tissue early.

In breast tissue, local circadian clocks function to modulate cellular activity.  In abnormal breast tissue, changes in gene expression patterns, intrinsic factors such as genetic defects or ageing, and extrinsic factors such as irregular shift work disrupt the cell cycle, promoting angiogenesis [2]. Angiogenesis is the biological process that stimulates growth of new blood vessels from pre-existing vessels. An impact of these changes is the disruption of the circadian clocks in breast tissue cells [2,3]. Changes in the body’s central circadian clock modify otherwise normal circadian rhythms (a 24-hour cycle in the biochemical, physiological, or behavioral processes of living entities) [3].

Also, some of these new blood vessels that form due to the process of angiogenesis lack smooth muscle, and hence, do not respond to normal physiological control mechanisms like vasodilation and vasoconstriction [4,5]. This lack of vascular receptivity leads to a more constant blood flow in the abnormal area which alters the skin temperature circadian rhythm [4].

Cyrcadia Health has developed AprisTM which is a non-invasive, non-compressive and non-radiogenic wearable system that captures these thermo-circadian rhythm alterations over a period of time (four-dimensional system) to detect any early breast tissue abnormalities.

References

  • 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
  • 2. Blakeman V et al.  Circadian Clocks and Breast Cancer.  Breast Cancer Res.  2016; 18(1): 89.
  • 3. Keith LG, Oleszczuk JJ, Laguens M. Circadian rhythm chaos: a new breast cancer marker. Int J Fertil Womens Med 2001; 46(5):238-247.
  • 4. Farrar WB, Patricia R, Sexton RN, Marsh W, Olsen J. Scientific exhibit presented at the 76th Annual clinical congress of the American college of surgeons. San Francisco, California; An evaluation of a new objective method for breast cancer screening. October 8–11, 1990.
  • 5. Filho AL, Lopes JM, Schmitt FC. Angiogenesis and Breast. J Clin Oncol 2010.Technology

AprisTM uses a pair of wearable conformable patches, one for each breast. Each patch has eight embedded digital temperature sensors that transmit temperature data to a Bluetooth enabled Data Recording Device (DRD). In order to be able to be used in all patient population, the patches are available in six different sizes.

To ensure that the system is able to handle large volumes of incoming patient data and report the results back to the user directly, AprisTM TM utilizes a cloud-based back-end architecture. Cybersecurity and patient privacy are critical issues for devices connected to the internet, and so, the architecture was developed using Microsoft Azure which has passed the strict global data security and privacy regulations.

The DRD stores the measurement data until a local Bluetooth connection can be established with a smartphone (or similar Internet enabled device) which has the Cyrcadia Mobile Application (App) installed. The App receives the recorded data and transfers it to the Local Data Manager for storage and for further transmission to the Core Lab where Cyrcadia’s proprietary patented analytics framework resides. In the Core Lab, the data is analyzed, and the results are sent back to the Local Data Manager and also stored in the Core Lab Central Database. The Local Data Manager reports the results back to the App and the prescribing physician who can then discuss the results with the patient.

Clinical Trials

Initial Clinical Studies

The initial phase I, II and population studies were conducted at three centers – Clem Plam Breast Clinic, La Plata, Argentina, Ohio State University (OSU) and Green Memorial Hospital (GMH), Ohio. In a preliminary analysis using data from the patients enrolled at OSU, it was observed that the system had a sensitivity of 91% (21 out of 23 cancers were detected), whereas the sensitivity of mammography was 83%. It was concluded that “the term ‘false positive’ should be used with caution since the system was positive for three cancers missed by mammography which were either from premenopausal or peri-menopausal women with dense parenchyma, with tumor sizes as small as 0.5 cm as well as micro-calcifications. Patient data which are positive on the system in the absence of mammographic or physical evidence of cancer does not preclude the presence of cancer at its earliest stages. These patients may be considered at “high risk” for the disease which may become clinically evident at a future date.”

Another analysis was conducted with data from all three hospitals. After removing outliers (data affected by loose sensors and out-of-range values), the final dataset had 93 benign and 108 malignant samples. These samples were used for building Cyrcadia’s proprietary patented analytics framework. An accuracy of 78%, sensitivity of 83.56%, and specificity of 71.53% were obtained using this analytics framework. Accuracy is defined as the percentage of benign and malignant samples identified correctly. Sensitivity is defined as percentage of malignant samples correctly identified as malignant by the system, and specificity is the percentage of benign samples correctly identified as benign.

Pilot Studies for AprisTM TM Validation

A pilot study of 173 patients was designed to validate the results of the initial studies. Enrollment happened at El Camino Hospital, Mountain View, CA and Ohio State University’s James Cancer Hospital, Columbus, Ohio. 66 patients have been enrolled so far, and 47 patients had valid data recordings. An interim analysis was conducted on these samples. An accuracy of 81.82%, sensitivity of 100%, and specificity of 75% were observed.

Updated analytics 

In the first-generation system used in the initial clinical studies, temperature data was acquired at a five-minute sampling rate for 24 hours. The updated second-generation system had the capability of sampling every 10 seconds. In order to verify if the higher sampling rate of 1 minute resulted in getting similar or better accuracies at a lowered wear time of 2 hours, several analytical experiments were conducted on the data from the pilot studies. An analytical model that can work on 2 hours at 1-minute sampling rate data was developed. This model resulted in a higher accuracy of 84%, sensitivity of 90.16%, and specificity of 84%.

Performance in dense breasts

Among the 47 women enrolled so far in the pilot studies, 28 were identified as having dense breast tissue.  Of the 28 women with dense breasts, seven were confirmed through biopsy and corresponding histological analysis to have malignant lesions.  Cyrcadia’s technology (2-hour @ 1 min model) accurately identified malignancy in 6 of the 7 cases (85.7%). However, mammography had categorized only 3 out of these 7 cases as BI-RADS 5 (42.9%).  This is important considering women with dense breast tissue represents up to 40% of the population.   

AprisTM can Change Breast Cancer Monitoring!

  • A unique wearable technology that measures thermo-circadian rhythm alterations in skin surface temperature over a period of time (four-dimensional system: time, temperature, sensor X and Y locations)
  • Adjunctive solution to current accepted imaging technologies 
    • If positive on AprisTM, recommend mammogram/ultrasound
    • If lesion is not visible yet, recommend close monitoring and continue life style changes based prevention
  • Dense tissue screening alternative for female population
  • A good screening alternative for young women
  • Additive screening source to reduce unnecessary biopsies
  • Cost-effective
  • Suitable for mass screening in low income countries
  • Non-invasive

AprisTM can Change How Women Manage their Breast Health!

  • Private, home based breast screening data collection, no need to travel to the clinic for testing
    • earliest possible detection as it allows for women to start using in their 20s
    • better alternative to monthly self-exams
  • Easy to use, non-compressive, non-irradiative
  • Automated discrete physician alert about early abnormalities
  • Connected health to physician, family and friends ensures routine use
  • Non-invasive