Breast Cancer: Early diagnosis using materials immortalisation

Lead Research Organisation: CRANFIELD UNIVERSITY
Department Name: Cranfield Defence and Security


Within the UK there are >55000 new cases of breast cancer diagnosed every year (world-wide >1.7 million) and the economic cost of breast cancer to the UK is >£1.5bn per annum. Early and accurate diagnoses are critical for the most effective treatments and reduced costs. Current diagnostic inadequacies are characterised by (i) an >80% false positive rate for mammography, (ii) significant overtreatment of some breast cancers, and, (iii) equivocal histopathology leading to uncertain prognoses.

This proposal will generate a new understanding of the physicochemistry of involved tissues and, as a result, will identify potential new biomarkers and diagnostic methods. We will adopt a new, multidisciplinary approach to disease diagnosis, and combine the expertise of senior clinicians with material scientists to study tissue physicochemistry. We will also exploit a distinct, retrospective approach to sampling that will enable access to unprecedented patient numbers. Successful outcomes from this work will have significant impacts for understanding disease and development of accurate breast cancer diagnostics.

Calcifications within breast tissues are used as a primary marker of malignancy although the precipitation mechanism of biologically derived calcifications remains a matter of considerable debate. In contrast, the capacity of apatites to incorporate 'foreign', environmental ions at the time of precipitation is incontrovertible. Thus chemical features of tissue physiology at the point of formation become immortalised within calcifications. Precipitation of calcific phases in vivo is triggered by slight modifications to tissue chemistry and this, in the case of breast tissue, occurs at the very onset of the cancer.

Our primary hypothesis then is that apatite calcification physicochemical characteristics may be employed as novel biomarkers of cancer. The primary aim of this project is to determine and understand the underpinning physicochemical characteristics of breast tissue calcifications to enable future development of in vivo, accurate diagnostic probes. The project will (a) identify archived specimen populations representing a wide range of tumour subtypes for material analyses, (b) exploit cutting edge physical methods of high resolution calcification characterisation and, (c) relate calcification physicochemistry to clinical diagnosis and prognosis.

Successful outcomes from this work will have significant impacts for understanding disease and development of accurate breast cancer diagnostics.

Technical Summary

Breast cancer remains a major cause of cancer death, with more than 11,500 deaths per year in the UK, despite advances in detection and treatment. Improvements in both early diagnostic and prognostic methods are required, not only to reduce breast cancer mortality, but also to reduce the large number of unnecessary interventions resulting from overdiagnosis and also address the very poor positive predictive value of screening.

A primary marker for malignancy is the particular morphological and distributive nature of microcalcifications observed through mammography. However, little is known definitively about the natural history, chemistry or microstructure of these ectopic precipitates. A common consensus is that both oxalates and apatites form two major groups ('type I' and 'type II' respectively). However, in contrast to the somewhat stolid and phlegmatic oxalates, apatites have extremely flexible molecular structures that are able to accommodate high levels of foreign cations and anions. This enigmatic material then, has the inherent ability to immortalise chemical features of the microenvironment/tissue in which it precipitates, and is thus potentially a rich target for novel biomarkers.

This proposal builds on pilot studies that have demonstrated correlations between chemical characteristics of breast calcifications and tumour type. We will adopt a multi-analytical, retrospective examination of tumour subtypes to generate a new understanding of the materials physicochemistry of calcifications. As a result, we expect this will identify important new biomarkers that will ultimately enable in vivo (at the mammography stage), novel diagnostic methods capable of high accuracy identification of breast cancers.

Planned Impact

The ultimate goal of this research is to provide clinicians with a new in vivo tool for the diagnosis and prognosis of breast cancers. This will be applied at the same diagnostic point as mammography and will prevent large numbers of unnecessary invasive procedures and surgeries. Thus groups who will directly benefit include:

> Patients (there are >55000 new cases of breast cancer diagnosed annually in the UK) who will receive a more rapid and accurate diagnosis without the requirement for subsequent invasive biopsies,

> Patients diagnosed with breast cancer who have equivocal prognoses as our approach will produce a test with enhanced outcome prediction,

> Clinical teams that will have resources released through more efficient and reliable evidence based patient management intelligence,

> The NHS will benefit through cost savings (the economic cost of breast cancer to the UK is >£1.5bn per annum),

> Medical diagnostic companies that will exploit the intellectual property generated and thus will create jobs, enhance business revenues and significantly increase exports from the UK.

Potentially, tracking the physicochemistry of breast tissues in response to the onset of cancer (the aim of the project) will lead to a better understanding of fundamental physiological processes. Full advantage of this could be taken by researchers (and ultimately patients) such as:

> Those examining calcifying tissues associated with other cancers (e.g. ovarian and prostate cancer) where similar new biomarkers could be identified and exploited,

> Those searching for new cancer therapies who may consider exploiting the potential active role of calcification in the tumour development and spread,

> Those exploring processes and conditions found within aging populations such as osteoporosis where the micro-characterisation tools being developed within our proposal may find utility in revealing local mineral modifications.

More immediate beneficiaries are other research groups who are currently studying breast cancers in terms of enhancing diagnostics. For example, our proposal involves the identification of new and accurate biomarkers and these will form the basis of diagnostic probes for these other groups. We also recognise that the researchers involved with this project will benefit from the enhanced networking and training provided throughout the work. In particular, we are very confident that the PDRA careers will benefit from this project as they will be in demand to move the work forward to subsequent stages. We have clear impact goals to take full advantage of the outcomes from this project, both in the short and mid-terms. These are described with the proposal.


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Arnold E (2022) Thermally dynamic examination of local order in nanocrystalline hydroxyapatite in Journal of Solid State Chemistry

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Bouzy P (2021) A time-course Raman spectroscopic analysis of spontaneous in vitro microcalcifications in a breast cancer cell line. in Laboratory investigation; a journal of technical methods and pathology

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Gosling S (2019) Calcification Microstructure Reflects Breast Tissue Microenvironment. in Journal of mammary gland biology and neoplasia

Description Multimodality X-ray transmission and diffraction scanner for molecular analysis of cancer specimens
Amount £800,000 (GBP)
Funding ID 7R33CA256102-02 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2022 
End 04/2024
Description Prostate Cancer: High Accuracy Early Diagnosis based on Tissue Microenvironments
Amount £99,993 (GBP)
Funding ID EDDPMA-May21\100010 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2022 
End 06/2023
Description Calcification diagnostics 
Organisation Gloucestershire Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Provide technical input
Collaborator Contribution Developed a new research area
Impact several publications
Start Year 2007
Description Combined Raman and X-ray Scattering 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution We are contributing the data, skills and knowledge from the EPSRC grant to a new consortium.
Collaborator Contribution This is a new consortium that has evolved during the past 2 months. It is designed to realise the findings from two EPSRC funded research grants and combine the outputs of both studies into a single progressive grant with significant added value.
Impact The initial output from the consortium will be an EPSRC grant submission due to occur in 2017.
Start Year 2017
Description Duke Diagnostic Imaging 
Organisation Duke University
Country United States 
Sector Academic/University 
PI Contribution Duke University have a research team that is developing a new imaging modality for rapid examination of tissue specimens, including bone. Duke approached the Cranfield team to discuss how Cranfield's expertise in interpretation of X-ray scatter data from bone may be used for diagnostics. Thus Cranfield provides the data interpretation component of this collaboration.
Collaborator Contribution Duke University have been using a novel imaging approach by exploiting coded apertures to provide rapid, high resolution, depth resolved imaging based upon transmission X-ray imaging and orthogonal scattering data (e.g. James R. Spencer, Joshua E. Carter, Crystal K. Leung, Shannon J. McCall, Joel A. Greenberg, and Anuj J. Kapadia "Coded aperture coherent scatter spectral imaging for assessment of breast cancers: an ex-vivo demonstration", Proc. SPIE 10132, Medical Imaging 2017: Physics of Medical Imaging, 101324K (9 March 2017); This recently resulted in the first prototype that has been placed (Feb 2020) within a clinical Pathology Department for a full evaluation.
Impact The collaboration is a little early to have produced any definitive outputs. However, in collaboration, an NIH grant was submitted (Feb 2020) to support the work through its next stages. This is a multi-disciplinary collaboration with contributions from the physics community (understanding the optical features of the instrument), medical physics (providing an interface to the clinical community), crystallography (signal interpretation) and medicine (providing tissue specimens and clinical direction).
Start Year 2019
Description NISTA Diagnostics 
Organisation Nista Diagnostics
Country United States 
Sector Private 
PI Contribution Our team is providing a component of the technical support to enable proper interpretation of data.
Collaborator Contribution This is a new collaboration that started in Oct 2019. This new US medical diagnostics company Nista Diagnostics Inc, are attempting to augment the pathological assessment of biological tissues through the use of X-ray scattering to examine a wide range of conditions. Nista made an approach to the Cranfield team as they were aware of the work we had been undertaking on osteoporosis and disease in other tissues. Nista have requested that the Cranfield team undertake all the essential 'up-front' work to commence a small clinical trial within the UK at two Centres and then manage the trials. The networks formed as a component of the EPSRC grant have enabled this to be undertaken quickly and we hope to be starting the trials within 2020.
Impact This is a commercial, multidisciplinary collaboration that is within early gestation stages, hence there are no definitive outputs as yet.
Start Year 2019
Title Convergent FCG Probe 
Description This invention is based upon a convergent focal construct geometry and, in the first instance, will be exploited as a virtual biopsy probe to replace the need for conventional, invasive biopsy procedures. It will be developed from proof of concept with research monies currently being applied for. 
IP Reference  
Protection Patent application published
Year Protection Granted 2021
Licensed No
Impact The patent was filed in 2021 and the proof of concept work has yet to be undertaken.
Title SMALL. Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screen-detected breast cancers 
Description Funded by the NIHR HTA programme, award 17/42/32 Phase III multicentre randomised trial comparing surgery with vacuum assisted excision (VAE) for screen-detected good prognosis cancers. Co-I on MRC-Capture is a Co-investigator and is providing knowledge from the MRC-Capture grant to this trial. Also a member of the Trial Management Group and provides expert central opinion on imaging regarding adequacy of excision for national sites as of February 2023, 231 patients had been recruited from 32 centres. 
Type Support Tool - For Medical Intervention
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2022
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 17/42/32
Impact None 
Description Cancer Grand Challenges Virtual Summit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A Poster (virtual): Multimodal characterization of microcalcifications for prediction of DCIS progression presented at the CRUK Cancer Grand Challenges Virtual Summit 2022.
Year(s) Of Engagement Activity 2022
Description Champalimaud Research Symposium 2022 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster (virtual): X-ray and spectroscopic investigation of the prostate cancer tissue environment presented at the Champalimaud Research Symposium 2022: Tumour Microenvironment - from cancer initiation to metastasis
Year(s) Of Engagement Activity 2022
Description Denver X-ray Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Oral presentation at the Denver X-ray Conference : Identifying disease biomarkers through X-ray diffraction of breast calcifications (Robert Snyder Student Travel Award winner)
Year(s) Of Engagement Activity 2022
Description Research4Gloucestershire 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Research4Gloucestershire is hosting the first Gloucestershire Festival of Health and Social Care Research. This month-long event will see a range of digital and in person research workshops, seminars, and panel discussions; focusing on the themes of Digital Transformation, Research for Public and Patient Benefit, Mental Health, and Workforce.
Presentations are to be followed by a workshop for attendees focusing on how collaboration may be achieved across Gloucestershire to develop a community of research that will support the health and wellbeing for people in Gloucestershire.
The event is targeted towards Health and Care Professionals from all disciplines, and students in a Health and Social Care subject at the University of Gloucestershire.
Year(s) Of Engagement Activity 2023
Description STEM for Britain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact STEM for Britain poster competition. Poster: Using X-rays to understand breast cancer presented to diverse audience.
Year(s) Of Engagement Activity 2022
Description The enigmatic breast microcalcification 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a scientific article written by the research team for practitioners to raise the profile of breast calcification impacts. The 'RadMagazine' is taken by Radiology Departments throughout the UK and beyond and, as such, is read by thousands of practicing Radiologists and Radiographers. The article was published in January 2023.
Year(s) Of Engagement Activity 2023