Breast Cancer: Early diagnosis using materials immortalisation

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.

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.

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.