CAPTURE: A NEW APPROACH TO BREAST CANCER DIAGNOSIS
BACKGROUND
TUMOUR SUBTYPES
Breast cancer is very heterogeneous, with tumour subtypes varying greatly in histological appearance and prognosis. Verification of any proposed relationship between calcification physicochemistry and malignancy needs to address this heterogeneity by evaluating a broad spectrum of specimens. Prospective studies using fresh specimens inevitably involve slow recruitment and haphazard coverage of subtypes, as some are particularly uncommon. In addition, there are ethical limitations in sampling of fresh tissue destined for pathology assessment. This has implications for the inclusion of small tumours that are all required for diagnosis and prognostication and cannot therefore be included in such studies. In contrast, our approach uses pathology archives that offer a rich source of material for research, allowing systematic selection of subtypes, and exploration of the universality or limitations of calcification composition as a diagnostic aid and prognostic indicator.
Right Image: Image depicting breast cancer progression. Adapted from https://www.saintjohnscancer.org/breast/breast-cancer/types-of-breast-cancer/
TECHNOLOGY
In preliminary studies, we have developed unique methods for systematically locating calcifications within 5 µm sections cut from archive tissue blocks, and for the first time, made quantitative measurements of breast calcification elemental composition. These have shown, for example, significantly elevated sodium content in calcifications associated with malignancy, which is consistent with tissue sodium MRI measurements in breast cancer, and the observation that intracellular levels of sodium are elevated within tumour cells. Moreover, we have also developed methods for obtaining high quality X-ray diffraction measurements from calcifications within these histological sections, which have revealed clear differences in precipitation conditions in benign and malignant tissue. These are exciting preliminary results but specimen numbers were low, subtypes limited and no complementary or corroborative spectroscopic measurements were undertaken. In order to build towards clinically exploitable tests, it is necessary to measure a broader range of specimens covering a range of lesion and tumour subtypes, and a wider array of minor and trace elements. Left Image: 5 µm breast tissue section mounted in a bespoke sample holder.
CALCIFICATION PHYSICOCHEMISTRY & CLINICAL IMPLICATIONS
Calcification chemistry may also be important indicator of the propensity of a tumour to metastasize. Bone is the most frequent site for metastasis in breast cancer (particularly forms such as the most common oestrogen receptor positive tumours), and the term “osteomimicry” has been adopted to describe the way in which tumour cells can enhance their ability to survive and multiply in bone tissue by acquiring a bone-cell-like phenotype. Measurement of calcification composition and crystallographic properties may indicate whether these calcifications are the products of osteoblast-like metastasis-ready tumour cells. To test this hypothesis, we will relate measured calcification properties directly to long-term patient outcome, with particular reference to bone metastasis.
Right Image: Positron emission tomography (PET) image highlighting a tumour in the left breast of the patient.
