Could microcalcification crystallography help to predict which DCIS cases might progress to invasive breast cancer?

DCIS is the presence of abnormal but non-invasive cells in the breast milk ducts. In a small number of DCIS cases, the abnormal cells can break out of the milk ducts and become invasive breast cancer.

Although DCIS has a low risk of becoming invasive breast cancer, there is currently no way to accurately predict the cases that will progress to cancer, and those that won’t. As a result, treatment – that may include surgery, radiation and hormone therapy – is generally recommended for all cases.

To combat overtreatment in DCIS, the PRECISION team is working to identify biomarkers that can distinguish between people with high-risk DCIS who require treatment from those who could safely consider an active-monitoring approach.

In a recent study, led by PRECISION collaborator Professor Keith Rogers of Cranfield University, UK, researchers used X-ray crystallography and electron microscopy to analyse DCIS microcalcifications – small deposits of calcium that show as white specks on a mammogram and are seen in most DCIS cases.

They hypothesised that the features of the microenvironment in DCIS that promote invasion may be immortalised within the chemical makeup of the microcalcifications and subsequently retrieved as crystallographic biomarkers of disease progression.

“Our primary aim was to be able to differentiate between patients who had had DCIS, without having any kind of recurrence, and those that had recurrence after their initial DCIS diagnosis.” 

Dr Sarah Gosling, Cancer Grand Challenges Future Leader and postdoctoral researcher at Keele University, UK.

Sarah conducted the research during her PhD in Keith’s laboratory at Cranfield University.

“We did this by looking at the calcifications present in samples of DCIS – looking at what they’re made of, the structure of the things that they’re made of, and whether there’s actually differences that we can identify between the two patient groups. The exciting bit of the research is that we did find differences, and we were able to build these differences into a model of whether or not patients would recur.”

 

They analysed 353 microcalcifications in total, isolated from breast tissue samples of 124 people with DCIS either with no known recurrence or with ipsilateral (same breast) invasive breast cancer recurrence.  

The researchers found significant differences in the size, crystallographic features and chemistry of the microcalcifications between the two groups, including the crystal maturity of the mineral hydroxyapatite, the relative mass of the mineral whitlockite, the crystallinity (level of order within the crystal) of whitlockite and, elementally, the sodium to calcium ion ratio.

On average, ipsilateral invasive recurrent microcalcifications were about 33% larger than the microcalcifications of the non-recurrent group. With regards to the crystal properties, hydroxyapatite crystals in the invasive group were more mature with higher crystallinity than those in the non-recurrent group. The relative mass of whitlockite was significantly lower in the invasive group than in the non-recurrent group. The sodium to calcium ion ratio was lower in the non-recurrent group.

Using 11 crystallographic and elemental features, the team built a predictive model of DCIS upstaging. The performance of the model was similar to that of a radiologist’s performance analysis to predict DCIS upstaging.  

Although this work is not immediately applicable to the clinic, the researchers hope that in the future crystallographic features of microcalcifications could be used as biomarkers to complement existing analyses of breast mammograms, to assist with risk stratification in DCIS.

Read the full paper in Scientific Reports.

The PRECISION team is supported by Cancer Research UK and the Dutch Cancer Society.

Image: Scanning electron image of a single DCIS calcification, taken by Dr Sarah Gosling.