Does the tissue micro-environment contribute to radiotherapy resistance in breast cancer?

Background Post operative radiotherapy is routinely given to women following breast conserving surgery (BCS) for both ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC) to achieve local control.

However, some patients still experience local recurrences, and in both DCIS and invasive disease this is associated with worse long-term outcomes.

There are currently no good biomarkers that predict radio-resistance in breast cancer but such knowledge would allow dose escalation with radio- sensitising agents in more radioresistant cancers.

It is also likely that the mechanisms of radioresistance are similar in DCIS and IBC as invasive disease is often accompanied by occult DCIS.

We have extensively analysed the intrinsic genomic changes (copy number changes, driver mutations and gene expression generated from laser micro-dissected DCIS) in a large series of primary DCIS with long term follow up and have been unable to identify a signature of recurrence following radiotherapy.

This suggests that the tumour microenvironment (TME) rather than just the intrinsic features of the tumour cells contributes to radiation resistance following radiotherapy.

Aims To analyse the TME in DCIS that has not recurred following BCS and radiotherapy and compare to those cases that have recurred in order to identify a signature of radiation resistance. This will then be validated in two cohorts of IBC.

Methods We plan to generate whole transcriptome data on the TME using the nanoString GeoMx Digital Spatial Profiler on 50 DCIS samples who developed an ipsilateral invasive recurrence despite radiotherapy following BCS (ie: the radioresistant group) and 50 DCIS treated by BCS and radiotherapy that did not develop a recurrence after 10-years follow up.

Any signatures associated with radiation resistance in DCIS will be tested in two independent cohorts of IBC: 200 samples from the KHP biobank, of which 100 have relapsed; and 100 samples from the IMPORT Trials of which 67 have developed an ipsilateral relapse following radiotherapy.

The IMPORT samples also have tissue from the paired recurrence available enabling us able to study the changes that are induced in the TME by radiation and relate this to dose per fraction in the IMPORT-high samples. How the results of this research will be used.

The long-term strategy is to identify a signature of radio-resistance in breast cancer, once preliminary data has been generated this will be used to apply for further funding to validate in different datasets and test within a clinical trial setting.