Prevention of breast cancer in high risk women by monitoring microrna expression in nipple aspirate fluid.

Breast cancer develops by the stepwise accumulation of interacting epigenetic
and genetic events over time. While genetic events are specific processes that
differ greatly between patients, epigenetic events are more generally occurring
in breast cancer development. Therefore, epigenetic monitoring (in addition to
genetic monitoring) could be a breakthrough in breast cancer screening and
prevention. Gene promoter hypermethylation has been described as a common
epigenetic mechanism to silence tumor suppressor gene expression adding to
breast cancer development. Another system that is currently considered to
initiate and sustain epigenetic change is miRNAs. miRNAs are small
non-protein-coding RNA molecules, which can play important regulatory roles in
posttranscriptional gene expression.

In women at high risk, not all women will develop breast cancer. Diagnostically
there is a need for better procedures that will predict accurately who will and
who will not develop breast cancer. In a previous study, we showed significant
differences in methylation levels between NAF from cancerous breasts and NAF
from healthy controls. Differences in methylation were however not large enough
to warrant further studies to work towards a clinically useful test. This was
especially true for the comparison between the affected and the non-affected
breast of the same patient, which is of crucial relevance in view of our
objective to implement NAF as a new screening method. Therefore, we aim to
assess the occurrence and changes over time of microRNA expression patterns in
nipple aspirate fluids of women at high risk for breast cancer to determine
risks and correcting timing of interventions.

Furthermore, blood samples will be taken to identify biomarkers of breast
cancer in blood.

To establish biomarkers in nipple aspirate fluid, follow them in time and link
them to breast cancer development at its earliest stage in women at high risk
for breast cancer. Threshold values of biomarkers will be determined that point
to a significant risk of imminent breast cancer development, thereby indicating
the right time of prophylactic breast surgery in these high-risk women.

Annual nipple aspiration is performed on women at high (>20% lifetime) risk for
breast cancer for ten years

A one time dose of 4 IE oxytocin nasal spray is adminstered prior to the nipple
aspiration procedure. Nipple fluid is obtained through use of a vacuum system.
In women at increased breast cancer risk blood will be collected (2 tubes for
serum, 1 tube for plasma) to storage in the Biobank.

This project aims to set up a program to monitor development of molecular
biomarker changes in nipple aspirate fluid to optimally time preventive breast
surgery in women at high risk of developing breast cancer. The ultimate goal is
to provide a new screening method in this high-risk population, with a > 20%
life-time risk of developing breast cancer. This will allow on one hand
postponing or avoiding a mutilating operation as much as possible (reducing
morbidity), while on the other hand development of invasive breast cancer will
be prevented (reducing mortality). Oxytocin-supported nipple fluid aspiration
is very well tolerated as has been demonstrated in our previous study.