Triple negative breast cancer research project

Investigators: Professor Shani Paluch Shimon, Professor Bella Kaufman and Dr. Maya Dadiani Sheba Medical Center, Israel

Background
The most aggressive subtype of breast cancer is termed “triple-negative “(TNBC), as these tumours lack three common proteins that respond to targeted therapies. The only treatment option for these patients is standard chemotherapy. Unfortunately, women diagnosed with breast cancer at an early age are more likely to have triple negative breast cancer, as are women who harbor a genetic mutation in BRCA gene. This project started with clinical observations that indicated that while BRCA-associated TNBCs are considered highly sensitive to chemotherapy this chemo-sensitivity doesn’t appear to translate into a survival benefit [1]. This is in stark contrast to TNBC BRCA-non-carriers, for whom a complete response following pre-surgery therapy is an established surrogate for improved survival.

Hypothesis
One plausible explanation for this tumour response/lack of improved outcome paradox could be accounted for by differences in cancer stem cells or progenitor cells between BRCA-associated and BRCA-WT tumours. Cancer stem cells are rare immortal cells within a tumour that can self-renew by dividing and are often resistant to chemotherapy. Cancer stem cells are considered an important mechanism for treatment resistance and relapse. Recent studies demonstrated an expanded progenitor cells [2][3] population associated with BRCA1 mutation. This a priori aberrant population in BRCA carriers can lead to increased rate of self-renewal of the genetically unstable breast stem cells post chemotherapy.

Aim of the project
The project goal was to decipher the incongruence between chemo-sensitivity and survival benefit in BRCA-associated TNBC. For this purpose, the translational breast cancer research group at Sheba Medical Centre focused on characterizing the cancer stem cells populations in TNBC tumours comparing survival parameters between BRCA-carriers and non-carriers. The study focused on a retrospective cohort of 83 TNBC patients treated at Sheba Medical Centre between 2002 and 2015.

Results
The results have important prognostic implications as well as potential therapeutic implications for targeting the resistant stem cell population in TNBC patients.