CCBIO Seminar - Synnøve Yndestad

Speaker: Synnøve Yndestad, researcher at the Department of Clinical Science, UiB
Title: Homology Repair Deficiency in Breast Cancer; Lessons from the  PETREMAC trial
Host: Carina Strell
Where: Auditorium 4, BB-building
When: June 20, 2024 at 14.30-15.30

No registration necessary. 

Abstract: Inactivating mutations in BRCA1/2 disrupts the cells ability to repair double strand breaks by Homologous Recombination Repair (HRR), and tumors without HRR capacity are commonly refered to as beeing Homology Repair Deficient (HRD). HRD causes replication stress and genomic instabilitiy and tumors with HRD therefore have a characeristic genomic scar.

By targeting the repair of single strand breaks by inhibiting PARP, we can induce synthetic letahlity and cell death in cells with HRD. The PARP inhibitor olaparib was approved by the FDA in january 2018 for breast cancer patients with germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. Olaparib has fewer side effects and is better tolerated than chemotherapy, and replacing chemotherapy with olaparib may spare patients from severe side effects.

Germline BRCA-mutations is not the only route to a HRD tumor. Germline mutations in other HRR genes such as PALB2, somatic mutations in HRR genes as well as epigenetic alterations can cause inactivation of HRR genes leading to HRD. The majority of patients suffering from breast cancer with the characterstic HRD genomic scar, does not have a germline BRCA-mutation. This indicates that more patients could benefit from olaparib treatment, and there is a need to identify the exact mechanism that rendes the tumor sensitive to PARP inhibition. 

Triple-Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis that had few treatment options besides chemotherapy before the recent introduction of immunotherapy. TNBC has a high degree of genomic instability and frequently show the genomic signatures associated with HRD.

The PETREMAC trial was a multicenter phase II trial headed from Bergen that included treatment naïve stage II/III breast cancer patients. The patients were stratified to eight different neoadjuvant treatment regimens based on ER, PGR and HER2 expression as well as TP53 mutation status. The TNBC patients were given 10 weeks olaparib monotherapy treatment regardless of germline BRCA1/2 status. Only a minority of theese was found to have germline HRR mutations, but still 56,3% responded to olaparib monotherapy. 
We have explored defects in the HRR pathway in both TNBC and across the other breast cancer subtypes in PETREMAC to pinpoint alterations beyond germline mutations that may predict response to olaparib. We found alterations in a limited number of genes, fulfilling a strict definition of HRR genes to correlate strongly to loss of RAD51 foci, a functional test of HRD. We found that the main driver of HRD in breast cancer across subtypes was not due to germline or somatic mutations, but inactivation of HRR through BRCA1 promoter methylation.