Medical Biology - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemThe role of venetoclax in the treatment of breast cancer( 2023-03)Breast cancer is the most commonly diagnosed cancer in women. The 5-year overall survival for metastatic breast cancer is approximately 30%. Despite rapid developments of new systemic therapies, cancer progression is almost inevitable. Ongoing research about treatment-resistance in breast cancer and mechanisms to overcome this are crucial to improving the lives of women with metastatic disease. Apoptosis is an important process for eliminating cancer cells. The BCL-2 pro-survival proteins and BH3-only proteins are key regulators of cell death. Cancer cells can evade apoptosis through over-expression of the pro-survival proteins. A new class of drug, the BH3 mimetics, inhibit the pro-survival proteins and have undergone extensive investigation in haematological malignancies. These drugs target BCL-2, BCLxL and MCL-1 and have shown promising activity in pre-clinical models. Venetoclax is a BH3 mimetic that specifically and potently binds to BCL-2. Venetoclax has transformed the treatment landscape for BCL-2- positive chronic lymphocytic leukaemia. It achieved fast-track FDA approval due to its success in the clinic. BCL-2 is overexpressed in approximately 70% of oestrogen receptor-positive metastatic breast cancers and approximately 30% of triple negative breast cancers. The aim of this thesis is to investigate the role of venetoclax in the treatment of BCL-2-positive breast cancer. We aim to achieve this through the design and implementation of three phase 1b clinical trials combining venetoclax with standard systemic therapy in the following clinical settings: (1) oestrogen receptor-positive and BCL-2-positive breast cancer in any line of metastatic treatment, (2) oestrogen receptor and BCL-2- positive breast cancer in the early lines of metastatic treatment (1st – 3rd line), (3) metastatic triple negative breast cancer. These clinical trials will firstly explore the safety and tolerability of venetoclax when combined with standard systemic therapy in metastatic breast cancer. Secondly, they will provide data on efficacy, survival and exploratory endpoints that inform future phase II and phase III studies. Findings from these later phase studies would determine whether venetoclax improves clinical outcomes in breast cancer and identify which patient subset might benefit. It is anticipated that due to the rapidly growing drug development in the area of BH3 mimetics, venetoclax may not be the most clinically relevant BH3 mimetic in the future. Therefore our clinical trial protocols could form a basis for future studies that investigate the next generation of BH3 mimetics or novel therapies targeting pro-survival proteins. The mBEP phase Ib clinical trial treated women with oestrogen receptor-positive and BCL-2-postive breast cancer in any line of metastatic treatment. This is the only study forming my thesis that has reached the primary and secondary endpoints. mBEP showed that the combination of tamoxifen and venetoclax was safe and tolerable. Secondary endpoints have confirmed that there is no adverse survival outcome from the addition of venetoclax to standard of care endocrine therapy.