Combination Therapy with Trastuzumab and Niraparib: Quantifying Early Proliferative Alterations in HER2+ Breast
Ameer Mansur1, Patrick N Song2,3, Yun Lu2,3
1Department of Biomedical Engineering, The University of Alabama, Birmingham, AL 35233, USA.
Abstract:
HER2-targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2-targeted therapies, have demonstrated sensitivity to poly-(ADP-ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2- breast cancer cells. Further, we evaluated the utility of 3'-Deoxy-3'-[18F]-fluorothymidine positron emission tomography ([18F]FLT-PET) imaging for early response assessment in a HER2+ patient derived xenograft (PDX) model of breast cancer. In vitro, we observed decreased cell viability. In vivo, we observed decreased inhibition in tumor growth in combination therapies, compared to vehicle and monotherapy-treated cohorts. Early assessment of cellular proliferation corresponds to endpoint cell viability. Standard summary statistics of [18F]FLT uptake from PET were insensitive to early proliferative changes. Meanwhile, histogram analysis of [18F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [18F]FLT-PET quantification in heterogeneous models of HER2+ breast cancer.
Insights
Combining trastuzumab with poly-(ADP-ribose) polymerase (PARP) inhibitors shows promise for HER2+ breast cancer. Early [18F]FLT-PET imaging may track treatment response, but requires optimized quantification for heterogeneous tumors.
Area of Science:
- Oncology
- Molecular Biology
- Radiochemistry
Background:
- HER2-targeted therapies improve survival in HER2+ breast cancer but face resistance.
- Poly-(ADP-ribose) polymerase (PARP) inhibitors show efficacy in HER2+ breast cancer, independent of DNA repair status.
- Understanding early biological changes is crucial for optimizing combination therapies.
Purpose of the Study:
- To investigate biological factors preceding cell viability changes with combined trastuzumab and PARP inhibition.
- To evaluate 3'-Deoxy-3'-[18F]-fluorothymidine positron emission tomography ([18F]FLT-PET) for early response assessment in HER2+ breast cancer models.
Main Methods:
- In vitro and in vivo evaluation of treatment response in HER2+ and HER2- breast cancer cells.
- Utilizing patient-derived xenograft (PDX) models for in vivo studies.
- Assessing cellular proliferation using [18F]FLT-PET imaging.
Main Results:
- Combination therapy decreased cell viability in vitro and inhibited tumor growth in vivo.
- Early cellular proliferation changes correlated with endpoint cell viability.
- [18F]FLT-PET histogram analysis showed potential for imaging proliferation biomarkers, though standard metrics were insensitive.
Conclusions:
- Combined trastuzumab and PARP inhibition is a potential therapeutic strategy for HER2+ breast cancer.
- Optimization of [18F]FLT-PET quantification is needed for heterogeneous HER2+ breast cancer models.
- Early proliferation imaging may predict treatment response.
