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Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies
Marilyne Labrie1,2, Allen Li3, Allison Creason4
1Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. labriem@ohsu.edu.
Abstract:
In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.
Insights
This study explored how triple-negative breast cancer (TNBC) adapts to poly-ADP-ribose polymerase inhibitors (PARPi). Identifying emergent resistance mechanisms can guide personalized combination therapies for better patient outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Triple-negative breast cancer (TNBC) presents significant treatment challenges.
- Mechanisms of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) in TNBC are not fully understood.
- Tumor-immune microenvironment interactions are crucial in cancer progression and treatment response.
Purpose of the Study:
- To assess the feasibility of real-time deep analysis of serial tumor samples from TNBC patients.
- To identify emerging mechanisms of resistance and therapeutic opportunities during PARPi treatment.
- To correlate tumor and immune state changes with response to PARPi.
Main Methods:
- Pilot study involving serial tumor sample analysis from TNBC patients undergoing PARPi therapy.
- Deep analysis of tumor protein networks and immune cell infiltration.
- Comparison of molecular profiles between an exceptional responder and a rapid progressor.
Main Results:
- An exceptional responder with BRCA-mutant basal breast cancer showed significant tumor destruction and CD8 effector cell infiltration, linked to STING-mediated immune activation.
- Tumor cells in the exceptional responder exhibited extensive protein network rewiring under PARPi.
- A rapid progressor with luminal androgen receptor breast cancer displayed minimal changes, indicating indifference to PARPi.
Conclusions:
- Real-time analysis of serial tumor samples can reveal emergent resistance mechanisms to PARPi in TNBC.
- PARPi treatment can induce significant changes in tumor cell networks and the immune microenvironment, influencing treatment response.
- Identifying these emergent changes enables the selection of patient-specific combination therapies for improved outcomes.
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