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Breast cancer brain metastases genomic profiling identifies alterations targetable by immune-checkpoint and PARP
A Giannoudis1, E S Sokol2, T Bhogal1,3
1Institute of Systems, Molecular and Integrative Biology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
Abstract:
Understanding the genomic landscape of breast cancer brain metastases (BCBMs) is key to developing targeted treatments. In this study, targetable genomic profiling was performed on 822 BCBMs, 11,988 local breast cancer (BC) biopsies and 15,516 non-central nervous system (N-CNS) metastases (all unpaired samples) collected during the course of routine clinical care by Foundation Medicine Inc (Boston, MA). Clinically relevant genomic alterations were significantly enriched in BCBMs compared to local BCs and N-CNS metastases. Homologous recombination deficiency as measured by BRCA1/2 alteration prevalence and loss-of-heterozygosity and immune checkpoint inhibitor (ICI) biomarkers [Tumor mutation burden (TMB)-High, Microsatellite instability (MSI)-High, PD-L1/L2)] were significantly more prevalent in BCBM than local BC and N-CNS. High PD-L1 protein expression was observed in ER-negative/HER2-negative BCBMs (48.3% vs 50.0% in local BCs, 21.4% in N-CNS). Our data highlights that a high proportion of BCBMs are potentially amenable to treatment with targeted therapeutic agents including PARP inhibitors and ICIs.
Insights
Genomic profiling of breast cancer brain metastases (BCBMs) reveals significantly enriched targetable alterations. These findings suggest BCBMs are highly responsive to targeted therapies like PARP inhibitors and immune checkpoint inhibitors (ICIs).
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Breast cancer brain metastases (BCBMs) present unique challenges in treatment.
- Understanding the specific genomic alterations in BCBMs is crucial for developing effective therapies.
Purpose of the Study:
- To characterize the genomic landscape of BCBMs.
- To identify targetable genomic alterations and biomarkers for immune checkpoint inhibitor (ICI) therapy in BCBMs.
- To compare the genomic profile of BCBMs with local breast cancer (BC) and non-central nervous system (N-CNS) metastases.
Main Methods:
- Targetable genomic profiling was performed on 822 BCBMs, 11,988 local BC biopsies, and 15,516 N-CNS metastases.
- Analysis included BRCA1/2 alterations, loss-of-heterozygosity, tumor mutation burden (TMB)-High, microsatellite instability (MSI)-High, and PD-L1/L2 expression.
Main Results:
- Clinically relevant genomic alterations were significantly enriched in BCBMs compared to local BC and N-CNS metastases.
- Homologous recombination deficiency (HRD) biomarkers and ICI biomarkers (TMB-High, MSI-High) were more prevalent in BCBMs.
- High PD-L1 protein expression was noted in 48.3% of ER-negative/HER2-negative BCBMs.
Conclusions:
- BCBMs exhibit a distinct genomic profile with a higher prevalence of targetable alterations.
- A significant proportion of BCBMs may benefit from targeted therapies, including PARP inhibitors and ICIs.
- These findings support the use of comprehensive genomic profiling for guiding treatment decisions in BCBM patients.
