Introduction: Breast Cancer
Brain Metastasis – A Growing Health Challenge
Breast cancer is the most commonly diagnosed cancer among women worldwide, with an increasing incidence in recent years. Although early detection and advances in treatment have significantly improved patient outcomes, metastatic breast cancer remains a major clinical challenge.1 Metastasis, the spread of cancer cells from the primary tumour to distant organs, is responsible for most breast cancer-related deaths. One of the most concerning sites of metastasis is the brain, as breast cancer brain metastases (BCBM) are associated with high morbidity and mortality. The rising incidence of BCBM can be attributed to several factors:2
Improved systemic treatment: Advances in targeted, hormonal, and immunotherapies have led to better primary tumour control and reduced distant metastases. Consequently, breast cancer patients live longer, increasing the likelihood of brain metastases developing over time.
Limited penetration of drugs into the brain: Many systemic treatments used for breast cancer cannot cross the blood-brain barrier (BBB) effectively. This highly selective barrier protects the brain from potentially harmful substances. However, the limited penetration of these drugs into the brain can result in inadequate treatment of cancer cells that have already metastasized to the brain or are in the process of doing so. This may lead to the development and growth of BCBM even when the primary tumour and other metastases are well controlled.
Improved diagnostic techniques: The development and widespread use of advanced imaging techniques, such as magnetic resonance imaging (MRI), have made it possible to detect brain metastases at earlier stages and with greater accuracy. However, this has also increased the reported incidence of BCBM. Moreover, specific breast cancer subtypes are more likely to develop BCBM,1, 3 including:
HER2-positive breast cancer: This subtype, characterized by the overexpression of the human epidermal growth factor receptor 2 (HER2), has a higher propensity for brain metastasis. Targeted therapies against HER2, such as Trastuzumab and Pertuzumab, have improved the overall survival of patients with HER2-positive breast cancer. Still, they have limited penetration across the BBB, continuing the risk of BCBM.
Triple-negative breast cancer (TNBC): TNBC lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, which makes it more aggressive and challenging to treat. This subtype is associated with a higher risk of developing BCBM, partly due to its aggressive biology and the lack of targeted therapies available.
Unravelling the Mechanism of Action: How PARP Inhibitors Target DNA Repair to Combat Cancer
PARP (poly ADP ribose polymerase) enzymes play a crucial role in the repair of single-strand DNA breaks through the base excision repair pathway. Inhibition of PARP enzymes by PARP inhibitors leads to accumulating unrepaired single-strand DNA breaks, which can be converted into double-strand breaks during DNA replication. Since cells with BRCA mutations have an impaired ability to repair double-strand breaks through homologous recombination (HR) repair, accumulating these breaks can lead to genomic instability and, ultimately, cell death.4 The mechanism of action of PARP inhibitors is summarized in Figure 1.
Emerging evidence has revealed that PARP inhibitors can also be effective in HR-deficient (HRD) cells independent of BRCA mutations.5 HRD can be caused by various factors, including mutations in other HR-related genes (such as RAD51 or PALB2), epigenetic changes, or alterations in gene expression. This has broadened the potential application of PARP inhibitors to a broader range of cancers with HRD beyond those with BRCA mutations.
PARP inhibitors have shown promise as a therapy for breast cancer patients, particularly those with germline BRCA1/2 gene mutations. However, their potential role in treating breast cancer brain metastasis remains an area of ongoing research. Interestingly, recent studies have suggested that specific PARP inhibitors, such as Pamipirab, can, to some extent, cross the BBB, making them potential candidates for treating brain metastasis.6 First, however, it is crucial to develop reliable biomarkers to identify patients with HRD who are most likely to benefit from PARP inhibitor therapy, irrespective of their BRCA status.
Expanding the Scope of PARP Inhibitor Therapy: Harnessing HRD Biomarkers Beyond BRCA Mutations Numerous potential biomarkers and assays have been developed or are under investigation to assess HRD in tumour samples:7, 8
Genomic Scar Assays: These assays measure specific genomic aberrations or “scars” characteristic of HRD tumours. The Myriad my-Choice HRD and Foundation Medicine’s Foundation-Focus CDxBRCA tests are the most well-known genomic scar assays. Both of these tests assess three genomic parameters: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). A combined HRD score is calculated based on these parameters, with higher scores indicating a higher likelihood of HRD.
Mutational Signatures: Specific patterns of somatic mutations, known as mutational signatures, can provide insights into a tumour’s underlying DNA repair deficiencies. Whole-genome or whole-exome sequencing data can be used to identify these mutational signatures, which may help to determine whether a tumour is HRD and potentially responsive to PARP inhibitors.
Gene Expression Profiling: Measuring the expression levels of specific genes involved in the HR pathway can help to identify tumours with HRD. Gene expression profiling can be performed using RNA sequencing or microarray analysis techniques. A distinct gene expression pattern associated with HRD may indicate that the tumour could be sensitive to PARP inhibitor therapy.
Functional Assays: These assays directly measure the activity of the HR pathway in tumour cells. For example, the RAD51 foci formation assay evaluates the recruitment of RAD51 to DNA damage sites, which indicates functional HR. A reduced capacity to form RAD51 foci may suggest HRD and potential sensitivity to PARP inhibitors.
While these biomarkers and assays show promise in identifying HRD tumours that may benefit from PARP inhibitor therapy, further research is needed to validate their accuracy and clinical utility. Furthermore, as our understanding of HRD improves, a combination of multiple biomarkers will likely be used to select patients who are most likely to respond to PARP inhibitors, regardless of their BRCA status.
Adapting to Survive: The Complex Dynamics of Resistance to PARP Inhibitor Therapy
Unfortunately, both mutated-BRCA and non-mutated-BRCA tumours can develop resistance to PARP inhibitors through various mechanisms, summarized in Figure 2. Some of the common factors contributing to PARP inhibitor resistance include:9, 10
Reduced drug uptake or increased efflux: Resistance to PARP inhibitors may arise from alterations in drug transport mechanisms (i.e., ABCB1 network), such as reduced drug uptake into cancer cells or increased drug efflux, which decreases intracellular drug concentrations and ultimately reduces the drug’s efficacy.
Alterations in PARP expression or activity: Changes in the expression or activity of PARP enzymes can contribute to resistance. For example, some tumours develop resistance by downregulating PARP1 expression, rendering the PARP inhibitor ineffective. In other cases, the cancer cells might express PARP mutants resistant to the inhibitor’s effects.
Restoration of homologous recombination (HR): PARP inhibitors exploit synthetic lethality by targeting cancer cells with HR deficiencies. However, tumours can develop resistance by restoring HR function, which can occur through secondary mutations in the BRCA1/2 genes or upregulation of other genes involved in the HR pathway.
Activation of alternative DNA repair pathways: Tumour cells can overcome PARP inhibitor-induced DNA damage by compensating with alternative DNA repair pathways, such as non-homologous end joining (NHEJ), allowing them to repair and survive DNA damage.
Epigenetic changes: Alterations in the epigenetic regulation of DNA repair genes can also contribute to PARP inhibitor resistance. For example, changes in the methylation status of specific genes involved in the HR pathway might restore HR function, enabling the cancer cells to repair DNA damage more efficiently. Adaptation of cellular signalling pathways: Cancer cells can adapt to PARP inhibitors by activating alternative signalling pathways that promote cell survival, proliferation, and DNA repair. These adaptive changes can help the cells overcome the cytotoxic effects of PARP inhibitors and contribute to therapy resistance.
To overcome PARP inhibitor resistance, researchers are exploring combination therapies targeting multiple pathways, developing new PARP inhibitors with improved efficacy, and better identifying patients most likely to benefit from PARP inhibitor treatment, and just as significantly to help maintain a patient’s quality of life by reducing drug concentrations.
Boosting the Battle: Approaches to Enhance PARP Inhibitor Sensitivity
Several ongoing clinical trials are exploring novel strategies to overcome PARP inhibitor resistance in cancer treatment, including breast cancer. Some of these exciting trials include:
NCT02157792:11 This Phase I study evaluates the combination of Berzosertib, an ATR kinase inhibitor, with the PARP inhibitor Olaparib in patients with advanced solid tumours, including those who have progressed on prior PARP inhibitor therapy. The rationale behind this combination is that ATR inhibition can further compromise DNA repair pathways in cancer cells, potentially enhancing the cytotoxic effects of PARP inhibitors.
NCT03579316:12 This Phase II trial investigates the combination of Adavosertib, a WEE1 inhibitor, with Olaparib in patients with advanced solid tumours, including those resistant to prior PARP inhibitor treatment. WEE1 inhibition may cause replication stress and genomic instability, which could sensitize cancer cells to PARP inhibition.
NCT02861573:13 This Phase I/II trial evaluates the combination of the immune checkpoint inhibitor Pembrolizumab with Olaparib in patients with advanced solid tumours, including those who have received prior PARP inhibitor therapy. Combining PARP inhibitors with immunotherapies might help overcome resistance by stimulating anti-tumour immune responses.
NCT02734004:14 This Phase Ib/ II trial assesses the combination of the anti-PD-L1 antibody Durvalumab with Olaparib and chemotherapy in patients with advanced solid tumours, including those resistant to prior PARP inhibitors. This trial aims to determine whether adding immune checkpoint blockade and chemotherapy to PARP inhibitor therapy can improve outcomes in resistant patients.
The use of PARP inhibitors in BCBM holds significant promise for improving patient outcomes. By exploiting DNA repair deficiencies in cancer cells, PARP inhibitors have shown imposing activity in treating BRCA-mutated and HRD breast cancer. However, resistance to PARP inhibitors remains a significant challenge. Ongoing clinical trials exploring novel strategies to overcome resistance, such as combining PARP inhibitors with immunotherapy or other targeted agents, offer hope for further improving the effectiveness of these drugs. Additionally, identifying reliable biomarkers to predict response to PARP inhibitors in HRD patients, regardless of BRCA status, could help expand the patient population that may benefit from this treatment. With continued research, PARP inhibitors may become an essential component of the treatment armamentarium for BCBM and improve outcomes for patients with this devastating condition.
References available upon request
Written by Dr. Jason McGrath (Postdoctoral researcher), Dr. Gordon Daly (Ph.D. researcher), Mr. Luke Cox (Research assistant), Dr. Damir Vareslija (Lecturer and Principal Investigator), and Prof. Leonie Young (Professor, Scientific Director Beaumont RCSI Cancer Centre).
Department of Surgery, Royal College of Surgeons in Ireland & Beaumont Hospital.
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