PARP inhibitors are a significant advancement in targeted breast cancer treatment. These medications interfere with cancer cells’ ability to repair their DNA, leading to cell death. They offer a specialized approach by exploiting specific weaknesses within cancer cells, minimizing harm to healthy cells.
Understanding DNA Repair and PARP
Our cells contain DNA, which holds all the instructions for cell function. DNA is constantly susceptible to damage from various sources. Cells possess intricate repair systems to fix this damage, maintaining genomic stability and preventing disease.
One key player in this repair process is the enzyme Poly ADP-ribose polymerase (PARP), particularly PARP1. PARP1 is an abundant nuclear protein that becomes active when it detects single-strand breaks in DNA. Its role involves modifying itself and other proteins by attaching chains of poly(ADP-ribose) (PAR), a process called PARylation. This PARylation activity helps recruit other repair machinery, like XRCC1, to the site of damage, facilitating the repair of these single-strand breaks through a pathway known as base excision repair.
How PARP Inhibitors Target Breast Cancer
PARP inhibitors disrupt DNA repair, specifically in cancer cells with already impaired DNA repair pathways. This concept is known as “synthetic lethality,” where the individual loss of either a gene or a protein function is tolerable for a cell, but the simultaneous loss of both leads to cell death. In the context of breast cancer, PARP inhibitors are particularly effective in tumors with mutations in the BRCA1 or BRCA2 genes.
BRCA1 and BRCA2 proteins are involved in a different DNA repair pathway called homologous recombination repair (HRR), which fixes more severe DNA damage, specifically double-strand breaks. When PARP is inhibited, single-strand breaks accumulate and can convert into double-strand breaks during DNA replication. Healthy cells with functional BRCA proteins can repair these breaks using HRR. However, in cancer cells with BRCA1/2 mutations and a faulty HRR pathway, these unrepaired double-strand breaks lead to genomic instability and ultimately, cancer cell death.
This approach primarily benefits patients with HER2-negative breast cancer, especially those with inherited BRCA1/2 mutations, including metastatic and high-risk early-stage cases. They also show promise in triple-negative breast cancer, a subtype often associated with BRCA mutations. The effectiveness stems from PARP inhibitors trapping the PARP enzyme on the DNA, obstructing replication and requiring BRCA-dependent homologous recombination to resolve.
Who Qualifies for PARP Inhibitor Treatment
Eligibility for PARP inhibitor treatment largely depends on the patient’s genetic profile. Genetic testing for germline BRCA1/2 mutations is a primary criterion, as these mutations indicate a deficiency in homologous recombination repair, making cancer cells more susceptible to PARP inhibition. These tests can detect inherited gene alterations in patient samples, commonly using blood, saliva, or cheek-swab tests.
PARP inhibitors are approved for specific types of breast cancer, including HER2-negative metastatic breast cancer and high-risk HER2-negative early-stage breast cancer that has received prior chemotherapy. For early-stage breast cancer, eligibility often requires a high-risk status, such as positive lymph nodes or residual disease after neoadjuvant chemotherapy. Olaparib and talazoparib are two PARP inhibitors approved for breast cancer treatment.
Beyond BRCA mutations, researchers are investigating whether other genomic signatures associated with homologous recombination deficiency (HRD) or mutations in other DNA damage repair genes might also qualify patients for PARP inhibitor therapy. Genetic counseling is recommended to help identify individuals who may benefit from this targeted treatment approach.
Navigating PARP Inhibitor Treatment
Patients undergoing PARP inhibitor treatment typically take the medication orally, often in pill form, once or twice daily. The specific duration of therapy can vary depending on the individual’s response to treatment and the stage of their cancer. For some patients, PARP inhibitors may be a standalone therapy, while others may receive them in combination with other cancer treatments like chemotherapy or endocrine therapy.
Common side effects include fatigue, nausea, vomiting, abdominal pain, diarrhea or constipation, changes in taste, dizziness, and headaches. Hematologic side effects, such as anemia (low red blood cells), neutropenia (low white blood cells), and thrombocytopenia (low platelets), are also frequently observed. These side effects are generally manageable through supportive care, such as anti-emetics for nausea, loperamide for diarrhea, or laxatives for constipation.
Regular monitoring, particularly in the initial few months of treatment, is important to manage side effects effectively. This often involves blood tests to track blood cell counts and kidney function. In cases of significant anemia, a temporary dose interruption or reduction may be necessary, and in some instances, a blood transfusion might be considered. While rare, more serious delayed side effects like myelodysplastic syndrome or acute myeloid leukemia have been reported, requiring careful observation for persistent or recurrent low blood cell counts.