Risk of seizures in a population of women with BRCA-positive metastatic breast cancer from an electronic health record database in the United States

Breast cancer (BC) is the leading cancer type and ranks second among the causes of cancer-related mortality among women in the United States, with estimates indicating that 287,850 new cases will be diagnosed in 2022 and that 43,250 deaths will be attributable to it during the year [1]. Although advances in treatment have raised the five-year survival rate among women with localized BC at diagnosis to 99%, lower survival rates persist for women diagnosed with regional and particularly for women with distant disease (86 and 28%, respectively) [1].

While most breast tumors arise sporadically in the general population, a small subset (10–15%) are associated with genetic mutations, of which a majority (~ 60%) are associated with the BRCA1 and BRCA2 genes (BReast CAncer susceptibility genes 1 and 2) [2‐4]. Women who inherit a germline BRCA mutation are at a significantly increased risk for the development of breast cancer and ovarian cancer. Women face an approximately 72 and 69% risk of developing breast cancer associated with BRCA1 and BRCA2 mutations, respectively, by the age of 80, compared with 12% among women in the general population [3, 5]. Among BRCA mutations detected in women with breast cancer overall, approximately one-third may be somatic in origin [6, 7].

The three major molecular subtypes (or molecular phenotypes) of breast tumors based on the presence or absence of markers or overexpression of estrogen, progesterone (hormone) receptors (ER+ and/or PR+; collectively referred to as HR+), and the human epidermal growth factor 2 (HER2) are clinically meaningful to better characterize prognosis. Overall survival for women diagnosed with metastatic breast cancer also differs by molecular subtype and remains particularly low (10–13 months) for women with triple-negative tumors compared with the other molecular phenotypes (4–5 years) [8‐11]. Accordingly, treatment guidelines for both non-metastatic and metastatic breast cancer are also specified by molecular subtype [8, 12]. Women diagnosed with metastatic breast cancer and HR+ phenotype receive endocrine therapy prior to the development of resistance to endocrine agents and single-agent chemotherapy thereafter, while patients with HER2+ tumors receive a combination of HER2+ targeting agents and chemotherapy in addition to endocrine therapy (the last only if the HER2+ tumors are also HR+) and patients with triple-negative tumors receive single-agent chemotherapy [8, 12]. Additional options available for the treatment of metastatic tumors harboring germline BRCA mutations include the poly [adenosine diphosphate-ribose] polymerase (PARP) inhibitors olaparib and talazoparib [13, 14]. These agents were approved in 2018 and are used in later lines of therapy for patients with HR+ and triple-negative tumors [8].

Organ sites associated with metastases from breast tumors include liver, bones, lungs, and/or brain. Diagnosed brain metastases in particular have been reported in 24% of breast cancer cases [15], with breast cancer ranking second among all causes of brain metastases [16]. The brain is the first site of metastasis in 12% of patients with breast cancer [17]. However, there is a paucity of data on rates of seizures among breast cancer patients with brain metastases and on potential risk factors associated with seizures in this patient population. Early reports on seizures in patients with brain metastases documented seizure frequencies ranging between 20 and 35% [18‐20], but these studies included all cancer patients with brain metastases and not only breast cancer patients. A more recent review of 106 studies documented seizures in 12% of breast cancer patients with diagnosed brain metastases but did not explore the potential risk factors for seizures in these patients [15]. Other studies have reported agents used for cancer chemotherapy (e.g., methotrexate, fludarabine, cytarabine, vincristine, etoposide, and cisplatin) and other drugs prescribed to cancer patients (e.g., antidepressants such as tricyclics and bupropion, neuroleptic agents such as clozapine and phenothiazines, and antibiotics such as penicillin and β-lactams) as being epileptogenic [20‐23]; however, no data are available on the incidence of seizures following the use of more recently approved therapeutic agents such as PARP inhibitors or on seizure rates categorized by molecular subtypes of breast cancer. This study was therefore undertaken with the objective of estimating, in a large real-world dataset, the incidence of seizures in patients with metastatic breast cancer who harbor mutations in the BRCA1 or BRCA2 genes, and examining factors associated with the development of seizures.

Data pertaining to the risk of seizures among women with advanced or metastatic breast cancer is limited, particularly when considering women who may harbor a mutation in the high risk BRCA1 and BRCA2 breast cancer predisposition genes. This study identified a large cohort of 7941 women with BRCA-associated metastatic breast cancer treated at centers across the United States as represented in a large EHR database and estimated the overall incidence rate of seizures to be 11.83 (95% CI: 11.35,12.33) per 100 patient-years after index diagnosis of metastatic disease.

The group of women with the highest seizure incidence rates of 16.83 events (95% CI: 15.34, 18.46) per 100 patient-years were those affected with triple-negative breast cancer. Additional risk groups were women with diagnosed brain metastases (incidence rate = 42.55 [95% CI: 28.59, 63.30] per 100 patient-years), and women with a history of seizures (incidence rate = 34.76 [95% CI: 23.24, 52.01] per 100 patient-years.

Overall, patients with brain metastasis or a history of seizures had higher seizure incidence rates, which is consistent with clinical impressions and previous studies [15]. TNBC and HER2−/HR+ patients showed a higher risk of developing seizures over the course of the study. Patients with these phenotypes were also at higher risk when metastasis was in the brain and if they had a history of anticonvulsant use. Although our study was limited in the sample size available for analyses of PARP inhibitor-treated patients, seizure incidence rates in this patient population appeared to be higher than in patients who were not treated with PARP inhibitors (76.58 per 100 person-years vs 7.20 per 100 person-years).

A notable strength of this study was the use of unstructured NLP fields in addition to the structured data (ICD9/10 diagnosis codes) to identify the seizure outcome. In a prior study, we showed how the combination of structured and unstructured data to identify adverse event outcomes is superior to using structured data alone [28].

Although BRCA mutation-positive status was discernable in the EHR data from unstructured NLP fields, a limitation of our study was the incomplete available information related to BRCA1 and BRCA2 status. Specifically, 5383 (67.8%) patients did not have details on which gene (BRCA1 versus BRCA2) was implicated. Furthermore, the Optum® EHR database did not provide differentiation on whether the BRCA mutation was a somatic or germline variant. Further, while large, we used a single EHR database for this study. This may introduce biases in terms of types of patients (e.g. the high proportion of Caucasian and Midwestern patients) and the types of treating physicians. The database does not contain information regarding healthcare access, lifestyle, or socio-economic status, which may also introduce bias into our analyses.

This study provides novel real-world evidence on the incidence rates of seizures affecting a large population of women with metastatic BRCA-associated breast cancer who received care in clinics across the U.S. The study highlights the importance of understanding patients’ molecular subtypes associated with breast cancer when assessing seizure risk. The seizure incidence rate was highest in the subgroup of women with TNBC, and significantly higher for women with diagnosed brain metastases, with a history of seizures/anti-convulsive therapy, as well as those receiving PARP inhibitor therapy. These findings have implications for clinical practice as well as for drug development when considering the benefit-risk of new oncologic therapeutic agents (such as PARP inhibitors studied here) that, once approved, are mainly introduced for treating patients with advanced disease (distant metastases) who have failed several lines of therapy. Further work may characterize seizure risk across all stages of BRCA-associated breast cancer.