Isolated Brain Metastasis in BRCA2-Mutated HR+ HER2- Breast Cancer
Background
Brain metastases are a recognized complication of advanced breast cancer, occurring most frequently in triple-negative and HER2+ subtypes. BRCA1 mutation carriers, who often present with triple-negative disease, demonstrate a higher incidence of central nervous system (CNS) involvement. In contrast, BRCA2 mutations are typically associated with HR+ HER2- breast cancers, in which brain metastases are less common. Despite their lower incidence, CNS involvement in BRCA2-associated breast cancer can occur and may present atypically, sometimes as a solitary lesion or with rapid progression.1 Understanding the clinical course of such cases is important for timely recognition, appropriate surveillance, and management strategies tailored to this patient population.
Presentation
A 39-year-old woman with a history of stage II (T2N0M0) estrogen receptor (ER)–positive, progesterone receptor–positive, HER2-negative breast cancer harboring a germline BRCA2 mutation was evaluated. At the time of her initial diagnosis, notable high-risk features included an Oncotype DX recurrence score of 37, histologic grade 3, and a Ki-67 proliferation index of 75%. She was treated with neoadjuvant chemotherapy consisting of dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel. This was followed by bilateral mastectomies, which demonstrated a complete pathologic response with negative margins and no nodal involvement (0/4 nodes). She subsequently received post-mastectomy radiation, adjuvant endocrine therapy with goserelin and a nonsteroidal aromatase inhibitor, as well as a risk-reducing total abdominal hysterectomy with bilateral salpingo-oophorectomy. Goserelin was subsequently discontinued.
The patient remained clinically well and tolerated adjuvant therapy for approximately 2 years until presenting to the local emergency department with a 2-week history of new-onset headaches, memory impairment, and progressive forgetfulness, accompanied by nausea and vomiting. Non-contrast head computed tomography (CT) demonstrated a 5.7 × 4.8 × 4.7 cm intra-axial mass in the left frontal lobe, associated with local mass effect, compression of the left lateral ventricle, and dilatation of the right lateral ventricle suggestive of entrapment. Notably, a head CT obtained 14 months earlier for evaluation of a palpable scalp abnormality had revealed no acute intracranial findings.
Differential Diagnosis
Two primary differential diagnoses were considered for this patient. Given the rapid enlargement of the left frontal lobe mass compared with head imaging 14 months earlier, as well as its substantial size, a glioblastoma multiforme was suspected. Her history also prompted consideration of metastatic breast cancer.
Clinical Workup
During the hospitalization following the initial CT finding of a frontal lobe mass, neurosurgery was consulted to assist with diagnostic evaluation and management planning. Preoperative imaging included magnetic resonance imaging (MRI) and magnetic resonance angiography of the brain, which confirmed a large left frontal lobe mass measuring 5.7 × 4.8 × 4.6 cm (the initial non-contrast CT showed a measurement of 4.7, whereas this later MRI showed 4.6, reflecting the use of two different imaging modalities), associated with significant mass effect, an 11-mm rightward midline shift, and partial effacement of the suprasellar cistern. Additional advanced neuroimaging was obtained, including a CT head stealth without contrast and functional MRI with tractography for stereotactic surgical planning. Postoperatively, a brain MRI with and without contrast using a tumor protocol was performed.
Systemic staging was carried out with mammography and breast ultrasound; a contrast-enhanced CT of the chest, abdomen, and pelvis; and a nuclear bone scan. All demonstrated no evidence of extracranial metastatic disease. The patient remains on a structured surveillance program, consisting of serial brain MRIs with and without contrast; CT scans of the chest, abdomen, and pelvis; and bone scans at 3-month intervals.
Diagnosis
Both intraoperative pathology and cytology were consistent with metastatic breast carcinoma. Immunohistochemical analysis of the surgical specimen demonstrated tumor cells diffusely and strongly positive for GATA3 (nuclear) and CK7 (cytoplasmic), while negative for CK20. Breast biomarker profiling revealed ER positivity (Allred score 8), progesterone receptor negativity (Allred score 0), and HER2 negativity (IHC 1+). Cytologic evaluation of the thin-prep specimen showed cohesive clusters of malignant epithelial cells with enlarged nuclei and nuclear crowding, in a background of mixed inflammatory cells and macrophages. Comprehensive genomic profiling with a 648-gene next-generation sequencing panel of the brain tissue confirmed the presence of a germline BRCA2 p.Q3034 stop-gain loss-of-function mutation, along with 5 additional variants of uncertain significance.
Treatment
The patient underwent a left frontal craniotomy with gross tumor resection, followed by a 10-day dexamethasone taper and 1000 mg of levetiracetam twice daily for seizure prophylaxis. Postoperatively, she received adjuvant fractionated stereotactic radiosurgery to the resection cavity, delivered as 30 Gy in 5 fractions. This approach was selected given the size of the cavity, solitary nature of the lesion, her young age, good performance status, and the goal of minimizing long-term neurocognitive sequelae.
Systemically, she continued a nonsteroidal aromatase inhibitor and a twice-daily 300-mg dose of olaparib was added considering her germline BRCA2 mutation.2 She remains on this doublet therapy. Neuro-oncology remains closely involved in her care. She was prescribed Boswellia serrata (4,200-4,500 mg daily) as an adjunct treatment for early radiation-related injury or necrosis, supported by studies suggesting safety and feasibility in grades 1-3 radiation necrosis.3
She also participated in skilled speech therapy, with targeted rehabilitation of language function, which had been her most prominent presenting deficit. Her levetiracetam dose was gradually tapered, and she currently remains on 500 mg twice daily.
Discussion
This patient was not a candidate for adjuvant CDK4/6 inhibitor therapy, as she achieved a complete pathologic response at surgery and had no lymph node involvement. Had she been diagnosed after the results of the NATALEE trial and the subsequent approval of adjuvant ribociclib in September 2024, she likely would have qualified for treatment.
The NATALEE trial evaluated ribociclib in combination with adjuvant endocrine therapy for patients with stage II or III HR+ HER2- early breast cancer. The study demonstrated a significant invasive disease-free survival benefit with 3 years of ribociclib, with discontinuation permitted in the event of intolerable toxicity or recurrence. Although BRCA mutation status was not a stratification factor, the trial did not exclude patients with germline BRCA mutations.4
Importantly, this patient would not have met eligibility criteria for adjuvant abemaciclib.
Another adjuvant treatment option for patients with high-risk HER2- breast cancer harboring a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant is olaparib, administered after completion of local therapy and either neoadjuvant or adjuvant chemotherapy. This recommendation is supported by the OlympiA trial, which demonstrated that 1 year of adjuvant olaparib significantly improved invasive disease-free survival and distant disease-free survival compared with placebo.5
At the time of surgery, this patient was not eligible for adjuvant olaparib, as she was considered lower risk due to node-negative status and the absence of residual disease. Talazoparib is not currently an option in the early-stage setting.
In the metastatic setting, however, both poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are recommended as first-line treatment options for patients with germline BRCA1/2 mutations, according to National Comprehensive Cancer Network guidelines.6 In this case, olaparib was selected due to its side effect profile. Talazoparib is associated with higher rates of hematologic toxicity, whereas olaparib is more often linked to gastrointestinal adverse effects such as nausea and diarrhea. Given that the patient’s metastatic disease is ER+, anastrozole was continued in combination with olaparib.
The Advanced Practitioner’s Role
It is important to recognize the high-risk features of a patient’s breast cancer. During follow-up visits, providers should evaluate not only stage, but also histologic grade, Ki-67 proliferation index, and recurrence scores such as Oncotype DX. This comprehensive assessment guides advanced practitioners (APs) in conducting a thorough history and review of systems, allowing for earlier identification of potential metastatic disease. When clinical concerns arise, timely diagnostic work-up and multidisciplinary collaboration with physicians and subspecialists are essential.
Access to targeted therapies, including agents such as olaparib, may require financial navigation. Pharmacists and social workers play a key role in facilitating access through knowledge of drug-assistance programs and supportive resources. Additionally, referral to rehabilitation services may be appropriate to optimize patient function and quality of life. APs are integral in providing ongoing patient education, emotional support, and symptom management throughout the metastatic disease trajectory.
Follow-up care requires close monitoring of treatment-related toxicities, as well as vigilance for physical and clinical indicators of progression. Coordination with the primary oncologist and relevant subspecialty teams like neurology in these cases ensures appropriate restaging and continuity of care.
Finally, APs must remain current with evolving clinical evidence and guideline updates to ensure patients have access to the most effective therapies. Real-time access to online resources can support clinical decision-making at the point of care. Notably, this patient’s adjuvant treatment options would likely have differed if she had been treated under today’s standards of care.
Conclusion
This case underscores that although brain metastases are less frequent in BRCA2-associated breast cancer compared with BRCA1-associated disease, they can develop rapidly and present as an isolated metastatic focus. It highlights the importance of maintaining a high index of suspicion for neurologic symptoms in BRCA2 carriers and suggests that CNS surveillance, including more thorough neurologic assessments by clinicians, should be considered to enable timely diagnosis and management.
References
- Garber HR, Raghavendra AS, Lehner M, et al. Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer. NPJ Breast Cancer. 2022;8(1):46. doi:10.1038/s41523-022-00407-z
- AstraZeneca Pharmaceuticals LP. Lynparza (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2025.
- Upadhyay R, Elguindy ANM, Salts L, et al. Boswellia serrata for cerebral radiation necrosis after radiosurgery for brain metastases. International Journal of Radiation Oncology, Biology, Physics. 2025;122(5):1282-1291. doi:10.1016/j.ijrobp.2025.02.016
- Hortobagyi GN, Lacko A, Sohn J, et al. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: Final invasive disease-free survival results from the NATALEE trial. Annals of Oncology. 2025;36(2):149-157. doi:10.1016/j.annonc.2024.10.015
- Geyer CE Jr, Garber JE, Gelber RD, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Annals of Oncology. 2022;33(12):1250-1268. doi:10.1016/j.annonc.2022.09.159
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2025. Published 2025. Accessed August 24, 2025. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bopp.pdf