We presented a case of HR+/HER2 − breast cancer with cystic brain metastases. The following clinicopathological characteristics were observed: (1) a missense mutation in PIK3CA (exon 10, c.1633G > A [p.Glu545Lys]) in circulating tumor DNA from peripheral blood; (2) abemaciclib significantly reduced the size of cystic brain metastases; (3) treatment with abemaciclib combined with fulvestrant as salvage therapy was effective after successive treatment with palbociclib and everolimus.
Cystic brain metastases are more common in patients with primary lung cancer than in patients with breast cancer. They have been noted in patients with lung cancer with ALK rearrangement and RET fusion gene mutations [4–5]. However, breast cancer with cystic brain metastases resulting from a gene mutation is rarely seen. In the present case, the missense mutation in PIK3CA (exon 10, c.1633G > A [p.Glu545Lys]) was a somatic mutation. This mutation is related to the occurrence of breast cancer [6], but it has not yet been reported to correlate with brain metastases. The mutation was identified at the time of the appearance of cystic brain metastases after treatment with palbociclib combined with exemestane. Further investigation will be required to identify if this observation was coincidental or if there is an association between this mutation and cystic brain metastases.
The patient in the present case had multiple cystic brain metastases, with a maximum diameter of > 3 cm. Therefore, whole-brain radiotherapy was preferred. However, considering the limited efficacy of radiotherapy alone for cystic brain metastases, drug treatments were also used. The PI3KCA mutation observed in this patient is not considered a hot-spot mutation according to previous research. Instead, the PIK3CA E542K, E545X, and H1047X mutations are classified as hot-spot mutations owing to their longer PFS time with alpelisib plus fulvestrant treatment (PI3Kα inhibitor) compared with fulvestrant alone in the SOLAR-1 study [7]. These hot-spot mutations also correlated with a longer PFS time when applying alpelisib after the progression of AI with a CDK4/6 inhibitor in the BYLieve study [8]. However, alpelisib was not available to us in the present study. Instead, we used everolimus (an mTOR inhibitor) to target the downstream PI3K/Akt/mTOR signal pathway. Unfortunately, the results were not satisfactory; the PFS time was only 3.5 months, which is not comparable to the PFS time of 8.8 months observed with everolimus plus exemestane treatment in patients with the PIK3CA H1047 mutation [9]. Thus, the reduction in the size of cystic brain metastases is mainly considered to be the effect of whole-brain radiotherapy.
Given that CyberKnife stereotactic radiotherapy demonstrates a PFS time of only 3 months in patients with cystic brain metastases [1], effective drug treatments are still needed to consolidate the effect of radiotherapy. In this study, treatment with abemaciclib and fulvestrant controlled extracranial bone metastases for > 6 months, and significantly reduced the size of cystic brain metastases after 3 months, which demonstrates the advantage of abemaciclib in penetrating the blood–brain–barrier.
Preclinical studies have shown that abemaciclib inhibits the growth of ependymoma and glioblastoma in xenograft tumor models [10–11]. Moreover, a phase I clinical trial of abemaciclib showed that its concentration in cerebrospinal fluid was similar to that in plasma [12]. In a phase 2 clinical trial [13], three patients with HR+/HER2 − brain metastases resulting from breast cancer underwent resection of brain lesions after 5–14 days of abemaciclib treatment (200 mg bid). The concentration of abemaciclib in brain metastatic tissue was similar to that in cerebrospinal fluid and plasma. In the 58 patients with HR+/HER2 − brain metastases from breast cancer, 46.6% underwent whole-brain radiotherapy, 34.5% underwent stereotactic radiotherapy, 6.9% underwent surgical resection for brain metastases, 70.7% underwent endocrine therapy, and 27.6% underwent targeted therapy. In those treated with abemaciclib (200 mg bid) with or without endocrine therapy, the size of the brain metastases reduced in 38% of patients, while 5.2% of patients achieved PR [13]. In this study, we reported a rare case of breast cancer with cystic brain metastases. Abemaciclib combined with fulvestrant reduced the size of the brain metastases after 3 months. This observation proves that abemaciclib has unique advantages in the treatment of cystic brain metastases.
The MONARCH 3 clinical trial [14] showed that abemaciclib combined with fulvestrant as a second-line therapy for patients with HR+/HER2 − breast cancer with extracranial metastases has significant survival benefits, with a median PFS time of 16.4 months and a median OS time of 46.7 months. In the present case, the patient experienced progressive disease after undergoing chemotherapy, aromatase inhibition, and targeted therapy with palbociclib and everolimus. Abemaciclib combined with fulvestrant as the fourth-line therapy showed benefit in terms of a PFS time of > 6 months. A multicenter retrospective study showed that patients undergoing treatment with abemaciclib with or without endocrine therapy achieved a median PFS time of 5.3 months and a median OS time of 17.2 months, even after undergoing five lines of previous treatment [15]. In this study, the PFS time of the patient is already > 6 months as of March 25, 2022, with good tolerance. Therefore, the benefit of abemaciclib combined with fulvestrant might apply to all lines of treatment, and the survival benefit may be greater the earlier it is used.
In conclusion, we reported a case in which treatment with abemaciclib combined with fulvestrant as the fourth-line salvage therapy for metastatic breast cancer was effective in reducing cystic brain metastases, leading to a good quality of life for the patient. In the future, clinical research into the treatment of HR+/HER2 − cystic brain metastases resulting from breast cancer should be conducted.