DOI: https://doi.org/10.21203/rs.3.rs-1489087/v1
Cystic brain metastases in patients with breast cancer are rare. They have a worse prognosis than solid brain metastases, and they are less sensitive to radiotherapy. We report a case of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer with cystic brain metastases. The patient underwent treatment with docetaxel combined with capecitabine for 5 months, followed by anastrozole maintenance therapy for 10 months and palbociclib combined with exemestane for 22 months. Cystic brain metastases emerged and bone metastases increased in number. A missense mutation in PIK3CA (exon 10, c.1633G > A [p.Glu545Lys]) was detected by whole-exome next-generation sequencing of peripheral blood samples. After whole-brain radiotherapy (40 Gy/20 fx) combined with 3 months of treatment with everolimus and fulvestrant, cystic brain metastases demonstrated partial regression (PR), but extracranial bone metastases continued to increase in number. Thus, the patient underwent fourth-line treatment with abemaciclib (100 mg bid) combined with fulvestrant (500 mg). Three months later, cystic brain metastases significantly demonstrated PR and extracranial bone metastases were stable, without obvious adverse effects. This is the first report of abemaciclib combined with fulvestrant in the treatment of cystic brain metastases in a patient with HR+/HER2 − breast cancer.
The incidence of cystic brain metastases is very low, and the proportion of primary tumors that originate from breast cancer is second only to lung cancer [1]. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer accounts for 45.7% of all cystic brain metastases resulting from breast cancer. Three factors are significantly associated with an increased risk of cystic lesions, including an age of ≤ 40 years at the first breast cancer diagnosis, an age of ≤ 45 years at the onset of brain metastases, and a poor histological grade. Compared with solid brain metastases, cystic brain metastases are larger. Moreover, cystic brain metastases are associated with a shorter progression-free survival (PFS) time, and they have a median overall survival (OS) time of only 10.2 months. They are relatively insensitive to radiotherapy; in fact, only patients with HER2 − breast cancer benefit from radiotherapy [10]. Therefore, effective drug therapies are needed to improve the curative effect. Abemaciclib has been approved for the treatment of HR+/HER2 − metastatic breast cancer and has the advantage of passing through the blood–brain–barrier [2–3]. The present study reported that in a patient with HR+/HER2 − metastatic breast cancer with cystic brain metastases, 3-month abemaciclib treatment at 3 months after radiotherapy led to a significant reduction in the size of cystic brain metastases.
A 49-year-old female presented with two masses in the left breast. She underwent modified radical mastectomy for left breast cancer in March 2018. Postoperative pathology confirmed that the 3.5 × 3 × 2-cm mass in the outer upper quadrant and the 1 × 0.8 × 0.8-cm mass in the inner quadrant were non-specific invasive breast cancer (grade II, left axillary lymph node 16/17[+]). Immunohistochemistry showed the following results: ER (90%+++), PR (75%+++), ki67 (35%+), HER2 (1+). One month after surgery, positron emission tomography/computed tomography showed multiple lung metastases, left hilar lymph node metastases, mediastinal lymph node metastases, left internal mammary lymph node metastases, and multiple bone metastases (C6 and L5 vertebral bodies, right third rib, left fourth rib, and right pubic bone). The patient was diagnosed with HR+/HER2 − metastatic breast cancer. The treatment and outcomes are shown in Table 1.
| Treatment | Regimen | Efficacy | Start and end dates of treatment | PFS time (months) | PD details |
|---|---|---|---|---|---|
| First-line treatment | Docetaxel + capecitabine q3w × 6 cycles, followed by 10 months of anastrozole maintenance therapy | PR | 2018.4.25– 2018.8.13 | 15 | Metastatic lung, left hilar lymph node, mediastinal lymph node, and right hilar lymph node lesions were enlarged |
| Second-line treatment | Palbociclib + exemestane | PR | 2019.7.25– 2021.5.17 | 22 | Brain metastases emerged and bone metastases increased in number |
| Third-line treatment | Whole-brain radiotherapy (40 Gy/20 fx) + everolimus + fulvestrant | Intracranial PR | 2021.5.25– 2021.6.21 | 3.5 | Bone metastases increased in number |
| Everolimus + fulvestrant | 2021.6.22– 2021.9.8 | ||||
| Fourth-line treatment | Abemaciclib + fulvestrant | Intracranial PR, extracranial SD | 2021.9.14– 2021.12.9 | > 6 | |
| Abemaciclib + fulvestrant | Waiting assessment | 2021.12.9–present |
Docetaxel, 75 mg/m2 ivgtt on day 1 Q3W; capecitabine, 1 g/m2 bid per os on days 1–14 Q3W; anastrozole, 1 mg qd per os; palbociclib, 100 mg on days 1–21 per os Q4W; exemestane, 25 mg qd per os; everolimus, 10 mg qd per os; fulvestrant, 500 mg Q4W im (on days 1, 15, and 28 im the first three times); abemaciclib, 100 mg bid per os. PFS, progression-free survival; PD, progressive disease; PR, partial regression; SD, stable disease.
After 22 months of treatment with palbociclib combined with exemestane, the patient developed brain metastases for the first time. All of the lesions were cystic, with a maximum diameter of > 3 cm. The number of bone metastases increased, and both extracranial and intracranial progressive diseases were observed. A missense mutation in PIK3CA (exon 10, c.1633G > A [p.Glu545Lys]) was detected by whole-exome next-generation sequencing of peripheral blood samples, and the mutation rate was 12.05%. After whole-brain radiotherapy (40 Gy/20 fx) combined with 3 months of treatment with everolimus and fulvestrant, the cystic brain metastases partially disappeared and decreased in size, but the number of bone metastases increased. Fourth-line treatment was continued to retain fulvestrant, and everolimus was changed to abemaciclib (100 mg bid). After 3 months, the size of cystic brain metastases significantly decreased (Fig. 1), extracranial bone metastases were stable, and the patient had no noticeable side effects, such as diarrhea, bone marrow suppression, or liver and kidney dysfunction. The patient’s quality of life was very good.
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.
Zhaohui Chu declares that no funds, grants, or other support were received during the preparation of this manuscript.
Zhaohui Chu has no relevant financial or non-financial interests to disclose.
The patient provided full written informed consent for publication of the material contained in this report.