Introduction
Among females, breast cancer is the most common
malignancy worldwide and it is also the leading cause of
cancer-associated death (1).
Statistical results indicate that human epidermal growth factor
receptor 2 (HER2)-positive breast cancer accounts for 15–20%
(2) and this subtype of breast
cancer accounts for 22.6% in China (3). HER2-positive breast cancer is
comparatively more aggressive and has a poor prognosis (4). Although the use of anti-HER2 therapy
has significantly improved the prognosis of HER2-positive advanced
breast cancer, when drug resistance occurs, the treatment effect
will be poor and the tumor will progress (5,6).
Therefore, it is required to adopt new treatments to overcome drug
resistance.
Tumor angiogenesis is closely related to tumor
growth, invasion and metastasis. Therefore, anti-angiogenesis may
be one of the effective methods to treat cancer (7–9).
Bevacizumab, an anti-angiogenic monoclonal antibody, has
demonstrated anti-tumor activity in advanced breast cancer
(10–13). In addition, anti-angiogenic drugs
have been applied in the treatment of advanced breast cancer
(14–16).
Apatinib is a highly selective tyrosine kinase
inhibitor (TKI) that targets vascular endothelial growth factor
receptor-2 (VEGFR2). Apatinib was first used for the treatment of
advanced gastric cancer (17). Two
phase II clinical studies indicated that apatinib monotherapy had
good efficacy in the treatment of pretreated advanced breast cancer
(18,19). An observational study suggested
that apatinib combined with chemotherapy has potential efficacy in
the treatment of previously treated advanced breast cancer
(20). However, studies on the use
of apatinib for the treatment of HER2-positive advanced breast
cancer with brain metastasis are scarce. In the present study,
apatinib combined with trastuzumab and albumin-bound paclitaxel
were used to treat a patient with refractory HER2-positive breast
cancer with brain metastasis, and good efficacy was achieved. This
case is reported below.
Case report
In April 2014, a 42-year-old Chinese female
underwent radical surgery for left breast cancer at an external
hospital and the axillary lymph nodes on the same side were
removed. Pathological inspection revealed invasive non-specific
breast carcinoma (Grade III). The size of the tumor was 1.0×1.0 cm,
19 lymph node metastases were detected in 23 left axillary lymph
nodes and the postoperative stage was pT1N3M0, stage IIIC. The
immunohistochemistry results were as follows: Estrogen receptor
(ER), 85%+; progesterone receptor (PR), 15%+; HER-2, 2+; Ki-67,
45%+; fluorescence in situ hybridization (FISH) detection,
HER-2 gene amplification (+). The patient received six cycles of
adjuvant chemotherapy with paclitaxel combined with lobaplatin,
followed by one-month endocrine therapy with tamoxifen. The patient
refused to receive adjuvant radiotherapy and anti-HER2 targeted
therapy.
In March 2021, multiple metastases in the bone and
lymph node were detected by computed tomography (CT) and brain
magnetic resonance imaging (MRI) revealed multiple brain
metastases. The patient underwent left axillary lymph node biopsy
and the pathological diagnosis was metastasis of breast cancer with
the following immunohistochemical results: ER, 90%+; PR, 15%+;
HER-2, 2+; Ki67, 60%+; and FISH detection, HER-2 gene amplification
(+). The patient then received capecitabine plus pyrotinib for 8
months as the first-line treatment. The best tumor response of
intracranial and extracranial lesions was stable disease based on
CT and MRI examination. In November 2021, reexamination by brain
MRI indicated that the left parieto occipital lobe metastatic tumor
was enlarged and the evaluation indicated progressive disease. The
patient received second-line treatment with pyrotinib plus
trastuzumab (Herceptin®) and capecitabine. One month
later, the brain metastases progressed again. Table I provides the medical timeline of
the patient's treatment prior to presenting at our hospital.
 | Table I.Summary of the timeline of the
patient's past medical history. |
Table I.
Summary of the timeline of the
patient's past medical history.
| Treatment time | Therapy | Response
evaluation | DFS or PFS |
|---|
| April 2014-October
2014 | Radical surgery and
adjuvant therapy (TP for 6 cycles, tamoxifen for 1 month) | - | 83 months |
| March 2021-November
2021 | Capecitabine +
pyrotinib | SD | 8 months |
| November
2021-December 2021 | Herceptin +
capecitabine + pyrotinib | PD | 1 month |
In December 2021, the patient was admitted to our
hospital, the National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese
Academy of Medical Sciences and Peking Union Medical College
(Shenzhen, China), for the first time, after having received
second-line palliative chemotherapy at other hospitals. The patient
complained of headache and vomiting. CT of the whole body revealed
multiple lymph node and bone metastases, as well as suspected lung
metastasis. Brain MRI indicated two huge brain metastases (one in
the right temporooccipital parietal lobe and the other in the left
occipital parietal lobe), involving adjacent meninges, accompanied
by obvious edema; the midline structure shifted to the left and the
right lateral ventricle and the third ventricle moved to the left
under pressure.
As the brain metastases of this patient had
progressed significantly after using small molecule anti-HER2 TKI
drugs, the brain metastases were now huge and accompanied by
obvious edema. After multi-disciplinary discussion, consideration
was given to the following points: i) The radiotherapy department
had no indication for radiotherapy, so it was recommended to
perform a neurosurgery consultation to consider palliative surgery;
ii) the neurosurgery department indicated that it may be able to
perform palliative surgery, but the risk is relatively high and the
patient's condition should be fully informed; iii) after careful
consideration, the patient and the patient's family refused
surgical treatment of the patient. Finally, the combined treatment
plan of apatinib [250 mg per os (po) once per day (qd)] plus
trastuzumab (Zercepac®) [6 mg/kg, intravenous drip, day
1 of every 3 weeks] and albumin-bound paclitaxel (130
mg/m2, intravenous drip, days 1 and 8 of every 3 weeks)
was formulated and the patient began to receive the third-line
treatment from mid-December 2021. The patient also received
conventional intervention with mannitol and dexamethasone for
dehydration. After one cycle of combined treatment, the patient
complained that the severity of the headache and vomiting had
decreased. Brain MRIs are provided in Fig. 1, Fig.
2, Fig. 3. Brain MRI
examination after 2 cycles of combination treatment indicated that
peritumoral brain edema was significantly reduced (Fig. 1B) and two brain metastases were
significantly reduced (Figs. 2B
and 3B). After 4, 6 and 8 cycles
of combination treatment, further reductions of peritumoral brain
edema were found (Fig. 1C-E). The
right temporooccipital parietal lobe metastasis (Fig. 2C-E) and the left occipital parietal
lobe metastasis were further reduced after 4, 6 and 8 cycles of
combination treatment (Fig. 3C-E),
and the efficacy was rated as partial response. The patient
tolerated the treatment well and no grade 3 or 4 adverse events
were observed during the whole treatment period. In September 2022,
brain MRI indicated progress in brain metastases and systemic CT
suggested that extracranial metastases remained stable. The
progression-free survival was 9 months for the third-line
treatment.
When the brain metastases of this patient progressed
again, neurosurgery and radiotherapy experts were invited for
consultation again, but the patient and the patient's family still
refused the surgery and did not consider radiotherapy for the time
being. Therefore, the medical anti-tumor treatment plan was
adjusted as follows: Apatinib (250 mg po qd) plus inetetamab
(Cipterbin®, anti-HER2 recombinant human monoclonal
antibody; 6 mg/kg, intravenous drip, day 1 of every 3 weeks, with 8
mg/kg for the first cycle) and oral vinorelbine (80
mg/m2, po, days 1 and 8 of every 3 weeks, with 60
mg/m2 for the first cycle). To date, three cycles of the
aforementioned treatment with a combination of apatinib, inetetamab
and oral vinorelbine have been performed and a comprehensive review
and evaluation will be performed before the next cycle. At present,
the patient has no obvious headache, vomiting or other
complaints/symptoms.
Discussion
At present, the treatment options for brain
metastasis of breast cancer include local treatment, systematic
treatment or combination of multiple treatments. Local treatment
includes surgery, stereotactic radiosurgery (SRS) and whole-brain
radiation therapy (WBRT). Systemic therapy includes chemotherapy
and targeted therapy. Certain studies have indicated that surgery
may improve the overall survival (OS) of patients with brain
metastases from breast cancer, but it is usually only applicable to
patients with obvious symptoms, good general condition and limited
brain metastasis lesions (21,22).
Most patients with brain metastases from breast cancer receive
radiotherapy (23). Patients with
good performance and localized brain metastases receive SRS, while
patients with poor performance or extensive brain metastases
usually receive WBRT (23). One
study indicated that WBRT combined with SRS had no benefit
regarding OS, while increasing the risk of neurocognitive toxicity
compared with SRS alone (24).
Therefore, the latest consensus guidelines recommend complete
resection or SRS for limited brain metastases, and adjuvant WBRT
should not be conducted subsequently (25). In terms of systematic treatment,
the application of chemotherapy in brain metastasis from breast
cancer is limited. However, due to the use of anti-HER2 therapy in
HER2-positive subtypes, systematic therapy has achieved good
results. The exploratory study on central nervous system metastasis
in the EMILIA phase III study shows that T-DM1 may prolong the OS
of patients with brain metastasis of breast cancer (26). The subgroup analysis of the
DESTINY-Breast 01 study on brain metastasis of breast cancer
indicated that trastuzumab deruxtecan (T-DXd, DS8201) has achieved
encouraging therapeutic benefits for patients with brain metastasis
of breast cancer (27).
Small-molecule anti-HER2 TKI drugs, such as
lapatinib, neratinib, tucatinib and pyrotinib, may also be used for
the systematic treatment of brain metastases in patients with
HER2-positive breast cancer. However, the treatment of
HER2-targeted drug-resistant patients is an important clinical
challenge. The present study reported a case in which the
combination of apatinib with trastuzumab and albumin-bound
paclitaxel effectively controlled refractory brain metastases after
the failure of pyrotinib therapy. The reduction of the brain
metastases from breast cancer and alleviation of the brain edema
lasted 9 months.
Angiogenesis is closely related to HER2 signal
transduction at the molecular level (28). A previous study indicated that
VEGFR2-positive stromal vessel counts were higher in HER2-positive
breast cancer compared with other subtypes. These data indicate
that the influence of HER2 on tumorigenesis may be partially
mediated by the stimulation of angiogenesis, which provides a
strong theoretical basis for the use of anti-angiogenic drugs in
HER2-positive breast cancer (29).
In another preclinical study, the authors observed that HER2
overexpression was associated with upregulation of VEGF in human
breast cancer cell lines (30).
Several clinical studies suggested that trastuzumab combined with
bevacizumab was effective in the treatment of HER2-positive
advanced breast cancer (31–33).
In addition, a phase II study suggested that lapatinib combined
with bevacizumab was effective in patients with HER2-positive
advanced breast cancer (34).
Due to the existence of the blood-brain barrier
(BBB), which has low permeability and strong expression of multiple
specific efflux transporters, the entry of numerous drugs into the
brain is limited (35). Therefore,
numerous anti-tumor drugs cannot achieve any therapeutic effects on
brain metastases.
Apatinib is a highly selective and effective VEGFR
TKI, which has high affinity for VEGFR2. The molecular weight of
apatinib is small, and thus, it may easily pass through the BBB and
its potential effect on brain metastasis may be better than that of
other agents. Furthermore, apatinib is administered orally, which
avoids injection, reduces hospitalization and the drug is taken
orally every day to maintain a stable blood concentration. Two
phase II clinical studies demonstrated the efficacy of apatinib in
patients with advanced triple negative and non-triple negative
breast cancer (18,19). Of note, three patients with brain
metastasis were included in the study of triple negative breast
cancer above, but the therapeutic effect on brain metastasis with
apatinib was not described in detail. The mechanism of apatinib
penetrating the BBB remains elusive and there is also a lack of
large randomized controlled studies to confirm its efficacy in
patients with breast cancer with brain metastasis. However, in
certain cases, the beneficial effect of apatinib on brain tumors
has been reported. Apatinib has been reported to be effective in
the treatment of brain glioma (36). One case report indicated that
apatinib was effective in the treatment of brain edema caused by
brain metastases (37). In
addition, two case reports demonstrated the efficacy of apatinib
monotherapy or in combination for the treatment of brain metastases
of advanced triple negative breast cancer (38,39).
However, to the best of our knowledge, no previous case report on
apatinib for the treatment of a patient with HER2-positive breast
cancer with brain metastasis, particularly after anti-HER2
treatment resistance, has been published to date.
The present case was a patient with HER2-positive
advanced breast cancer that was progressing with small molecule
anti-HER2 TKI drugs, with a heavy brain metastasis load and obvious
brain edema. The radiotherapy department was unable to perform
brain radiotherapy, the neurosurgery department determined that the
operation was risky and the patient and the patient's family
refused the operation. It was only possible to treat the brain
metastases by using drugs. Compared with standard paclitaxel,
albumin-bound paclitaxel has better efficacy and higher safety in
the treatment of advanced breast cancer (40). A study indicated that albumin is
able to penetrate the BBB and drugs conjugated with albumin can
also penetrate the BBB, and thus, anti-tumor drugs conjugated with
albumin may serve a role in the treatment of intracranial tumors
(41).
Considering the molecular subtype, brain metastases
and previous resistance to small-molecule TKI drugs of the patient
of the present study, the regimen of apatinib combined with
trastuzumab and albumin-bound paclitaxel was finally adopted.
Surprisingly, this combination regimen produced remarkable results.
After two courses of treatment, the patient's headache and vomiting
symptoms were significantly diminished, brain MRI indicated that
brain metastases were significantly reduced and brain edema was
significantly alleviated. This may be due to the synergistic
anti-tumor effect of apatinib and albumin-bound paclitaxel through
the BBB.
In conclusion, the present study reported on the
treatment of apatinib combined with trastuzumab and albumin-bound
paclitaxel for a patient with HER2-positive advanced breast cancer
with brain metastases who developed resistance to anti-HER2 drugs.
The curative effect of the combined treatment of this patient is
good. The symptoms of headache and vomiting were significantly
improved and the brain metastases were significantly reduced. This
case demonstrates the therapeutic effect of apatinib on brain
metastases of HER2-positive breast cancer. In the future, further
large-scale clinical trials are needed to clarify the role of
apatinib in patients with refractory brain metastasis of breast
cancer and HER2-targeted drug resistance.
Acknowledgements
Not applicable.
Funding
This work was supported by funds from Shenzhen Basic Research
Program (2018, grant no. JCYJ20180306171227129), the National
Natural Science Foundation of China (grant no. 81671750, 2016) and
the National Natural Science Foundation of Guangdong Province
(grant no. 2016A030312008).
Availability of data and materials
The datasets used and/or analyzed during the current
study are available from the corresponding author on reasonable
request.
Authors' contributions
JH and CD designed the study and wrote the
manuscript. JH, XC and LS confirmed the authenticity of all the raw
data analyzed and interpreted the data. XC and JG obtained medical
images (MRI scans) and analyzed patient data. YM and HZ contributed
to the study conception, overall design and quality control. All
authors read and approved the final manuscript.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the
patient for publication of the case report, including publication
of all clinical details and diagnostic images.
Competing interests
The authors declare that they have no competing
interests.
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