Introduction
Breast cancer is the most common cancer among women
in China, with a rising global incidence (1). Approximately 15–25% of breast cancer
cases are classified as triple-negative breast cancer (TNBC), a
subtype characterized by the absence of progesterone, estrogen and
human epidermal growth factor receptor-2 (HER-2) expression
(2). TNBC predominantly affects
younger women, is associated with a poor prognosis and has a high
risk of metastasis (3). Despite
advancements in treatment options, such as poly (ADP-ribose)
polymerase inhibitors for BRCA-mutated patients, immunotherapy
targeting programmed cell death-1 (PD-L1) positive tumors, and
antibody-drug conjugates, chemotherapy remains the primary
treatment for TNBC (4). However,
extensive clinical research and practice indicate limited benefits
from chemotherapy, with a median overall survival of 12.5 to 13.4
months and a median progression-free survival (PFS) of 2.8 to 5.3
months (5–8), highlighting the need for additional
treatment options (9). Given the
critical role of angiogenesis in tumor growth and metastasis,
anti-angiogenic therapy is an important strategy in managing
metastatic breast cancer (mBC) (10). The vascular endothelial growth
factor (VEGF)/VEGF receptor (VEGFR) signaling pathway is critical
in tumor angiogenesis and essential for tumor growth and metastasis
(11). Previous studies have shown
that patients with TNBC have higher VEGF levels compared with
patients that are non-TNBC (12).
Apatinib, an oral tyrosine kinase inhibitor (TKI), selectively
targets VEGFR-2 to inhibit tumor angiogenesis (13). In 2014, a multicenter phase II trial
by Hu et al (14) found that
apatinib monotherapy showed potential efficacy in heavily
pretreated patients with TNBC, with a median PFS time of 3.3 months
and overall survival time of 10.6 months. The results indicate that
an apatinib dose of 500 mg rather than 750 mg is the recommended
starting dose for the heavily pretreated mTNBC patients, with a
measurable rate of partial response and PFS. In another phase II
trial, camrelizumab (an immune checkpoint inhibitor) combined with
apatinib was administered to patients with advanced TNBC who had
received fewer than three lines of systemic therapy (15). The combination demonstrated good
efficacy and safety, with a median PFS of 3.7 months. Additionally,
a phase II trial involving locally advanced and patients with
metastatic TNBC who had received at least one line of chemotherapy
(including anthracyclines or taxanes) treated with camrelizumab
plus apatinib and eribulin (16)
showed a median PFS of 8.1 months, with manageable toxicity.
Vinorelbine, a semisynthetic vinca alkaloid
chemotherapeutic agent, inhibits microtubule assembly, blocking
mitosis at the G2-M phase and leading to cell death
(17–19). Compared with intravenous
administration, oral administration provides higher quality of life
and lower disease burden for patients (20). Oral vinorelbine, either as
monotherapy or in combination with other agents (capecitabine and
trastuzumab), has shown efficacy in treating mBC (21). Previous studies reported that the
objective response rate (ORR) for oral vinorelbine monotherapy as
first-line treatment for mBC was 29–31%, with a median PFS of 17.4
weeks to 5.2 months (22,23). However, when combined with
capecitabine as first-line therapy, the ORR increased to 44.2–51%,
and the PFS reached 8.4 months (24,25).
Approximately 1% of the global population suffers
from schizophrenia (SCZ) (26).
Previous meta-analyses have shown that women with SCZ have an
increased risk of developing breast cancer compared with the
general female population (27–29). A
retrospective study in 2010 indicated that SCZ does not affect the
treatment process or outcomes for patients with breast cancer
(30). The current understanding of
the relationship between SCZ and breast cancer remains limited, but
both conditions require long-term care (31–33).
Oral vinorelbine monotherapy for first-line
treatment of mBC has shown low ORRs and short median PFS (22,23).
Current research data suggests that anti-angiogenic drugs are
primarily used for second-line and beyond treatment in advanced
breast cancer, with limited use in first-line treatment (34). The present report examined the
efficacy and safety of the combination of oral vinorelbine and
apatinib in first-line treatment of a patient with advanced TNBC
and SCZ, after failure of anthracyclines and taxanes in the
adjuvant setting.
Case report
A 52-year-old female patient with a history of
pregnancy and no family hereditary diseases, weighing 79 kg, with a
height of 152 cm, a body surface area of 1.78 m2, a BMI
of 37.65 kg/m2 and an Eastern Cooperative Oncology Group
performance status of 1 was first admitted to National Cancer
Center/National Clinical Research Center for Cancer/Cancer Hospital
and Shenzhen Hospital, Chinese Academy of Medical Sciences and
Peking Union Medical College (Shenzhen, China) in January 2018. In
July 2013, the patient had visited an external hospital due to
bilateral breast mass and underwent a bilateral modified radical
mastectomy for breast cancer (data not shown). Postoperative
pathology reported: Primarily ductal carcinoma in situ in
both breasts, with local infiltration, histological grade II for
the infiltrative part, no vascular invasion, right breast tumor
size 7.5×5×4 cm, left breast tumor size 2.5×2 cm, left axillary
lymph nodes 0/18, right axillary lymph nodes 0/28.
Immunohistochemistry results: ER(−), PR(−), CerbB-2(−), Ki-67
(20–30% +). From September 2013 to February 2014, the patient
received 4 cycles of EC regimen chemotherapy (epirubicin 150 mg IV
+ cyclophosphamide 1 g IV, every 3 weeks) followed by 4 cycles of T
regimen chemotherapy (docetaxel 180 mg IV, every 3 weeks). The
patient also underwent adjuvant radiotherapy, followed by regular
follow-ups twice a year. In November 2017, the patient noticed a
gradually enlarging left cervical lymph node, accompanied by a
cough and left chest wall pain. The patient presented to the
National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of
Medical Sciences and Peking Union Medical College for the first
time in January 2018. A thoracoabdominal enhanced CT scan revealed
multiple nodules in the chest wall, the largest being ~1.8×1.4 cm,
with enhancement observed post-contrast, which suggested metastatic
tumors. There was the destruction of the sternum bone with the
formation of soft tissue masses, indicating metastasis. Multiple
lymph node metastases were detected in the bilateral
supraclavicular fossa and mediastinum, the largest being ~2.2×1.5
cm. Multiple liver metastases were found, with the largest located
in segment S2 of the left lobe, ~3.0×3.0 cm. Multiple lymph nodes
in the bilateral neck regions II–IV were also identified, the
largest being ~1.4×1.3 cm, which was suggestive of metastasis.
Metastatic sites included the chest wall, sternal bone destruction
with soft tissue masses, multiple lymph nodes (bilateral
supraclavicular, mediastinal and bilateral cervical), and the
liver. Imaging showing significant metastatic lesions (Fig. 1). At 2 days post-admission in
January 2018, the patient underwent a fine-needle aspiration biopsy
of the left cervical lymph node. Postoperative pathology, performed
as previously described (35),
confirmed mBC to the lymph nodes. Immunohistochemistry results
showed ER(−), PR(−), Ki67 (~80% +), AR (30% positive cells,
moderate staining intensity), HER-2 (2+), CK5/6(−), TOPOII (~50%+),
E-Cad(+), EGFR(+) and p53 (100%, mutant type) and HER-2
fluorescence in situ hybridization gene testing was negative
(Figs. 2 and 3). The patient exhibited progressive
disease (PD), with a disease-free survival of 53 months. The
patient had a history of SCZ for >10 years, was currently
treated with risperidone dispersible tablets and benzhexol, and was
regularly followed at Kangning Hospital (a specialized psychiatric
hospital; Shenzhen, China) with stable disease control. The patient
also had a history of diabetes and hypertension; ongoing treatment
for hypertension and diabetes has kept these conditions stable.
 | Figure 3.Immunohistochemical and FISH analysis
of metastatic breast cancer: (A) Immunohistochemistry for Ki-67
(proliferation index ~80%; magnification, ×100). (B)
Immunohistochemistry for p53 (100% positive, mutant type;
magnification, ×100). (C) Immunohistochemistry for E-cadherin
(positive; magnification, ×100). (D) FISH analysis for HER2 gene
(no amplification, HER2:CEP17 ratio <2; magnification, ×400).
(E) Immunohistochemistry for AR (30% positive cells, moderate
staining intensity; magnification, ×200). (F) Immunohistochemistry
for TOPOIIA (~50% positive; magnification, ×200). AR, androgen
receptor; CEP17, chromosome enumeration probe 17; FISH,
fluorescence in situ hybridization; HER2, human epidermal growth
factor receptor 2; Ki-67, marker of proliferation Ki-67; p53, tumor
protein p53; TOPOIIA, DNA topoisomerase II α. |
Overall, the patient had a history of SCZ and breast
cancer, with recurrence and metastasis of breast cancer; however,
the patient's treatment adherence was poor and refused intravenous
chemotherapy. Considering the diagnosis of TNBC, which is known for
its aggressive biological behavior, high drug resistance, limited
treatment options and poor prognosis, angiogenesis is a critical
factor in tumor progression and metastasis. Combining drugs with
different mechanisms of action can provide survival benefits. A
study has shown that anti-angiogenic agents combined with
chemotherapy can significantly extend PFS time (16). Following biopsy and diagnosis, at 2
days post-admission in January 2018, the patient began first-line
treatment with oral vinorelbine capsules (140 mg on days 1 and 8,
every 3 weeks) combined with the small-molecule anti-angiogenic
drug apatinib at a reduced dose of 0.25 g (one tablet), once daily.
Concurrently, 4 mg zoledronic acid (intravenous infusion every 4
weeks) was administered to prevent bone destruction, along with
calcium supplementation and symptomatic pain relief. The
chemotherapy-induced adverse reactions included grade I nausea and
grade I neutropenia, which were well-tolerated. Apatinib-related
adverse events were closely monitored. Given that standard-dose
apatinib (0.5 g once daily) is associated with frequent
hypertension, a reduced dose of 0.25 g once daily was administered.
The patient had pre-existing hypertension and diabetes mellitus,
both well-controlled using oral valsartan-hydrochlorothiazide and
metformin. During apatinib treatment, blood pressure remained
stable without the need for additional antihypertensive therapy.
Urinalysis performed every 2–4 weeks was mostly negative for
protein; trace to 1+ proteinuria was noted on isolated occasions,
which could not be definitively attributed to apatinib given the
patient's long-standing diabetes. The patient developed grade 1
hand-foot syndrome, which was effectively managed with oral
mecobalamin and topical moisturizers. The patients SCZ remained
stable throughout and maintained regular follow-ups at Kangning
Hospital while continuing the prescribed risperidone and benzhexol.
No structured psychiatric scale was used, but clinical assessments
confirmed no worsening of psychotic symptoms. After one treatment
cycle, the chest wall mass decreased in size, and the cough
improved. After two cycles, the efficacy evaluation indicated
partial response PR (Fig. 4).
Treatment continued with evaluations every two cycles, and the
patient-maintained PR (Fig. 5).
After seven treatment cycles, between December 2018 and March 2019,
the patient discontinued treatment for 3 months. At the end of
March 2019, the patient returned for a follow-up chest and upper
abdominal CT scan, which revealed multiple lymph node metastases in
the anterior mediastinum, with the largest short diameter of ~2 cm,
showing progression from previous scans. The sternum and body bone
metastases had worsened (Fig. 6),
indicating PD due to the first discontinuation of medication. The
time from first-line initiation to this first progression was ~14
months but this was not a treatment-refractory progression; rather,
it followed patient-led discontinuation.
 | Figure 4.Chest and abdominal CT scans showing
response to oral vinorelbine combined with apatinib: Baseline
images and images after two cycles of treatment are shown. The
efficacy was evaluated as partial response. (A-1, B-1) Chest wall
metastasis, (A-2, B-2) Sternal bone destruction with soft tissue
mass formation, (A-3, B-3) Left supraclavicular lymph node
metastasis, (A-4, B-4) Mediastinal lymph node metastasis and (A-5,
B-5) Liver metastasis. Metastatic lesion size reduction: (A-1)
1.8×1.4 cm to (B-1): 0 cm, (A-2) 4.2×3.5 cm to (B-2): 1×1 cm, (A-3)
2.0×2.5 cm to (B-3): 1.2×1.0 cm, (A-4) 2.2×1.5 cm to (B-4): 0.8×0.5
cm and (A-5) 3.0×3.0 cm to (B-5): 1.0×0.5 cm. Red arrows indicate
metastases. CT, computed tomography. |
 | Figure 5.Chest and abdominal CT scans showing
sustained partial response after multiple cycles of oral
vinorelbine combined with apatinib. (A-1, B-1 and C-1) Chest wall
metastasis. (A-2, B-2 and C-2) Sternal bone destruction with soft
tissue mass formation. (A-3, B-3 and C-3) Left supraclavicular
lymph node metastasis. (A-4, B-4 and C-3) Mediastinal lymph node
metastasis. (A-5, B-5 and C-3) Liver metastasis. (A-1, A-2, A-3,
A-4 and A-5) Baseline images (January 2018), (B-1, B-2, B-3, B-4
and B-5) images after two cycles (March 2018), and (C-1, C-2, C-3,
C-4 and C-5) images after multiple cycles (December 2018) are
shown. Metastatic lesion size reduction: (A-1) 1.8×1.4 cm to (B-1)
0 cm to (C-1) 0 cm, (A-2) 4.2×3.5 cm to (B-2) 1×1 cm to (C-2) 1×0.8
cm, (A-3) 2.0×2.5 cm to (B-3) 1.2×1.0 cm to (C-3) 1.0×1.0 cm, (A-4)
2.2×1.5 cm to (B-4) 0.8×0.5 cm to (C-4) 0.8×0.4 cm and (A-5)
3.0×3.0 cm to (B-5) 1.0×0.5 cm to (C-5) 0 cm. CT, computed
tomography. |
 | Figure 6.Chest and abdominal CT scans showing
disease progression after discontinuation of oral vinorelbine and
apatinib. (A-1 and B-1) Chest wall metastasis. (A-2 and B-2)
Sternal bone destruction with soft-tissue mass formation. (A-3 and
B-3) Left supraclavicular lymph node metastasis. (A-4 and B-4)
Mediastinal lymph node metastasis. (A-5 and B-5) Liver metastasis.
(A-1, A-2, A-3, A-4 and A-5) Baseline images (December 2018) and
(B-1, B-2, B-3, B-4 and B-5) images after treatment discontinuation
(March 2019) are shown. Metastatic lesion size enlargement: (A-1) 0
to (B-1) 0 cm, (A-2) 1×0.8 to (B-2) 2×1.5 cm, (A-3) 1.0×1.0 to
(B-3) 2×2.2 cm, (A-4) 0.8×0.4 to (B-4) 2.0×1.5 cm and (A-5) 0 cm to
(B-5) 0 cm. CT, computed tomography. |
Due to disease progression after discontinuation of
treatment, the patient resumed the aforementioned vinorelbine plus
apatinib regimen at the end of March 2019. After two cycles, a
follow-up CT scan indicated multiple left anterior mediastinal
lymph node metastases, with the largest short diameter reduced to
~1.2 cm, showing notable improvement. The sternal and body bone
metastases showed reduced osteolytic components and increased
osteogenic changes, indicating improvement. The efficacy was
evaluated as PR (Fig. 7). The
patient continued the treatment regimen, maintaining PR on
subsequent evaluations (Fig. 8).
After being discharged in January 2020, the patient did not return
for treatment due to the COVID-19 pandemic. In April 2020, a
follow-up CT scan revealed multiple lymph nodes in the mediastinal
3A area, appearing slightly enlarged and possibly fused, with the
largest short diameter of ~1.1 cm, raising suspicion of lymph node
metastasis. The efficacy was evaluated as PD due to the second
discontinuation of medication (Fig.
9).
 | Figure 7.Chest and abdominal CT scans showing
re-partial response after resuming oral vinorelbine and apatinib:
(A-1 and B-1) Chest wall metastasis. (A-2 and B-2) Sternal bone
destruction with soft-tissue mass formation. (A-3 and B-3) Left
supraclavicular lymph node metastasis. (A-4 and B-4) Mediastinal
lymph node metastasis. (A-5 and B-5) Liver metastasis. (A-1, A-2,
A-3, A-4 and A-5) Baseline images (March 2019) and (B-1, B-2, B-3,
B-4 and B-5) images after two cycles of treatment (May 2019) are
shown. Metastatic lesion size reduction: (A-1) 0 cm to (B-1) 0 cm,
(A-2) 2×1.5 cm to (B-2) 1×0.8 cm, (A-3) 2×2.2 cm to (B-3) 1×1 cm,
(A-4) 2.0×1.5 cm to (B-4)1.8×1.0 cm and (A-5) 0 cm to (B-5) 0 cm.
CT, computed tomography. |
 | Figure 8.Chest and abdominal CT scans showing
sustained partial response after multiple cycles of resumed
treatment. (A-1 and B-1) Chest wall metastasis. (A-2 and B-2)
Sternal bone destruction with soft-tissue mass formation. (A-3 and
B-3) Left supraclavicular lymph node metastasis. (A-4 and B-4)
Mediastinal lymph node metastasis. (A-5 and B-5) Liver metastasis.
(A-1, A-2, A-3, A-4 and A-5) Baseline images (May 2019) and (B-1,
B-2, B-3, B-4 and B-5) images after multiple cycles (January 2020)
are shown. Metastatic lesion size reduction: (A-1) 0 cm to (B-1) 0
cm, (A-2) 1×0.8 cm to (B-2) 0.5×0.5 cm, (A-3) 1×1 cm to (B-3) 1×1
cm, (A-4) 1.8×1.0 cm to (B-4) 1.8×0.9 cm and (A-5) 0 cm to (B-5) 0
cm. CT, computed tomography. |
 | Figure 9.Chest and abdominal CT scans showing
disease progression after the second discontinuation of oral
vinorelbine and apatinib. (A-1 and B-1) Chest wall metastasis. (A-2
and B-2) Sternal bone destruction with soft-tissue mass formation.
(A-3 and B-3) Left supraclavicular lymph node metastasis. (A-4 and
B-4) Mediastinal lymph node metastasis. (A-5 and B-5) Liver
metastasis. (A-1, A-2, A-3, A-4 and A-5) Baseline images (January
2020) and (B-1, B-2, B-3, B-4 and B-5) images after treatment
discontinuation (April 2020) are shown. Metastatic lesion size
enlargement: (A-1) 0 cm to (B-1) 0 cm, (A-2) 0.5×0.5 cm to (B-2)
2×2 cm, (A-3) 1×1 cm to (B-3) 1.5×1.2 cm, (A-4) 1.8×0.9 cm to (B-4)
2×1.2 cm and (A-5) 0 cm to (B-5) 0 cm. CT, computed tomography. |
Due to disease progression likely associated with
the treatment discontinuation during the pandemic, the patient
resumed the vinorelbine soft capsules plus apatinib regimen for one
cycle. In May 2020, a follow-up CT scan of the neck, chest and
upper abdomen revealed multiple left anterior mediastinal lymph
node metastases, reduced in size compared with previous scans. The
lymph nodes in the mediastinal 3A area also decreased in size. The
efficacy was evaluated as PR (Fig.
10). The patient continued the same treatment regimen but did
not follow a regular treatment schedule from August 2022. In
February 2023, a follow-up CT scan of the neck, chest, abdomen and
pelvis indicated multiple enlarged lymph nodes in the right
supraclavicular area and mediastinal 3A area, indicating an
increase in size and number, with the largest measuring ~2.3×2.2
cm, which suggested metastasis. Multiple sternal and body bone
metastases with increased osteogenic changes were observed,
accompanied by thickening of the soft tissues behind the sternum
and the presence of a mass, partially worsening from previous
scans. The largest mass measured ~3.3×1.5 cm and had indistinct
borders with the posterior aortic arch, adjacent pericardium and
bilateral internal mammary areas, which suggested metastasis. The
irregular medication adherence led to disease progression, and the
efficacy was evaluated as PD (Fig.
11).
 | Figure 10.Chest and abdominal CT scans showing
re-partial response after resuming oral vinorelbine and apatinib
during the COVID-19 pandemic. (A-1 and B-1) Chest wall metastasis.
(A-2 and B-2) Sternal bone destruction with soft-tissue mass
formation. (A-3 and B-3) Left supraclavicular lymph node
metastasis. (A-4 and B-4) Mediastinal lymph node metastasis. (A-5
and B-5) Liver metastasis. (A-1, A-2, A-3, A-4 and A-5) Baseline
images (April 2020) and (B-1, B-2, B-3, B-4 and B-5) images after
one cycle of treatment (May 2020) are shown. Metastatic lesion size
reduction: (A-1) 0 cm to (B-1) 0 cm, (A-2) 2×2 cm to (B-2) 0.8×0.7
cm, (A-3) 1.5×1.2 cm to (B-3) 1.0×0.8 cm, (A-4) 2×1.2 cm to (B-4)
1.2×0.8 cm and (A-5) 0 cm to (B-5) 0 cm. CT, computed
tomography. |
 | Figure 11.Chest and abdominal CT scans showing
disease progression due to irregular use of oral vinorelbine and
apatinib. (A-1 and B-1) Chest wall metastasis. (A-2 and B-2)
Sternal bone destruction with soft-tissue mass formation. (A-3 and
B-3) Left supraclavicular lymph node metastasis. (A-4 and B-4)
Mediastinal lymph node metastasis. (A-5 and B-5) Liver metastasis.
(A-1, A-2, A-3, A-4 and A-5) Baseline images (May 2020) and (B-1,
B-2, B-3, B-4 and B-5) images after irregular treatment (February
2023) are shown. Metastatic lesion size enlargement: (A-1) 0 cm to
(B-1) 0 cm, (A-2) 0.8×0.7 cm to (B-2) 1.8×2 cm, (A-3) 1.0×0.8 cm to
(B-3) 1.5×1.4 cm, (A-4) 1.2×0.8 cm to (B-4) 1.8×1.1 cm and (A-5) 0
cm to (B-5) 0 cm. CT, computed tomography. |
Given the patient's localized lymph node progression
and no evidence of prior liver metastases, continuing the original
treatment regimen was recommended. However, as apatinib is a
self-funded medication, the patient refused to continue with
apatinib treatment. Therefore, from February 2023, the patient was
maintained on oral vinorelbine monotherapy. A follow-up CT scan in
June 2023, showed a reduction in the size of the cervical lymph
nodes, with the tumor assessment showing stable disease (SD) with
some reduction SDa (Fig. 12),
though not achieving PR, which indicated the efficacy of the
monotherapy. In January 2024, a follow-up CT scan revealed multiple
enlarged metastatic lymph nodes in the right supraclavicular area,
mediastinal 3A area and left internal mammary area, which had
increased in size compared with the previous scan. There was also
thickening of the soft tissues behind the sternum and a worsened
mass, with the largest lesion measuring ~3.4×2.2 cm. The efficacy
was evaluated as PD (Fig. 13). Due
to the patient's refusal to continue apatinib or intravenous
antitumor therapy, a second-line treatment regimen of oral
vinorelbine (140 mg taken orally on days 1 and 8, every 3 weeks)
plus capecitabine (1.0 g taken orally twice a day for 14 days,
followed by a 7-day rest, every 3 weeks), both within the scope of
medical insurance reimbursement, was initiated in January 2024. The
final CT scan in April 2024, showed that the tumor was stable but
with some enlargement SDb (Fig.
14). The patient discontinued the medication intermittently. At
the end of December 2025, the tumor progression was rechecked. The
patient had low expression of HER2. Since mid-December 2025, the
patient has received 6 cycles of trastuzumab deruxtecan treatment,
and the best assessment of efficacy is PR.
 | Figure 13.Chest and abdominal CT scans showing
disease progression with vinorelbine monotherapy. (A-1 and B-1)
Chest wall metastasis. (A-2 and B-2) Sternal bone destruction with
soft-tissue mass formation. (A-3 and B-3) Left supraclavicular
lymph node metastasis. (A-4 and B-4) Mediastinal lymph node
metastasis. (A-5 and B-5) Liver metastasis. (A-1, A-2, A-3, A-4 and
A-5) Baseline images (July 2023) and (B-1, B-2, B-3, B-4 and B-5)
images after vinorelbine treatment (January 2024) are shown.
Metastatic lesion size enlargement: (A-1) 0 cm to (B-1) 0 cm, (A-2)
1.6×1.7 cm to (B-2) 2.1×2.0 cm, (A-3) 1.4×1.4 cm to (B-3) 2.0×1.9
cm, (A-4) 1.6×1.0 cm to (B-4) 2.4×2.0 cm and (A-5) 0 cm to (B-5) 0
cm. CT, computed tomography. |
 | Figure 14.Chest and abdominal CT scans showing
steady augmentation (SDb) with vinorelbine combined with
capecitabine. (A-1 and B-1) Chest wall metastasis. (A-2 and B-2)
Sternal bone destruction with soft-tissue mass formation. (A-3 and
B-3) Left supraclavicular lymph node metastasis. (A-4 and B-4)
Mediastinal lymph node metastasis. (A-5 and B-5) Liver metastasis.
(A-1, A-2, A-3, A-4 and A-5) Baseline images (January 2024) and
(B-1, B-2, B-3, B-4 and B-5) images after treatment (April 2024)
are shown. Metastatic lesion size enlargement: (A-1) 0 cm to (B-1)
0 cm, (A-2) 2.1×2.0 cm to (B-2) 2.1×2.2 cm, (A-3) 2.0×1.9 cm to
(B-3) 2.0×2.2 cm, (A-4) 2.4×2.0 cm to (B-4) 2.5×2.1 cm, (A-5) 0 cm
to (B-5) 0 cm. CT, computed tomography. |
Overall, from the start of first-line therapy in
January 2018 to the last follow-up in April 2024, the patient
maintained disease control (albeit with several interruptions) for
>6 years.
Discussion
TNBC is associated with poor prognosis, especially
in heavily pretreated patients (19). Chemotherapy remains a critical
component in TNBC treatment, but extensive clinical studies and
practices have shown limited benefits, with a median PFS of 2.8 to
5.3 months for pretreated TNBC (20–23).
There is an urgent need for new treatment strategies. Angiogenesis
is closely linked to tumor growth and metastasis, making
anti-angiogenic therapy an important strategy in the treatment of
mBC (24).
Apatinib is a highly selective and effective VEGFR
TKI with a high affinity for VEGFR2. It selectively binds to and
inhibits VEGFR-2 activity, blocking tumor angiogenesis and
inhibiting tumor growth (10).
Additionally, apatinib is administered orally, avoiding injections
and reducing hospitalization, with daily dosing to maintain stable
blood drug levels. A previous study demonstrated the benefits of
apatinib for patients with TNBC (14). The combination of anti-angiogenic
drugs with chemotherapy may act synergistically, though further
research is needed to confirm and improve patient outcomes
(26). In the present case, the
combination of apatinib with oral vinorelbine was well-tolerated
with only grade 1 nausea, grade 1 neutropenia and grade 1 hand-foot
syndrome. Notably, a reduced apatinib dose (0.25 g daily) was used
to minimize toxicity. Despite the patient's baseline hypertension
and diabetes, no grade >2 hypertension or clinically significant
proteinuria developed. Mild, intermittent proteinuria (trace to 1+)
was observed but could not be unequivocally separated from diabetic
nephropathy. The patient's SCZ remained stable under regular
psychiatric follow-up at Kangning Hospital. These observations
suggested that low-dose apatinib combined with oral vinorelbine has
a manageable safety profile, even in a patient with multiple
comorbidities and a major psychiatric disorder.
TNBC is known for its high risk of recurrence and
metastasis. For first-line treatment, if patients are sensitive,
re-administration of taxanes can be considered. For those resistant
to taxanes, options include vinorelbine, capecitabine, gemcitabine,
platinum-based regimens or immunotherapy. However, most of these
chemotherapeutic agents require intravenous administration, with
limited options available for oral chemotherapy (23). The present study reported a case of
a patient with SCZ, whose condition was managed with long-term oral
medication. Given the patient's adherence and the risk of
exacerbating SCZ, an oral antitumor treatment regimen was chosen.
Although anti-angiogenic drugs are mainly used in second-line and
beyond for advanced TNBC, a study has confirmed the efficacy of
combining chemotherapy with anti-angiogenic drugs (14). Low-dose apatinib not only reduced
toxic side effects but also showed good efficacy and safety when
combined with chemotherapy in the present case. For the present
patient, an individualized treatment plan was implemented,
combining oral vinorelbine capsules with the oral anti-angiogenic
drug apatinib. This regimen achieved a long period of disease
control (>6 years from the start of first-line therapy, despite
several interruptions). However, it is should be noted that the
patient did not experience a continuous 6-year PFS. The first
progression occurred after voluntary treatment cessation at 14
months; subsequent progressions were also related to non-adherence
or the COVID-19 pandemic. Each time the original regimen was
reintroduced, a PR was regained. Therefore, the durable disease
control reflects intermittent treatment benefit, rather than a
single unbroken PFS. However, due to poor adherence and the impact
of the COVID-19 pandemic, treatment interruptions led to disease
progression. Upon resuming vinorelbine and apatinib, partial
remission remained achievable. Since apatinib is an off-label drug
not covered by insurance, the patient signed an informed consent
form for off-label use before treatment and initially agreed to the
regimen. However, the patient eventually discontinued apatinib due
to its cost and switched to vinorelbine monotherapy. The
best-evaluated efficacy of monotherapy was SDa. Although
vinorelbine alone had some efficacy, it was less effective than the
combination of vinorelbine and apatinib. The disease eventually
progressed, and the patient refused intravenous chemotherapy.
Consequently, the second-line treatment was adjusted to a
combination of vinorelbine and capecitabine (dual vinorelbine),
with the best-evaluated efficacy SDb.
A direct comparison between the combination and
vinorelbine alone or vinorelbine plus capecitabine is not feasible
due to sequential treatment, changing tumor biology and different
lines of therapy. Vinorelbine alone was given after prolonged prior
exposure, and vinorelbine plus capecitabine was used in a more
treatment-refractory setting. Thus, it cannot be concluded that the
combination is superior to either of these subsequent regimens. The
most robust observation is that retreatment with the original
combination after a break led to partial remission. It could be
considered that if the patient had no financial constraints and
maintained good adherence to the vinorelbine plus apatinib regimen,
the disease may have been better controlled, potentially achieving
an even longer PFS (>6 years). Throughout the treatment, the
patient experienced mild side effects and tolerated the regimen
well, highlighting the importance of individualized treatment to
improve symptoms, enhance quality of life and extend survival for
patients with advanced breast cancer.
In the current case report, the treatment strategy
for a patient with advanced breast cancer is presented, which
highlighted the sustained efficacy of using vinorelbine capsules in
a cross-line approach. For advanced breast cancer, it is essential
to avoid immediate medication changes upon disease progression and
to assess the metastasis sites. Initially, the patient's metastases
included the chest wall, multiple lymph nodes, sternum and liver.
Following treatment with vinorelbine capsules and apatinib, the
liver lesions achieved clinical complete remission (CR). A previous
study suggested that vinorelbine alone may not be highly effective
against liver metastases (36),
highlighting the significant benefit of combining chemotherapy with
anti-angiogenic therapy (14).
During treatment, the patient experienced disease progression twice
due to treatment discontinuation and once due to irregular
medication adherence. After evaluating the disease progression, the
medication was not changed, but continued with the original
regimen, achieving partial remission. Later, due to financial
constraints, the patient discontinued apatinib and continued with
vinorelbine monotherapy, leading to disease progression. Given the
patient's refusal of intravenous chemotherapy and the limited oral
treatment options (such as capecitabine), and considering that
liver lesions remained in clinical CR while progression was mainly
in multiple lymph nodes and bones without new lesions or metastasis
to vital organs such as the lungs or brain, a cross-line approach
with vinorelbine capsules combined with capecitabine was
chosen.
The present case and previous related studies
(14,26) indicated that the combination of
chemotherapy and anti-angiogenic drugs has a synergistic effect.
This combination shows efficacy in second-line and subsequent lines
of treatments, and provides greater benefits in first-line
treatment. Consequently, it could be suggested that the combination
of chemotherapy and anti-angiogenic drugs can achieve notable
efficacy in first-line treatment, and potentially extend PFS beyond
the median PFS reported in previous studies. However, given the
single-case nature, these findings are hypothesis-generating rather
than definitive. Further prospective studies are needed to confirm
this hypothesis.
Notably, key molecular data are missing from the
present study. Germline BRCA status and PD-L1 expression were not
tested. These tests were recommended to the patient, but the
patients family declined due to the out-of-pocket cost and the
patient's multiple comorbidities. In addition, given the patient's
poor adherence and refusal of intravenous therapy, the clinical
utility of these tests for guiding treatment in this specific
setting was considered limited. Therefore, potential homologous
recombination deficiency or immunotherapy responsiveness could not
be evaluated in the present case. This limitation underscores that
the present findings are specific to a highly selected patient
population.
Additionally, throughout the treatment, the
patient's SCZ remained stable without exacerbation. SCZ is a
chronic disorder with an unknown etiology. Data on the natural
progression of breast cancer in patients with SCZ are limited.
Meta-analyses have indicated a 31% increased risk of breast cancer
in patients with SCZ, though significant heterogeneity exists among
studies (3,37). Clinical data on patients with breast
cancer with SCZ are scarce due to the lower incidence of breast
cancer among women with SCZ (1),
the low genetic correlation between the two diseases (24,25),
and the small proportion of SCZ genetic factors influencing breast
cancer risk (27). A prospective
cohort study revealed that the treatment protocol from consent to
chemotherapy for patients with breast cancer with SCZ is comparable
to that of patients without SCZ. A history of severe mental illness
should not automatically exclude individuals from research studies.
Furthermore, there was no observed correlation between disease
progression and worsening psychological symptoms during treatment
(38). Evidence suggests that SCZ
does not affect the treatment process or prognosis of breast
cancer. The relationship between breast cancer and SCZ is complex,
with limited studies addressing the management of patients with
cancer and SCZ. A previous study reported that patients with SCZ
might struggle to adhere to comprehensive treatment plans, often
facing difficulties in daily functioning and social interactions,
which imposes a significant economic burden (10). Various behaviors may complicate
clinical management; patients with SCZ are 4–6 times more likely to
exhibit violent behavior compared with the general population
(11), and the suicide rate is
5–13% higher. The risk of developing breast cancer from long-term
use of antipsychotic medications remains controversial.
During the COVID-19 pandemic, numerous patients with
cancer experienced delays in receiving intravenous treatments. Oral
vinorelbine capsules combined with apatinib offers a convenient
treatment alternative for patients with advanced TNBC. In
conclusion, the present case report illustrates that vinorelbine
capsules combined with low-dose apatinib as first-line treatment
achieved tumor control in a patient with advanced TNBC and SCZ who
progressed after anthracycline and taxane adjuvant therapy. The
regimen was well-tolerated, with only mild adverse events, and did
not worsen psychiatric symptoms. However, the findings are limited
to a single patient, and molecular characterization (such as BRCA
and PD-L1 status) was not performed. Direct comparisons with other
regimens are confounded by treatment history and adherence issues.
This approach may represent a personalized strategy for similar
complex patients with contraindications to intravenous therapy, but
requires prospective validation.
Acknowledgements
Not applicable.
Funding
The present study was supported by Shenzhen High-level Hospital
Construction (grant no. SZXK013) and Sanming Project of Medicine in
Shenzhen (grant nos. SZSM202211012 and SZSM202411002).
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
XB and CD designed the study and wrote the
manuscript. DW, WK, ML and XB obtained medical images and examined
patient information. XB, XC, LS and LC contributed to the study's
conceptualization, general design and quality assurance. XB, ML,
XC, LS and LC confirm the authenticity of all the raw data. All
authors have read and approved the final version of the
manuscript.
Ethics approval and consent to
participate
All procedures performed in studies involving human
participants were in accordance with the 1964 Helsinki declaration
and its later amendments or comparable ethical standards. The
present study was granted an exemption from ethics approval
approved by the Ethics Committee of National Cancer Center/National
Clinical Research Center for Cancer/Cancer Hospital and Shenzhen
Hospital, Chinese Academy of Medical Sciences and Peking Union
Medical College (Shenzhen, China).
Patient consent for publication
The patient's daughter provided written informed
consent for the publication of this case report and any related
images.
Competing interests
The authors declare that they have no competing
interests.
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