Several tumor markers and biomarkers, both tissue-
and serum-based, are currently used in the management of patients
with breast cancer (1-4),
among which, carbohydrate antigen 15-3 (CA 15-3) is considered a
specific tumor marker for breast cancer. At present, the main
utility of CA 15-3 is monitoring therapy in patients with advanced
breast cancer, especially in women with non-evaluable disease. Most
expert panels advise against the routine use of CA 15-3 in the
surveillance of asymptomatic patients who have undergone surgery
for breast cancer (5).
Systemic sclerosis (SSc) is a multi-system
autoimmune disorder characterized by autoantibody production,
endothelial damage with obliterative microvascular disease,
inflammation, and fibrosis affecting the skin and internal organs
(6,7). Cardiopulmonary involvement is a
common manifestation in SSc, which presents as either interstitial
lung disease (ILD) or pulmonary arterial hypertension (8), and is currently the leading cause of
disease-related morbidity and mortality in patients with
scleroderma (9). The most studied
and characterized biomarker for ILD is Krebs von den Lungen 6
(KL-6) (10,11). CA 15-3 is the shed or soluble form
of MUC-1 protein. MUC1 is strongly expressed by atypical and/or
regenerating type II pneumocytes in tissue sections obtained from
patients with ILDs (12-14).
Although CA 15-3 has been investigated as a biomarker in SSc-ILD,
its role remains unclear (15-17).
Herein, we report a case of coexisting SSc and recurrent breast
cancer who showed improvement in high CA 15-3 levels with
amelioration of ILD without any systemic cancer treatment.
A 60-year-old woman underwent mastectomy with
axillary lymph node dissection at JA Hiroshima General Hospital
(Hatsukaichi, Japan) in October 2014 after preoperative
chemotherapy (four cycles of docetaxel and trastuzumab, followed by
four cycles of cyclophosphamide, epirubicin, and fluorouracil) for
estrogen receptor-negative, HER2-positive right breast invasive
ductal cancer, T2N1M0 stage IIB (18). Postoperative radiation therapy with
50 Gy in 25 fractions to the supraclavicular lymph nodes and chest
wall was performed, followed by 14 cycles of 3-weekly
trastuzumab.
At 63 years old, contrast-enhanced computed
tomography (CT) performed as postoperative follow-up indicated
brain metastasis in the right occipital lobe without liver, lung,
or bone metastasis. She underwent γ-knife radiosurgery (20 Gy)
followed by the administration of perutuzumab, trastuzumab, and
weekly paclitaxel. After four cycles of perutuzumab, trastuzumab,
and weekly paclitaxel, she experienced shortness of breath with
minimal exertion, so the fifth course was canceled. CT revealed
ground-glass opacities and linear shadows in the peripheral lower
lobes of both lungs (Fig. 1).
Although the development of lung involvement associated with breast
cancer such as carcinomatous lymphangitis was initially suspected,
because of the increase in CA 15-3, we investigated other possible
causes of ILD (Fig. 2). From only
CT image, the possibility of interstitial lung disease due to
trastuzumab or pertuzumab cannot be ruled out (19). Bilateral sclerodactyly and facial
skin thickness were found on clinical examination without a history
of Raynaud's phenomenon and the finding of nail fold bleeding. A
test for anti-nuclear antibodies with a nucleolar pattern was
positive, at a titer of 1:320. Anti-double stranded DNA antibody,
specific antibodies against centromere, SSA/SSB, Scl-70, RNP, and
RNA polymerase III were negative. Pulmonary function tests showed a
severely reduced %VC of 50.8%, indicating restrictive ventilatory
impairment. Skin biopsies taken from the left index finger base and
extension side of the left elbow demonstrated increased thickness
of the dermis composed of broad and sclerotic collagen bundles
extending to the underlying subcutis without inflammatory cell
infiltration in hematoxylin and eosin stained-samples. These
findings were consistent with the late stage of scleroderma
(Fig. 3). From these findings, the
diagnosis of SSc-ILD was made according to the diagnostic criteria
for SSc proposed by the Ministry of Health, Labour and Welfare of
Japan. The treatment for recurrent breast cancer was discontinued,
and combination prednisone (PSL) (15 mg/day) and intravenous
cyclophosphamide (IVCY) (500 mg/4 weeks) therapy was administered
for induction treatment of SSc-ILD. PSL was tapered and
discontinued at 1 year and IVCY was given five times in total. At 6
months after the start of treatment, her symptoms, including cough
and dyspnea, had improved. CA 15-3 and KL-6 levels decreased
simultaneously, reflecting the therapeutic effect (Fig. 2), and CT showed improvement in the
ground-glass opacities in the peripheral lower lobes of both lungs
as compared with those before treatment (Fig. 4). This patient is receiving
treatment for SSc-ILD. The patient's SSc-ILD has not worsening and
her breast cancer has not recurred despite not receiving treatment
for four years.
SSc is a devastating disease of unknown etiology
that is characterized by systemic, immunological, vascular, and
fibrotic abnormalities and a heterogeneous clinical course.
Fibrosis, the hallmark of the disease, can affect the skin and
internal organs, including lung (20). As is well known, pulmonary
involvement is one of the most important features of SSc and often
the leading cause of exitus. SSc-ILD is one of the most severe
complications and is the main cause of SSc-related deaths (9,21);
however, review of contemporary literature suggests improved
survival among patients with SSc-ILD due to more aggressive
monitoring and treatment (22,23).
In clinical trials of SSc-ILD, change in forced vital capacity
(FVC) is commonly used as a primary outcome measure, as low FVC
predicts morbidity and mortality (24). Two landmark clinical trials, SLS-I
(25) and SLS-II (26), established cyclophosphamide and
mycophenolate mofetil as disease modifying therapies for SSc
patients with active ILD.
Taxanes, as well as other antineoplastic agents,
have many toxic effects. Therefore, whether the etiology of the
present case is drug-induced remains unclear. Taxane-induced
scleroderma-like skin changes were first reported in 1995, and
clinical characteristics include preceding edema, absence of
Raynaud's phenomenon, and negative scleroderma-specific
autoantibodies (46-49).
The clinical course is refractory to treatment and commonly
progressive even after discontinuation of the trigger drugs
(50). However, unlike the present
study, previous reports showed mainly skin disorders without ILD.
In addition, the positivity of anti-nuclear antibodies with a
nucleolar pattern in this case, which suggested the existence of
SSc-specific antibodies against RNA polymerase III, Th/To, U3-RNP,
and PM-Scl, helped us determine the diagnosis of SSc regardless of
taxane exposure (51).
CA 15-3 is the shed or soluble form of MUC-1
protein. MUC1 is a transmembrane mucin with marked overexpression
in human breast cancers as compared with that in normal ductal
breast epithelial cells (52). On
the other hand, MUC1 is strongly expressed by atypical and/or
regenerating type II pneumocytes in tissue sections obtained from
patients with ILDs (12-14).
Serum levels of KL-6, an N-terminal subunit of MUC-1 protein,
increases in the acute exacerbation of idiopathic pulmonary
fibrosis (IPF). Serum levels of KL-6 correlate with IPF severity
and prognosis (53). As both KL-6
and CA 15-3 exist in different positions of MUC1(54), CA 15-3 may retain significant
potential as an alternative biomarker for KL-6 in fibrotic lung
diseases (16-18,55).
In primary breast cancer, various studies have demonstrated that
elevated serum CA15-3 values at diagnosis are associated with
higher breast cancer stage, tumor size, positive axillary lymph
nodes, and worse overall survival and disease-free survival
(56-60).
In metastatic breast cancer, CA15-3 was measured serially in a
number of studies assessing their applications in early detection
of disease progression and monitoring therapy response (61-65).
On the other hand, CA15-3 was previously shown to be elevated in
serum of SSc-ILD patients and was associated with severe ILD
measured by fibrosis on HRCT, decreased FVC and DLCO and the
presence of dyspnoea (16,66). In a study performed by Celeste
et al on 221 SSc patients, among which 168 with ILD, CA15-3
serum levels were found to correlate with the extent of fibrosis
detected on HRCT as well as to be predictive for progression-free
survival, with progression being defined by a decline in either FVC
or DLCO (17). The present study
suggested that oncologists treating the patients with breast cancer
should know CA15-3 is also associated with the condition of ILD.
The concentration of some tumor-associated antigens (TAA) such as
CA19-9 and CA125 were reported to be elevated in the sera of
patients with SSc or systemic lupus erythematosus in comparison to
healthy subjects (67). Because of
public insurance coverage, the number of TAA for patients with
breast cancer that could be measured at one time is limited. CEA
could be measured for patients with breast cancer at the same time.
In this patient, CEA did not show outlier or abnormal changes.
Meanwhile, KL-6 has been reported as a tumor marker
in not only lung cancer, but also gastrointestinal, hepatic,
pancreatic, and breast cancers (68,69).
Kohno, the developer of KL-6 monoclonal antibody, noted that the
serum levels of KL-6 mucin were elevated in patients with
pulmonary, breast, and pancreatic adenocarcinomas (12). Elevation of KL-6 mucin in serum is
significantly associated with the behavior of breast cancer
(70) or lung cancer (68). Immunohistochemical analyses have
clarified KL-6 mucin's clinicopathological significance in
digestive organ cancer tissues. As the expression profile and
clinicopathological significance of KL-6 mucin differ among each
organ or disease, the biological role of KL-6 mucin might have a
different importance in each location and state (68). Thus, the nature of KL-6 mucin
remains unclear, and further investigations of KL-6 mucin in cancer
are expected in the future.
In conclusion, serum levels of CA 15-3 correlated
with the condition of SSc-ILD in a patient with recurrent breast
cancer. This case suggests the importance of considering a
differential diagnosis including ILD concurrently while screening
for the progression of recurrent breast cancer when encountering
patients with breast cancer and elevated levels of CA 15-3.
The authors would like to thank Mrs. Takamoto and
Mrs. Nishimoto (Nursing Department, Hiroshima General Hospital) for
their special help with breast cancer nursing care.
Funding: No funding was received.
All data generated or analyzed during this study are
included in this published article.
MO wrote the draft and critically revised the
manuscript for important intellectual content. MO performed
surgical and post-operative treatment. MO, YK, TS and KK
contributed to the conception of the work, and interpreted and
revised the results of the CT included in this report. YY treated
the patient for SSc-ILD. YD diagnosed the disease pathologically.
YY, SM, AT, AO, IN, MS, KI, MW, and YD collected and analyzed both
the clinical laboratory and histopathological data. MO and YY
confirm the authenticity of all the raw data. All authors read and
approved the final manuscript.
Not applicable.
Written informed consent was obtained from the
patient for publication of this case report and any accompanying
images.
The authors declare that they have no competing
interests.
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