Download Complete response of brain metastases from breast cancer after

　Case Report
Kitasato Med J 2013; 43: 145-150　Complete response of brain metastases from breast cancer after
therapy with lapatinib plus capecitabine: case report
Mariko Kikuchi, Yoshimasa Kosaka, Norihiko Sengoku, Yoko Kohno, Hiroshi Nishimiya,
Mina Waraya, Hiroshi Katoh, Takumo Enomoto, Hirokazu Tanino,
Masaru Kuranami, Masahiko Watanabe
Department of Surgery, Kitasato University School of Medicine
A 60-year-old postmenopausal woman presented with a lump in her right breast. Physical examination
revealed a 3-cm breast tumor and right axillary lymphadenopathy. The patient was diagnosed with
breast cancer in the right breast and underwent mastectomy and right axillary lymphadenectomy. The
pathological findings were: 1.5 cm tumor, invasive ductal carcinoma (Grade 3 [poorly differentiated]),
lymph node metastases (+) estrogen receptor (-) progesterone receptor (-) HER2 (3+) T1N2M0 and
stage IIIA. Multiple bone metastases were detected 24 months after surgery, for which the patient
underwent radiation therapy. In addition, trastuzumab monotherapy was initiated. Multiple brain
metastases were detected 32 months after surgery, and whole brain radiation therapy was administered.
Metastases to the lung, liver, and spleen were simultaneously detected. The brain metastases became
worse 41 months after surgery. Therefore, combination therapy consisting of lapatinib plus capecitabine
was initiated. There was complete resolution of the brain metastases after 4 months of therapy. We
described a HER2-positive breast cancer patient with metastatic disease, who achieved complete
response of her brain metastases due to lapatinib plus capecitabine therapy.
Key words: HER2-positive metastatic breast cancer, lapatinib, capecitabine, brain metastases,
complete response
indicated that lapatinib provides favorable responses, only
a few studies have shown that lapatinib achieved complete
response (CR) in patients with brain metastases.5,6
Here, we report a patient with brain metastases from
HER2-positive breast cancer who was successfully treated
using lapatinib plus capecitabine (LC).
Introduction
M
olecularly targeted drugs have improved the
prognosis of patients with human epidermal
growth factor receptor-2 (HER2)-positive breast cancer.
Lapatinib is a specific inhibitor of tyrosine kinase activity
in both the epidermal growth factor receptor (EGFR)
and HER2. 1 A phase III clinical study of lapatinib
combined with capecitabine (EGF100151) for women
with advanced breast cancer that had progressed on
trastuzumab revealed that the response rate (RR) and
clinical benefit rate (CBR) were 23.7% and 29.3%,
respectively, which indicated that this combination was
more effective than capecitabine alone, with a RR of
13.9% and CBR of 17.4%.2 Patients with HER2-positive
breast cancer frequently develop brain metastases, which
have poor prognosis. Therefore, appropriate treatments
for patients with HER2-positive breast cancer metastatic
to the brain are needed.3,4 Although several studies of
treatments for patients with metastatic breast cancer have
Case Report
The patient was a 60-year-old Japanese postmenopausal
woman who presented with a lump in her right breast.
Physical examination revealed a 3-cm tumor in her right
breast and right axillary lymphadenopathy. The patient
was diagnosed with invasive ductal carcinoma (T1N2M0,
stage IIIA) and underwent a mastectomy with axillary
lymph node dissection.
The histopathologic findings included a 1.5 -cm
invasive ductal carcinoma (Grade 3 [poorly differentiated])
and axillary lymph node metastases (5/22).
Immunohistological analysis showed a HER2-type breast
Received 28 February 2013, accepted 2 April 2013
Correspondence to: Yoshimasa Kosaka, Department of Surgery, Kitasato University School of Medicine
1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
E-mail: [email protected]
145
Kikuchi, et al.
cancer (negative for expression of estrogen and
progesterone receptors and positive for expression of
HER2). The patient refused postoperative adjuvant
therapy and was closely observed. A compression fracture
of the cervical spine occurred 24 months after surgery,
and multiple bone metastases were found. She received
radiation therapy to her cervical spine (total dose, 30 Gy)
and trastuzumab monotherapy. Seven months after
initiation of trastuzumab therapy, multiple metastases in
the brain, lung, liver, and spleen were discovered. The
patient's only symptom was vertigo without paralysis.
Since multiple brain metastases were observed, the
patient underwent whole brain radiotherapy (WBRT),
receiving a total dose of 20 Gy. She continued to receive
trastuzumab therapy, and 9 months after WBRT, the brain
metastases had increased in size, and the patient's tumormarker levels (including carcinoembryonic antigen
[CEA] and cancer antigen 15-3 [CA 15-3]) had also
increased. LC was then initiated as a second-line
treatment.
Lapatinib was administered at a dose of 1,250 mg/
day orally and capecitabine was given at a dose of 2,000
A. Three metastatic brain tumors B. The tumors resolved after 4 months
(maximum, 1.2 cm) in both frontal of lapatinib plus capecitabine
lobes, and 6 tumors (maximum, 1.5 cm) combination therapy.
in the cerebellar hemispheres, were
revealed by computed tomography
(CT) before radiation therapy and
lapatinib plus capecitabine
combination therapy.
Figure 1. Head CT
A. Multiple metastases to the lung were B. The sizes of the tumors in the lung
detected on CT prior to treatment.
decreased after treatment.
Figure 2. Chest CT
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Complete response of brain metastases from breast cancer
A. A 1.3-cm metastatic
tumor in S5 of the liver
was detected on
ultrasonography (US)
prior to treatments.
B. The liver tumor
decreased to 0.6 cm after
treatments.
C. A 4.2-cm metastatic
tumor in the spleen was
detected on US prior to
treatments.
D. The splenic tumor
decreased to 2.4 cm after
treatments.
Figure 3. Ultrasonography
A. Abnormal accumulation of 99mtechnetium B. 99Technetium accumulation at the
in the skull, sternum, vertebral body, bilateral metastatic sites disappeared after
pelvic bones, and femurs was detected on treatments.
bone scintigraphy prior to treatment.
Figure 4. Bone scintigraphy
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Kikuchi, et al.
mg/m2/day for 14 days of a 21-day cycle. Four months
after the initiation of LC therapy, computed tomography
showed complete resolution of the brain metastases and
a partial response (PR) of the lung metastases (Figures 1
and 2, respectively). Abdominal ultrasonography and
bone scintigraphy revealed PR of the liver, spleen, and
bone metastases (Figures 2-4, respectively).
The levels of CEA and CA 15-3 increased with the
appearance of the bone metastases and then decreased
after trastuzumab initiation. The levels increased again
after exacerbation of the brain metastases, but decreased
after the initiation of LC therapy (Figure 5).
patients with HER2-positive breast cancer.16-19 However,
these drugs have a limited effect on brain metastases
because they cannot penetrate the blood-brain barrier
(BBB). Therefore, trastuzumab and chemotherapy are
not first-line treatments for brain metastases.
Small tumors and a low number of metastatic foci in
the brain should be treated using surgery and stereotactic
radiosurgery (SRS).20 In the patient in the present study,
WBRT was administered because she had multiple brain
metastases. Additionally, trastuzumab, a recombinant
humanized monoclonal antibody against HER2, was
administered as a systemic therapy. WBRT induced
stable disease, but the brain metastases increased 9 months
after RT, and there were increases in tumor marker levels.
LC was then chosen as the subsequent therapeutic
regimen.
Lapatinib is a small-molecule inhibitor (943 Da) of
the intracellular tyrosine kinase domains of both EGFR
and HER2. Data indicate that it penetrates the BBB,
whereas trastuzumab, with a high molecular mass
(148,000 Da), does not efficiently cross the BBB, which
accounts for its poor efficacy against brain metastases.
Lapatinib is used for advanced or metastatic HER2positive breast cancer resistant to anthracyclines, taxanes,
Discussion
The prognosis of breast cancer patients has improved
with advances in cancer therapeutics. However, 25%34% of patients develop brain metastases.7 In particular,
patients with HER2-positive breast cancer have a high
risk of brain metastases.8,9 One-third of patients with
HER2-positive metastatic breast cancer who are being
treated with trastuzumab develop brain metastases, which
occur within 2 years.3,10-15 Trastuzumab and chemotherapy
are effective against metastases to extracranial organs in
Figure 5. Tumor marker
Tumor marker levels increased with the appearance of bone metastases and decreased
once after trastuzumab initiation. The tumor marker levels subsequently increased
with the exacerbation of brain metastases but decreased after lapatinib plus capecitabine
therapy.
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Complete response of brain metastases from breast cancer
3. Clayton AJ, Danson S, Jolly S, et al. Incidence of
cerebral metastases in patients treated with
trastuzumab for metastatic breast cancer. Br J Cancer
2004; 91: 639-43.
4. Lin NU, Bellon JR, and Winer EP. CNS metastases
in breast cancer. J Clin Oncol 2004; 22: 3608-17.
5. Ro J, Park S, Kim SB, et al. Clinical outcomes of
HER2-positive metastatic breast cancer patients with
brain metastasis treated with lapatinib and
capecitabine: an open-label expanded access study
in Korea. BMC Cancer 2012; 12: 322.
6. Abboud M, Saghir NS, Salame J, et al. Complete
response of brain metastases from breast cancer
overexpressing Her-2/neu to radiation and concurrent
Lapatinib and Capecitabine. Breast J 2010; 16: 6446.
7. Shmueli E, Wigler N, and Inbar M. Central nervous
system progression among patients with metastatic
breast cancer responding to trastuzumab treatment.
Eur J Cancer 2004; 40: 379-82.
8. Pestalozzi BC, Zahrieh D, Price KN, et al. Identifying
breast cancer patients at risk for Central Nervous
System (CNS) metastases in trials of the International
Breast Cancer Study Group (IBCSG). Ann Oncol
2006; 17: 935-44.
9. Gabos Z, Sinha R, Hanson J, et al. Prognostic
significance of human epidermal growth factor
receptor positivity for the development of brain
metastasis after newly diagnosed breast cancer. J
Clin Oncol 2006; 24: 5658-63.
10. Park YH, Park MJ, Ji SH, et al. Trastuzumab
treatment improves brain metastasis outcomes
through control and durable prolongation of systemic
extracranial disease in HER2-overexpressing breast
cancer patients. Br J Cancer 2009; 100: 894-900.
11. Bendell JC, Domchek SM, Burstein HJ, et al. Central
nervous system metastases in women who receive
trastuzumab-based therapy for metastatic breast
carcinoma. Cancer 2003; 97: 2972-7.
12. Lin NU, Dieras V, Paul D, et al. Multicenter phase II
study of lapatinib in patients with brain metastases
from HER2-positive breast cancer. Clin Cancer Res
2009; 15: 1452-9.
13. Metro G, Sperduti I, Russillo M, et al. Clinical utility
of continuing trastuzumab beyond brain progression
in HER-2 positive metastatic breast cancer.
Oncologist 2007; 12: 1467-9; author reply 1469-71.
14. Ono M, Ando M, Yunokawa M, et al. Brain
metastases in patients who receive trastuzumabcontaining chemotherapy for HER2-overexpressing
metastatic breast cancer. Int J Clin Oncol 2009; 14:
48-52.
15. Duchnowska R, Dziadziuszko R, CzartoryskaArlukowicz B, et al. Risk factors for brain relapse in
HER2-positive metastatic breast cancer patients.
Breast Cancer Res Treat 2009; 117: 297-303.
and trastuzumab and is recommended for combined use
with capecitabine. Lin et al.12 conducted a phase II clinical
study of lapatinib for patients with brain metastases from
HER2-positive breast cancer. PR was achieved in 10
(20%) of 50 patients who received LC therapy. Of these
50 patients, the tumor sizes of 11 (22%) patients were
decreased more than 50%, and those of 20 (40%) patients
was decreased more than 20%.12
Although Lin et al.21,22 have also conducted several
lapatinib clinical trials on patients with HER2-positive
breast cancer metastasizing to the brain, CR was not
achieved in any patient. Ro et al.5 administered LC to
patients with HER2-positive breast cancer metastasizing
to the brain. CR was achieved in 2 of 47 patients who
received WBRT.5 Abboud et al.6 reported 1 patient with
brain metastases from HER2-positive breast cancer who
achieved CR after LC. Because there have been few
case reports on patients with CR of brain metastases
from breast cancer after LC therapy, the present study
provides additional support for the efficacy of LC. The
present study suggests that LC therapy may have a
significant efficacy for brain metastases from breast
cancer.
Diarrhea, hand-foot syndrome, nausea, vomiting, and
skin eruption have frequently been reported as adverse
effects of lapatinib therapy. Serious adverse events such
as interstitial pneumonia and cardiac disorders have also
been reported.2 Serious adverse events did not occur in
the patient in the present study.
The efficacy of pertuzumab for metastatic breast
cancer, an anti-HER2 humanized monoclonal antibody
that inhibits receptor dimerization, was recently
reported.23 The therapeutic options for patients with
HER2-positive breast cancer will likely, therefore,
increase in the near future. We reported a patient with
brain metastases from HER2-positive breast cancer, who
achieved complete response to lapatinib plus capecitabine
combination therapy.
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