Japanese Journal of Clinical Oncology 33:229-231 (2003)
© 2003 Foundation for Promotion of Cancer Research
Durable Remission of Leptomeningeal Metastasis of Breast Cancer with Letrozole: a Case Report and Implications of Biomarkers on Treatment Selection
1 Division of Medical Oncology, Department of Internal Medicine, Akdeniz University Medical School, Antalya and 2 Department of Radiology, Radon Medical Center, Antalya, Turkey
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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We report a breast cancer patient with leptomeningeal carcinomatosis (LM) who showed an excellent objective and subjective response to letrozole, with a progression-free survival of 16 months. We think that despite the poor prognosis and short survival of patients with LM, early diagnosis and treatment with appropriate hormonal manipulation may improve the outcome and achieve prolonged palliation in selected hormone-positive breast cancer patients with LM. Possible clues predicting the response were also evaluated in the context of literature data.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Neoplastic meningitis occurs in ~5% of patients with cancer and is being recognized with increasing frequency as imaging studies improve and as patients live longer. Among solid tumors, breast cancer is the primary tumor most frequently associated with leptomeningeal metastasis (LM). About 2–5% of patients with breast cancer will develop LM, usually late in the course of their disease (1,2). Tumor cells reach the leptomeninges by direct extension or hematogenous spread and disseminate throughout the neuraxis by the flow of the cerebrospinal fluid (CSF). The most common sign is multiple cranial nerve palsies, but headache, backache, polyradiculopathies, incontinence, confusional state, lower motor neuron weakness and sensory abnormalities may be the principal manifestation. Focal neurological signs and seizures may be seen and about half the patients develop hydrocephalus (2,3). The prognosis is poor with a median survival of 2–4 months; therefore, most treatment interventions are palliative. Radiotherapy should be given to sites of bulky or symptomatic tumor. Intrathecal chemotherapy is most effective in patients with lymphoma, leukemia and breast cancer. However, intrathecal treatment requires invasive procedures, preferably implantation of an Ommaya reservoir or repeated lumbar punctures.
To the best of our knowledge, there are only two cases of LM from breast cancer that were treated solely with hormonal manipulation (3). Tamoxifen was the preferred agent and treatment of LM with aromatose inhibitors has not previously been reported.
We report here a case of LM from breast cancer that was treated with letrozole and long-term survival of more than 21 months.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 41-year-old premenopausal woman with grade II lobular carcinoma with negative axillary lymph nodes underwent left mastectomy in May 1998. After adjuvant chemotherapy with CMF, persistent amenorrhea was established. She was not offered tamoxifen because the tumor was ER negative in first evaluation. In May 2000, the patient was admitted with a supraclavicular mass. Biopsy revealed lymph node metastasis and staging demonstrated bone metastases. Estrogen receptor was positive (30% +) and progesterone receptor was negative by immunohistochemistry, and treatment with tamoxifen was started. In February 2001 she experienced headache, insomnia, nausea, lightheadedness, vomiting and diplopia. Neurological examination revealed slight left papilledema and paralysis of the left sixth cranial nerve with normal strength, reflexes and sensory function. Magnetic resonance imaging showed cerebral and cerebellar LM. CSF analysis was negative for tumor cells, with a protein content of 49 mg/dl, a markedly decreased glucose level of 28 mg/dl and a slightly increased pressure. Serum CA-15.3 level was increased (from 63 to >300 IU/ml; normal <35 IU/ml). Computed tomography of the abdomen and thorax was normal. Bone scintigraphic imaging ruled out progression of bone metastasis. LM was diagnosed with positive imaging, strict neurological symptoms and signs, although cytology was negative. She was treated with palliative whole brain radiotherapy (RT) (300 cGy/day, total 3000 cGy) and six doses of intrathecal methotrexate after RT. Her complaints improved though neurological signs did not completely resolve. She received one cycle of cisplatin and etoposide; however, chemotherapy was stopped owing to long-lasting grade four neutropenia. In May 2001, the patient re-experienced headache, lightheadedness and diplopia. She was re-evaluated and progression of LM was established with MRI and positive CSF analysis for tumor cells consistent with breast cancer. Letrozole 2.5 mg/day was started and 1–2 months later her complaints resolved completely. Her CA-15.3 level decreased simultaneously. The patient continued letrozole treatment for a further 16 months without any problems. In August 2002, letrozole was stopped because of a local recurrence proved by a skin biopsy; however, no LM progression was noted. The relapsed tumor showed positive staining for estrogen receptor (90% +++), P-glycoprotein (90% ++), glutathione S-transferase (GST) (80% ++) and ErBB2/HER2-Neu (90% +++). Progesterone receptor was negative. The CA-15.3 level was also increased and megestrol acetate 160 mg/day was started. She gave a good response and local skin findings were improved. However, in December 2002 the patient again complained of headache, lightheadedness and low back pain. Neurological examination was normal. CSF analysis was cytologically positive, showing numerous malignant cells. The patient was treated first with intrathecal methotrexate and then cytosine arabinoside. However, she died in December 2002 due to progression of LM.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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Diagnosis of LM may not be completely straightforward at all times. Thus, first analysis of CSF cytology was negative in our case. However, in the initial lumbar puncture a positive cytology is found in only 50% of patients with neoplastic meningitis. The probability of diagnosis increases to 85% with three or more lumbar punctures (1). When LM is clinically suspected, neither a negative imaging study nor a single negative CSF cytology can rule out LM. Some radiological findings are highly suggestive or even diagnostic of LM. For example, the differential diagnosis is fairly limited when multiple subarachnoidal mass lesions are seen on MRI in a cancer patient with progressive neurological symptoms. Studies of experimental LM have demonstrated that these meningeal tumor deposits are well vascularized. This is also suggested by contrast enhancement of meningeal tumor after intravenous contrast administration on MRI scanning (3,4). As a conclusion, although initial cytology was negative in our patient, diagnosis of LM was certain because of typical symptoms, neurological signs and apparent MRI findings. Diagnosis was also confirmed with positive cytology during the first progression of disease and before the administration of letrozole.
Prompt initiation of whole-brain radiotherapy with or without intrathecal chemotherapy may be important for recovery from cranial nerve symptoms (5). Our case also showed an improvement with radiotherapy and intrathecal therapy. Since, after a primary partial response, an objectively demonstrated progression occurred before letrozole treatment, we do not think that this second very good response could be a prolonged effect of radiotherapy or chemotherapy.
ER status conversion is a relatively frequent event. Both from positive to negative and from negative to positive conversion may occur. Conversions from ER+ to ER– occur more often when the time interval between assays was less than 1 year, while conversions from ER– to ER+ tended to occur late and such patients had a longer survival than those whose recurrence was classified again as ER– (6). Our patient showed a conversion from negative to positive as the disease progressed. Therefore, when treating breast cancer patients, it is important to re-evaluate hormone receptors during relapse. We also know that false negativity may pose a problem in the diagnosis of hormonal receptors and there is considerable interlaboratory variability (7). Initial evaluation of ER in our case also might have been false negative or after surgery, yet unknown factors might cause proliferation of small amounts of hormone-positive tumor cells that were under the cut-off value of the first laboratory. We did not have the chance to re-evaluate the primary tumor for both hormone receptors and HER2-neu to clarify this issue.
An attempt to analyze the clinical course of difficult cases such as the present one, by using available immunohistochemical markers, might be helpful for the future treatment of other similar cases. Furthermore, the use of immunohistochemical and molecular analysis of cancer-associated proteins has been important in understanding tumor biology. Immunohistochemical studies in breast cancer have led to the identification of new predictive markers and novel targets with roles in therapeutics. It has been shown previously that high expression of HER2 predicts a poor response to a CMF regimen (8). Similarly, HER2 overexpression of estrogen receptor-positive tumors was shown previously to be less sensitive to tamoxifen (9). Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase enzyme without interfering with adrenal steroid biosynthesis (10,11). We feel that HER2 positivity in our case might have contributed to the poor response to tamoxifen and favorable response to letrozole, as it was shown previously that HER2 status may be linked with inferior response to tamoxifen but superior response to letrozole (12).
Two different multidrug resistance mechanisms (MDR), ATP-binding cassette transporter P-glycoprotein and detoxification enzyme GST, were also strongly positive in our case. These resistance parameters might have contributed to the failure of the chemotherapeutics and radiotherapy administered to the patient. One of the mechanisms for the efficacy of megestrol acetate may be its chemosensitizing effect for MDR tumors (13). Therefore, this case is also suggestive of the complex relation between hormone receptor positivity, HER2 and ABL transporters.
Despite the poor prognosis and short survival of LM patients, early diagnosis and treatment with hormonal therapy may improve the outcome for hormone-positive breast cancer patients with LM. We conclude that letrozole may potentially be beneficial in postmenopausal breast cancer patients with LM with hormone- and HER2-positive disease.
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FOOTNOTES |
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+ For reprints and all correspondence: Mustafa Ozdogan, Akdeniz Universitesi Tip Fakultesi, Ic Hastaliklari ABD, Onkoloji BD, Antalya, Turkey. E-mail: mustafa0051{at}hotmail.com
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REFERENCES |
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Received February 4, 2003; accepted April 4, 2003
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