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CASE REPORT
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The unexpected effect of the combination of lapatinib and capecitabin in cranial metastasis


 Department of Medical Oncology, Inonu University, Malatya, Turkey

Date of Submission24-Aug-2021
Date of Decision14-Sep-2021
Date of Web Publication02-May-2022

Correspondence Address:
Ahmet Gulmez,
Department of Medical Oncology, Inonu University, Malatya
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1440_21

 > Abstract 


Cranial metastasis (CM) is a serious problem in breast cancer patients. In patients with CM, quality of life is adversely affected and the survival of patients is reduced. It is also very difficult to manage breast cancer patients with cranial metastases whose life expectancy is generally 1 year or less. There is no case report in the literature of CM with more than 5 years of progression-free survival (PFS) with oncological treatment. I presented a rare case about the widespread CM developed with tamoxifen treatment in an advanced breast cancer patient who completed chemotherapy and radiotherapy after primary surgery. Systemic treatment was started as a combination of capecitabine and lapatinib after whole-brain radiotherapy was applied to the patient with extensive CM. At the end of about 3 years, there is complete response of cranial metastases, and PFS is over 5 years. The treatment was well tolerated, and she is still being followed up in the 74th month of this treatment without recurrence. There are no case reports of HER-2-positive breast cancer patients with such widespread cranial metastases in complete remission at 34 months of systemic therapy and 74 months of PFS. Our article is unique in this respect. It should be kept in mind that it is not appropriate to change the treatment plan of patients with only one case report. Although the options have increased with the use of new generation antihuman epidermal growth factor receptor 2 treatments, lapatinib can be a very effective treatment tool in selected patients.

Keywords: Brain metastasis, breast cancer, Her-2-positive, tyrosine kinase inhibitor



How to cite this URL:
Gulmez A. The unexpected effect of the combination of lapatinib and capecitabin in cranial metastasis. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=344586




 > Introduction Top


Intracranial metastasis is a clinical event that should be kept in mind in breast cancer patients, especially triple-negative and Her-2-positive patients. Because intracranial metastasis seriously affects the patient's quality of life and survival. The median overall survival (OS) of the patient with cranial metastasis (CM) is below 1 year.[1] Patients treated with anti-Her-2 therapy in Her-2-positive patients have significantly better survival. In this article, I will present a breast cancer patient with prolonged progression-free survival (PFS) and prolonged OS after intracranial metastasis in a Her-2-positive patient under the treatment of lapatinib plus capecitabine combination. The incidence of central nervous system (CNS) metastases is currently increasing due to the availability of new medications or an increase in patient survival achieved through new combinations with limited CNS penetration.[2]

Approximately 20%–45% of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer will develop parenchymal CM.[3] This incidence is particularly high and remains the same in patients with or without trastuzumab.[4] Median survival after CM in HER2-positive patients receiving trastuzumab is longer compared to Her-2-positive patients who did not receive trastuzumab and Her-2-negative patients (11.9 vs. 3 months vs. 3.6 months).[5]

The fact that trastuzumab has a poor blood–brain barrier (BBB) transition[6] has sparked interest in alternative anti-HER2 agents with improved BBB permeability. Lapatinib; HER-2 is a small, lipophilic anticancer agent previously approved for the treatment of HER-2-positive metastatic breast cancer that has progressed after treatment with a taxane, anthracycline, and trastuzumab.[7]

The standard treatment of patients with multiple CM is intracranial radiotherapy followed by systemic therapy. In this article, I present a patient with multiple cranial metastases who had prolonged PFS and OS under the treatment of capecitabine and lapatinib after intracranial radiotherapy. This is a clinical description of systemic chemotherapy and tyrosine kinase inhibitor (TKI) combination therapy, which provides a good association with radiotherapy in sequential use in terms of efficacy in breast cancer patients with cranial metastases.


 > Case Presentation Top


The patient was started to be examined after detecting a mass in her breast. As a result of the physical and radiographic examinations, two masses were detected in the left breast of the patient. In addition, ultrasonography showed multiple malignant-looking lymphadenopathies with an increased roundness index in the left axillary region. Biopsy was consistent with ER-, PR-, and Cerb-B2+3 IBC. The patient was operated as modified radical mastectomy and axillary dissection without neoadjuvant treatment by the general surgeon. In the postoperative pathology report, invasive ductal carcinoma with a diameter of 3 cm × 2 cm and 1.5 cm were detected in two different foci. In the immunohistochemical analysis, ER, PR 1+, and Cerb-B2+3 were detected by immunohistochemically. In the pathology report of axillary dissection, 21 metastatic lymph nodes were detected. Systemic screening was performed with thorax and abdominal tomography after surgery. The patient whose pathological staging was detected as T2N3M0 was started with 4 AC (adriamycin–cyclophosphamide) followed by 4 paclitaxel + trastuzumab treatment. At the end of the chemotherapy, the treatment of trastuzumab was completed for 1 year and adding tamoxifen. In the 2nd year of tamoxifen treatment, the patient was admitted to the emergency room with a complaint of headache. Multiple metastatic lesions and vasogenic edema areas were detected in the patient with contrast-enhanced cranial imaging [Figure 1]. Radiotherapy, dexamethasone, and mannitol treatment were initiated by discussing the patient's current status with radiation oncology. No other metastatic lesion was detected in the patient who received external whole-brain radiotherapy (WBR) with a total dose of 30 Gy in 10 fractions, 300 cGy in each fraction. Since pertuzumab or tucatinib treatment was not available at this time and considering the intracranial efficiency of TKIs, treatment of capecitabine and lapatinib was started. Lapatinib 1250 mg/day and capecitabine 1000 mg/m2 twice daily for 14 days every 21 days. Since then, the patient's follow-up was done with positron emission tomography/computed tomography (PET/CT) and cranial magnetic resonance imaging MRI. The cranial imaging taken 2 months after the completion of intracranial radiotherapy revealed that metastatic lesions regressed. With combination therapy, major radiological response developed in intracranial masses after 31 months [Figure 2]. The patient is being followed as PFS with PET/CT and cranial MRI radiological findings at the 74th month under capecitabine and lapatinib treatment. Radiology images of regression of intracranial metastases are shown in [Figure 3]. Moreover, the last PET/CT imaging of the patient is presented in [Figure 4]. The patient continues to be treated and followed as stable disease. Treatment and follow-up of the patient continue as stable disease.
Figure 1: Brain magnetic resonance imaging image at the time of diagnosis of cranial metastasis

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Figure 2: Brain magnetic resonance imaging image at the end of the 31th month of treatment

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Figure 3: Brain magnetic resonance imaging image at the end of the 74th month of treatment

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Figure 4: Positron emission tomography/computed tomography image at the end of the 74th month of treatment

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 > Discussion Top


In breast cancer patients with multiple cranial metastases, the primary treatment approach is WBR. Most systemic treatments cannot achieve sufficient intracranial efficacy due to BBB. Distortions occur in BBB after WBR, and the intracranial passage of various agents increases.

Some agents have shown some efficacy in intracranial parenchymal metastases. The main chemotherapies used are cisplatin, carboplatin, capecitabine, temozolomide, topotecan, irinotecan, methotrexate, and liposomal doxorubicin.[3] Trastuzumab, an HER-2 antibody, has a significant positive therapeutic effect on HER-2-positive systemic breast cancers but shows minimal transport throughout the BBB.[8] On the other hand, TKIs with a small molecular weight, such as lapatinib, better penetrance through to the BB. In a Phase 2 study on lapatinib (LANDSCAPE), lapatinib + capecitabine combination was found to have 67% response rate and 5.5 months PFS in breast cancer patients with HER2+ CM who did not receive intracranial radiotherapy.[9] The combination of capecitabine and lapatinib has a tolerable side effect profile. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. TDM-1 can also be used as an alternative to capecitabine and lapatinib combination.[10] In a recently published study, it was found that the combination of tucatinib + trastuzumab + capecitabine significantly improved PFS and OS in comparison to placebo in breast cancer patients with Her-2-positive cranial metastases who previously received multiple series therapy.[11] Based on this information, in breast cancer patients with Her-2-positive intracranial metastases, the treatment of lapatinib plus capecitabine is a tolerable and effective combination. Dehydration, renal failure, and skin side effects can be followed closely.

In a previously published study, HER-2-positive breast cancer patient with CM was followed up for 34 months in remission with this combination regimen.[12] This case report has the longest known PFS in the literature. However, in this case report that I have presented, there is a remission of more than 5 years despite widespread CM. In this patient, the treatment efficacy above expectations may be due to some factors. One study explains the following mechanism as a cause of this situation: lapatinib has been shown to clearly lower thymidylate synthase (TS) activity, thus increasing the effectiveness of capecitabine. In addition, as capecitabine decreases the activity of p-AKT and p-P42/44, the efficiency of lapatinib increases. Specifically, lapatinib, and capecitabine modulated molecular determinants of each other's response. For this reason, simultaneous dosing appeared to be the most suitable method for combining these agents. This association also showed the potential to overcome breast cancer resistance associated with TS overexpression. As in this study, this may be one of the mechanisms by which our patient benefits from treatment above expectations.[13]

The patient I presented with multiple cranial metastases has over 5-year PFS with the same treatment. In the literature review, I could not detect a PFS of up to 5 years in a patient with extensive intracranial metastasis. As a result, in HER2-positive metastatic breast cancer, the drugs to be used in the 1st and 2nd lines clearly determined. However, it is generally considered that the combination of capecitabine and lapatinib is not good enough. This case report showed that this dual combination is a very competent treatment when used in the appropriate patient. Therefore, this case report is unique and will contribute to the literature.


 > Conclusion Top


This is a clinical description of systemic chemotherapy and TKI combination therapy, which provides a good association with radiotherapy in sequential use in terms of efficacy in breast cancer patients with CM. This article has the best response and longest PFS reported with capecitabine plus lapatinib combination treatment for HER-2-positive metastatic breast cancer patient with widespread CM. Breast cancer patients with cranial metastases are underrepresented in clinical trials. Despite this impressive result, it should be kept in mind that it is not appropriate to change the treatment plan of patients with a single case report. We hope that this case report will guide a clinical trial with TKIs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Znidaric T, Gugic J, Marinko T, Gojkovic Horvat A, Paulin Kosir MS, Golo D, et al. Breast cancer patients with brain metastases or leptomeningeal disease: 10-year results of a national cohort with validation of prognostic indexes. Breast J 2019;25:1117-25.  Back to cited text no. 1
    
2.
Groves MD. New strategies in the management of leptomeningeal metastases. Arch Neurol 2010;67:305-12.  Back to cited text no. 2
    
3.
Lin NU, Winer EP. Brain metastases: The HER2 paradigm. Clin Cancer Res 2007;13:1648-55.  Back to cited text no. 3
    
4.
Lai R, Dang CT, Malkin MG, Abrey LE. The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma. Cancer 2004;101:810-6.  Back to cited text no. 4
    
5.
Church DN, Modgil R, Guglani S, Bahl A, Hopkins K, Braybrooke JP, et al. Extended survival in women with brain metastases from HER2 overexpressing breast cancer. Am J Clin Oncol 2008;31:250-4.  Back to cited text no. 5
    
6.
Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91:639-43.  Back to cited text no. 6
    
7.
Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R, et al. FDA drug approval summary: Lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 2008;13:1114-9.  Back to cited text no. 7
    
8.
Pestalozzi BC. Correction: Meningeal carcinomatosis from breast carcinoma responsive to trastuzumab. J Clin Oncol 2001;19:4091.  Back to cited text no. 8
    
9.
Bachelot T, Romieu G, Campone M, Diéras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): A single-group phase 2 study. Lancet Oncol 2013;14:64-71.  Back to cited text no. 9
    
10.
Gelmon KA, Boyle FM, Kaufman B, Huntsman DG, Manikhas A. Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31. Journal of Clinical Oncology 2015;33:1574-83.  Back to cited text no. 10
    
11.
Diéras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2 positive advanced breast cancer (EMILIA): A descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:732-42.  Back to cited text no. 11
    
12.
Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020;382:597-609.  Back to cited text no. 12
    
13.
Mailliez A, Servent V, Bonneterre J, Le Rhun E. Brain metastases of Her2-positive breast cancer: A case of 34 months' remission with lapatinib plus capecitabine. Case Rep Oncol 2014;7:555-9.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

 
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