145

　Case Report Kitasato Med J 2013; 43: 145-150　

Complete response of brain metastases from breast cancer aftertherapy 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 examinationrevealed a 3-cm breast tumor and right axillary lymphadenopathy. The patient was diagnosed withbreast cancer in the right breast and underwent mastectomy and right axillary lymphadenectomy. Thepathological findings were: 1.5 cm tumor, invasive ductal carcinoma (Grade 3 [poorly differentiated]),lymph node metastases (+) estrogen receptor (-) progesterone receptor (-) HER2 (3+) T1N2M0 andstage IIIA. Multiple bone metastases were detected 24 months after surgery, for which the patientunderwent radiation therapy. In addition, trastuzumab monotherapy was initiated. Multiple brainmetastases 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 becameworse 41 months after surgery. Therefore, combination therapy consisting of lapatinib plus capecitabinewas initiated. There was complete resolution of the brain metastases after 4 months of therapy. Wedescribed a HER2-positive breast cancer patient with metastatic disease, who achieved completeresponse of her brain metastases due to lapatinib plus capecitabine therapy.

Key words: HER2-positive metastatic breast cancer, lapatinib, capecitabine, brain metastases,complete response

Introduction

olecularly targeted drugs have improved theprognosis of patients with human epidermal

growth factor receptor-2 (HER2)-positive breast cancer.Lapatinib is a specific inhibitor of tyrosine kinase activityin both the epidermal growth factor receptor (EGFR)and HER2.1 A phase III clinical study of lapatinibcombined with capecitabine (EGF100151) for womenwith advanced breast cancer that had progressed ontrastuzumab revealed that the response rate (RR) andclinical benefit rate (CBR) were 23.7% and 29.3%,respectively, which indicated that this combination wasmore effective than capecitabine alone, with a RR of13.9% and CBR of 17.4%.2 Patients with HER2-positivebreast cancer frequently develop brain metastases, whichhave poor prognosis. Therefore, appropriate treatmentsfor patients with HER2-positive breast cancer metastaticto the brain are needed.3,4 Although several studies oftreatments for patients with metastatic breast cancer have

indicated that lapatinib provides favorable responses, onlya few studies have shown that lapatinib achieved completeresponse (CR) in patients with brain metastases.5,6

Here, we report a patient with brain metastases fromHER2-positive breast cancer who was successfully treatedusing lapatinib plus capecitabine (LC).

Case Report

The patient was a 60-year-old Japanese postmenopausalwoman who presented with a lump in her right breast.Physical examination revealed a 3-cm tumor in her rightbreast and right axillary lymphadenopathy. The patientwas diagnosed with invasive ductal carcinoma (T1N2M0,stage IIIA) and underwent a mastectomy with axillarylymph node dissection.

The histopathologic findings included a 1.5 -cminvasive ductal carcinoma (Grade 3 [poorly differentiated])and axi l lary lymph node metastases (5/22) .Immunohistological analysis showed a HER2-type breast

M

Received 28 February 2013, accepted 2 April 2013Correspondence to: Yoshimasa Kosaka, Department of Surgery, Kitasato University School of Medicine1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, JapanE-mail: y-kosaka@med.kitasato-u.ac.jp

146

Figure 2. Chest CT

cancer (negative for expression of estrogen andprogesterone receptors and positive for expression ofHER2). The patient refused postoperative adjuvanttherapy and was closely observed. A compression fractureof the cervical spine occurred 24 months after surgery,and multiple bone metastases were found. She receivedradiation therapy to her cervical spine (total dose, 30 Gy)and trastuzumab monotherapy. Seven months afterinitiation of trastuzumab therapy, multiple metastases inthe brain, lung, liver, and spleen were discovered. Thepatient's only symptom was vertigo without paralysis.

Kikuchi, et al.

A. Multiple metastases to the lung weredetected on CT prior to treatment.

B. The sizes of the tumors in the lungdecreased after treatment.

Figure 1. Head CT

A. Three metastatic brain tumors(maximum, 1.2 cm) in both frontallobes, and 6 tumors (maximum, 1.5 cm)in the cerebellar hemispheres, wererevealed by computed tomography(CT) before radiation therapy andl a p a t i n i b p l u s c a p e c i t a b i n ecombination therapy.

B. The tumors resolved after 4 monthsof lapat inib plus capeci tabinecombination therapy.

Since multiple brain metastases were observed, thepatient underwent whole brain radiotherapy (WBRT),receiving a total dose of 20 Gy. She continued to receivetrastuzumab therapy, and 9 months after WBRT, the brainmetastases had increased in size, and the patient's tumor-marker levels (including carcinoembryonic antigen[CEA] and cancer antigen 15-3 [CA 15-3]) had alsoincreased. LC was then initiated as a second-linetreatment.

Lapatinib was administered at a dose of 1,250 mg/day orally and capecitabine was given at a dose of 2,000

147

Figure 4. Bone scintigraphy

Complete response of brain metastases from breast cancer

A. A 1.3-cm metastatictumor in S5 of the liverw a s d e t e c t e d o nultrasonography (US)prior to treatments.

B . The l ive r tumordecreased to 0.6 cm aftertreatments.

Figure 3. Ultrasonography

C. A 4.2-cm metastatictumor in the spleen wasdetected on US prior totreatments.

D. The splenic tumordecreased to 2.4 cm aftertreatments.

A. Abnormal accumulation of 99mtechnetiumin the skull, sternum, vertebral body, bilateralpelvic bones, and femurs was detected onbone scintigraphy prior to treatment.

B. 99Technetium accumulation at themetastatic sites disappeared aftertreatments.

148

mg/m2/day for 14 days of a 21-day cycle. Four monthsafter the initiation of LC therapy, computed tomographyshowed complete resolution of the brain metastases anda partial response (PR) of the lung metastases (Figures 1and 2, respectively). Abdominal ultrasonography andbone scintigraphy revealed PR of the liver, spleen, andbone metastases (Figures 2-4, respectively).

The levels of CEA and CA 15-3 increased with theappearance of the bone metastases and then decreasedafter trastuzumab initiation. The levels increased againafter exacerbation of the brain metastases, but decreasedafter the initiation of LC therapy (Figure 5).

Discussion

The prognosis of breast cancer patients has improvedwith advances in cancer therapeutics. However, 25%-34% of patients develop brain metastases.7 In particular,patients with HER2-positive breast cancer have a highrisk of brain metastases.8,9 One-third of patients withHER2-positive metastatic breast cancer who are beingtreated with trastuzumab develop brain metastases, whichoccur within 2 years.3,10-15 Trastuzumab and chemotherapyare effective against metastases to extracranial organs in

patients with HER2-positive breast cancer.16-19 However,these drugs have a limited effect on brain metastasesbecause they cannot penetrate the blood-brain barrier(BBB). Therefore, trastuzumab and chemotherapy arenot first-line treatments for brain metastases.

Small tumors and a low number of metastatic foci inthe brain should be treated using surgery and stereotacticradiosurgery (SRS).20 In the patient in the present study,WBRT was administered because she had multiple brainmetastases. Additionally, trastuzumab, a recombinanthumanized monoclonal antibody against HER2, wasadministered as a systemic therapy. WBRT inducedstable disease, but the brain metastases increased 9 monthsafter RT, and there were increases in tumor marker levels.LC was then chosen as the subsequent therapeuticregimen.

Lapatinib is a small-molecule inhibitor (943 Da) ofthe intracellular tyrosine kinase domains of both EGFRand HER2. Data indicate that it penetrates the BBB,whereas trastuzumab, with a high molecular mass(148,000 Da), does not efficiently cross the BBB, whichaccounts for its poor efficacy against brain metastases.

Lapatinib is used for advanced or metastatic HER2-positive breast cancer resistant to anthracyclines, taxanes,

Figure 5. Tumor marker

Tumor marker levels increased with the appearance of bone metastases and decreasedonce after trastuzumab initiation. The tumor marker levels subsequently increasedwith the exacerbation of brain metastases but decreased after lapatinib plus capecitabinetherapy.

Kikuchi, et al.

149

and trastuzumab and is recommended for combined usewith capecitabine. Lin et al.12 conducted a phase II clinicalstudy of lapatinib for patients with brain metastases fromHER2-positive breast cancer. PR was achieved in 10(20%) of 50 patients who received LC therapy. Of these50 patients, the tumor sizes of 11 (22%) patients weredecreased more than 50%, and those of 20 (40%) patientswas decreased more than 20%.12

Although Lin et al.21,22 have also conducted severallapatinib clinical trials on patients with HER2-positivebreast cancer metastasizing to the brain, CR was notachieved in any patient. Ro et al.5 administered LC topatients with HER2-positive breast cancer metastasizingto the brain. CR was achieved in 2 of 47 patients whoreceived WBRT.5 Abboud et al.6 reported 1 patient withbrain metastases from HER2-positive breast cancer whoachieved CR after LC. Because there have been fewcase reports on patients with CR of brain metastasesfrom breast cancer after LC therapy, the present studyprovides additional support for the efficacy of LC. Thepresent study suggests that LC therapy may have asignificant efficacy for brain metastases from breastcancer.

Diarrhea, hand-foot syndrome, nausea, vomiting, andskin eruption have frequently been reported as adverseeffects of lapatinib therapy. Serious adverse events suchas interstitial pneumonia and cardiac disorders have alsobeen reported.2 Serious adverse events did not occur inthe patient in the present study.

The efficacy of pertuzumab for metastatic breastcancer, an anti-HER2 humanized monoclonal antibodythat inhibits receptor dimerization, was recentlyreported.23 The therapeutic options for patients withHER2-positive breast cancer will likely, therefore,increase in the near future. We reported a patient withbrain metastases from HER2-positive breast cancer, whoachieved complete response to lapatinib plus capecitabinecombination therapy.

References

1. Geyer CE, Forster J, Lindquist D, et al. Lapatinibplus capecitabine for HER2-positive advanced breastcancer. N Engl J Med 2006; 355: 2733-43.

2. Cameron D, Casey M, Press M, et al. A phase IIIrandomized comparison of lapatinib plus capecitabineversus capecitabine alone in women with advancedbreast cancer that has progressed on trastuzumab:updated efficacy and biomarker analyses. BreastCancer Res Treat 2008; 112: 533-43.

3. Clayton AJ, Danson S, Jolly S, et al. Incidence ofcerebral metastases in patients treated withtrastuzumab for metastatic breast cancer. Br J Cancer2004; 91: 639-43.

4. Lin NU, Bellon JR, and Winer EP. CNS metastasesin breast cancer. J Clin Oncol 2004; 22: 3608-17.

5. Ro J, Park S, Kim SB, et al. Clinical outcomes ofHER2-positive metastatic breast cancer patients withbrain metastasis treated with lapatinib andcapecitabine: an open-label expanded access studyin Korea. BMC Cancer 2012; 12: 322.

6. Abboud M, Saghir NS, Salame J, et al. Completeresponse of brain metastases from breast canceroverexpressing Her-2/neu to radiation and concurrentLapatinib and Capecitabine. Breast J 2010; 16: 644-6.

7. Shmueli E, Wigler N, and Inbar M. Central nervoussystem progression among patients with metastaticbreast cancer responding to trastuzumab treatment.Eur J Cancer 2004; 40: 379-82.

8. Pestalozzi BC, Zahrieh D, Price KN, et al. Identifyingbreast cancer patients at risk for Central NervousSystem (CNS) metastases in trials of the InternationalBreast Cancer Study Group (IBCSG). Ann Oncol2006; 17: 935-44.

9. Gabos Z, Sinha R, Hanson J, et al. Prognosticsignificance of human epidermal growth factorreceptor positivity for the development of brainmetastasis after newly diagnosed breast cancer. JClin Oncol 2006; 24: 5658-63.

10. Park YH, Park MJ, Ji SH, et al. Trastuzumabtreatment improves brain metastasis outcomesthrough control and durable prolongation of systemicextracranial disease in HER2-overexpressing breastcancer patients. Br J Cancer 2009; 100: 894-900.

11. Bendell JC, Domchek SM, Burstein HJ, et al. Centralnervous system metastases in women who receivetrastuzumab-based therapy for metastatic breastcarcinoma. Cancer 2003; 97: 2972-7.

12. Lin NU, Dieras V, Paul D, et al. Multicenter phase IIstudy of lapatinib in patients with brain metastasesfrom HER2-positive breast cancer. Clin Cancer Res2009; 15: 1452-9.

13. Metro G, Sperduti I, Russillo M, et al. Clinical utilityof continuing trastuzumab beyond brain progressionin HER-2 positive metastatic breast cancer.Oncologist 2007; 12: 1467-9; author reply 1469-71.

14. Ono M, Ando M, Yunokawa M, et al. Brainmetastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressingmetastatic breast cancer. Int J Clin Oncol 2009; 14:48-52.

15. Duchnowska R, Dziadziuszko R, Czartoryska-Arlukowicz B, et al. Risk factors for brain relapse inHER2-positive metastatic breast cancer patients.Breast Cancer Res Treat 2009; 117: 297-303.

Complete response of brain metastases from breast cancer

150

16. Slamon DJ, Leyland-Jones B, Shak S, et al. Use ofchemotherapy plus a monoclonal antibody against

HER2 for metastatic breast cancer that overexpresses

HER2. N Engl J Med 2001; 344: 783-92.17. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy

and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastaticbreast cancer. J Clin Oncol 2002; 20: 719-26.

18. Romond EH, Perez EA, Bryant J, et al. Trastuzumabplus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673-84.

19. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, etal. Trastuzumab after adjuvant chemotherapy inHER2-positive breast cancer. N Engl J Med 2005;353: 1659-72.

20. Patchell RA, Tibbs PA, Regine WF, et al. Directdecompressive surgical resection in the treatment ofspinal cord compression caused by metastatic cancer:a randomised trial. Lancet 2005; 366: 643-8.

21. Lin NU, Carey LA, Liu MC, et al. Phase II trial oflapatinib for brain metastases in patients with humanepidermal growth factor receptor 2-positive breastcancer. J Clin Oncol 2008; 26: 1993-9.

22. Lin NU, Eierman W, Greil R, et al. Randomizedphase II study of lapatinib plus capecitabine orlapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol2012; 105: 613-20.

23. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plustrastuzumab plus docetaxel for metastatic breastcancer. N Engl J Med 2012; 366: 109-19.

Kikuchi, et al.