Extended trastuzumab therapy improves the survival of HER2‑positive breast cancer patients following surgery and radiotherapy for brain metastases

Okita,Yoshiko; Narita,Yoshitaka; Suzuki,Tsuyoshi; Arita,Hideyuki; Yonemori,Kan; Kinoshita,Takayuki; Fujiwara,Yasuhiro; Tsuda,Hitoshi; Komoike,Yoshifumi; Nakagawa,Hidemitsu; Tamaki,Yasuhiro; Tomita,Yasuhiko; Shibui,Soichiro; Maruno,Motohiko

doi:10.3892/mco.2013.162

Extended trastuzumab therapy improves the survival of HER2‑positive breast cancer patients following surgery and radiotherapy for brain metastases

Authors:
- Yoshiko Okita
- Yoshitaka Narita
- Tsuyoshi Suzuki
- Hideyuki Arita
- Kan Yonemori
- Takayuki Kinoshita
- Yasuhiro Fujiwara
- Hitoshi Tsuda
- Yoshifumi Komoike
- Hidemitsu Nakagawa
- Yasuhiro Tamaki
- Yasuhiko Tomita
- Soichiro Shibui
- Motohiko Maruno
View Affiliations

Affiliations: Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 5378511, Japan, Department of Neurosurgery and Neuro‑Oncology, National Cancer Center, Tokyo 1040045, Japan, Department of Breast and Medical Oncology, National Cancer Center, Tokyo 1040045, Japan, Department of Breast Surgery, National Cancer Center, Tokyo 1040045, Japan, Department of Pathology and Clinical Laboratories, National Cancer Center, Tokyo 1040045, Japan, Department of Breast and Endocrine Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 5378511, Japan, Department of Pathology and Cytology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 5378511, Japan
Published online on: July 29, 2013 https://doi.org/10.3892/mco.2013.162
Pages: 995-1001

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Brain metastases usually present late during the course of breast cancer and are associated with an unfavorable prognosis. It was previously demonstrated that the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) may be altered in the time window between the emergence of the primary breast tumor and the development of metastases. The aim of this study was to compare the expression of ER, PR and HER2 in pathology samples of primary breast cancer and brain metastases in order to evaluate whether previously administered therapy was able to modify this status and determine whether biomarker alterations affect prognosis after the development of brain metastases. Data were collected from 62 patients who were initially diagnosed with breast cancer that had metastasized to the brain. The ER, PR and HER2 status of the samples from the primary tumors and the brain metastases was determined. Differences in the immunohistochemical profiles of ER, PR or HER2 between the primary tumors and the brain metastases in 17 patients (29.3%) were identified. The patients with HER2‑positive brain metastases who received trastuzumab had no leptomeningeal metastases and exhibited a longer survival time after brain metastases compared to the HER2‑positive patients who did not receive trastuzumab and the patients with HER2‑negative brain metastases (P=0.0005). Our results suggested that the patients treated with trastuzumab following surgery and radiotherapy for brain metastases exhibited a better prognosis. Thus, the HER2 status in brain metastases requires re‑evaluation and extended trastuzumab therapy is recommended after brain metastases.

View Figures

View References

1.	Bogina G, Bortesi L, Marconi M, Venturini M, Lunardi G, Coati F, Massocco A, Manfrin E, Pegoraro C and Zamboni G: Comparison of hormonal receptor and HER-2 status between breast primary tumours and relapsing tumours: clinical implications of progesterone receptor loss. Virchows Arch. 459:1–10. 2011. View Article : Google Scholar
2.	Broom RJ, Tang PA, Simmons C, Bordeleau L, Mulligan AM, O’Malley FP, Miller N, Andrulis IL, Brenner DM and Clemons MJ: Changes in estrogen receptor, progesterone receptor and Her-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res. 29:1557–1562. 2009.
3.	Guarneri V, Giovannelli S, Ficarra G, Bettelli S, Maiorana A, Piacentini F, Barbieri E, Dieci MV, D’Amico R, Jovic G and Conte P: Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Oncologist. 13:838–844. 2008. View Article : Google Scholar
4.	Nishimura R, Osako T, Okumura Y, Tashima R, Toyozumi Y and Arima N: Changes in the ER, PgR, HER2, p53 and Ki-67 biological markers between primary and recurrent breast cancer: discordance rates and prognosis. World J Surg Oncol. 9:1312011. View Article : Google Scholar : PubMed/NCBI
5.	Yonemori K, Tsuta K, Shimizu C, Hatanaka Y, Hashizume K, Ono M, Nakanishi Y, Hasegawa T, Miyakita Y, Narita Y, Shibui S and Fujiwara Y: Immunohistochemical profiles of brain metastases from breast cancer. J Neurooncol. 90:223–228. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR and Dowsett M: Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res. 55:3331–3338. 1995.PubMed/NCBI
7.	Edgerton SM, Moore D II, Merkel D and Thor AD: erbB-2 (HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol. 11:214–221. 2003. View Article : Google Scholar : PubMed/NCBI
8.	Kerbel RS: Growth dominance of the metastatic cancer cell: cellular and molecular aspects. Adv Cancer Res. 55:87–132. 1990. View Article : Google Scholar : PubMed/NCBI
9.	Pertschuk LP, Axiotis CA, Feldman JG, Kim YD, Karavattayhayyil SJ and Braithwaite L: Marked intratumoral heterogeneity of the proto-oncogene Her-2/neu determined by three different detection systems. Breast J. 5:369–374. 1999. View Article : Google Scholar
10.	Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, Verhest A, Bernard-Marty C, Piccart MJ and Larsimont D: Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol. 13:1036–1043. 2002. View Article : Google Scholar : PubMed/NCBI
11.	Sari E, Guler G, Hayran M, Gullu I, Altundag K and Ozisik Y: Comparative study of the immunohistochemical detection of hormone receptor status and HER-2 expression in primary and paired recurrent/metastatic lesions of patients with breast cancer. Med Oncol. 28:57–63. 2011. View Article : Google Scholar
12.	Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 14:737–744. 1996.
13.	Harvey JM, Clark GM, Osborne CK and Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 17:1474–1481. 1999.
14.	Perren A, Weng LP, Boag AH, Ziebold U, Thakore K, Dahia PL, Komminoth P, Lees JA, Mulligan LM, Mutter GL and Eng C: Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 155:1253–1260. 1999. View Article : Google Scholar : PubMed/NCBI
15.	Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG and Byhardt R: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 37:745–751. 1997. View Article : Google Scholar
16.	Flowers A and Levin VA: Management of brain metastases from breast carcinoma. Oncology (Williston Park). 7:21–26; discussion 31–34, 1993.
17.	Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, Bunnell C, Rue M, Gelman R and Winer E: Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 97:2972–2977. 2003. View Article : Google Scholar
18.	Kirsch DG, Ledezma CJ, Mathews CS, Bhan AK, Ancukiewicz M, Hochberg FH and Loeffler JS: Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol. 23:2114–2117. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Le Scodan R, Jouanneau L, Massard C, Gutierrez M, Kirova Y, Cherel P, Gachet J, Labib A and Mouret-Fourme E: Brain metastases from breast cancer: prognostic significance of HER-2 overexpression, effect of trastuzumab and cause of death. BMC Cancer. 11:3952011.PubMed/NCBI
20.	Nam BH, Kim SY, Han HS, Kwon Y, Lee KS, Kim TH and Ro J: Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res. 10:R202008. View Article : Google Scholar : PubMed/NCBI
21.	Park IH, Ro J, Lee KS, Nam BH, Kwon Y and Shin KH: Trastuzumab treatment beyond brain progression in HER2-positive metastatic breast cancer. Ann Oncol. 20:56–62. 2009. View Article : Google Scholar : PubMed/NCBI
22.	Duchnowska R, Dziadziuszko R, Czartoryska-Arlukowicz B, Radecka B, Szostakiewicz B, Sosinska-Mielcarek K, Karpinska A, Staroslawska E, Kubiatowski T and Szczylik C: Risk factors for brain relapse in HER2-positive metastatic breast cancer patients. Breast Cancer Res Treat. 117:297–303. 2009. View Article : Google Scholar : PubMed/NCBI
23.	Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 353:1673–1684. 2005. View Article : Google Scholar : PubMed/NCBI
24.	Smith I, Procter M, Gelber RD, et al: HERA study team: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 369:29–36. 2007.
25.	van Vulpen M, Kal HB, Taphoorn MJ and El-Sharouni SY: Changes in blood-brain barrier permeability induced by radiotherapy: Implications for timing of chemotherapy? (Review). Oncol Rep. 9:683–688. 2002.PubMed/NCBI
26.	Maki DD and Grossman RI: Patterns of disease spread in meta-static breast carcinoma: influence of estrogen and progesterone receptor status. AJNR Am J Neuroradiol. 21:1064–1066. 2000.PubMed/NCBI
27.	Samaan NA, Buzdar AU, Aldinger KA, Schultz PN, Yang KP, Romsdahl MM and Martin R: Estrogen receptor: a prognostic factor in breast cancer. Cancer. 47:554–560. 1981. View Article : Google Scholar : PubMed/NCBI
28.	Tham YL, Sexton K, Kramer R, Hilsenbeck S and Elledge R: Primary breast cancer phenotypes associated with propensity for central nervous system metastases. Cancer. 107:696–704. 2006. View Article : Google Scholar : PubMed/NCBI
29.	Leyland-Jones B: Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol. 27:5278–5286. 2009. View Article : Google Scholar : PubMed/NCBI
30.	No authors listed. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 351:1451–1467. 1998.
31.	Schneeweiss A, Marme F, Ruiz A, Manikhas AG, Bottini A, Wolf M, Sinn HP, Mansouri K, Kennedy L and Bauknecht T: A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant treatment of early breast cancer. Ann Oncol. 22:609–617. 2011. View Article : Google Scholar
32.	Yonemori K, Tsuta K, Ono M, Shimizu C, Hirakawa A, Hasegawa T, Hatanaka Y, Narita Y, Shibui S and Fujiwara Y: Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer. Cancer. 116:302–308. 2010. View Article : Google Scholar : PubMed/NCBI
33.	Konecny G, Pauletti G, Pegram M, et al: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 95:142–153. 2003. View Article : Google Scholar
34.	Gong Y, Booser DJ and Sneige N: Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer. 103:1763–1769. 2005. View Article : Google Scholar : PubMed/NCBI
35.	Lower EE, Glass E, Blau R and Harman S: HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat. 113:301–306. 2009. View Article : Google Scholar : PubMed/NCBI
36.	Niehans GA, Singleton TP, Dykoski D and Kiang DT: Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst. 85:1230–1235. 1993. View Article : Google Scholar : PubMed/NCBI
37.	Pectasides D, Gaglia A, Arapantoni-Dadioti P, Bobota A, Valavanis C, Kostopoulou V, Mylonakis N, Karabelis A, Pectasides M and Economopoulos T: HER-2/neu status of primary breast cancer and corresponding metastatic sites in patients with advanced breast cancer treated with trastuzumab-based therapy. Anticancer Res. 26:647–653. 2006.PubMed/NCBI
38.	Regitnig P, Schippinger W, Lindbauer M, Samonigg H and Lax SF: Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol. 203:918–926. 2004. View Article : Google Scholar : PubMed/NCBI
39.	Shimizu C, Fukutomi T, Tsuda H, Akashi-Tanaka S, Watanabe T, Nanasawa T and Sugihara K: c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues. J Surg Oncol. 73:17–20. 2000. View Article : Google Scholar : PubMed/NCBI
40.	Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C and Hadary A: Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer. 93:552–556. 2005. View Article : Google Scholar : PubMed/NCBI
41.	Fuchs IB, Loebbecke M, Buhler H, Stoltenburg-Didinger G, Heine B, Lichtenegger W and Schaller G: HER2 in brain metastases: issues of concordance, survival, and treatment. J Clin Oncol. 20:4130–4133. 2002. View Article : Google Scholar : PubMed/NCBI
42.	Liedtke C, Broglio K, Moulder S, et al: Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol. 20:1953–1958. 2009. View Article : Google Scholar : PubMed/NCBI
43.	Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 355:2733–2743. 2006. View Article : Google Scholar : PubMed/NCBI