Medicina (Buenos Aires)
versión On-line ISSN 1669-9106
Medicina (B. Aires) v.64 n.1 Buenos Aires ene./feb. 2004
Trastuzumab in the treatment of advanced breast cancer. Our single-center experience and spotlights of the latest national consensus meeting
Dirección postal: Dra. Adriana Tomadoni, Lafuente 723, 1406 Buenos Aires, Argentina. Fax: (54-11) 4469-9200 e-mail: email@example.com
Human epidermal growth factor receptor (HER 2) is amplified in 25 to 30% of breast cancer patients and those whose tumors demonstrate HER 2 gene amplification and protein overexpression have an inferior prognosis manifested by shorter disease-free and overall survival. Trastuzumab, the humanized murine anti-HER 2 monoclonal antibody, inhibits tumor growth when used alone and has synergistic and additive effects when used with chemotherapeutic agents (paclitacel-doxorrubicine). At the present time, the accurate diagnostic assessment of HER 2 is essential for appropriate application of the humanized anti HER 2 monoclonal antibody, trastuzumab, for the treatment of patients with metastatic breast cancer.FDA has approved its use for patients with metastatic breast cancer with HER 2 over-expression since 1998, as a first line treatment in association with paclitaxel or as a second or third line monotherapy. In Argentina, two Consensus Meetings of HER 2 Diagnosis have taken place: the first one on May 15th, 2002 and the second on April 11th, 2003, supported by Roche Laboratories (Herceptin®). In this paper, some topics of these meetings are reviewed. Our single-public center experience is discussed.
Key-words: Trastuzumab; Breast cancer; Her 2; Diagnosis
Trastuzumab en el tratamiento del cáncer de mama avanzado. Nuestra experiencia y aspectos de la última Reunión Nacional de Consenso. El receptor para el factor humano de crecimiento epidérmico (HER 2) se encuentra amplificado en el 25 a 30% de los cánceres de mama y aquellas pacientes con tumores que amplifiquen el gen HER 2 y sobreexpresen su proteína tienen un peor pronóstico que se traduce en menor sobreviva global y tiempo libre de enfermedad. Usado como monodroga, Trastuzumab, el anticuerpo monoclonal murino humanizado anti-HER 2, inhibe el crecimiento tumoral y posee efectos sinérgicos y aditivos cuando se agrega a otros agentes quimioterápicos (paclitaxel-doxorrubicina). La determinación diagnóstica precisa del HER 2 es esencial para establecer el uso racional de trastuzumab en el tratamiento de pacientes con cáncer de mama metastático. La FDA aprobó su uso para pacientes con cáncer de mama metastático que sobreexpresen el HER 2 desde 1998, como primera línea terapeútica asociado a paclitaxel o como monodroga en segunda o tercera líneas. En Argentina, se realizaron dos Reuniones de Consenso para Diagnóstico de HER 2: la primera el 15 de mayo de 2002 y la segunda el 11 de abril de 2003, auspiciadas por Laboratorios Roche (Herceptin®). En esta publicación, exponemos los temas destacados de ambos encuentros. Discutimos también nuestra experiencia en la determinación de HER 2 y tratamiento con trastuzumab.
Palabras clave: Trastuzumab; C áncer de mama; Her 2; Diagnóstico
A growth factor receptor gene, human epidermal growth factor receptor (HER 2), is amplified in 25 to 30 percent of breast cancers and in these cases the encoded protein is present in abnormally high levels in the malignant cells1. Patients whose tumors demonstrate HER 2 gene amplification and protein overexpression have an inferior prognosis manifested by shorter disease-free and overall survival2. The American Society of Clinical Oncology has emphasized the importance of the determination of HER 2 overexpression in every patient with breast cancer at the moment of the initial diagnosis or upon its recurrence3. Trastuzumab is a biological anticancer agent. This humanized murine anti-HER 2 monoclonal antibody inhibits tumor growth when used alone and has synergistic and additive effects when used with chemotherapeutic agents (paclitacel-doxorrubicine). Recent clinical trials implicating HER 2 in modified responses to anti-estrogens and anthracyclins4, 5 have stimulated interest in accurate and reliable identification of patients with carcinomas driven by HER 2 amplification and overexpression6, although these findings remain unconfirmed at present by prospective clinical trials7. However, the accurate diagnostic assessment of HER 2 is essential for appropriate application of the humanized anti HER 2 monoclonal antibody trastuzumab to the treatment of patients with metastatic breast cancer. In fact, FDA approved its use for patients with metastatic breast cancer with HER 2 overexpression since 1998 as a first line treatment in association with paclitaxel or as a second or third line monotherapy8.
Vogel et al.9 conducted a randomized clinical trial to evaluate the efficacy and safety of first line, single-agent Trastuzumab in women with HER 2-overexpressing metastatic breast cancer. The results showed an objective response rate of 26%, and no benefits for those women with 2+HER 2 overexpression.
Slamon et al.10 in his randomized clinical trial, used Trastuzumab in combination with paclitaxel. The trial showed that trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER 2. The addition of trastuzumab to chemotherapy was associated with longer time to disease progression (median, 7.4 vs. 4.6 months), a higher rate of objective response (50% vs. 32%), a longer duration of response (median, 9.1 vs. 6.1months) and a low rate of death at one year (22% vs. 33%).
The recommended dose of trastuzumab as single or combined agent is a standard loading dose of 4mg/kg followed by 2mg/kg weekly11. If objective response is achieved, the agent must be followed until toxicity, progression or death. The most important reported adverse event is cardiac dysfunction. It is dose inde-pendent and mostly reversible after drug discon-tinuation12. In fact, trastuzumab should be discontinued if significant heart failure develops.The incidence is greatest in patients receiving concomitant trastuzumab with anthracycline plus cyclophosphamide (27%). It is substantially lower in those receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3 to 7%). Most trastuzumab-treated patients developing cardiac failure are symptomatic (75%). The most common treatment-related adverse events are chills, asthenia, fever, pain and nausea13. Trastuzumab is available in vials of 440mg which cost $ 4,700.
The debate about which diagnostic system is the most accurate for the determination of the HER 2 status of a patients tumor is a frequent topic of discussion among pathologists7, 14, 15. Briefly: the methods available for determination of HER 2 over-expression are: Inmunohis-tochemical studies (IHC): Herceptest (Dako, Inc.), Pathway (Ventana, Inc.).
Fluorescence in situ hybritization (FISH): PathVysion (Vysis, Inc.). Although, based on current literature, FISH detection of HER 2 gen amplification may provide more accurate information in the selection of patients for treatment with targeted therapies such as Trastuzumab but this method is not yet widely available.The cost of each determination for a private patient is around $550. Therefore, screening by IHC for HER 2 protein, backed by rigorous quality controls and FISH testing of equivocal cases with intermediate staining intensity, remains the current practice. The different test kits for HER 2 protein determination (each targeting different epitopes on the HER 2 receptor) cost from $4,980 to $995. Each kit is used for 30 or 35 determinations. The cost of each determination goes from $175 to $ 50. An important factor in correlation between Herceptest® and FISH results is the experience of the pathologic centre. Discrepancies are greatest for small local laboratories.
To achieve acceptable levels of performance it will be important for laboratories initiating their own analyses to gather experience of testing and scoring of tumors on training sets and to participate regularly in a quality assurance scheme16, 17. In our country two Consensus Meetings of HER 2 Diagnosis took place: the first one on May 15th, 2002 and the second on April 11th, 2003, supported by Roche Laboratories (Herceptin®)18. In both two, the Consensus determined:
- When and who assess HER 2 status?: When trastuzumab could be a treatment choice or when testing for HER 2 status could be particularly relevant if a new chemotherapy line should be considered (anthracycline-based therapy).
- Recommended methods: IHC or FISH.There were also suggestions regarding antibodies/probe; sample preparation; what to report; score IHC; IHC interpretation; FISH methodology. Finally an algorithm for Trastuzumab use was suggested (Fig. 1).
Fig. 1.- Algorithm for Trastuzumab use. Consensus Meeting HER2, March 15th, 2002
The National Hospital Profesor Alejandro Posadas is a policlinic center of 550 beds in the western outskirts of Buenos Aires city. The Oncology Department receives 12.000 consultations per year and 4000 chemothe-rapeutic treatments are carried out in its Daily Hospital.
Materials and Methods
During 2001, we used a Herceptest kit (IHC- Dako, Inc.) to determine HER2-overexpression in premenopausal women with metastatic breast cancer with a negative estrogenic receptor status. Positive HER2 status rendered them eligible for second or third line treatment with tratuzumab alone or with paclitaxel. Thirty determinations were done using recient samples or archival histopathological blocks. In the meantime, one patient had her HER2 test carried out by FISH method in an external laboratory (Fig. 2).
Fig. 2.- Diagnostic algorithm.
We observed strict adherence to the manufacturers instructions. The guidelines for scoring were those recommended in the first National Consensus Meeting18:
- 0/1+ Negative
- 0: no staining or less than 10% of tumoral cells staining.
- 1+: weak staining, less intense staining in more than 10% of tumoral cells. Cells with parcial membrane staining.
- 2+/3+ Positive
- 2+: weak to moderate complete membrane staining in more than 10% of the malignant cells.
- 3+: strong and complete membrane staining in more than 10% of the malignant cells.
From these 31 patients, 23 (74.19%) were negative: 17=0 (73.9%); 6=1+ (26%). Eight (25.8%)proved to be positive: 6=3+ (75%); 2=2+ (25%, one of them by FISH).We decided that the six patients with HER2 +++ and the one with ++ by FISH were to receive trastuzumab as mono-therapy (n=3) or in combination with paclitaxel (n=3). The patient with ++ by IHC was to confirm the result with a FISH test (Table 1). From the seven patients to whom we prescribed Trastuzumab, six got the drug: 4 through their medical insurance, one through the Public Health Ministry and the last through the Ministry the first time and by her medical insurance afterwards. One patient never got the drug.
TABLE 1.- Patients receiving Trastuzumab
From these six patients: 3 (50%) received trastuzumab during eight months or more, since their complete response last from 8 to 24 months and the drug was administered once weekly all over this period of no evidence of disease. The other three had partial response of short duration (n=2) or no benefit at all (n=1).
In one patient we observed: hot flushes in the cheeks during the loading dose, transient hepatic transaminases elevation that did not require additional intervention or discontinuation of the treatment and a decline in the left ventricular ejection fraction measured in the regular monitoring without clinical expression. In this case trastuzumab was discontinued. No treatment-related adverse events were registered in the other patients.
According to the published data and our preliminary experience, trastuzumab therapy showed promising results in a percentage of women with metastatic breast cancer over-expressing HER 2, that is: approximately 25% of all patients with metastatic breast cancer. It proved to be a safe, active and well-tolerated biological treatment. The main difficulties registered in a public general hospital were:
1) To obtain the experience and training of the involved personnel depended on having the diagnostic test kits available to do a reasonable number of assays a year to ensure the quality of the results. The economic factor was one but not the only limitation point. In part, this could be solved by sending the samples to another referential center which kindly do the tests.
2) To use the FISH method to retest the ambiguous cases (HER 2=2+) since it is not yet widely available.
3) Trastuzumab was difficult to obtain from certain medical insurances and from public sources.
4) Handling the anxiety and frustration of patients and relatives who did not get the drug in the proper way and time was not a minor problem in our daily clinical practice.
1. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the Her-2/neu proto oncogene in human breast and ovarian cancer. Science 1989; 244: 707-12. [ Links ]
2. Ravdin PM, Channess GC. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers. A review. Gene 1995; 159: 19-27. [ Links ]
3. Bast RC, Ravdin P, Hayes DF, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: 1865-78. [ Links ]
4. Jukkola A, Bloigu R, Soini Y, Savolainen ER, Holli K, Blanco G. E-erbB-2 positivity is a factor for poor prognosis in breast cancer and poor response to hormonal or chemotherapy treatment in advance disease. Eur J Cancer 2001; 37: 347-54. [ Links ]
5. Mass R. The role of Her-2 expression in predicting response to therapy in breast cancer. Semin Oncol 2000; 27: 46-52. [ Links ]
6. Muss H, Berry D, Thor A, et al. Lack of interaction of tamoxifen (T) use and ErbB-2 (Her-2) Neu (H) expression in CALGB 8541: a randomized adjuvant trial of three different doses of cyclophosphamide, doxorubicin and fluorouracil (CAF) in node TS1 positive primary breast cancer (BC). Proc Am Soc Clin Oncol 1999; 18: 68a. [ Links ]
7. Bartlett J, Mallon E, Cooke T. The clinical evaluation of Her-2 status: which test to use?. J Pathol 2003; 199: 411-7. [ Links ]
8. Golbenberg MM. Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther 1999; 21: 309-18. [ Links ]
9. Vogel CL, Cableigh MA, Tripathy D, et al. Efficacy and safety of Trastuzumab as a single agent in first-line treatment of Her-2 overexpressing metastatic breast cancer. J Clin Oncol 2000; 20: 719-26. [ Links ]
10. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against Her 2 for metastatic breast cancer that overexpresses Her 2. N Engl J Med 2001; 344: 783-92. [ Links ]
11. Leyland-Jones B. Dose scheduling-Herceptin®. Oncology 2001; G1 (suppl 2): 31-6. [ Links ]
12. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215-21. [ Links ]
13. Cook-Brurs N. Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 2001; G1 (Suppl 2): 58-66. [ Links ]
14. Dowsett M, Bartlett J, Ellis IO, et al. Correlation between immunohistochemistry (Hercept test) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol 2003; 199: 418-23. [ Links ]
15. Bilous M, Dowsett M, Hanna W, et al. Current perspectives on Her 2 testing: a review of National Testing Guideliness. Mod Pathol 2003; 16: 173-82. [ Links ]
16. Reunión de Consenso HER 2, 15 de marzo 2002. Roche Laboratorios. Material impreso por el auspiciante. [ Links ]
17. Diagnóstico de HER 2. Segunda Reunión de Consenso, 11 de abril de 2003. Roche Laboratorios. Material impreso por el auspiciante. [ Links ]