|IAP Australasian Division News||
Our division's website is up and running.
You can access it at http://www.iap-aus.org.au Within the site you will find information about the division, next year's annual scientific meeting, newsletters, links to other sites of pathological interest, information about contacting the secretariat and information about becoming a member. In addition, I am developing a member's page. I will post one interesting educational case per month.
To access the member's page you need to know the username and password. I have made the user name "iapmember" and the password "rokitansky". You need to enter these in lower case. I would like to hear from members as to what they would like to see put on the website and how I can improve it. You can contact me at firstname.lastname@example.org or phone me on (02) – 9845 6222.
Prize Winners and Commendations in the Poster Display Competition
No. 6: "Methylation Status of BCL6 Distinguishes DNA Samples from Benign
and Malignant Lymphoproliferative Disorders"
No.25: "The Value of HPV DNA Typing in the distinction between Adenocarcinomas
of Endocervical and Endometrial Origin in Biopsy material"
Poster No.7: "Kikuchis Lymphadenitis: Fine Needle Aspiration Cytology Diagnosis of Four Cases in Australia" Psarianos T, Chandraratnam E, Tomlinson J.
No.28: "Primary Non Hodgkin’s Lymphoma of The Central Nervous System"
Poster No.2: "Identification of Molecular Markers in DCIS Recurrence" Provenzano E, Kavanagh A, Marr G, Giles G, Venter D, Armes J.
No.16: "Fine Needle Aspiration in Assessment of Primary and Metastatic
Gastrointestinal Stromal Tumours"
Metastatic breast cancer is at the present time an incurable disease but many women can have prolonged disease control with the use of chemotherapy or endocrine therapy. In recent years increasing understanding of the biology of breast cancer has led to the identification of a number of novel therapeutic targets. One such target is the human epidermal growth factor receptor-2 (HER2), which is a member of the best studied growth factor receptor systems in breast cancer.
Slamon and colleagues demonstrated that the median survival from first diagnosis in patients with high HER2 expression is less than half that in patients with HER2-negative tumours (3 versus approximately 6-7 years). In addition HER2-positive tumours may respond to certain types of cytotoxic agents and to hormonal therapy in a different manner to those that are HER2-negative.
HERCEPTIN PIVOTAL TRIALS
A multinational, multicentre study of trastuzumab was performed in 222 women with HER2-positive metastatic breast cancer who had relapsed following one or two cytotoxic chemotherapy regimens. Patients with weak (2+) or complete membrane staining of >10% of tumour cells (3+) on IHC using either one of two antibodies (CB11 or 4D5) were defined as HER2-positive. Patients received i.v. trastuzumab at an initial dose of 4mg/kg followed by 2 mg/kg weekly.
Overall Response Rate : 15%
Approximately 40% of patients experienced infusion-associated symptoms,
including fever and chills, which occurred primarily with the first infusion
A randomized, placebo-controlled phase III trial was performed in 469 women with metastatic breast cancer. HER2 positive patients were defined as in the monotherapy study.
Half the patients were randomised to receive trastuzumab.
Table 1: Efficacy of trastuzumab when given in combination with chemotherapy in metastatic breast cancer.
It is important to realise that, at 25 months of follow up, 65% of patients whose disease progressed on chemotherapy alone were switched to trastuzumab with or without chemotherapy which generated a potential bias against the trastuzumab-treated group as the study progressed.
Adverse events were that were mild to moderate in severity were increased among patients receiving trastuzumab. Trastuzumab treated patients also experienced infusion associated symptoms. Cardiac dysfunction cases were most frequently seen among patients who received trastuzumab plus an anthracycline. A total of 38/148 patients treated with anthracycline plus trastuzumab compared to 10/135 receiving anthracycline alone experienced cardiac dysfunction. Corresponding figures for patients receiving paclitaxel plus trastuzumab or paclitaxel alone were 11/91 and 1/95, respectively. The number of patients with symptomatic heart failure was low.
Data from pivotal trials indicate that trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer. Trastuzumab when added to chemotherapy, increased TTP, response rate and median survival compared with chemotherapy alone. The safety profile of trastuzumab was favourable.
However, data indicate that there is a risk of cardiac dysfunction in patients receiving trastuzumab. This appears to be related to previous or concomitant anthracycline exposure, and it is recommended that women with pre-existing heart disease or high cumulative anthracycline exposure are treated with caution. One prerequisite for using trastuzumab is that the HER2 status be established. Immunohistochemistry (IHC) is widely available and the proposed initial test.
If this test is not strongly positive (+++) it is proposed that fluorescence in situ hybridization is a useful alternative. It is less widely available, requires specialized equipment and has not been correlated with clinical outcomes. At the present time trastuzumab could be considered as a single agent or in combination with paclitaxel for metastatic breast cancer that is HER2-positive. Studies combining trastuzumab with either vinorelbine or platinum agents have also been shown to be highly active. Phase III trials are currently randomizing to assess the effect of trastuzumab in the adjuvant setting.
There is currently considerable interest in the receptor protein HER2 (c-erbB-2, Her2/neu), because of its role as a prognostic factor in invasive breast carcinoma. Overexpression of HER2 has been shown to predict response to chemotherapy and, more recently, it has become a target for specific antibody therapy using Herceptin.
The percentage of invasive breast carcinomas that overexpress HER2 varies depending on the method used in the assay and the method of selection of the patients tested. However, it is likely that around 15–20% of invasive carcinomas will show HER2 gene amplification, and protein overexpression is associated with gene amplification in over 95% of cases. Of the tests available to assess HER2 in the pathology laboratory, immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) are the two most likely to be considered. Both methods have their advantages and disadvantages with regard to accuracy, reproducibility, ease of application and cost.
The HER2 Testing Advisory Board*, composed of pathologists from private and public laboratories throughout Australia, meets regularly to analyse the Australian and international data on HER2 testing and the response to therapy. This data is currently accruing at a rapid rate. Given this dynamic environment, it is difficult to advise a testing regimen that will stand the test of time. The testing algorithm below is supported by the data currently available. However, regardless of the type of test that is adopted by a laboratory, there is a paramount need for the rigorous use of both internal and external controls. National and international quality assurance programmes in pathology are now including HER2 in their immunohistochemistry modules, and all laboratories performing HER2 testing should subscribe to these.
Algorithm for HER2 Testing
*The HER2 Testing Advisory Board was convened and funded by Roche Products Pty Limited.
Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17: 2639–2674.
Dowsett M, Cooke T, Ellis I et al. Assessment of HER2 status in breast cancer: why, when and how? Eur J Cancer 2000; 36: 170–176.
Pegram M, Slamon D. Biological rationale for HER2/neu (cerbB2) as a target for monoclonal antibody therapy. Semin Oncology 2000; 5 (Suppl 9): 13–19.
Stebbing J, Copson E, O’Reilly S. Herceptin (trastuzamab) in advanced breast cancer. Cancer Treat Rev 2000; 26: 287–290.
Walker R. The significance of histological determination of HER-2 status in breast cancer. The Breast 2000; 9: 130–133.
Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783_92.
Mass RD, Press M, Anderson S et al Improved survival benefit from herceptin (trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc ASCO 2001; 20: 85.